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Diurnal patterns of blood glucose, serum free fatty acids, insulin, glucagon and growth hormone in normal and juvenile diabetics
Abstract
Summary Blood glucose, serum free fatty acids,-insulin, -glucagon and -growth hormone have been measured half-hourly in five newly diagnosed, untreated, male patients with classic juvenile diabetes and in five healthy male subjects during a 24-h period of daily life. —Blood glucose, serum insulin and -free fatty acids followed, on the whole, the expected pattern. Serum gluoagon showed a fairly constant level during day and night in both groups. — In the non-diabetic subjects, serum growth hormone was low during most of the day. Only two peaks were observed before 10 p.m. Four of the subjects showed peaks at precisely the same time, namely at 10.30 p.m. and 1.30 a.m. Two showed peaks at 5.00–5.30 p.m. The mean serum growth hormone concentration during the 24-h period was 1.98 ng/ml. — In the juvenile diabetics, the growth hormone was higher and the level fluctuated much more, showing more frequent and higher peaks than in the non-diabetics. The mean serum growth hormone concentration during the 24-h period was 7.26 ng/ml, i.e. three to four times higher than in the non-diabetics.
... It has been demonstrated that evening insulin response pattern in normal subjects resembles to that of a diabetic patient. [8,10] Having frequent meals outside of the high insulin sensitivity phase of the day might expose the patient on a daily basis to a transient phase of adverse metabolic conditions leading to CAD. Having greater part of the daily calories within the 'high' insulin sensitivity phase can prevent a period of increase in circulating FFA levels, thereby protecting against progression of CAD. ...
... Having greater part of the daily calories within the 'high' insulin sensitivity phase can prevent a period of increase in circulating FFA levels, thereby protecting against progression of CAD. [8,9,10] Also circadian misