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Insulin and Amylin Release Are Both Diminished in First-Degree Relatives of Subjects With Type 2 Diabetes
Abstract
To determine whether first-degree relatives of individuals with type 2 diabetes, who are at high risk of subsequently developing hyperglycemia, manifest alterations in beta-cell function including an alteration in the co-release of insulin and amylin.
In 30 first-degree relatives and 24 matched subjects with no family history of diabetes, beta-cell function was measured as the intravenous glucose-induced acute insulin response (AIR(g)) and acute amylin response (AAR(g)). The insulin sensitivity index (S(I)) was quantified and used to account for the role of insulin sensitivity to modulate beta-cell function (S(I) x beta-cell function).
Fasting plasma glucose (5.3 +/- 0.1 vs. 5.1 +/- 0.1 mmol/l; means +/- SEM), immunoreactive insulin (IRI) (68 +/- 7 vs. 57 +/- 6 pmol/l) and amylin-like immunoreactivity (ALI) (5.5 +/- 0.6 vs. 4.7 +/- 0.7 pmol/l) were similar in relatives and control subjects, respectively. Relatives were insulin resistant compared with control subjects (S(I): 4.86 +/- 0.63 vs. 7.20 +/- 0.78 x 10(-5) min(-1). pmol(-1). l(-1), P = 0.01), but their AIR(g) (392 +/- 59 vs. 386 +/- 50 pmol/l) and AAR(g) (5.9 +/- 0.9 vs. 6.1 +/- 0.8 pmol/l) did not differ. When beta-cell function was determined relative to insulin sensitivity, in the first-degree relatives, both AIR(g) (S(I) x AIR(g): 1.60 +/- 0.23 vs. 2.44 +/- 0.31 x 10(-2) min(-1), P < 0.05) and AAR(g) (S(I) x AAR(g): 2.39 +/- 0.35 vs. 4.06 +/- 0.56 x 10(-4) min(-1), P < 0.05) were reduced. The molar proportion of ALI to IRI was not altered in high-risk subjects (1.75 +/- 0.16 vs. 1.71 +/- 0.15%).
First-degree relatives of subjects with type 2 diabetes have diminished beta-cell function at a time when they are not hyperglycemic, and this reduction affects insulin and amylin responses proportionally. Thus, an altered amylin-to-insulin ratio is not likely to identify individuals at high risk of developing type 2 diabetes.
... The molar ratio of IAPP to insulin in the circulation of healthy humans is about 1% to 3% (461)(462)(463). Accordingly, the abundance of proIAPP in the circulation is lower than proinsulin, making it more difficult to measure and to discriminate the different conversion intermediates. ...
... Islet Amyloid Polypeptide in the Assessment of β-cell Function IAPP was originally identified as the unique peptide component of islet amyloid deposits (162,163). The peptide is co-released with insulin in response to glucose and nonglucose secretagogues (461)(462)(463)(563)(564)(565)(566)(567)(568). Its physiological function is not well appreciated, but roles for gastric emptying and appetite regulation have been suggested (569,570). ...
... In time, these assays may provide new biomarkers for β-cell function. Using a number of different immunoassays that measure the intact peptide, it is now well recognized that the amount of IAPP produced, stored, and released by the β cell is approximately 1% to 3% that of insulin (461)(462)(463). Importantly, as the clearance of IAPP is slower than that of insulin, the molar ratio will vary depending on when sampling is performed relative to the administration of the stimulus (566). ...
The pathogenesis of hyperglycemia observed in most forms of diabetes is intimately tied to the islet β cell. Impairments in propeptide processing and secretory function along with the loss of these vital cells is demonstrable not only in those in whom the diagnosis is established, but typically also in individuals who are at increased risk of developing the disease. Biomarkers are used to inform on the state of a biological process, pathological condition or response to an intervention and are increasingly being used for predicting, diagnosing and prognosticating disease. They are also proving to be of use in the different forms of diabetes in both research and clinical settings. This review focuses on the β cell, addressing the potential utility of genetic markers, circulating molecules, immune cell phenotyping, and imaging approaches as biomarkers of cellular function and loss of this critical cell. Further, we consider how these biomarkers complement the more long-established, dynamic and often complex measurements of β-cell secretory function that themselves could be considered biomarkers.
... 19,20 Non-obese, first-degree relatives (FDRs) of T2D patients even when featuring normal glucose tolerance (NGT) exhibit impaired sensitivity to insulin and subcutaneous adipose tissue (SAT) dysfunction. [21][22][23][24][25] Since adverse events in these fat depots occur long before the onset of T2D, it has been suggested that SAT may have a significant impact on T2D susceptibility. In particular, insulin resistance and progression from NGT to T2D is due, at least in part, to adipocyte hypertrophy, which characterizes the SAT in the FDRs, similar as in obese individuals, but independent of obesity itself. ...
... Healthy FDRs of T2D individuals feature high risk of diabetes and have multiple metabolic abnormalities, including reduced sensitivity to insulin and impaired islet cell function even when glucose tolerance is normal. [21][22][23][24][25] Inappropriate body fat distribution has been hypothesized as a key factor behind the diabetes risk in FDRs. 52 Even though visceral adipose tissue (VAT) is associated with insulin resistance and the increased risk for the development of T2D in obesity, its impact in FDRs is less clear. ...
First‐degree relatives (FDRs) of type 2 diabetics (T2D) feature dysfunction of subcutaneous adipose tissue (SAT) long before T2D onset. miRNAs have a role in adipocyte precursor cells (APC) differentiation and in adipocyte identity. Thus, impaired miRNA expression may contribute to SAT dysfunction in FDRs. In the present work, we have explored changes in miRNA expression associated with T2D family history which may affect gene expression in SAT APCs from FDRs. Small RNA‐seq was performed in APCs from healthy FDRs and matched controls and omics data were validated by qPCR. Integrative analyses of APC miRNome and transcriptome from FDRs revealed down‐regulated hsa‐miR‐23a‐5p, ‐193a‐5p and ‐193b‐5p accompanied by up‐regulated Insulin‐like Growth Factor 2 (IGF2) gene which proved to be their direct target. The expression changes in these marks were associated with SAT adipocyte hypertrophy in FDRs. APCs from FDRs further demonstrated reduced capability to differentiate into adipocytes. Treatment with IGF2 protein decreased APC adipogenesis, while over‐expression of hsa‐miR‐23a‐5p, ‐193a‐5p and ‐193b‐5p enhanced adipogenesis by IGF2 targeting. Indeed, IGF2 increased the Wnt Family Member 10B gene expression in APCs. Down‐regulation of the three miRNAs and IGF2 up‐regulation was also observed in Peripheral Blood Leukocytes (PBLs) from FDRs. In conclusion, APCs from FDRs feature a specific miRNA/gene profile, which associates with SAT adipocyte hypertrophy and appears to contribute to impaired adipogenesis. PBL detection of this profile may help in identifying adipocyte hypertrophy in individuals at high risk of T2D.
... Islet amyloid polypeptide (IAPP or amylin), the main constituent of insoluble amyloid deposits in pancreatic islets of individuals with type 2 diabetes (T2D), is secreted from pancreatic beta cells at a level of approximately 1% that of insulin (Kautzky-Willer et al. 1994, Dechenes et al. 1998, Knowles et al. 2002. The unique property of IAPP to aggregate and form islet amyloid is implicated in the pathology of T2D due to its toxic effects on beta cells and, more recently, its pro-inflammatory properties. ...
... Indeed, we recently reported disproportionately elevated levels of the proIAPP processing intermediate hproIAPP 1-48 in T1D (Courtade et al. 2017a) suggesting that, along with impaired proinsulin processing (Roder et al. 1994, Hartling et al. 1997, Truyen et al. 2005, Rodriguez-Calvo et al. 2017, impaired proIAPP processing may be a characteristic of beta cells in T1D. While IAPP is normally secreted relative to insulin at a molar ratio of approximately 1:100 (Kautzky-Willer et al. 1994, Dechenes et al. 1998, Knowles et al. 2002, Hull et al. 2004, the ratio of IAPP:insulin secretion or expression may increase in states of beta cell dysfunction (O'Brien et al. 1991, Pieber et al. 1993, Hiramatsu et al. 1994, Mulder et al. 1995a, Ahrén & Gutniak 1997, Hull et al. 2004, Krizhanovskii et al. 2017. Interestingly, a small study from the Better Diabetes Diagnosis cohort revealed that ~11% of children with T1D had markedly elevated plasma IAPP levels relative to C-peptide and pro-insulin levels at diagnosis (Paulsson et al. 2014). ...
Islet amyloid polypeptide (IAPP), the main component of islet amyloid in type 2 diabetes and islet transplants, is now recognized as a contributor to beta cell dysfunction. Increasingly, evidence warrants its investigation in type 1 diabetes owing to both its immunomodulatory and metabolic actions. Autoreactive T cells to IAPP-derived epitopes have been described in humans, suggesting that IAPP is an islet autoantigen in type 1 diabetes. In addition, although aggregates of IAPP have not been implicated in type 1 diabetes, they are potent pro-inflammatory stimuli to innate immune cells, and thus, could influence autoimmunity. IAPP aggregates also occur rapidly in transplanted islets and likely contribute to islet transplant failure in type 1 diabetes through sterile inflammation. In addition, since type 1 diabetes is a disease of both insulin and IAPP deficiency, clinical trials have examined the potential benefits of IAPP replacement in type 1 diabetes with the injectable IAPP analogue, pramlintide. Pramlintide limits postprandial hyperglycemia by delaying gastric emptying and suppressing hyperglucagonemia, underlining the possible role of IAPP in postprandial glucose metabolism. Here, we review IAPP in the context of type 1 diabetes: from its potential involvement in type 1 diabetes pathogenesis, through its role in glucose metabolism and use of IAPP analogues as therapeutics, to its potential role in clinical islet transplant failure and considerations in this regard for future beta cell replacement strategies.
... IAPP is co-localized (5,6) and co-secreted with insulin (7). The IAPP/insulin ratio is normally low, with IAPP levels approximately 1% of insulin levels (8)(9)(10)(11)(12). IAPP exerts its effects through binding to the calcitonin receptor in complex with either the receptor activity modifying protein-1 (RAMP1) or RAMP3 (13). ...
... Interestingly, mice fed a high-fat diet (HFD) are characterized by increased plasma IAPP levels (15,16), and in human IAPP transgenic mice islet amyloid appears after a long-term HFD intake (17). In this context it may seem contradictory that in T2DM not only insulin but also IAPP secretion is impaired (10,11). However, in vitro studies indicate that insulin prevents IAPP aggregation (18), and it may be that a change in IAPP/insulin ratio, rather than an increase of IAPP per se, is important for amyloid formation. ...
Background: Enhanced IAPP production may contribute to islet amyloid formation in type 2 diabetes. The objective of this study was to determine the effects of the saturated fatty acid palmitate on IAPP levels in human β-cells.
Methods: EndoC-βH1 cells and human islets were cultured in the presence of sodium palmitate. Effects on IAPP/insulin mRNA expression and secretion were determined using real-time qPCR/ELISA. Pharmacological activators and/or inhibitors and RNAi were used to determine the underlying mechanisms.
Results: We observed that EndoC-βH1 cells exposed to palmitate for 72 h displayed decreased expression of Pdx-1 and MafA and increased expression of thioredoxin-interacting protein (TXNIP), reduced insulin mRNA expression and glucose-induced insulin secretion, as well as increased IAPP mRNA expression and secretion. Further, these effects were independent of fatty acid oxidation, but abolished in response to GPR40 inhibition/downregulation. In human islets both a high glucose concentration and palmitate promoted increased IAPP mRNA levels, resulting in an augmented IAPP/insulin mRNA ratio. This was paralleled by elevated IAPP/insulin protein secretion and content ratios.
Conclusions: Addition of exogenous palmitate to human β-cells increased the IAPP/insulin expression ratio, an effect contributed to by activation of GPR40. These findings may be pertinent to our understanding of the islet amyloid formation process.
... The progressive dysfunction of β-cells in T2DM results in the decrease in levels of both insulin and amylin [32], leading to the need for hormone therapy at advanced stages of the disease [33]. Along with insulin, therapeutic replacement of amylin, as originally suggested [34], is nowadays recommended for a more tight control of glycemia in individuals with either type 1 or type 2 diabetes mellitus (T1DM or T2DM, respectively) [10, 33,[35][36][37][38][39][40][41]. ...
... Along with insulin, therapeutic replacement of amylin, as originally suggested [34], is nowadays recommended for a more tight control of glycemia in individuals with either type 1 or type 2 diabetes mellitus (T1DM or T2DM, respectively) [10, 33,[35][36][37][38][39][40][41]. The dissimilar levels of expression, metabolism and distribution does not allows the use of a insulin:amylin concentration ratio for clinical purposes [32,42,43], as well as a lack in the correlation between insulin sensitivity and β-cell function [44]. In fact, a correlation between circulating amylin concentration and HOMA might display a more clinical realistic correlation in the diagnostic and monitoring scenario. ...
Amylin is a pancreatic hormone cosecreted with insulin that exerts unique roles in metabolism and glucose homeostasis. The therapeutic restoration of postprandial and basal amylin levels is highly desirable in diabetes mellitus. Protein conjugation with the biocompatible polymer polyethylene glycol (PEG) has been shown to extend the biological effects of biopharmaceuticals. We have designed a PEGylated human amylin by using the aminoreactive compound methoxylpolyethylene glycol succinimidyl carbonate (mPEGsc). The synthesis in organic solvent resulted in high yields of monoPEGylated human amylin, which showed large stability against aggregation, an 8 times increase in half-life in vivo compared to the non-conjugated amylin, and pharmacological activity as shown by modulation of cAMP production in MCF-7 cell line, decrease in glucagon and modulation of glycemia following subcutaneous administration in mice. Altogether these data reveal the potential use of PEGylated human amylin for the restoration of fasting amylin levels.
... First-degree relatives of subjects with type 2 diabetes mellitus (FDRs) frequently have both insulin resistance [19] and beta cell dysfunction [20] and bear a 40% lifetime risk for developing type 2 diabetes mellitus [21]. With such a background of the pathophysiology of glucose metabolism in FDRs, investigating the circulating levels of novel adipocytokines, such as visfatin and vaspin, in this group is worthwhile. ...
... Impaired glucose metabolism is common in FDRs [19]. They also have defects in beta cell function at a time when they are not hyperglycemic, and this reduction affects insulin and amylin responses to glucose stimulation [20]. Since both insulin sensitivity and beta cell dysfunction predict conversion to diabetes [32,33], FDRs are at increased risk of type 2 diabetes [21]. ...
... This results in their low baseline serum concentrations and decreased or absence response of these hormones to caloric intake, leading to chronic hyperglycemia. Type 2 diabetes (90% of diabetes) is characterized by hyperglycemia, insulin resistance and abnormal beta cell function (23). 30% or more of type 2 diabetes patients will bene t from insulin therapy to control blood glucose (24). ...
Objective
Oxidative stress decreases the ability of β-cells to secrete insulin through glucolipotoxicity of the pancreatic islets. Flavonoids modulate insulin and amylin secretion through mainly antioxidant activities. Coumarins isomers of flavonoids have direct effects on the cardiovascular system, not linked to antioxidant activities. This study aim to investigate in vivo the direct effects of 5,7-dimethoxycoumarin (Citropten) fractions present in grapefruit peel on insulin and amylin secretions in normal male Wistar rats.
Methods
Methanol extract of grapefruit peels was fractionated using vacuum assisted liquid chromatography with n-Hexane, Ethyl acetate and Methanol. Gas Chromatography Mass Spectrometry analysis reported ethyl acetate fraction with highest concentration (85.66%) of 5,7-dimethoxycoumarin. Intraperitoneal Glucose Tolerance Test was performed on 5 sets of 5 rats receiving intraperitoneally: 1) negative control, 1ml of sterile water 2) positive control, 0.2mg/kg glimepiride, 3) ethyl acetate fraction containing 20mg/kg 5,7-dimethoxycoumarin, 4) methanol fraction containing 20mg/kg 5,7-dimethoxycoumarin 5a)1ml H2O2 (0.6%, 6%) plus 20mg/kg 5,7-dimethoxycoumarin, and 5b)1000mg/kg Vitamin C plus 20mg/kg 5,7-dimethoxycoumarin.
Results
Results showed Ethyl acetate fractions containing 10mg/kg and 20mg/kg dimethoxycoumarin had comparable plasma glucose control with glimepiride. Both ethyl acetate and methanol fractions of 5,7- dimethoxycoumarin had indirect insulin secretion effect, but directly induced amylin synthesis and secretion 3-fold that of glimepiride.
Conclusion
5,7-dimethoxycoumarin will find special application in diabetics with chronic complications. Since the overall plasma glucose regulation is achieved through amylin and insulin synergy, attention should be shifted from insulin-based to amylin-based therapy, and also shifted from regulating blood glucose level to regulating its absorption in the GIT.
... Conversely, FDR of T2DM patients without impairment of glucose homeostasis show diminished β-cell function with reduction in insulin and amylin responses indicating that genetic predisposition for impaired β-cell function might play a role in the early pathogenesis of T2DM. 214 The pathological process of β-cell dysfunction in the pathogenesis of T2DM seems to be of multifactorial origin with glucose, dyslipidaemia, inflammatory processes and ER stress playing a role in the maladaptation of β cells. [215][216][217] Chronically elevated levels of FFA have been implied in the pathogenesis of both IR and β-cell dysfunction, 218 and the detrimental effects of FFAs on β-cell function have been referred to as lipotoxicity. ...
The most common form of diabetes mellitus, type 2 diabetes mellitus (T2DM), is characterized by impaired insulin sensitivity of skeletal muscle, liver and adipose tissue, termed insulin resistance (IR), and by inadequate insulin secretion by pancreatic β cells, termed β-cell dysfunction. Recent studies propose that the brain may also contribute to IR and to the pathogenesis of T2DM. There is growing evidence that IR is the earliest detectable abnormality, whereas β-cell exhaustion is mandatory for manifesting overt T2DM. The current concepts of possible mechanisms underlying IR are lipid overflow (lipotoxicity), abnormal energy balance and mitochondrial function, subclinical inflammation, and central neuronal mechanisms. Here we review the relative roles of these mechanisms for the development of T2DM.
... Amylin is co-secreted along with insulin by the β-cells in the Langerhans islets [5,6], though also found in some non-β-cells [7]. Amylin and insulin are differently expressed and metabolized [8][9][10]. ...
The secretory granule of the pancreatic β-cells is a zinc-rich environment copopulated with the hormones amylin and insulin. The human amylin is shown to interact with zinc ions with major contribution from the single histidine residue, which is absent in amylin from other species such as cat, rhesus and rodents. We report here the interaction of murine amylin with zinc ions in vitro. The self-assembly of murine amylin is tightly regulated by zinc and pH. Ion mobility mass spectrometry revealed zinc interaction with monomers and oligomers. Nuclear magnetic resonance confirms the binding of zinc to murine amylin. The aggregation process of murine amylin into amyloid fibrils is accelerated by zinc. Collectively these data suggest a general role of zinc in the modulation of amylin variants oligomerization and amyloid fibril formation.
... • Rođaci u prvom koljenu bolesnika s dijabetesom tipa 2 često imaju poremećen neoksidativni metabolizam glukoze (indikator inzulinske rezistencije) prije nego razviju šećernu bolest [15]. Mogu imati i disfunkciju beta stanica, koja se vidi u smanjenom otpuštanju inzulina i amilina u odgovoru na stimulaciju glukozom [16]. ...
... Even when the glucose level is still within the normal range, -cell function decreases progressively with a corresponding increase of fasting glucose (42). First-degree relatives of individuals with type 2 diabetes, who are genetically at increased risk, also have impaired -cell function, even though they may still have normal glucose tolerance (43). Data from groups of first-degree relatives with different ethnic backgrounds suggest that common processes underlie the development of type 2 diabetes -namely, insulin resistance and -cell dysfunction -and that the degree of abnormality of insulin release is the dominant determinant of differences in glucose tolerance between individuals (44)). ...
... In particular, it has often been underlined that (1) 39 % of affected individuals have at least one affected parent [22]; (2) among monozygotic twin pairs with one affected twin, approximately 90 % of unaffected twins eventually develop the disease through his or her life [23]; (3) the lifetime risk for a first-degree relative of a patient with type 2 diabetes is 5-10 times higher than that of age-and weight-matched subjects without a family history of diabetes [19]; and (4) first-degree relatives of patients with type 2 diabetes frequently have impaired nonoxidative glucose metabolism (indicative of insulin resistance) long before they develop type 2 diabetes. In addition, they may have beta-cell dysfunction, as evidenced by decreases in insulin and amylin release in response to glucose stimulation [24]. All of these findings have been considered to be determined by genetic variability and have prompted significant research efforts aiming at identifying risk genes. ...
The known genetic variability (common DNA polymorphisms) does not account either for the current epidemics of type 2 diabetes or for the family transmission of this disorder. However, clinical, epidemiological and, more recently, experimental evidence indicates that environmental factors have an extraordinary impact on the natural history of type 2 diabetes. Some of these environmental hits are often shared in family groups and proved to be capable to induce epigenetic changes which alter the function of genes affecting major diabetes traits. Thus, epigenetic mechanisms may explain the environmental origin as well as the familial aggregation of type 2 diabetes much easier than common polymorphisms. In the murine model, exposure of parents to environmental hits known to cause epigenetic changes reprograms insulin sensitivity as well as beta-cell function in the progeny, indicating that certain epigenetic changes can be transgenerationally transmitted. Studies from different laboratories revealed that, in humans, lifestyle intervention modulates the epigenome and reverts environmentally induced epigenetic modifications at specific target genes. Finally, specific human epigenotypes have been identified which predict adiposity and type 2 diabetes with much greater power than any polymorphism so far identified. These epigenotypes can be recognized in easily accessible white cells from peripheral blood, indicating that, in the future, epigenetic profiling may enable effective type 2 diabetes prediction. This review discusses recent evidence from the literature supporting the immediate need for further investigation to uncover the power of epigenetics in the prediction, prevention and treatment of type 2 diabetes.
... In addition, though there are limitations, our results in humans might suggest the long-term deterioration of b-cells could have an association with IAPPto-insulin ratio. Although most cross-sectional studies with serum samples suggest the parallel deterioration of IAPP and insulin secretion in several stages of type 2 diabetes 27,28,29 , little is known about the longitudinal change. Our 5-year longitudinal design might prove advantageous in the detection of a subtle change in IAPP-to-insulin ratio in b-cell granules. ...
Aims/Introduction
Islet amyloid polypeptide (IAPP) is a main component of islet amyloid in type 2 diabetes and cosecreted from β‐cell with insulin. Clinical evidence from the patients with S20G mutation of the IAPP gene, as well as experimental evidence that insulin could inhibit amyloid formation of IAPP, suggests that a gradual reduction of insulin could be related to the cytotoxicity associated with S20G‐IAPP through long‐term deterioration of β‐cells in type 2 diabetes. Our objective was to show an effect of human insulin on S20G‐IAPP associated cytotoxicity.
Materials and Methods
We analyzed the cytotoxicity associated with S20G‐IAPP by controlling human insulin expression using adenovirus vectors with micro ribonucleic acid specifically against human insulin in endocrine AtT‐20ins cells, which express human insulin permanently. Additionally, we carried out a follow‐up study of circulating IAPP and insulin in type 2 diabetic patients.
Results
S20G‐IAPP expression was associated with a decrease in viability and an increase in terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate‐biotin nick end labeling‐positive cells in AtT‐20ins cells. Furthermore, downregulation of human insulin enhanced the cytotoxicity associated with S20G‐IAPP, and induced the cytotoxicity associated with wild‐type (WT)‐IAPP. Reduction of ubiquitin carboxy‐terminal hydrolase L1 activity enhanced cytotoxicity under the downregulation of human insulin expression in both S20G‐ and WT‐IAPP transduced cells. A 5‐year follow up of type 2 diabetic patients showed a disproportionate increase of serum fasting IAPP‐to‐insulin ratio from baseline.
Conclusions
Human insulin plays a protective role against the cytotoxicity associated with S20G‐IAPP, as well as WT‐IAPP. The findings could suggest long‐term deterioration of insulin secretion associates with IAPP linked cytotoxicity in type 2 diabetes.
... IAPP, like C Peptide, the peptide created when pro insulin is split into insulin and C-peptide, is cleared by the kidneys. In contrast, insulin clearance is a complex process involving the liver, kidney, and muscle as major participants (25) This variation in clearance rates, as well as recorded IAPP plasma levels following stimulation of β-cells for peptide release with glucose or non glucose response suggest a physiological ratio of IAPP to insulin closer to 1/100 (23, 26,27,28). This level is in good agreement with in-vitro experimental observations (29). ...
The inverse scattering problem is based on the scattering theory in physics, where measured data such as radiation from an object is used to determine the unique structure of the object in question. This approach has been widely successful in fields ranging from geophysics and medical imaging, to quantum field theory. In 1996 Henrik Flyvbjerg suggested that a similar approach could be used to study a reaction far from equilibrium of the self-assembly of a nucleation dependent biopolymer and, under certain conditions, uniquely determine the kinetics of the assembly. Here we use this approach to elucidate the unique structure of human islet amyloid polypeptide, also known as amylin, in-vitro. We use a systematic phenomenological analysis of the amount of monomer in fibril, of amylin, for various initial concentrations from an unstructured monomer pool. Using the assumption that nucleation is the rate-limiting step in fibril formation, we invoke mass action to develop our model. We find that the fibrillogenesis of amylin is well described by a nucleation dependent polymerization event that is characteristic of the sigmoidal shape
... OGTT: After a 10-12 h overnight fast, the subjects ingested a solution containing 75 grams of glucose, and venous blood samples were obtained at 0, 30, 60, 90, and 120 minute for determination of plasma glucose, plasma insulin and C-peptide. Criteria for the diagnosis of diabetes, impaired fasting glucose, and impaired glucose tolerance (IGT) were made according to ADA criteria (7). HOMA IR , HOMA ISI , AUC Glucose values were also calculated with data obtained from the OGTT results (8,9,10 ...
We designed this study to observe the DM prevalence, insulin resistance, beta cell reserve and the interaction of these parameters in the first degree relatives of Type 2 diabetic patients in Turkish population.
125 subjects were included in the study. 25 subjects without the first degree diabetic relatives were selected as the control group; they were matched by age, BMI, socio-economical, cultural and environmental factors. (OGTT), (IVGTT), (GST), and (ITT), were performed on all subjects and controls.
12 (9.6 %) DM and 23 (18. 4 %) impaired glucose tolerance (IGT) cases of 125 subjects were diagnosed according to OGTT results. The mean BMI of diabetic subjects was significantly higher than of controls and subjects with normal glucose tolerance (p<0.05). When compared to the control group, the mean AUCinsulin levels were significantly lower in diabetic subjects (p<0.05). To observe the correlation between HOMAIR and KITT values, a statistically significant correlation was found (p<0.05, r: 0.222). There was a deficiency in the C-peptide response to glucagon stimulation in diabetic relatives (p<0.05, F: 4.59 One Way ANOVA).
We demonstrated that the first degree relatives of Type 2 diabetic patients constitute a high risk group for DM, IGT and insulin resistance by using four different tests in Turkish population.The significant finding(s) of the study: We demonstrated a high prevalence of glucose metabolism disorders in the relatives of type 2 diabetic patients.This study adds our knowledge; insulin resistance and decreased beta cell reserve occur before diabetes mellitus begin in relatives (Tab. 5, Ref. 42).
... Impaired glucose metabolism is common in FDRs [13]. They also have defects in b cell function when they are not hyperglycemic, and this reduction affects insulin and amylin responses to glucose stimulation [21]. Since both insulin sensitivity and b cell dysfunction predict conversion to diabetes [14,22], FDRs are at increased risk of type 2 diabetes [15]. ...
It has been suggested that adipose-derived cytokines act as insulin sensitizers/insulin-mimetics and some others may induce insulin resistance. In order to elucidate the potential role of novel adipocytokines in the pre-diabetes states, circulating levels of novel adipocytokines were evaluated in first-degree relatives of subjects with type 2 diabetes mellitus (FDRs).
Serum omentin-1, adiponectin and retinol-binding protein 4 (RBP4) levels were measured in 179 subjects (90 glucose tolerant FDRs and 89 age- and sex-matched healthy controls) using enzyme-linked immunosorbent assay (ELISA) methods.
There was no significant difference between the two groups regarding serum RBP4 concentrations. However, serum omentin-1 (median [interquartile range], 6.18 [4.06-11.52]ng/ml versus 10.50 [4.30-20.60]ng/ml, p=0.004) and adiponectin (mean±SD, 10.07±4.0 μg/ml versus 20.66±8.12 μg/ml, p<0.0001) levels were significantly lower in FDRs when compared with the controls. In multiple logistic regression analysis, FDRs showed a significant association with lower circulating omentin-1 and adiponectin levels, even after adjustments were made for age, sex, body mass index, blood pressure measures, and biochemical parameters including glucose status, lipid profile, insulin levels and HOMA-IR (OR=0.49, CI [0.30-0.79]; p=0.004 and OR=0.74, CI [0.67-0.82]; p<0.0001, respectively). However, FDRs did not show a significant association with serum RBP4 levels in different models of regression analyses.
The FDRs showed significant associations with lower omentin-1 and adiponectin levels. A potential role for these adipokines in the FDRs' increased risk of diabetes needs to be further elucidated.
... Previous studies have shown that defects in addition to insulin deficiency contribute to after-meal hyperglycemia. Both insulin and amylin are secreted by -cells, and, in individuals with abnormal -cell function, glucose-and mixed mealstimulated secretion of both hormones is delayed and reduced (7)(8)(9). Insulin deficiency impairs suppression of hepatic glucose production and enhancement of glucose uptake by tissues that normally limit postmeal hyperglycemia. Amylin deficiency accelerates gastric emptying, increases glucagon secretion, and alters satiety mechanisms (10,11). ...
To compare the efficacy and safety of adding mealtime pramlintide or rapid-acting insulin analogs (RAIAs) to basal insulin for patients with inadequately controlled type 2 diabetes.
In a 24-week open-label, multicenter study, 113 patients were randomly assigned 1:1 to addition of mealtime pramlintide (120 microg) or a titrated RAIA to basal insulin and prior oral antihyperglycemic drugs (OADs). At screening, patients were insulin naive or had been receiving <50 units/day basal insulin for <6 months. The basal insulin dosage was titrated from day 1, seeking fasting plasma glucose (FPG) > or =70-<100 mg/dl. Pramlintide and an RAIA were initiated on day 1 and week 4, respectively. The proportion of patients achieving A1C < or =7.0% without weight gain or severe hypoglycemia at week 24 was the primary end point.
More pramlintide- than RAIA-treated patients achieved the primary end point (30 vs. 11%, P = 0.018) with a similar dose of basal insulin. Pramlintide and an RAIA yielded similar mean +/- SEM values for FPG and A1C at 24 weeks (122 +/- 7 vs. 123 +/- 5 mg/dl and 7.2 +/- 0.2 vs. 7.0 +/- 0.1%, respectively) and similar least squares mean reductions from baseline to end point (-31 +/- 6 vs. -34 +/- 6 mg/dl and -1.1 +/- 0.2 vs. -1.3 +/- 0.2%, respectively). RAIAs but not pramlintide caused weight gain (+4.7 +/- 0.7 vs. +0.0 +/- 0.7 kg, P < 0.0001). Fewer patients reported mild to moderate hypoglycemia with pramlintide than with the RAIA (55 vs. 82%), but more patients reported nausea (21 vs. 0%). No severe hypoglycemia occurred in either group.
In patients taking basal insulin and OADs, premeal fixed-dose pramlintide improved glycemic control as effectively as titrated RAIAs. The pramlintide regimen sometimes caused nausea but no weight gain and less hypoglycemia.
... While these studies provide compelling evidence for a role of hIAPP in the ER stress response, it is important to note that both studies utilized expression or treatment of hIAPP at levels that are significantly higher than is normally seen. In normal humans the circulating levels of hIAPP are approximately 2% of insulin levels [37] and in fact, levels of hIAPP in human diabetes are decreased rather than increased [38,39]. Our hIAPP transgenic mice produce hIAPP at a 1:1 ratio with endogenous mouse IAPP, and at a 2:100 level with insulin [30] providing a model of islet amyloid formation more akin to the physiological levels of hIAPP relative to insulin. ...
Supraphysiological levels of the amyloidogenic peptide human islet amyloid polypeptide have been associated with beta cell endoplasmic reticulum (ER) stress. However, in human type 2 diabetes, levels of human IAPP are equivalent or decreased relative to matched controls. Thus, we sought to investigate whether ER stress is induced during amyloidogenesis at physiological levels of human IAPP.
Islets from human IAPP transgenic mice that develop amyloid, and non-transgenic mice that do not, were cultured for up to 7 days in 11.1, 16.7 and 33.3 mmol/l glucose. Pancreases from human IAPP transgenic and non-transgenic mice and humans with or without type 2 diabetes were also evaluated. Amyloid formation was determined histologically. ER stress was determined in islets by quantifying mRNA levels of Bip, Atf4 and Chop (also known as Ddit3) and alternate splicing of Xbp1 mRNA, or in pancreases by immunostaining for immunoglobulin heavy chain-binding protein (BIP), C/EBP homologous protein (CHOP) and X-box binding protein 1 (XBP1).
Amyloid formation in human IAPP transgenic islets was associated with reduced beta cell area in a glucose- and time-dependent manner. However, amyloid formation was not associated with significant increases in expression of ER stress markers under any culture condition. Thapsigargin treatment, a positive control, did result in significant ER stress. Amyloid formation in vivo in pancreas samples from human IAPP transgenic mice or humans was not associated with upregulation of ER stress markers.
Our data suggest that ER stress is not an obligatory pathway mediating the toxic effects of amyloid formation at physiological levels of human IAPP.
Background
First-degree relatives of type 2 diabetics (FDR) exhibit a high risk of developing type 2 diabetes (T2D) and feature subcutaneous adipocyte hypertrophy, independent of obesity. In FDR, adipose cell abnormalities contribute to early insulin-resistance and are determined by adipocyte precursor cells (APCs) early senescence and impaired recruitment into the adipogenic pathway. Epigenetic mechanisms signal adipocyte differentiation, leading us to hypothesize that abnormal epigenetic modifications cause adipocyte dysfunction and enhance T2D risk. To test this hypothesis, we examined the genome-wide histone profile in APCs from the subcutaneous adipose tissue of healthy FDR.
Results
Sequencing-data analysis revealed 2644 regions differentially enriched in lysine 4 tri-methylated H3-histone (H3K4me3) in FDR compared to controls (CTRL) with significant enrichment in mitochondrial-related genes. These included TFAM, which regulates mitochondrial DNA (mtDNA) content and stability. In FDR APCs, a significant reduction in H3K4me3 abundance at the TFAM promoter was accompanied by a reduction in TFAM mRNA and protein levels. FDR APCs also exhibited reduced mtDNA content and mitochondrial-genome transcription. In parallel, FDR APCs exhibited impaired differentiation and TFAM induction during adipogenesis. In CTRL APCs, TFAM -siRNA reduced mtDNA content, mitochondrial transcription and adipocyte differentiation in parallel with upregulation of the CDKN1A and ZMAT3 senescence genes. Furthermore, TFAM -siRNA significantly expanded hydrogen peroxide (H 2 O 2 )-induced senescence, while H 2 O 2 did not affect TFAM expression.
Conclusions
Histone modifications regulate APCs ability to differentiate in mature cells, at least in part by modulating TFAM expression and affecting mitochondrial function. Reduced H3K4me3 enrichment at the TFAM promoter renders human APCs senescent and dysfunctional, increasing T2D risk.
Graphical abstract
Since the discovery of amylin no combined formulation with insulin has been made available. Amylin or its triple proline analogue pramlintide are not compatible in solution with insulin. The drug candidate hAmy-PEG5k is a novel monoPEGylated amylin derivative with improved physicochemical properties and retained similar pharmacological activity compared to free amylin and pramlintide. We have investigated the short- and long-term physicochemical compatibility of hAmy-PEG5k co-formulated with slow-acting human insulin analogues glargine or detemir. While human amylin promptly aggregates over a large range of pH, and both free and in the presence of regular, glargine or detemir insulin, the hAmy-PEG5k analogue is stable at these conditions as shown by Thioflavin T (ThT) binding assay. When hAmy-PEG5k (100 or 500 µg/mL) was added to the commercial formulations of either insulin glargine or detemir (95 IU/mL), the combinations remained stable after 6 months stored at 4 °C, as probed by ThT, dynamic light scattering (DLS) measurements and high performance liquid chromatography (HPLC) analyses, confirming the absence of amyloid fibers, minor aggregation products or loss of material. These results suggest hAmy-PEG5k and the insulin analogs glargine and detemir are physicochemically compatible and are candidate ready-to-use fixed-dose combinations.
Islet dysfunction is a hallmark of type 2 diabetes mellitus (T2DM). Compelling evidence suggests that accumulation of islet amyloid in the islets of Langerhans significantly contribute to β-cell dysfunction and diabetes. Emerging evidence implicates a role for cystic fibrosis transmembrane-conductance regulator in the regulation of insulin secretion from pancreatic islets. Impaired first-phase insulin responses and glucose homeostasis have also been reported in cystic fibrosis patients. The transforming growth factor-β protein superfamily is central regulators of pancreatic cell function, and has a key role in pancreas development and pancreatic disease, including diabetes and islet dysfunction. It is also becoming clear that islet inflammation plays a key role in the development of islet dysfunction. Inflammatory changes, including accumulation of macrophages, have been documented in type 2 diabetic islets. Islet dysfunction leads to hyperglycemia and ultimately the development of diabetes. In this review, we describe these risk factors and their associations with islet dysfunction.
Pengaruh ekstrak tempe kedelai hitam (Glycine soja) terhadap jumlah sel â pankreas tikus putih jantan (Rattus novergicus strain wistar) model DM tipe 2. Latar Belakang: Hiperglikemia kronis meningkatkan pembentukan radikal bebas yang menyebabkan stres oksidatif sehingga menurunkan jumlah sel β pankreas. Ekstrak tempe kedelai hitam mengandung zat antioksidan seperti isoflavon, polifenol, dan antosianin yang berpotensi mencegah sel β pankreas dari kerusakan yang disebabkan oleh hiperglikemia kronis dan dapat meningkatkan jumlah sel β pankreas. Tujuan: Membuktikan adanya pengaruh pemberian ekstrak tempe kedelai hitam terhadap jumlah sel β pankreas tikus putih jantan model DM tipe 2. Metode: Menggunakan rancangan post test controlled group, sampel penelitian dibagi menjadi 5 kelompok. Kelompok I (kontrol negatif), kelompok II (control positif) diberi streptozotosin dosis rendah secara berulang selama 5 hari, kelompok III (D1) ditambah ekstrak tempe kedelai hitam dosis 150 mg/kgBB/hari, kelompok IV (D2) ditambah ekstrak tempe kedelai hitam dosis 300 mg/kgBB/hari, kelompok V (D3) ditambah ekstrak tempe kedelai hitam dosis 450 mg/ kgBB/hari selama 14 hari. Hasil dan Diskusi: Rerata dari jumlah sel â pankreas pada kelompok negatif 91,86 sel/LP, positif 56,16 sel/LP, D1 60,88 sel/LP, D2 72,94 sel/LP,dan D3 84,66 sel/LP. Pemberian ekstrak tempe kedelai hitam berpengaruh bermakna terhadap peningkatan jumlah sel â pankreas tikus putih jantan model DM tipe 2 antar kelompok (p<0,05). Kesimpulan: Pemberian ekstrak tempe kedelai hitam meningkatkan jumlah sel â pankreas tikus putih jantan model DM tipe 2.
Amylin is a pancreatic peptide hormone co-secreted along with insulin by the β-cells. It is found in amyloid deposits in both type 2 diabetic individuals and elder non-diabetic. The triple proline amylinomimetic compound (25,28,29-Pro-human amylin) named pramlintide was designed aiming to solve the solubility and amyloid characteristics of human amylin. We have found by using ion mobility spectrometry-based mass spectrometry that pramlintide is able to assembly into multimers. Pramlintide formed amyloid fibrils in vitro in a pH-dependent kinetic process within a few hours, as followed by thioflavin T, quantification of soluble peptide and further characterized by transmission electron microscopy, atomic force microscopy and X-ray diffraction. These data indicate that pramlintide can form amyloid fibers.
AimsPancreatic islet amyloid deposition is a characteristic feature of type 2 diabetes mellitus (T2DM). Islet amyloid polypeptide (IAPP) is co-secreted with insulin, but its secretion profile and relationship to insulin and C-peptide in response to glucose and non-glucose stimuli has not been clearly defined. Methods
Forty subjects (13 NGT, 12 IGT and 15 T2DM) participated in an OGTT and two-step hyperglycemic (225 and 400 mg/dl) clamp (80 min/step) followed by an IV arginine bolus. Acute insulin (AIR), C-peptide (ACPR) and IAPP (AIAR) responses during each hyperglycemic step and following arginine (AIRArg) were assessed. ResultsAIR and ACPR during both hyperglycemic steps and after arginine progressively decreased from NGT to IGT to T2DM. Fasting IAPP concentrations were higher in T2DM compared to NGT and IGT subjects. The acute IAPP0–10 was markedly decreased only in T2DM, while the acute IAPP80–90 response during the second step (80–160 min) of hyperglycemic clamp and in response to arginine was markedly impaired in both IGT and T2DM. The ratio of IAPP/C-peptide during the first (225 mg/dl) and second step (400 mg/dl), and in response to arginine, was decreased in T2DM versus both NGT and IGT (p < 0.01). The acute IAPP0–10 correlated with ACPR0–10 (r = 0.665, p < 0.001) and AIR0–10 (r = 0.543, p < 0.001). Conclusions
Basal IAPP secretion is higher in T2DM and IGT versus NGT but is reduced in response to hyperglycemia and arginine. The IAPP/C-peptide ratio is reduced with prolonged and more severe hyperglycemia in T2DM individuals. Clinical trial registrationNCT00845182.
Amylin, a peptide hormone produced in the pancreas and in the brain, has well-established physiological roles in glycemic regulation and energy balance control. It improves postprandial blood glucose levels by suppressing gastric emptying and glucagon secretion; these beneficial effects have led to the FDA-approved use of the amylin analog pramlintide in the treatment of diabetes mellitus. Amylin also acts centrally as a satiation signal, reducing food intake and body weight. The ability of amylin to promote negative energy balance, along with its unique capacity to cooperatively facilitate or enhance the intake- and body weight-suppressive effects of other neuroendocrine signals like leptin, have made amylin a leading target for the development of novel pharmacotherapies for the treatment of obesity. In addition to these more widely studied effects, a growing body of literature suggests that amylin may play a role in processes related to cognition, including the neurodegeneration and cognitive deficits associated with Alzheimer's disease (AD). Although the function of amylin in AD is still unclear, intriguing recent reports indicate that amylin may improve cognitive ability and reduce hallmarks of neurodegeneration in the brain. The frequent comorbidity of diabetes mellitus and obesity, as well as the increased risk for and occurrence of AD associated with these metabolic diseases, suggests that amylin-based pharmaceutical strategies may provide multiple therapeutic benefits. This review will discuss the known effects of amylin on glycemic regulation, energy balance control, and cognitive/motivational processes. Particular focus will be devoted to the current and/or potential future clinical use of amylin pharmacotherapies for the treatment of diseases in each of these realms.
Background. The aim of this study was to assess the influence of meal-time (prandial) administration of small doses of rapid acting insulin analog on the plasma concentrations of proinsulin, insulin and C-peptide in type 2 diabetics with secondary failure of glimepiride therapy. Material and methods. 50 patients with type 2 diabetes treated with 4 mg of glimepiride daily, in whom glucose concentration exceeded 180 mg/dl at any time of day, were included in the study. A standard intravenous glucose tolerance test (IVGTT) was performed in all patients with determination of proinsulin, insulin and C-peptide concentrations at 0, 2, 4, 6, 8 and 10 minutes. On the same day, insulin therapy with subcutaneous injection of 4 units of lispro analog before the three main meals, 4-6 minutes after the beginning of the meal, was instituted in place of glimepiride. Insulin therapy was continued for five days. On the 6th day, an IVGTT was performed as described above and the patient was switched back to glimepiride 4 mg daily. The plasma concentrations of the abovementioned hypoglycaemic peptides before and after insulin therapy were compared between two groups: group A (n = 30) comprised patients with fasting hypoinsulinemia (< 36 pmol/l), group B (n = 20) comprised patients with fasting normoinsulinemia (36-144 pmol/l). Insulin sensitivity was calculated from the QUICKI formula (Katz and Nambi, 2000). Results. In group A, there was a significant increase in the concentration of hypoglycaemic peptides at 0 and 2 minutes of the IVGTT (P < 0.05), as well as a significant increase in the insulin sensitivity index (P < 0.05) due to the administration of meal-time insulin boluses. No such changes were observed in the group of patients with fasting normoinsulinemia. Conclusions. Short-term insulin therapy with the prandial bolus method can increase the basal and stimulated secretion of hypoglycemic peptides and decrease the proinsulin/insulin ratio in patients with secondary failure of sulfonylurea therapy who also have fasting hypoinsulinemia. In the fasting hypoinsulinemia group, decreased insulin sensitivity was noted after temporary institution of insulin therapy with the prandial bolus method.
In an otherwise enticing article by Schmitz et al. (1) in the February 2002 issue of Diabetes Care , the authors make several assertions that are difficult to support by the data presented in the article.
The authors discuss “early-phase” insulin secretion …
We appreciate the overall constructive criticisms given by Dr. Egger (1) and we respond as follows: The Captopril Prevention Project (CAPPP) Study was the first intervention trial in hypertensive patients to compare an ACE inhibitor–based therapy with conventional antihypertensive therapy, based on diuretics and/or β-blockers, regarding the effects on cardiovascular morbidity and mortality (2). As correctly pointed out by Dr. Egger, in the whole CAPPP study population, both diabetic and nondiabetic subjects combined, no difference was found between regimens in preventing the primary end point (i.e., the combination of fatal as well as nonfatal myocardial infarction and stroke and other cardiovascular deaths). In the whole CAPPP population, the risk of stroke was lower with conventional therapy than with captopril therapy, but this was not the case in the diabetic patients. We are just as puzzled by the result in the full cohort as are others, since this result is not supported by other studies. The contributory factors may have been a higher frequency of history of strokes and transient ischemic attacks at baseline in the captopril …
We agree with Hinke et al. (1) that metformin acts mainly through the inhibition of hepatic glucose output and the enhancement of peripheral insulin sensitivity, through unidentified molecular mechanisms in the liver and skeletal muscle. However, it has been observed that metformin could enhance glucose-induced insulin secretion in some experimental conditions (2), although the relevance of this effect for the antihyperglycemic action of metformin is questionable. Furthermore, glucagon-like peptide (GLP)-1 has been shown to increase insulin sensitivity and non–insulin-mediated glucose disposal (3,4), suggesting that DPP-IV inhibitors, which increase GLP-1 levels, could …
I thank Dr. Block (1) for the interest in our article (2) and the editor for the opportunity to clarify the point raised. As stated several times in our article (results, Table 2, conclusions), we define the early-phase period (i.e., where insulin secretory rates were calculated) as the initial 30 min of the prandial phase. The calculation of insulin secretion was as noted based on measurements of insulin and C-peptide, utilizing the classic combined model. Samples were drawn every 10 min during this part of the prandial period.
The cardinal issue in our article is the effect of the insulin secretagogue repaglinide on the meal-induced …
The pathogenesis of type 2 diabetes is complex, typically involving both insulin resistance and β-cell dysfunction, with both defects being present well before the development of frank hyperglycemia and the clinical diagnosis of diabetes. This chapter reviews the abnormalities in β-cell function observed in impaired glucose talerance and type 2 diabetes and elucidates some of the hypotheses regarding possible mechanisms responsible for the progressive failure of the β-cell over time.
With approximately 400 million people worldwide today being obese, we are facing a major public health problem due to the increasing prevalence of the related comorbidities such as type 2 diabetes, hypertension and coronary heart disease. To date, pharmacological treatment of obesity has been largely unsuccessful, only achieving modest and short-lasting reductions in body weight and with adverse effects. Scientific interest in recent years has concentrated on both the secretion and function of the incretin hormones, GLP-1 and GIP, and their suitability as new target drugs. The potential of GLP-1 to reduce gastric emptying, appetite and food intake makes it an attractive tool in the fight against obesity and several companies are developing weight lowering drugs based on GLP-1. Currently, it is not known whether the inhibiting effects of GLP-1 on gastric emptying, appetite and food intake are directly mediated by GLP-1, or if the effects are secondary to the robust insulin responses, and thereby amylin responses, elicited by GLP-1. The first study aimed to further elucidate the mechanisms of these effects in order to strengthen the development of anti-diabetic drugs with potential weight lowering capabilities. We found that GLP-1 mediates its effect on gastrointestinal motility, appetite, food intake and glucagon secretion directly and thereby in an amylin-independent fashion. In vitro and animal studies indicate that GIP exerts direct effects on adipose tissue and lipid metabolism, promoting fat deposition. Due to its therapeutic potential in obesity treatment, a rapidly increasing number of functional studies are investigating effects of acute and chronic loss of GIP signaling in glucose and lipid homeostasis. However, the physiological significance of GIP as a regulator of lipid metabolism in humans remains unclear. In the second study, we investigated the effects of GIP on the removal rate of plasma TAG and FFA concentrations, which were increased after either a mixed meal or infusion of Intralipid and insulin. Under these experimental conditions, we were not able to demonstrate any effects of GIP on the removal rate of either chylomicron-TAG or Intralipid-derived TAG concentrations. However, we found evidence for enhanced FFA re-esterification under conditions with combined high GIP and insulin concentrations. Based on findings from this study, the third study was designed to evaluate the direct effects of GIP on regional adipose tissue and splanchnic metabolism. Regional net substrate fluxes across the subcutaneous, abdominal adipose tissue and the splanchnic tissues were examined by direct measurements of arterio-venous concentration differences of various metabolites in combination with regional blood flow measurements (Fick's principle). GIP in combination with hyperinsulinemia and hyperglycemia increased blood flow, glucose uptake, and FFA re-esterification, resulting in increased TAG deposition in abdominal, subcutaneous adipose tissue. Finally, it was not possible to demonstrate any effect of GIP per se on net lipid metabolism in the splanchnic area either during fasting conditions or in combination with hyperinsulinemia and hyperglycemia.
Diabetes is associated with metabolic and vascular abnormalities. We investigated if arterial and venous constrictions are impaired in rat models of diabetes. Wistar rats (5 weeks old) were fed a normal or high-fructose diet (60% of caloric intake). On Day 14, half of the animals in each diet regimen were given streptozotocin (60 mg/kg, i.v.). On Day 35, plasma insulin and triglyceride were measured, and on Day 42, insulin sensitivity (via hyperinsulinemic euglycemic clamp), and pressor as well as mean circulatory filling pressure (index of venous tone) responses to noradrenaline were determined. The rats treated with streptozotocin or fructose-streptozotocin were hyperglycemic, hypoinsulinemic and insulin resistant, and they also had reduced potency (increased ED(50)) of pressor response and reduced venoconstriction to noradrenaline compared to the two groups not given streptozotocin. Plasma triglyceride was unchanged in streptozotocin-treated rats, moderately increased in fructose-fed rats, and markedly increased in fructose-streptozotocin-treated rats. Hyperglycemia, insulin resistance and alpha-adrenoceptor-mediated venous contractile dysfunction were more pronounced in the group given fructose-streptozotocin than that given streptozotocin alone. The presence of marked hypertriglyceridemia, insulin resistance and vascular dysfunction makes the fructose-streptozotocin-treated rats a suitable model for study of metabolic and vascular abnormalities in advanced type 2 diabetes.
There are many commonly known risk factors of type 2 diabetes. One of them is the occurrence of the disease in 1st degree relatives. THE AIM OF THE STUDY was: a) to evaluate the threat of type 2 diabetes in adult children of patients with type 2 diabetes, b) to analyze the frequency of type 2 diabetes and other disorders in offspring of parents with type 2 diabetes, c) to detect metabolic disorders before clinical manifestation and the development of macro- and microangiopathy, d) to introduce early prevention and treatment in case of disorders, e) to evaluate the influence of sex and age on the metabolic disorders.
Included in the study were 197 declared as healthy probands, children from parents with type 2 diabetes, aged 18-71 years, 71 men and 126 women. In 74 of the probands the father has type 2 diabetes, mean age 42 years, in 121 the mother, mean age 43 years. In one case both the father and the mother has diabetes type 2. All the offspring's were divided in age groups. Group 1:18-44 years, group 2 over 44 years and in subgroups depending on sex. All the examined offspring's has had following examinations: BMJ, fasting glycaemia 2 times, OGTT, cholesterol, TG, HDL, LDL insulinaemia, peptide C, HbA1c, indirect insulin resistance index.
Hyperglycemia was ascertained in 37%, including unknown diabetes type 2 in 25% in the group with a diabetic father. In the group with a diabetic mother unknown diabetes type 2 was shown in 23%. In the whole group 58% of the offspring's were overweight or obese, glycaemia disorders existed in 44%, especially in the age group over 44 years. More than half of the examined offspring's has an increased level of cholesterol and HbA1c, especially in sons of diabetic fathers, aged over 44 years. The increased level of insulin peptide C, HbA1c, BMI and blood pressure correlated with the age over 44 years and with the male sex.
1. Offspring of parents with type 2 diabetes is a group of high risk for the development of diabetes type 2. 2. Necessary is a complex examination and furthermore a close monitoring of the risk factors for diabetes, in offspring's of parents with type 2 diabetes.
Recently, data were presented showing that metformin increased plasma active glucagon-like peptide (GLP)-1[7–36NH2] concentrations in obese nondiabetic male patients (1), and it was suggested that metformin was a direct dipeptidyl peptidase (DP) IV inhibitor. Contradiction of this hypothesis is simply found by examining the modes of action of metformin and of the DP IV inhibitors. Although the specific molecular target of metformin is still unknown, biguanides generally act to sensitize peripheral tissues to insulin action (particularly, skeletal muscle) and inhibit hepatic gluconeogenesis and glycogenolysis (2,3,4). In contrast, DP IV inhibitors act to enhance the insulin response to a meal, via preservation of …
I have some questions about the opinions presented by Niskanen et al. in the December 2001 issue of Diabetes Care (1).
Was “after the fact” subanalysis designed with enough power to see the proposed difference? The subanalysis of 572 patients compared with the 10,985 patients in the Captopril Prevention Project (CAPPP) might not seem as robust as the original study. Even in the original powered-analysis study, the treatment regimens did not …
The prevalence of diabetes has risen substantially in the past decade. This increase has been linked to an “epidemic” of obesity (1). However, environmental toxins, most notably dioxins, have also been suggested as contributing factors.
Because direct exposure data, in the form of measured levels of toxicants in blood, etc., are not yet available from large populations, total air toxicants from the most recent Toxics Release Inventory (TRI) were used to evaluate the relationship between the prevalence of diabetes and environmental toxicants.
Data from the 2000 Behavioral Risk Factor Surveillance System (BRFSS) were used to determine diabetes prevalence, by state (1). These data are based on self-reports …
Several investigators have renewed interest in the role of tubulointerstitial injury in the progression of diabetic nephropathy (1,2). It was recently reported that the kidney is an important target organ for damage caused by smoking (3,4). Cigarette smoking increases carboxy-hemoglobin concentration, platelet aggregability, and fibrinogen concentration, all of which may cause tissue hypoxia and contribute to vascular damage. Smoking also has a direct deleterious effect on the proximal tubule (5). Cigarette smoking is known to promote the progression of diabetic nephropathy in clinical study (6), but its effect on tubulointerstitial injury has not been established.
We evaluated glomerular and tubulointerstitial structural findings on renal biopsy specimens taken from type 2 diabetic patients and determined the relationship between smoking and renal architecture. A total of 48 patients (32 men and 16 women) with type 2 diabetes underwent renal biopsy. Information on smoking …
Patients affected by type 1 diabetes appear to be more prone to infection than healthy subjects (1).
Recently, it has been shown that Helicobacter pylori ( H. pylori ) infection is common in type 1 diabetes (2) and that the use of a standard antibiotic therapy obtains a significantly lower eradication rate than in non–insulin-dependent diabetic subjects (3,4). Our aim was to assess the incidence of H. pylori re-infection after a successful therapy in type 1 diabetic patients. A total of 74 subjects previously infected by H. pylori were enrolled, including 34 type 1 diabetic subjects (16 women and 18 men, 42 ± 9 years of age) and 40 nondiabetic control subjects (17 women and 23 …
It is generally accepted that insulin resistance precedes the development of type 2 diabetes, but the precise mechanism that links insulin resistance to overt diabetes is not well understood. Genetic defects of the insulin receptor, although the prevalence is low, are regarded as one of the specific causes of diabetes (1). However, few studies have reported long-term observations of subjects with the insulin receptor mutation (2). Here, we describe a family with the abnormal insulin receptor who was followed-up for ∼20 years.
The proband is a 34-year-old Japanese woman. At 16 years of age, she noticed acanthosis nigricans in her axillae and groin. Her BMI was 19.0 kg/m2. Fasting glucose was normal, but fasting insulin concentration was as high as 240 pmol/l. Anti-insulin and anti–insulin receptor antibodies were negative. The 100-g oral glucose challenge …
A 34-year-old Korean man living in Tokyo was referred to us in January 1999 for control of his diabetes during cataract surgery. He told us that both disorders had first appeared when he was 22, along with hyperlipidemia. He had acute pancreatitis at 24, and acute appendicitis with peritonitis at 27. He was admitted to a hospital in 1998 for ileus. He has three siblings, the youngest of whom, a sister, had cataracts at 22, and her hair was streaked with gray. His father was diabetic and died at 52 from liver cancer. His mother has …
We have recently reported (1) that T-cell autoimmunity may be involved in so-called “fulminant” type 1 diabetes (characterized by diabetic ketoacidosis [DKA], low HbA1c level at onset, insulin deficiency, and negative islet-associated autoantibodies), which was originally proposed as a novel subtype of type 1B diabetes (2). In our previous report (1), we found a high serum level of interferon-inducible protein-10 (IP-10), an important chemokine inducing migration of activated T-cells to local lesions (3), and GAD-reactive CD4+ cells in the periphery of a patient, even though no islet-associated antibody was detected.
Here, we report another case of fulminant type 1 diabetes, a 48-year-old man who was proven to have not only a high serum IP-10 level and GAD-reactive CD4+ cells in the periphery but also …
Insulin resistance is common in hemoglobinopathy including thalassemias. Excessive iron deposition in the liver is associated with a high prevalence of glucose intolerance in patients with hemoglobinopathy requiring repeated blood transfusion (1). In Hong Kong, up to 8.5% of pregnant women have thalassemia trait (2), which is a minor form of thalassemia and does not require blood transfusion. Furthermore, nearly 50% of patients with type 2 diabetes <35 years of age have a family history of diabetes (3). Both conditions share the common feature of insulin resistance. We postulate that there may be a clustering of these disorders in susceptible individuals. We therefore conducted a case-control study of subjects with normal glucose tolerance to examine the relationship among thalassemias, liver function tests, and index of insulin …
The provision of diabetes care has shifted from the specialist to the generalist in primary care practice. Evidence suggests utilization of nonphysician providers in conjunction with physician-directed protocols improves glycemic control (1). The purpose of this study was to evaluate the impact of a pharmacist-managed diabetes clinic (PMC) on glycemic control and adherence to American Diabetes Association (ADA) standards of medical care in a collaborative physician-pharmacist practice. This was a retrospective analysis comparing patients referred to the PMC for diabetes management with a randomly selected group of patients with diabetes, managed exclusively by their primary care physicians. Only patients with a minimum of 3 months of laboratory data and two visits to the pharmacist or physicians were included.
Pharmacist-managed clinic patients (16 …
The insulin analog insulin glargine has a pharmacodynamic profile described as peakless and of longer duration than human NPH insulin (1). This allows for convenient once-daily dosing for coverage of basal insulin needs. We recently had the opportunity to examine whether this is the case in the following patient.
T.L. is a 53-year-old man with a history of type 1 diabetes for the past 16 years. Before hospitalization, he had a history of widely variable blood glucose levels, from 50 to 400 mg/dl, while using a 4-injection regimen of premeal insulin lispro and ultralente at dinner. He has no known diabetic complications. Before admission, he had a history of heavy ethanol abuse, with a daily intake of 48–72 oz wine or beer per day. On the day of admission, the patient developed left arm weakness and progressive loss of consciousness. A computed tomography scan revealed a …
The high prevalence of post-transplant glucose intolerance and insulin resistance (IR) is associated with older age, family history of diabetes, immunosuppressive drugs, and antihypertensive therapy. However, the potential determinants of post-transplant beta-cell dysfunction are largely unknown. The objective of the present study was to address this issue in detail. A total of 167 previously nondiabetic renal transplant recipients underwent a 75-g oral glucose tolerance test (OGTT)10 weeks after transplantation. Serum glucose and insulin were measured at 0, 1, and 2 hours. Three insulin release indices (Secr(AUC), Secr(1.phase), and Secr(2.phase)) were calculated to assess the insulin secretory response as the dependent variable. To account for variations in insulin sensitivity (IS), beta-cell function was also estimated as the disposition index (DI); the product of the IS index (ISI(TX)) and Secr(1.phase). Increasing age was strongly and independently associated with a blunted insulin secretory response even after adjustment for IS (P =.001). An 80-year-old recipient had an approximately 50% lower insulin release than a 20-year-old individual, based on the linear regression model. Cytomegalovirus (CMV) disease and treatment with furosemide were both independently associated with beta-cell dysfunction (DI; P <.001 and P =.008). Patients treated with angiotensin-converting enzyme (ACE)-inhibitors had an enhanced absolute insulin release, but the DI was similar in both treated and untreated recipients. We conclude that older age is an important determinant of beta-cell dysfunction after renal transplantation. CMV disease and treatment with furosemide may also negatively influence pancreatic insulin release in renal transplant recipients.
Diabetes mellitus type 2 develops worldwide in the dimensions of an epidemic disease. In order to reduce the personal burden of patients and the enormous costs for the health system, which are mainly due to diabetes complications, diabetes prevention is urgently needed. Regarding pathophysiology, type 2 diabetes develops on the basis of insulin resistance, together with increasing reduction of insulin secretion. This leads to postprandial blood glucose peaks (Impaired Glucose Tolerance, IGT), which furthermore increase insulin resistance (metabolic resistance) and decrease insulin secretion, finally resulting in manifestation of diabetes mellitus. Therefore it is a logical way of diabetes prevention, to treat postprandial blood glucose peaks in the early stadium of IGT. The STOP-NIDDM trial showed conclusively that acarbose reduces postprandial hyperglycemia and diabetes incidence for 36% in comparison to placebo in a group of IGT patients. At the same time the incidence of normal glucose tolerance increased significantly for 30%. The NNT ("number needed to treat") for acarbose to avoid one case of diabetes manifestation in patients with IGT, is eleven patients in 3.3 years. The preventive effect of acarbose is independent of age, gender or weight of the patients. So acarbose has the potential to reduce postprandial hyperglycemia, which is the driving force for diabetes, and thus can prevent diabetes mellitus type 2.
Amylin has been co-secreted from pancreatic islet β-cells in constant proportion with insulin in some studies. We measured basal and glucose-stimulated amylin and insulin secretion from isolated perfused pancreases of normal and diabetic fatty Zucker rats. Glucose concentrations in the perfusion buffer were increased then decreased in small steps to mimic physiologic changes occurring after a meal. The absolute rate of amylin secretion and the molar ratio of amylin to insulin secreted from diabetic pancreases increased dramatically when infused glucose concentrations fell. Similar changes also occurred in normal pancreases, although the absolute change in amylin secretion was smaller. These studies provide the first evidence that (i) there is a mechanism within the pancreas whereby independent secretion of amylin and insulin can occur, (ii) the molar ratio of amylin to insulin secreted from both normal and diabetic pancreases can vary over a wide range; and (iii) there are important differences in the kinetics of amylin and insulin secretion or their coupling to stimulation by glucose between the isolated pancreases of normal rats and those with genetically transmitted insulin resistance and diabetes mellitus.
We have evaluated the feasibility of using a mathematical model of glucose disappearance to estimate insulin sensitivity. Glucose was injected into conscious dogs at 100, 200, or 300 mg/kg. The measured time course of insulin was regarded as the "input," and the falling glucose concentration as the "output" of the physiological system storing and using glucose. Seven mathematical models of glucose uptake were compared to identify the representation most capable of simulating glucose disappearance. One specific nonlinear model was superior in that it 1) predicted the time course of glucose after glucose injection, 2) had four parameters that could be precisely estimated, and 3) described individual experiments with similar parameter values. Insulin sensitivity index (SI), defined as the dependence of fractional glucose disappearance on plasma insulin, was the ratio of two parameters of the chosen model and could be estimated with good reproducibility from the 300 mg/kg injection experiments (SI = 7.00 X 10(-4) +/- 24% (coefficient of variation) min-1/(microU/ml) (n = 8)). Thus, from a single glucose injection it is possible to obtain a quantitative index of insulin sensitivity that may have clinical applicability.
Deposition of amyloid in pancreatic islets is a common feature in human type 2 diabetic subjects but because of its insolubility and low tissue concentrations, the structure of its monomer has not been determined. We describe a peptide, of calculated molecular mass 3905 Da, that was a major protein component of amyloid-rich pancreatic extracts of three type 2 diabetic patients. After collagenase treatment, an extract containing 20-50% amyloid was solubilized by sonication into 70% formic acid and the peptide was purified by gel filtration followed by reverse-phase high-performance liquid chromatography. We term this peptide diabetes-associated peptide, as it was not detected in extracts of pancreas from any of six normal subjects. Diabetes-associated peptide contains 37 amino acids and is 46% identical to the sequences of rat and human calcitonin gene-related peptide, indicating that these peptides are related in evolution. Sequence identities with conserved residues of the insulin A chain were also seen in a 16-residue segment. On extraction, the islet amyloid is particulate and insoluble like the core particles of Alzheimer disease. Their monomers have similar molecular masses, each having a hydropathic region that can probably form beta-pleated sheets. The accumulation of amyloid, including diabetes-associated peptide, in islets may impair islet function in type 2 diabetes mellitus.
The relative roles of obesity, insulin resistance, insulin secretory dysfunction, and excess hepatic glucose production in the development of non-insulin-dependent diabetes mellitus (NIDDM) are controversial. We conducted a prospective study to determine which of these factors predicted the development of the disease in a group of Pima Indians.
A body-composition assessment, oral and intravenous glucose-tolerance tests, and a hyperinsulinemic--euglycemic clamp study were performed in 200 non-diabetic Pima Indians (87 women and 113 men; mean [+/- SD] age, 26 +/- 6 years). The subjects were followed yearly thereafter for an average of 5.3 years.
Diabetes developed in 38 subjects during follow-up. Obesity, insulin resistance (independent of obesity), and low acute plasma insulin response to intravenous glucose (with the degree of obesity and insulin resistance taken into account) were predictors of NIDDM: The six-year cumulative incidence of NIDDM was 39 percent in persons with values below the median for both insulin action and acute insulin response, 27 percent in those with values below the median for insulin action but above that for acute insulin response, 13 percent in those with values above the median for insulin action and below that for acute insulin response, and 0 in those with values originally above the median for both characteristics.
Insulin resistance is a major risk factor for the development of NIDDM: A low acute insulin response to glucose is an additional but weaker risk factor.
Amylin is a 37-amino-acid polypeptide synthesized in and secreted from pancreatic beta cells along with insulin. Its biological actions include the slowing and reduction of postmeal increases in plasma glucose concentrations. Studies of the basic amylin biology in humans have been hampered by the lack of a rapid, sensitive assay capable of measuring physiological concentrations of amylin in small volumes of plasma. We report here two sandwich-type immunoassays that use pairs of monoclonal antibodies, the fluorescent substrate 4-methylumbelliferyl phosphate, and the enzyme alkaline phosphatase. The minimum detectable concentration of amylin in 50 microL of plasma was 0.5 to 2 pmol/L, and the dynamic range was 2 to 100 pmol/L. The assays had average intraassay CVs of <10%, average interassay CVs of <15%, and good linearity on dilution and recovery of added amylin. The two assays use the same detection antibody, which binds to the carboxyl terminus of the molecule, but different capture antibodies. One of the assays measures only human amylin; the other also detects amylin-like peptides. Examples of measurements in human plasma are provided in subjects with impaired glucose tolerance and in nondiabetic controls.
Insulin sensitivity and insulin secretion are traits that are both genetically and environmentally determined.
The aim of this study was to describe the distribution of the insulin sensitivity index (Si), the acute insulin response, and glucose effectiveness (Sg) in young healthy Caucasians and to estimate the relative impact of anthropometric and environmental determinants on these variables.
The material included 380 unrelated Caucasian subjects (18-32 yr) with measurement of Si, Sg and insulin secretion during a combined intravenous glucose (0.3 grams/kg body weight) and tolbutamide (3 mg/kg body weight) tolerance test.
The distributions of Si and acute insulin response were skewed to the right, whereas the distribution of Sg was Gaussian distributed. Sg was 15% higher in women compared with men (P < 0.001). Waist circumference, body mass index, maximal aerobic capacity, and women's use of oral contraceptives were the most important determinants of Si. Approximately one-third of the variation of Si could be explained by these factors. Compared with individuals in the upper four-fifths of the distribution of Si, subjects with Si in the lowest fifth had higher waist circumference, higher blood pressure, lower VO2max, and lower glucose tolerance and fasting dyslipidemia and dysfibrinolysis. Only 10% of the variation in acute insulin response could be explained by measured determinants.
Estimates of body fat, maximal aerobic capacity, and women's use of oral contraceptives explain about one-third of the variation in Si in a population-based sample of young healthy Caucasians.
Type 2 diabetes mellitus is characterised by resistance of peripheral tissues to insulin and a relative deficiency of insulin secretion. To find out which is the earliest or primary determinant of disease, we used a minimum model of glucose disposal and insulin secretion based on intravenous glucose tolerance tests to estimate insulin sensitivity (SI), glucose effectiveness (ie, insulin-independent glucose removal rate, SG), and first-phase and second-phase beta-cell responsiveness in normoglycaemic offspring of couples who both had type 2 diabetes. 155 subjects from 86 families were followed-up for 6-25 years. More than 10 years before the development of diabetes, subjects who developed the disease had lower values of both SI (mean 3.2 [SD 2.4] vs 8.1 [6.7] 10(-3) I min-1 pmol-1 insulin; p < 0.0001) and SG (1.6 [0.9] vs 2.3 [1.2] 10(-2) min-1, p < 0.0001) than did those who remained normoglycaemic). For the subjects with both SI and SG below the group median, the cumulative incidence of type 2 diabetes during the 25 years was 76% (95% confidence interval 54-99). By contrast, no subject with both SI and SG above the median developed the disease. Subjects with low SI/high SG or high SI/low SG had intermediate risks. Insulin secretion, especially first phase, tended to be increased rather than decreased in this prediabetic phase and was appropriate for the level of insulin resistance. The development of type 2 diabetes is preceded by and predicted by defects in both insulin-dependent and insulin-independent glucose uptake; the defects are detectable when the patients are normoglycaemic and in most cases more than a decade before diagnosis of disease.
Insulin resistance and impaired insulin secretion are thought to be the primary defects in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). Disproportionately increased proinsulin relative to insulin levels are suggested to be an early indicator of a failing pancreas. We examined the relationship of fasting specific insulin, proinsulin, and 32, 33 split proinsulin concentrations, and the proinsulin: insulin ratio to the risk of developing NIDDM 3.5 years later in 65–74-year-old non-diabetic Finnish subjects participating in a populationbased study (n=892) on diabetes and heart disease. Altogether 69 subjects developed NIDDM over a 3.5-year follow-up (cases). The cases were compared to randomly-selected gender-matched control subjects (n=69) and control subjects matched for gender, glucose tolerance status (normal or impaired), and body mass index (n=69). There were no differences in insulin concentrations between cases and random or matched control subjects [median and interquartile range; 123 (77–154), 108 (74–143), 118 (83–145) pmol/l, p=0.271]. Random control subjects had lower proinsulin and 32,33 split proinsulin concentrations and split proinsulin: insulin ratios compared to cases [5.7 (3.8–9.0) vs 7.3 (4.8–10.0) pmol/l, p=0.005; 7.3 (4.5–13.0) vs 10.4 (7.1–18.0) pmol/l, p=0.002; 0.073 (0.057–0.110) vs 0.097 (0.060–0.135), p=0.003]. Matched control subjects had lower proinsulin concentrations and proinsulin: insulin ratios compared to cases [5.9 (4.0–7.7) vs 7.3 (4.8–10.0) pmol/l, p=0.019; 0.048 (0.035–0.071) vs 0.064 (0.045–0.100), p=0.008]. When cases were compared to matched control subjects a 1 SD increase in baseline proinsulin: insulin ratio was associated with a 1.37-fold risk (p=0.020) of developing diabetes. Moreover, this association was independent of fasting glucose concentration at baseline. Thus, in elderly prediabetic subjects disproportionately increased proinsulin concentration, an indicator of defective insulin secretion, is associated with conversion to diabetes over a short time period.
In 1960, immunoassays of insulin first demonstrated significant quantities of circulating hormone in non-insulin-dependent (type II) diabetes and for 30 yr have fostered debate as to whether a β-cell abnormality plays an etiological role in this syndrome. Early efforts to determine the adequacy of islet β-cell function showed that obesity and its associated insulin resistance were major confounding variables. Subsequently, it was recognized that glucose not only directly regulated insulin synthesis and secretion but moderated all other islet signals, including other substrates, hormones, and neural factors. When both obesity and glucose are taken into account, it becomes clear that patients with fasting hyperglycemia all have abnormal islet function. Type II diabetes is characterized by a defect in first-phase or acute glucose-induced insulin secretion and a deficiency in the ability of glucose to potentiate other islet nonglucose β-cell secretagogues. The resulting hyperglycemia compensates for the defective glucose potentiation and maintains nearly normal basal insulin levels and insulin responses to nonglucose secretagogues but does not correct the defect in first-phase glucose-induced insulin release.
Before the development of fasting hyperglycemia, only first-phase glucose-induced insulin secretion is obviously defective. This is because progressive islet failure is matched by rising glucose levels to maintain basal and second-phase insulin output. The relationship between islet function and fasting plasma glucose is steeply curvilinear, so that there is a 75% loss of β-cell function by the time the diagnostic level of 140 mg/dl is exceeded. This new steady state is characterized by glucose overproduction and inefficient utilization. Insulin resistance is also present in most patients and contributes to the hyperglycemia by augmenting the glucose levels needed for compensation. Decompensation and absolute hypoinsulinemia occur when the renal threshold for glucose is exceeded and prevents further elevation of circulating glucose.
The etiology of the islet β-cell lesion is not known, but a hypothesis based on basal hyperproinsulinemia and islet amyloid deposits in the pancreas of type II diabetes is reviewed. The recent discovery of the islet amyloid polypeptide (IAPP) or amylin, which is the major constituent of islet amyloid deposits, is integrated into this hypothesis. It is suggested that pro-IAPP and proinsulin processing and mature peptide secretion normally occur together and that abnormal processing, secondary to or in conjunction with defects in hormone secretion, lead to progressive accumulation of intracellular IAPP and pro-IAPP, which in cats, monkeys, and humans form intracellular fibrils and amyloid deposits with a loss of β-cell mass. This process is accelerated by increased β-cell demand from insulin resistance. Thus, type II diabetes is reviewed as a heterogenous disorder in which islet dysfunction plays a critical role. Insulin resistance interacts to produce the final syndrome, in which deposition of pancreatic islet amyloid is probably an important long-term contributor.
OBJECTIVE To determine whether insulin resistance or insulin deficiency is primary in the pathogenesis of type II diabetes. DESIGN Cohort analytic study of persons with normal glucose tolerance but with a high risk for developing type II diabetes (average follow-up time, 13 years). SETTING Outpatients had an intravenous glucose tolerance test and were contacted periodically to ascertain diagnoses of diabetes. PARTICIPANTS One hundred and fifty-five normal offspring, ranging in age from 16 to 60 years, of two parents with type II diabetes and 186 normal control subjects in the same age range who had no family history of diabetes. MEASUREMENTS AND MAIN RESULTS Two phenotypic characteristics distinguished the offspring of diabetic parents from control subjects. They had slower glucose removal rates (Kg) (P less than 0.01) and higher insulin levels (fasting and during the second phase of insulin response to intravenous glucose; P less than 0.0001) than did control subjects, even after adjustment for differences in obesity. Sixteen percent of the offspring developed type II diabetes. Mean Kg at baseline was 1.7%/min among offspring who subsequently developed diabetes, 2.2%/min among offspring who remained nondiabetic, and 2.3%/min among control subjects. Corresponding means for first-phase insulin were 498, 354, and 373 pM, respectively, whereas second-phase insulin means were 329, 117, and 87 pM, respectively. In multivariate analysis, low Kg and high serum insulin levels independently increased the risk for developing diabetes among the offspring of diabetic parents. CONCLUSIONS One to two decades before type II diabetes is diagnosed, reduced glucose clearance is already present. This reduced clearance is accompanied by compensatory hyperinsulinemia, not hypoinsulinemia, suggesting that the primary defect is in peripheral tissue response to insulin and glucose, not in the pancreatic beta cell.
To identify the pathogenic factors responsible for glucose intolerance of aging, we measured a variety of metabolic parameters, including insulin sensitivity and islet cell function, in 10 young (18-36 yr old) and 10 older (57-82 yr old) men of normal body weight. Subject groups had equivalent fasting plasma glucose and fat cell size values. Frequently sampled iv glucose tolerance tests were performed, and the data were analyzed by computer using the minimal model approach. This technique yields the following measures: S(I), the insulin sensitivity index; Φ1 and Φ2, indices of first and second phase β-cell responsiveness to glucose; n, fractional insulin clearance, and S(G), a measure of dynamic glucose disappearance dependent on glucose per se. We also evaluated β-cell responsiveness independently by measuring the plasma insulin response to arginine injections at three levels of glycemia and calculated potentiation slope from the relationship between the acute insulin response to arginine and the prestimulus glucose level. The older men were glucose intolerant (glucose disappearance rate 1.32% min-1) compared to the younger men (glucose disappearance rate, 2.21% min-1; P<0.01). This tolerance was the result of both a β-cell defect and insulin resistance. The potentiation slope (r=-0.67; P<0.02) and Φ2 (r=-0.47; P<0.05) both decreased with age. In addition, S(I) in the older group was diminished 63% (2.4 vs 6.5; 10-4 min-1/μU/ml; P<0.001) and was unrelated to differences in body fat. No differences were found in either n or S(G). These studies suggest that the diminished glucose tolerance of aging in normal weight men has multifactorial causality. Both β-cell dysfunction and insulin resistance are important. In contrast, we found little evidence for changes in insulin clearance or insulin-independent glucose disappearance contributing to age-related glucose intolerance.
Type II diabetes is a common disorder whose prevalence is increasing in the United States and throughout the world. Type II diabetes is also associated with several other metabolic abnormalities such as central obesity, hypertension, and dyslipidemia, which contributes to the very high rate of cardiovascular morbidity and mortality. The main pathologic defects in diabetes consist of excessive hepatic glucose production, peripheral insulin resistance, and defective beta-cell secretory function. The duration and severity of the hyperglycemia dictate the microvascular complications, no matter what the etiology of the glucose intolerance, and the goals of therapy should be similar to those of insulin-dependent type I diabetic patients. Initiation of nonpharmacologic therapy should be started as soon as the diagnosis is made. Pharmacologic agents should be initiated if the glycemic goals are not met with a 3-month trial of diet and exercise. The cornerstone of therapy consists of a regular exercise routine along with a diet consisting of 40% to 50% complex carbohydrates, 10% to 20% protein, and monounsaturated fats such as canola oil and olive oil. If nonpharmacologic therapy does not achieve adequate glycemic control, initiation of an oral antidiabetic agent is warranted. In addition to the sulfonylureas, which work by stimulating insulin secretion, we now have metformin, which inhibits excessive hepatic glucose production; acarbose, which delays the absorption of carbohydrates in the gut; and troglitazone, which reduces insulin, resistance primarily in skeletal muscle. The selection of an initial oral antidiabetic agent depends on patient characteristics such as the presence of obesity and dyslipidemia, the duration of diabetes, and other concomitant conditions. Combination therapy with two or three of the different classes of oral antidiabetic agents is effective and has been used throughout the world. When maximum doses of oral antidiabetic agents do not adequately control glycemia, insulin therapy is necessary. In selected patients, combination therapy consisting of bedtime intermediate-acting insulin in addition to daytime oral antidiabetic agent(s) can be an effective method to normalize glucose control without the need for rigorous insulin regimens. When combination therapy fails, a split-mixed regimen using premixed 70/30 insulin prebreakfast and predinner can be very effective in obese subjects. In thin insulin-requiring subjects with type II diabetes, more intensive regimens may be required. In general, the risk of severe hypoglycemia is quite low in patients with type II diabetes, and the main adverse effect of insulin therapy is weight gain. Prevention and aggressive treatment of glucose intolerance and the other adverse metabolic conditions associated with type II diabetes will not only have a positive effect on the quality of life but also provide long-term cost savings.
The contribution of proinsulin to the total serum immunoreactive insulin (IRI) was measured in 59 patients with maturity onset diabetes (23 being treated with diet alone and 36 with oral sulfonylurea agents) and compared to that in 44 control subjects. The percentage of proinsulin was increased in 11 patients and correlated with plasma glucose, but not with IRI. There was no difference between the drug-treated group and diet-treated group, or between patients taking different sulfonylurea agents. Sequential studies in one patient showed normalization of the proportion of proinsulin following lowering of the plasma glucose level. It is probably that the increased circulating proportion of proinsulin in hyperglycemic diabetic patients is secondary to beta cell exhaustion with release of less mature granules.
The relative contributions of impaired insulin secretion and of impaired tissue sensitivity to insulin to the glucose intolerance of aging were examined in 84 healthy volunteers, ranging in age from 21 to 84 yr, employing the hyperglycemie and euglycemic insulin clamp techniques, respectively.
HYPERGLYCEMIC CLAMP. The blood glucose concentration was acutely raised and was maintained at 125 mg/dl above basal levels for 2 h. Since the glucose concentration was held constant, the glucose infusion rate was an index of glucose metabolism (M). In young subjects, M averaged 9.48 ± 0.40 mg/kg · min compared with 6.48 ± 0.28 in old subjects (P < 0.001). When all subjects were considered together, a progressive age-related decline in M was observed (r = –0.665, P < 0.001). The plasma insulin response (I) was biphasic, with an early burst within the first 6 min, followed by a phase of gradually increasing insulin concentration. No difference in either the early or late phases of insulin secretion was observed between young and old subjects. Consequently, the M/l (×100) ratio, an index of tissue sensitivity to endogenous insulin, decreased from 14.90 ± 1.01 to 10.98 ± 0.81 mg/kg min per μU/ml (P < 0.005).
EUGLYCEMIC INSULIN CLAMP. The plasma insulin concentration was acutely raised and was maintained at about 100 μU/ml above basal levels by a primed continuous infusion of insulin. The blood glucose concentration was held constant at the basal level by a variable glucose infusion. M/I (×100), again, was a measure of tissue sensitivity to insulin (exogenous) and was decreased in old (4.95 ± 0.31 mg/kg · min per μU/ml) versus young (6.95 ± 0.45) subjects (P < 0.001). Hepatic glucose production was measured with tritiated glucose during the euglycemic clamp study; it declined similarly in young (to 0.13 ± 0.05 mg/kg · min) and old (to 0.09 ± 0.03 mg · min) subjects.
In conclusion, under the present experimental conditions, employing intravenous glucose and/or insulin, impaired tissue sensitivity to insulin is the primary factor responsible for the decrease in glucose tolerance observed with advancing age. Since hepatic glucose production is normally suppressed by insulin in old subjects, the site of insulin resistance must reside in peripheral tissues. Beta cell response to glucose, as determined by the hyperglycemie clamp technique, cannot account for the age-related decline in M.
Type 2 diabetes mellitus is characterised by resistance of peripheral tissues to insulin and a relative deficiency of insulin secretion. To find out which is the earliest or primary determinant of disease, we used a minimum model of glucose disposal and insulin secretion based on intravenous glucose tolerance tests to estimate insulin sensitivity (SI), glucose effectiveness (ie, insulin-independent glucose removal rate, SG), and first-phase and second-phase beta-cell responsiveness in normoglycaemic offspring of couples who both had type 2 diabetes. 155 subjects from 86 families were followed-up for 6-25 years. More than 10 years before the development of diabetes, subjects who developed the disease had lower values of both SI (mean 3.2 [SD 2.4] vs 8.1 [6.7] 10(-3) I min-1 pmol-1 insulin; p < 0.0001) and SG (1.6 [0.9] vs 2.3 [1.2] 10(-2) min-1, p < 0.0001) than did those who remained normoglycaemic). For the subjects with both SI and SG below the group median, the cumulative incidence of type 2 diabetes during the 25 years was 76% (95% confidence interval 54-99). By contrast, no subject with both SI and SG above the median developed the disease. Subjects with low SI/high SG or high SI/low SG had intermediate risks. Insulin secretion, especially first phase, tended to be increased rather than decreased in this prediabetic phase and was appropriate for the level of insulin resistance. The development of type 2 diabetes is preceded by and predicted by defects in both insulin-dependent and insulin-independent glucose uptake; the defects are detectable when the patients are normoglycaemic and in most cases more than a decade before diagnosis of disease.
We examined the response of plasma islet amyloid polypeptide (IAPP) to an oral glucose load in non-obese and obese subjects with normal glucose tolerance or impaired glucose tolerance (IGT), and in non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Plasma IAPP response to intravenous glucagon injection in NIDDM patients was also studied. Plasma IAPP concentration was determined by a sensitive and specific radioimmunoassay. Basal levels of plasma IAPP in non-obese subjects with normal glucose tolerance, IGT and NIDDM were not significantly different from each other. Non-obese subjects with IGT showed delayed and higher plasma IAPP response to oral glucose load compared to normal non-obese subjects. In NIDDM patients, IAPP response to glucose was delayed and lower when compared to normal non-obese subjects. Basal levels of plasma IAPP in normal obese subjects and obese subjects with IGT were significantly higher than those in normal non-obese subjects. Plasma IAPP response to glucose load in these obese subjects was higher than that in normal non-obese subjects. Plasma IAPP response was decreased in diabetic patients treated with diet, oral hypoglycemic agents and insulin in that order. We conclude that the secretion of IAPP is reduced with progression of NIDDM, although it appears to be rather augmented in IGT compared to normal non-obese subjects.
Rats from four experimental treatment groups, including fed controls, 24- to 30-h fasted, dexamethasone-treated, and intraperitoneal glucose-treated, were used to assess the effects of these treatments on the immunohistochemically detectable islet amyloid polypeptide (IAPP) content in the pancreatic islets. Isolated perfused pancreases from additional animals in these groups were used to assess insulin and IAPP secretion and relative amounts of these hormones secreted into the perfusate under low-glucose (2.75 mM) and high-glucose (16.7 mM) conditions. Insulin and IAPP concentrations in the perfusate were measured by radioimmunoassays. Titration of immunohistochemical staining revealed the highest levels of IAPP in the dexamethasone- and glucose-treated groups, followed by the fed controls; the least amount was observed in the fasted group. In the perfusion experiments, the dexamethasone-treated group had significantly higher IAPP secretion than did all of the other groups under stimulation with 16.7 mM glucose. In addition, both dexamethasone treatment and glucose treatment increased the relative amount of IAPP to insulin secretion during 16.7 mM glucose stimulation in comparison with fed controls and fasted groups. Fasting tended to have the opposite effect and significantly decreased the relative amount of IAPP to insulin secreted under stimulation with 16.7 mM glucose. In all groups, IAPP and insulin secretion were generally parallel, which is consistent with their colocalization in the beta-cell secretory vesicle and co-release after glucose stimulation. However, significant differences in the insulin-IAPP ratios between experimental groups is consistent with the hypothesis that production of IAPP and insulin are regulated differently in the beta-cell.(ABSTRACT TRUNCATED AT 250 WORDS)
In 1960, immunoassays of insulin first demonstrated significant quantities of circulating hormone in non-insulin-dependent (type II) diabetes and for 30 yr have fostered debate as to whether a beta-cell abnormality plays an etiological role in this syndrome. Early efforts to determine the adequacy of islet beta-cell function showed that obesity and its associated insulin resistance were major confounding variables. Subsequently, it was recognized that glucose not only directly regulated insulin synthesis and secretion but moderated all other islet signals, including other substrates, hormones, and neural factors. When both obesity and glucose are taken into account, it becomes clear that patients with fasting hyperglycemia all have abnormal islet function. Type II diabetes is characterized by a defect in first-phase or acute glucose-induced insulin secretion and a deficiency in the ability of glucose to potentiate other islet nonglucose beta-cell secretagogues. The resulting hyperglycemia compensates for the defective glucose potentiation and maintains nearly normal basal insulin levels and insulin responses to nonglucose secretagogues but does not correct the defect in first-phase glucose-induced insulin release. Before the development of fasting hyperglycemia, only first-phase glucose-induced insulin secretion is obviously defective. This is because progressive islet failure is matched by rising glucose levels to maintain basal and second-phase insulin output. The relationship between islet function and fasting plasma glucose is steeply curvilinear, so that there is a 75% loss of beta-cell function by the time the diagnostic level of 140 mg/dl is exceeded. This new steady state is characterized by glucose overproduction and inefficient utilization. Insulin resistance is also present in most patients and contributes to the hyperglycemia by augmenting the glucose levels needed for compensation. Decompensation and absolute hypoinsulinemia occur when the renal threshold for glucose is exceeded and prevents further elevation of circulating glucose. The etiology of the islet beta-cell lesion is not known, but a hypothesis based on basal hyperproinsulinemia and islet amyloid deposits in the pancreas of type II diabetes is reviewed. The recent discovery of the islet amyloid polypeptide (IAPP) or amylin, which is the major constituent of islet amyloid deposits, is integrated into this hypothesis. It is suggested that pro-IAPP and proinsulin processing and mature peptide secretion normally occur together and that abnormal processing, secondary to or in conjunction with defects in hormone secretion, lead to progressive accumulation of intracellular IAPP and pro-IAPP, which in cats, monkeys, and humans form intracellular fibrils and amyloid deposits with a loss of beta-cell mass.(ABSTRACT TRUNCATED AT 400 WORDS)
Fasting plasma islet amyloid polypeptide concentrations and their responses to an oral glucose load were determined in non-diabetic control subjects and patients with abnormal glucose tolerance in relation to the responses of insulin or C-peptide. Plasma islet amyloid polypeptide was measured by radioimmunoassay. In the non-diabetic control subjects, fasting plasma islet amyloid polypeptide was 6.4 +/- 0.5 fmol/ml (mean +/- SEM) and was about 1/7 less in molar basis than in insulin. The fasting islet amyloid polypeptide level rose in obese patients and fell in patients with Type 1 (insulin-dependent) diabetes mellitus. In non-obese patients with impaired glucose tolerance and Type 2 (non-insulin-dependent) diabetic patients without insulin therapy, the level was equal to that of the control subjects, but a low concentration of islet amyloid polypeptide relative to insulin or C-peptide was observed in the non-obese Type 2 diabetic group. The patterns of plasma islet amyloid polypeptide responses after oral glucose were similar to those of insulin or C-peptide. However, compared to non-obese patients, a hyper-response of islet amyloid polypeptide relative to C-peptide was noted in obese patients who had a hyper-response of insulin relative to C-peptide. This study suggests that basal hypo-secretion of islet amyloid polypeptide relative to insulin exists in non-obese Type 2 diabetes and that circulating islet amyloid polypeptide may act physiologically with insulin to modulate the glucose metabolism.
Islet amyloid polypeptide (IAPP) has been identified as the major constituent of the pancreatic amyloid of non-insulin-dependent diabetes mellitus (NIDDM) and is also present in normal beta-cell secretory granules. To determine whether IAPP is a pancreatic secretory product, we measured the quantity of IAPP-like immunoreactivity (IAPP-LI), insulin, and glucagon released into 5 ml of incubation medium during a 2-h incubation of monolayer cultures (n = 5) of neonatal (3- to 5-day-old) Sprague-Dawley rat pancreases under three conditions: 1.67 mM glucose, 16.7 mM glucose, and 16.7 mM glucose plus 10 mM arginine and 0.1 mM isobutylmethylxanthine (IBMX). The quantity of IAPP-LI, insulin, and glucagon in the cell extract was also determined. Mean +/- SE IAPP-LI in the incubation medium increased from 0.041 +/- 0.003 pmol in 1.67 mM glucose to 0.168 +/- 0.029 pmol in 16.7 mM glucose (P less than 0.05) and 1.02 +/- 0.06 pmol in 16.7 mM glucose plus arginine and IBMX (P less than 0.05 vs. 1.67 or 16.7 mM glucose). Insulin secretion increased similarly from 4.34 +/- 0.27 to 20.2 +/- 0.6 pmol (P less than 0.05) and then to 135 +/- 5 pmol (P less than 0.05 vs. 1.67 or 16.7 mM glucose). Glucagon release tended to decrease with the increase in glucose concentration (0.39 +/- 0.01 vs. 0.33 +/- 0.02 pmol, P less than 0.1), whereas with the addition of arginine and IBMX to high glucose, glucagon release increased to 1.32 +/- 0.03 pmol (P less than 0.05 vs. 1.67 or 16.7 mM glucose).(ABSTRACT TRUNCATED AT 250 WORDS)
Fasting serum total immunoreactive insulin (IRI), true insulin, and true proinsulin (PI) were measured in 169 Pima Indians. The relationship of these variables to glucose tolerance, obesity, and parental diabetes was studied. Seventy-seven subjects had normal glucose tolerance, 46 had impaired glucose tolerance (IGT), and 46 had noninsulin-dependent diabetes mellitus (NIDDM) by WHO criteria. In subjects with normal glucose tolerance, the geometric mean ratio of PI to IRI (PI/IRI) was 10.8% (arithmetic mean, 12.5%), similar to that reported in other ethnic groups with lower prevalence rates of NIDDM. Parental diabetes had no effect on PI/IRI. Obese persons (body mass index, greater than or equal to 27 kg/m2) with normal glucose tolerance had PI/IRI of 9.3% compared with 16.3% for the nonobese (P less than 0.001), and PI/IRI was negatively correlated with body mass index (r = -0.34; P = 0.002). Proinsulin was disproportionately elevated in NIDDM (geometric mean PI/IRI, 19.9%; arithmetic mean, 23.6%), and the degree of elevation was related to the severity of hyperglycemia, but not the duration of diabetes. Subjects with IGT were more obese and had higher fasting plasma glucose (5.7 vs. 5.2 mmol/L; P = 0.025), true insulin (250 vs. 125 pmol/L; P less than 0.001), and PI concentrations (26 vs. 15 pmol/L; P less than 0.001) than those with normal glucose tolerance but similar mean PI/IRI (9.4 vs. 10.8%; P = 0.4). These findings indicate that Pima Indians with NIDDM have a disproportionate elevation of PI consistent with the hypothesis that beta-cell dysfunction associated with hyperglycemia leads to the release of proinsulin-rich immature granules.
Recent interest has focused on the potential role of amylin in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). This 37-amino acid peptide is found in extracellular amyloid deposits in approximately 50% of pancreatic islets of patients with NIDDM and has been shown to inhibit skeletal muscle glycogen synthesis in vitro. Immunocytochemical studies have colocalized amylin and insulin within beta-cell secretory granules in nondiabetic humans, provoking the following questions. Is amylin cosecreted with insulin? Are circulating amylin concentrations higher in patients with NIDDM either before or after food ingestion? To answer these questions, we developed a sensitive and specific immunoassay to measure plasma concentrations of amylin in humans. Use of this assay indicated that, in lean nondiabetic subjects, glucose ingestion resulted in an increase (P less than 0.001) in the plasma concentration of amylin (from 2.03 +/- 0.22 to 3.78 +/- 0.39 pM) and insulin (from 48.3 +/- 3.1 to 265 +/- 44 pM). There was a significant correlation between the concentrations of insulin and amylin (r = 0.74, P less than 0.001) and the increase in insulin and amylin concentration (r = 0.65, P less than 0.005). Fasting concentrations of amylin did not differ in diabetic and weight-matched nondiabetic subjects and showed a similar pattern of change after ingestion of a mixed meal. We conclude that amylin is secreted in response to ingestion of either glucose or a mixed meal and circulates at concentrations that do not differ in patients with NIDDM and nondiabetic subjects. It remains to be determined whether amylin at physiological concentrations influences carbohydrate metabolism and if so whether its effects differ in diabetic and nondiabetic humans.
Islet amyloid may have a pathological role in the development of Type 2 (non-insulin-dependent) diabetes mellitus. The prevalence of islet amyloid has been investigated on post-mortem pancreatic tissue from both diabetic and non-diabetic Pima Indian subjects who had previously been assessed by oral glucose tolerance tests. Islets were examined for amyloid deposits and for cellular immunoreactivity to pancreatic hormones and islet amyloid polypeptide, the constituent peptide of islet amyloid. Twenty of 26 diabetic subjects (77%) had islet amyloid, compared with one of 14 non-diabetic subjects (7%). Twelve of the diabetic subjects (46%) had amyloid in more than 10% of their islets, whereas only 4% of islets were affected in a single non-diabetic subject. Positive immunoreactivity for islet amyloid peptide was present in the islet amyloid and in islet cells in 54% of the diabetic and 50% of the non-diabetic subjects. Islet amyloid in diabetic Pima Indians may indicate a primary Beta-cell defect which interacts with insulin resistance to produce diabetes, or may develop as a result of Beta-cell dysfunction induced by insulin resistance and hyperglycaemia.
To determine the specific alteration in B-cell function caused by a somatostatin analog in man and to determine the effect of the induced insulin deficiency on insulin action, we administered octreotide (SMS 201-995; 50 micrograms twice daily) to nine healthy male subjects, aged 24-35 yr. B-Cell function was assessed by measuring the acute insulin response (AIR) to glucose (AIRglucose) at fasting glucose and to arginine (AIRarg) at glucose concentrations of fasting, approximately 14 and more than 28 mM after 2 (n = 7) and 8 days (n = 9) of octreotide. The AIRarg at more than 28 mM glucose (AIR500) is an estimate of B-cell secretory capacity, while the glucose level at which 50% of AIR500 occurs is termed PG50 and can provide an estimate of B-cell glucose sensitivity. Insulin sensitivity and the parameters describing glucose disposal were measured using Bergman's minimal model. Octreotide administration resulted in the development of mild fasting hyperglycemia, marked fasting hypoinsulinemia, as well as a marked reduction in AIRglucose [mean +/- SE; pretreatment, 260 +/- 48 pM; 1 day, 62 +/- 14 pM (P less than 0.005 vs. pretreatment); 8 days, 62 +/- 7 pM (P less than 0.005 vs. pretreatment)]. In addition, there was an associated marked reduction in iv glucose tolerance. While the AIRarg at fasting glucose (pretreatment, 233 +/- 27 pM; 2 days, 144 +/- 27 pM; 8 days 281 +/- 55 pM) and AIR500 (pretreatment 1000 +/- 178 pM; 2 days, 651 +/- 82 pM; 8 days, 1041 +/- 219 pM) remained unchanged, the AIRarg at 14 mM decreased significantly during octreotide [pretreatment 986 +/- 178 pM; 2 days, 363 +/- 62 pM (P less than 0.001 vs. pretreatment); 8 days, 623 +/- 130 pM (P less than 0.005 vs. pretreatment)], resulting in a rightward shift of the dose-response curve such that the estimated PG50 increased from 8.8 +/- 0.6 to 12.9 +/- 1.3 mM (P less than 0.05) after 2 days and was maintained for 8 days (11.2 +/- 0.8 mM; P less than 0.05 vs. pretreatment). Despite the development of marked insulin deficiency, the insulin sensitivity index (SI) did not change significantly (pretreatment, 11.34 +/- 1.59 x 10(-5); 1 day, 10.01 +/- 2.28 x 10(-5); 7 days, 9.65 +/- 1.69 x 10(-5) min-1/pM).(ABSTRACT TRUNCATED AT 400 WORDS)
To determine whether insulin resistance or insulin deficiency is primary in the pathogenesis of type II diabetes.
Cohort analytic study of persons with normal glucose tolerance but with a high risk for developing type II diabetes (average follow-up time, 13 years).
Outpatients had an intravenous glucose tolerance test and were contacted periodically to ascertain diagnoses of diabetes.
One hundred and fifty-five normal offspring, ranging in age from 16 to 60 years, of two parents with type II diabetes and 186 normal control subjects in the same age range who had no family history of diabetes.
Two phenotypic characteristics distinguished the offspring of diabetic parents from control subjects. They had slower glucose removal rates (Kg) (P less than 0.01) and higher insulin levels (fasting and during the second phase of insulin response to intravenous glucose; P less than 0.0001) than did control subjects, even after adjustment for differences in obesity. Sixteen percent of the offspring developed type II diabetes. Mean Kg at baseline was 1.7%/min among offspring who subsequently developed diabetes, 2.2%/min among offspring who remained nondiabetic, and 2.3%/min among control subjects. Corresponding means for first-phase insulin were 498, 354, and 373 pM, respectively, whereas second-phase insulin means were 329, 117, and 87 pM, respectively. In multivariate analysis, low Kg and high serum insulin levels independently increased the risk for developing diabetes among the offspring of diabetic parents.
One to two decades before type II diabetes is diagnosed, reduced glucose clearance is already present. This reduced clearance is accompanied by compensatory hyperinsulinemia, not hypoinsulinemia, suggesting that the primary defect is in peripheral tissue response to insulin and glucose, not in the pancreatic beta cell.
A highly specific two-site immunoradiometric assay for insulin was used to measure the plasma insulin response to 75 g glucose administered orally to 49 patients with non-insulin-dependent diabetes (NIDDM). The plasma insulin concentration 30 min after glucose ingestion was lower in the diabetic patients than in matched controls for both non-obese (11-83 pmol/l vs 136-297 pmol/l, p less than 0.01) and obese subjects (23-119 pmol/l vs 137-378 pmol/l, p less than 0.01). By means of another two-site immunoradiometric assay, the basal intact proinsulin level was found to be higher in the NIDDM patients than in the controls for both non-obese (7.1 [SEM 1.2] pmol/l vs 2.4 [0.4] pmol/l, p less than 0.01) and obese subjects (14.4 [2.2] pmol/l vs 5.9 [1.9] pmol/l, p less than 0.01). The basal level of 32-33 split proinsulin was also raised in NIDDM. Previous failure to show clear separation between normal and NIDDM insulin responses was probably due to the high concentrations of proinsulin-like molecules in the plasma of NIDDM patients. These substances cross-react as insulin in most, if not all, insulin radioimmunoassays but have very little biological insulin-like activity. It is therefore now possible and necessary to designate most NIDDM patients as insulin deficient.
To identify early metabolic abnormalities in non-insulin-dependent diabetes mellitus (NIDDM), we measured sensitivity to insulin and insulin secretion in 26 first-degree relatives of patients with NIDDM and compared these subjects both with 14 healthy control subjects with no family history of NIDDM and with 19 patients with NIDDM. The euglycemic insulin-clamp technique, indirect calorimetry, and infusion of [3-3H]glucose were used to assess insulin sensitivity. Total-body glucose metabolism was impaired in the first-degree relatives as compared with the controls (P less than 0.01). The defect in glucose metabolism was almost completely accounted for by a defect in nonoxidative glucose metabolism (primarily the storage of glucose as glycogen). The relatives with normal rates of metabolism (mean +/- SEM, 1.81 +/- 0.27 mg per kilogram of body weight per minute) and impaired rates (1.40 +/- 0.22 mg per kilogram per minute) in oral glucose-tolerance tests had the same degree of impairment in glucose storage as compared with healthy control subjects (3.76 +/- 0.55 mg per kilogram per minute; P less than 0.01 for both comparisons). During hyperglycemic clamping, first-phase insulin secretion was lacking in patients with NIDDM (P less than 0.01) and severely impaired in their relatives with impaired glucose tolerance (P less than 0.05) as compared with control subjects; insulin secretion was normal in the relatives with normal glucose tolerance. We conclude that impaired glucose metabolism is common in the first-degree relatives of patients with NIDDM, despite their normal results on oral glucose-tolerance tests. Both insulin resistance and impaired insulin secretion are necessary for the development of impaired glucose tolerance in these subjects.
Islet amyloid polypeptide is a novel 37 amino-acid-residues polypeptide which has been isolated from amyloid deposits in an insulinoma, and in human and cat islets of Langerhans. The molecule has 46% homology with the calcitonin gene-related peptide. Light microscopy examination of the pancreas shows that islet amyloid polypeptide immunoreactivity is restricted to the islet B cells. The present study utilized a rabbit antiserum against a synthetic peptide corresponding to positions 20-29 of islet amyloid polypeptide, a sequence without any amino-acid identity with calcitonin gene-related peptide. By applying the immunogold technique at the ultrastructural level, it was shown that both insulin and islet amyloid polypeptide immunoreactivity occurs in the central granular core of the human B cell secretory granules, while the A cells remain unlabelled. The demonstration that islet amyloid polypeptide is a granular protein of the B cells may indicate that it is released together with insulin. Further studies are necessary to evaluate the functional role of islet amyloid polypeptide.
Impaired islet function is a feature of non-insulin-dependent diabetes mellitus (NIDDM), which is manifested in part by disproportionate proinsulin release. A disproportionate increase in proinsulin also occurs in insulinomas, suggesting that enhanced proinsulin release results from an increase in synthesis and premature release of proinsulin-rich immature granules in both conditions. However, recent human and animal studies suggest that normal beta-cells respond to an increase in synthetic demand by enhancing their ability to process proinsulin. Thus, impaired processing of proinsulin is likely in NIDDM. A new point of similarity with insulinoma has been the demonstration of a novel pancreatic peptide isolated from insulinomas and the pancreas of patients with NIDDM. This peptide, named islet amyloid polypeptide or amylin, is also present in normal islets. Because of its association with two apparently dissimilar disease states, we propose a hypothesis that encompasses the observations related to proinsulin and islet amyloid polypeptide and suggest they are manifestations of the same abnormality. In this hypothesis, we suggest that this new pancreatic peptide is a normal participant in the process of proinsulin processing and storage. We also suggest that in the presence of defective proinsulin processing and insulin release, as occurs in NIDDM, hyperglycemia stimulates amylin biosynthesis so that this peptide is deposited in increased quantities in the islet as amyloid. This then further exacerbates the diabetic process, resulting in progressive hyperglycemia and deterioration in islet function.
Amyloid deposits localized to the islets of Langerhans are typical of non-insulin-dependent human diabetes mellitus and of diabetes mellitus in adult cats. Amyloid deposits also commonly occur in insulin-producing pancreatic tumors. We have purified a major protein--insulinoma or islet amyloid polypeptide (IAPP)--from human and cat islet amyloid and from amyloid of a human insulinoma. IAPP from human insulinoma contained 37 amino acid residues and had a theoretical molecular mass of 3850 Da. The amino acid sequence is unique but has greater than 40% identity with the human calcitonin gene-related peptide. A partial amino acid sequence of cat islet IAPP corresponding to positions 1-27 of human insulinoma IAPP was identical to the human IAPP except for substitutions in three positions. An antiserum raised to a synthetic human insulinoma IAPP-(7-17) undecapeptide showed specific immunohistochemical reactivity with human and cat islet amyloid and with islet B cells. The significance of this pancreatic neuropeptide-like protein is unknown, but it is suggested that it may exert an important endocrine regulatory effect.
Insulin resistance is thought by many to be the primary defect that results in non-insulin-dependent diabetes mellitus (NIDDM). An implication of this theory is that prediabetic persons have higher serum insulin levels than normal subjects. We assessed serum insulin concentrations in a cohort of 1497 nondiabetic Mexican Americans, a population at high risk for NIDDM, according to whether their parents or siblings had diabetes. It was assumed that prediabetic persons would be more likely to have strong family histories of diabetes. We found a stepwise increase in fasting insulin levels in nondiabetics with neither, one, or both parents with diabetes (69.8, 77.8, and 94.6 pmol per liter, respectively; P = 0.002). Similar results were observed for insulin sum (the total of insulin concentrations in the fasting state and at 30, 60, and 120 minutes after a 75-g oral glucose load). The differences in insulin sums according to family history remained statistically significant in analyses of covariance, which controlled for variations in body-mass index, body-fat distribution, and level of blood glucose. Subjects without diabetes who had a diabetic sibling had higher fasting concentrations of insulin than subjects without a diabetic sibling (83.2 vs. 69.6 pmol per liter), but the difference was not statistically significant. We conclude that prediabetic persons, who would be expected to be more numerous in kindreds with progressively stronger family histories of diabetes, have hyperinsulinemia. This supports the insulin-resistance hypothesis.
Impaired glucose tolerance often presages the development of non-insulin-dependent diabetes mellitus. We have studied insulin action and secretion in 24 Pima Indians before and after the development of impaired glucose tolerance and in 254 other subjects representing the whole spectrum of glucose tolerance, including subjects with overt non-insulin-dependent diabetes. The transition from normal to impaired glucose tolerance was associated with a decrease in glucose uptake during hyperinsulinemia, from 0.018 to 0.016 mmol per minute (from 3.3 to 2.8 mg per kilogram of fat-free body mass per minute) (P less than 0.0003). Mean plasma insulin concentrations increased during an oral glucose-tolerance test, from 1200 to 1770 pmol per liter (from 167 to 247 microU per milliliter). In 151 subjects with normal glucose tolerance, the insulin concentration measured during an oral glucose-tolerance test correlated with the plasma glucose concentration (r = 0.48, P less than or equal to 0.0001). This relation was used to predict an insulin concentration of 1550 pmol per liter (216 microU per milliliter) in subjects with impaired glucose tolerance (actual value, 1590 pmol per liter [222 microU per milliliter]; P not significant), suggesting that these subjects had normal secretion of insulin. In contrast, plasma insulin concentrations in the diabetics decreased as glucose concentrations increased (r = -0.75, P less than or equal to 0.0001), suggesting deficient secretion of insulin. This relative insulin deficiency first appears at the lower end of the second (diabetic) mode seen in population frequency distributions of plasma glucose concentrations. Our data show that impaired glucose tolerance in our study population is primarily due to impaired insulin action. In patients with non-insulin-dependent diabetes mellitus, by contrast, impaired insulin action and insulin secretory failure are both present.
The quantitative contributions of pancreatic responsiveness and insulin sensitivity to glucose tolerance were measured using the 'minimal modeling technique' in 18 lean and obese subjects (88-206% ideal body wt). The individual contributions of insulin secretion and action were measured by interpreting the dynamics of plasma glucose and insulin during the intravenous glucose tolerance test in terms of two mathematical models. One, the insulin kinetics model, yields parameters of first-phase (Φ1) and second-phase (Φ2) responsivity of the β-cells to glucose. The other glucose kinetics model yields the insulin sensitivity parameter, S(I). Lean and obese subjects were subdivided into good (K(G) > 1.5) and lower (K(G) < 1.5) glucose tolerance groups. The etiology of lower glucose tolerance was entirely different in lean and obese subjects. Lean, lower tolerance was related to pancreatic insufficiency (Φ2 77% lower than in good tolerance controls [P <0.03]), but insulin sensitivity was normal (P >0.5). In contrast, obese lower tolerance was entirely due to insulin resistance (S(I) diminished 60% [P < 0.01]); pancreatic responsiveness was not different from lean, good tolerance controls (Φ(I): P >0.06; Φ2: P >0.40). Subjects (regardless of weight) could be segregated into good and lower tolerance by the product of second-phase β-cell responsivity and insulin sensitivity (Φ2.S(I)). Thus, these two factors were primarily responsible for overall determination of glucose tolerance. The effect of Φ1 was to modulate the K(G) value within those groups whose overall tolerance was determined by Φ2.S(I). This Φ1 modulating influence was more pronounced among insulin sensitive (Φ1 vs. K(G), r = 0.79) than insulin resistant (obese, low tolerance; Φ1 vs. K(G), r = 0.91) subjects. This study demonstrate the feasibility of the minimal model technique to determine the etiology of impaired glucose tolerance.
Gestational diabetes mellitus (GDM) is associated with defects in insulin secretion and insulin action, and women with a history of GDM carry a high risk for the development of non-insulin-dependent diabetes mellitus (NIDDM). Assessment of subjects with a history of GDM who are currently normoglycemic should help elucidate some of the underlying defects in insulin secretion or action in the evolution of NIDDM. We have studied 14 women with normal oral glucose tolerance who had a history of GDM. They were compared with a group of control subjects who were matched for both body mass index (BMI) and waist-to-hip ratio (WHR). All subjects underwent tests for the determination of oral glucose tolerance, ultradian oscillations in insulin secretion during a 28-h glucose infusion, insulin secretion in response to intravenous glucose, glucose disappearance after intravenous glucose (Kg), and insulin sensitivity (SI) as measured by the Bergman minimal model method. The BMI in the post-GDM women was similar to that in the control subjects (24.9 +/- 1.2 vs. 25.4 +/- 1.4 kg/m2, respectively), as was the WHR ratio (0.80 +/- 0.01 vs. 0.76 +/- 0.01, respectively). The post-GDM women were slightly older (35.2 +/- 0.9 vs. 32.1 +/- 1.4 years, P = 0.04). The fasting plasma glucose levels were significantly higher in the post-GDM group than in the control group (4.9 +/- 0.1 vs. 4.4 +/- 0.1 mmol/l, respectively, P < 0.001) and remained higher at each of the subsequent determinations during the oral glucose tolerance test, although none had a result indicative of either diabetes or impaired glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
Disproportionate hyperproinsulinemia is one manifestation of the B-cell dysfunction observed in non-insulin-dependent diabetes mellitus (NIDDM), but it is unclear when this abnormality develops and whether it predicts the development of NIDDM. At baseline, measurements of proinsulin (PI) and immunoreactive insulin (IRI) levels were made in 87 second-generation Japanese-American men, a population at high risk for the subsequent development of NIDDM, and, by using World Health Organization criteria, subjects were categorized as having normal glucose tolerance (NGT; n = 49) or impaired glucose tolerance (IGT; n = 38). After a 5-year follow-up period, they were recategorized as NGT, IGT, or NIDDM using the same criteria. After 5 years, 16 subjects had developed NIDDM, while 71 had NGT or IGT. Individuals who developed NIDDM were more obese at baseline, measured as intra-abdominal fat (IAF) area on computed tomography (P = 0.046) but did not differ in age from those who continued to have NGT or IGT. At baseline, subjects who subsequently developed NIDDM had higher fasting glucose (P = 0.0042), 2-h glucose (P = 0.0002), fasting C-peptide (P = 0.0011), and fasting PI levels (P = 0.0033) and disproportionate hyperproinsulinemia (P = 0.056) than those who continued to have NGT or IGT after 5 years of follow-up. NIDDM incidence was positively correlated with the absolute fasting PI level (relative odds = 2.35; P = 0.0025), even after adjustment for fasting IRI, IAF, and body mass index (relative odds = 2.17; P = 0.013).(ABSTRACT TRUNCATED AT 250 WORDS)
Glucose disposal occurs by both insulin-independent and insulin-dependent mechanisms, the latter being determined by the interaction of insulin sensitivity and insulin secretion. To determine the role of insulin-independent and insulin-dependent factors in glucose tolerance, we performed intravenous glucose tolerance tests on 93 young healthy subjects (55 male, 38 female; 18-44 years of age; body mass index, 19.5-52.2 kg/m2). From these tests, we determined glucose tolerance as the glucose disappearance constant (Kg), calculated beta-cell function as the incremental insulin response to glucose for 19 min after an intravenous glucose bolus (IIR0-19), and derived an insulin sensitivity index (SI) and glucose effectiveness at basal insulin (SG) using the minimal model of glucose kinetics. To eliminate the effect of basal insulin on SG and estimate insulin-independent glucose uptake, we calculated glucose effectiveness at zero insulin (GEZI = SG - [SI x basal insulin]). Insulin-dependent glucose uptake was estimated as SI x IIR0-19, because the relationship between SI and beta-cell function has been shown to be hyperbolic. Using linear regression to determine the influence of these factors on glucose tolerance, we found that GEZI was significantly related to Kg (r = 0.70; P < 0.0001), suggesting a major contribution of insulin-independent glucose uptake to glucose disappearance. As expected, SI x IIR0-19 also correlated well with Kg (r = 0.74; P < 0.0001), confirming the importance of insulin-dependent glucose uptake to glucose tolerance. Although IIR0-19 alone correlated with Kg (r = 0.35; P = 0.0005), SI did not (r = 0.18; P > 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)
MINMOD provides an estimate of the error in the insulin sensitivity index (SI) and glucose effectiveness at basal insulin (Sg) as the fractional standard deviation (FSD). The validity of the FSD estimate has not been assessed in a large number of human studies, nor has a comparison of the accuracies achievable using the two different intravenous glucose tolerance test (IVGTT) protocols (glucose only and tolbutamide protocol) been performed. To address these two issues, we obtained the FSD value and performed Monte Carlo simulations for 237 IVGTT studies. The FSD underestimated the true error as determined as the coefficient of variation from Monte Carlo simulation (COV-MC) with the ratio of COV-MC to FSD being 3.07 +/- 0.20 (mean +/- SE) for SI using the tolbutamide protocol. Additionally, the mean COV-MC for glucose-only protocol was approximately two to three times that for the tolbutamide protocol for both SI and Sg. We conclude that FSD underestimates the true error in SI and Sg. Additionally, more accurate results are obtained from the tolbutamide protocol than with the glucose-only protocol.
Although it is generally accepted that islet amyloid polypeptide is cosecreted with insulin, relatively few data on its kinetics are available. We therefore studied the dynamics of islet amyloid polypeptide release following oral and frequently sampled intravenous glucose tolerance tests in comparison to insulin and C-peptide using mathematical model techniques in 14 control subjects, 10 obese and 11 hypertensive patients. The fractional clearance rate of islet amyloid polypeptide (0.034 +/- 0.004 min-1 in control subjects, 0.058 +/- 0.008 in the obese and 0.050 +/- 0.008 in the hypertensive patients) was significantly different (p < 0.01) in each group compared with that of insulin (0.14 +/- 0.03 min-1) and similar to that of C-peptide (0.061 +/- 0.007 min-1), at least in the insulin-resistant subjects. Based on the insulin sensitivity index derived from the minimal model analysis of intravenous glucose tolerance test data, both the hypertensive (2.4 +/- 0.4 min-1/(microU/ml); p < 0.0005) and the obese (2.7 +/- 0.5; p < 0.001) patients demonstrated severe insulin resistance compared to control subjects (8.1 +/- 1.3). Marked insulin hypersecretion was found in the hypertensive (57.6 +/- 5.2 nmol.l-1 in 180 min; p < 0.001) and obese (60.8 +/- 10.1; p < 0.003) patients in comparison with control subjects (32.4 +/- 3.2). The release of islet amyloid polypeptide was significantly higher in the hypertensive (83.1 +/- 16.6 pmol/l in 180 min; p < 0.02) and obese (78.6 +/- 13.1; p < 0.005) patients than in control subjects (40.5 +/- 6.4). No correlation was found between islet amyloid polypeptide release and the insulin sensitivity index in any group.(ABSTRACT TRUNCATED AT 250 WORDS)
To determine the potential for differential release of islet amyloid polypeptide and insulin, we performed studies in rat islet monolayer cultures under conditions known to impair regulated beta-cell secretion. In inhibiting concentrations of epinephrine or the absence of calcium, islet amyloid polypeptide was secreted through a constitutive pathway while insulin was not. These findings suggest a mechanism for persistent islet amyloid polypeptide secretion and amyloid accumulation when regulated insulin release is impaired as in Type 2 (non-insulin-dependent) diabetes mellitus and insulinomas.
To determine the relationship between insulin sensitivity and beta-cell function, we quantified the insulin sensitivity index using the minimal model in 93 relatively young, apparently healthy human subjects of varying degrees of obesity (55 male, 38 female; 18-44 yr of age; body mass index 19.5-52.2 kg/m2) and with fasting glucose levels < 6.4 mM. SI was compared with measures of body adiposity and beta-cell function. Although lean individuals showed a wide range of SI, body mass index and SI were related in a curvilinear manner (P < 0.0001) so that on average, an increase in body mass index was associated generally with a lower value for SI. The relationship between the SI and the beta-cell measures was more clearly curvilinear and reciprocal for fasting insulin (P < 0.0001), first-phase insulin response (AIRglucose; P < 0.0001), glucose potentiation slope (n = 56; P < 0.005), and beta-cell secretory capacity (AIRmax; n = 43; P < 0.0001). The curvilinear relationship between SI and the beta-cell measures could not be distinguished from a hyperbola, i.e., SI x beta-cell function = constant. This hyperbolic relationship described the data significantly better than a linear function (P < 0.05). The nature of this relationship is consistent with a regulated feedback loop control system such that for any difference in SI, a proportionate reciprocal difference occurs in insulin levels and responses in subjects with similar carbohydrate tolerance. We conclude that in human subjects with normal glucose tolerance and varying degrees of obesity, beta-cell function varies quantitatively with differences in insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)
Insulin resistance and impaired insulin secretion are thought to be the primary defects in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). Disproportionately increased proinsulin relative to insulin levels are suggested to be an early indicator of a failing pancreas. We examined the relationship of fasting specific insulin, proinsulin, and 32, 33 split proinsulin concentrations, and the proinsulin: insulin ration to the risk of developing NIDDM 3.5 years later in 65-74-year-old non-diabetic Finnish subjects participating in a population-based study (n=892) on diabetes and heart disease. Altogether 69 subjects developed NIDDM over a 3.5-year follow-up (cases). The cases were compared to randomly-selected gender-matched control subjects (n=69) and control subjects matched for gender, glucose tolerance status (normal or impaired), and body mass index (n=69). There were no differences in insulin concentrations between cases and random or matched control subjects [median and interquartile range: 123 (77-154), 108 (74-143), 118 (83-145) pmol/l, p=0.271]. Random control subjects had lower proinsulin and 32, 33 split proinsulin concentrations and split proinsulin: insulin ratios compared to cases [5.7 (3.8-9.0) vs 7.3 (4.8-10.0) pmol/l, p=0.005; 7.3 (4.5-13.0 vs 10.4 (7.1-18.0) pmol/l, p=0.002; 0.073 (0.057-0.110) vs 0.097 (0.060- 0.135), p=0.003]. Matched control subjects had lower proinsulin concentrations and proinsulin: insulin ratios compared to cases [5.9 (4.0-7.7) vs 7.3 (4.8-10.0) pmol/l, p=0.019; 0.048 (0.035-0.071) vs 0.064 (0.045-0.100), p=0.008]. When cases were compared to matched control subjects a 1 SD increase in baseline proinsulin: insulin ratio was associated with a 1.37-fold risk (p=0.020) of developing diabetes. Moreover, this association was independent of fasting glucose concentration at baseline. Thus, in elderly prediabetic subjects disproportionately increased proinsulin concentration, an indicator of defective insulin secretion, is associated with conversion to diabetes over a short time period.
To study the islet adaptation to reduced insulin sensitivity in normal and glucose intolerant post-menopausal women, we performed a euglycaemic, hyperinsulinaemic clamp in 108 randomly selected women, aged 58-59 years. Of the 20 women with the lowest insulin sensitivity, 11 had impaired glucose tolerance (IGT) whereas 9 had normal glucose tolerance (NGT). These women together with 15 women with medium insulin sensitivity and 16 women with high insulin sensitivity and NGT were further examined with arginine stimulation at three glucose levels (fasting, 14 and > 25 mmol/l). In NGT, the acute insulin response (AIR) to 5 g i.v. arginine at all three glucose levels and the slopeAIR, i.e. the glucose potentiation of insulin secretion, were markedly increased in the women with the lowest insulin sensitivity and NGT compared to those with medium or high insulin sensitivity. In contrast, in low insulin sensitivity, AIR was significantly lower in IGT than in NGT (at glucose 14 mmol/l p = 0.015, and at > 25 mmol/l p = 0.048). The potentiation of AIR induced by low insulin sensitivity in women with NGT was reduced by 74% (AIR at 14 mmol/l glucose) and 57% (AIR at > 25 mmol/l glucose), respectively, in women with IGT. Also the slopeAIR was lower in IGT than in NGT (p = 0.025); the increase in slope AIR due to low insulin sensitivity was abolished in IGT. In contrast, glucagon secretion was not different between women with IGT as opposed to NGT. We conclude that as long as there is an adequate beta-cell adaptation to low insulin sensitivity with increased insulin secretory capacity and glucose potentiation of insulin secretion, NGT persists.
Recent research indicates that islet amyloid pancreatic polypeptide (IAPP) might have a regulatory effect on beta-cell insulin processing and secretion. To study such interaction in more detail, IAPP secretion and kinetics and the serum concentrations of proinsulin were assessed both before and after delivery in lean pregnant women with gestational diabetes mellitus (GDM patients) in comparison to those with normal glucose tolerance (NGT) and to nonpregnant healthy lean (control) and obese insulin-resistant women during oral glucose tolerance tests. Kinetic analysis of IAPP was performed with mathematical modeling, providing indirect estimates of its secretion and fractional clearance. Total insulin secretion per 180 min was elevated by 30% in GDM patients (35 +/- 3 pmol/l) versus control subjects (27 +/- 1 pmol/l) (P < 0.05), but increased even more (190-250%) in obese insulin-resistant women, compared with all other groups (68 +/- 7 pmol/l, P < 0.0005). Pregnancy induced a more marked fourfold increase in apparent total IAPP secretion rate (TIR) (GDM patients, 172 +/- 31 pmol x 1(-1) x 3 h(-1); NGT subjects, 166 +/- 31 pmol x 1(-1) x 3 h(-1); control subjects, 40 +/- 1 pmol 1(-1) x 3 h(-1)) and a twofold rise in its fractional clearance versus control subjects (P < 0.01), whereas in GDM patients a 30% increase of IAPP secretion and a decreased clearance was found, compared with obese insulin-resistant women (TIR, 112 +/- 14 pmol x 1(-1) x 3 h(-1)). The increase in IAPP secretion in both pregnant groups was much higher than that of the insulin groups, resulting in a marked change of the IAPP-insulin cosecretion factor when compared with lean or obese nonpregnant women (P < 0.0005). Associated serum proinsulin and the postprandial (total divided by 180 min) proinsulin-to-insulin ratio were greater in GDM patients versus NGT and control subjects (0.11 +/- 0.01 vs. 0.07 +/- 0.01 and 0.08 +/- 0.01 pmol/l, P < 0.05), while the fasting proinsulin-to-insulin ratio was only increased in GDM patients versus control subjects (0.22 +/- 0.03 vs. 0.13 +/- 0.01 pmol/l, P < 0.05). After delivery, total IAPP secretion (52.4 +/- 1.5 pmol/l) was completely normalized in the GDM group, as were the clearance rate and the IAPP-insulin cosecretion factor. Similarly, serum proinsulin concentrations returned to normal, whereas proinsulin-to-insulin ratios remained elevated. In conclusion, IAPP hypersecretion is characteristic for pregnancy and might partially decrease hyperinsulinemia in pregnancy by inhibiting insulin secretion. Increased proinsulin concentrations and a raised proinsulin-to-insulin ratio, which did not abate following delivery, are specific to GDM and might thus serve as its marker and potentially even identify subjects at high risk for the development of NIDDM.
Impaired glucose tolerance (IGT) is associated with defects in both insulin secretion and action and carries a high risk for conversion to non-insulin-dependent diabetes mellitus (NIDDM). Troglitazone, an insulin sensitizing agent, reduces glucose concentrations in subjects with NIDDM and IGT but is not known to affect insulin secretion. We sought to determine the role of beta cell function in mediating improved glucose tolerance. Obese subjects with IGT received 12 wk of either 400 mg daily of troglitazone (n = 14) or placebo (n = 7) in a randomized, double-blind design. Study measures at baseline and after treatment were glucose and insulin responses to a 75-g oral glucose tolerance test, insulin sensitivity index (SI) assessed by a frequently sampled intravenous glucose tolerance test, insulin secretion rates during a graded glucose infusion, and beta cell glucose-sensing ability during an oscillatory glucose infusion. Troglitazone reduced integrated glucose and insulin responses to oral glucose by 10% (P = 0.03) and 39% (P = 0.003), respectively. SI increased from 1.3+/-0.3 to 2.6+/-0.4 x 10(-)5min-1pM-1 (P = 0.005). Average insulin secretion rates adjusted for SI over the glucose interval 5-11 mmol/liter were increased by 52% (P = 0.02), and the ability of the beta cell to entrain to an exogenous oscillatory glucose infusion, as evaluated by analysis of spectral power, was improved by 49% (P = 0.04). No significant changes in these parameters were demonstrated in the placebo group. In addition to increasing insulin sensitivity, we demonstrate that troglitazone improves the reduced beta cell response to glucose characteristic of subjects with IGT. This appears to be an important factor in the observed improvement in glucose tolerance.
The production of insulin from proinsulin involves cleavage of intact proinsulin into proinsulin conversion intermediates by the processing of enzymes PC2 and PC3 before fully processed insulin is produced. Intact proinsulin and these conversion intermediates are measured in many immunoreactive insulin (IRI) assays, and therefore contribute to the absolute IRI measurement. The proportion of basal IRI made up of proinsulin (PI)-like molecules (PI/IRI) is increased in NIDDM. Whether stimulated IRI levels are similarly made up of disproportionately increased PI/IRI or whether the relative proportions of proinsulin and its conversion intermediates are altered has not been evaluated. An index of the efficiency of proinsulin processing within the pancreatic beta-cell can be achieved by measuring PI/IRI immediately following acute stimulation of beta-cell secretion, and then determining the proportion of intact proinsulin and proinsulin conversion intermediates contributing to circulating proinsulin-like molecules. In this study, we determined the PI/IRI levels under basal and arginine-stimulated conditions in 17 healthy and 16 NIDDM subjects; high-performance liquid chromatography (HPLC) was also performed in a subset of these subjects to measure the relative contribution of intact proinsulin and its conversion intermediates to total proinsulin-like molecules. In NIDDM subjects, levels of both basal (44.6 +/- 9.6 vs. 9.3 +/- 1.5 pmol/l; P = 0.0007) and stimulated (64.0 +/- 12.7 vs. 19.8 +/- 2.8 pmol/l; P = 0.001) proinsulin-like molecules were higher than in healthy subjects. Although IRI was higher in NIDDM than in control subjects under basal conditions (106 +/- 19 vs. 65.1 +/- 8.1 pmol/l; P = 0.05), it was lower in NIDDM than in control subjects following stimulation (increment: 257 +/- 46 vs. 416 +/- 51 pmol/l; P = 0.03). PI/IRI ratios were increased in NIDDM subjects under both basal (43.3 +/- 5.0 vs. 14.0 +/- 1.3%; P < 0.0001) and stimulated (increment: 10.1 +/- 2.1 vs. 2.5 +/- 0.2%; P = 0.0006) conditions, compatible with the release of a disproportionately increased amount of proinsulin-like products. HPLC analysis revealed that, in the stimulated state, intact proinsulin made up 40.1 +/- 6.7% of proinsulin-like molecules in NIDDM individuals (n = 9) and 30.1 +/- 5.6% in healthy subjects (n = 7; NS). The remainder of the proinsulin-like molecules comprised the des-31,32-split proinsulin conversion intermediate. The increase in PI/IRI in NIDDM under basal and especially under stimulated conditions suggests that proinsulin conversion is indeed perturbed in this disorder. Because the relative proportions of intact and des-31,32-split proinsulin are similar in both healthy and NIDDM subjects, the orderly cleavage of proinsulin at its two junctions appears preserved. However, at the time of exocytosis, the secretory granule in the islet of NIDDM subjects contains an increased proportion of incompletely processed proinsulin, presumably reflecting a slower rate of conversion or granules' reduced time of residence in beta-cells.
Islet amyloid is a characteristic feature of type 2 diabetes. Its major component is the normal beta-cell secretory product amylin, or islet amyloid polypeptide (IAPP). To determine whether increased or disproportionate release of amylin may explain the propensity for amyloid deposition in type 2 diabetes, we measured plasma amylin-like immunoreactivity (ALI) and immunoreactive insulin (IRI) release in response to an oral glucose load in 94 Japanese-American subjects with normal glucose tolerance (NGT; n=56), impaired glucose tolerance (IGT; n=10), and type 2 diabetes (n=28) as defined by World Health Organization criteria. The incremental increase in ALI, IRI, and glucose (G) at 30 min after oral glucose ingestion was used to calculate deltaALI/deltaG and deltaIRI/deltaG as measures of beta-cell function. Overall glucose metabolism was assessed as the incremental glucose area (glucose AUC) during the 2 h of the oral glucose tolerance test. As expected, plasma glucose concentrations at both fasting (NGT, 5.0+/-0.4; IGT, 5.5+/-0.1; type 2 diabetes, 6.2+/-0.3 mmol/l; P < 0.0001) and 2 h (NGT, 6.7+/-0.1; IGT, 9.4+/-0.3; type 2 diabetes, 13.2 +/-0.5 mmol/l; P < 0.0001) were elevated in individuals with IGT and type 2 diabetes. In response to glucose ingestion, plasma IRI and ALI increased in all subjects, but these increments were lower in individuals with reduced glucose tolerance, as reflected in the deltaIRI/deltaG (NGT, 119+/-10.3; IGT, 60.7+/-7.1; type 2 diabetes, 49.7 +/-5.4 pmol/l; P < 0.0001) and deltaALI/deltaG (NGT, 2.6+/-0.2; IGT, 1.8+/-0.3; type 2 diabetes, 1.2+/-0.1 pmol/l; P < 0.0001). Moreover, these reductions in the 30-min incremental ALI and IRI responses were proportionate such that the molar ratio of ALI to IRI was not different among the three groups (NGT, 2.6+/-0.2; IGT, 2.9 +/-0.3; type 2 diabetes, 2.9+/-0.3%; NS). Further, the relationship between beta-cell function, measured as either deltaIRI/deltaG or deltaALI/deltaG, and glucose metabolism, assessed as glucose AUC, was nonlinear and inverse in nature, with r2 values of 0.38 (P < 0.0001) and 0.33 (P < 0.0001), respectively. We conclude that the reduced beta-cell function of IGT and type 2 diabetes includes proportionate reductions in both IRI and ALI release. Thus, it is unlikely that the development of islet amyloid in type 2 diabetes is the result of increased release of ALI.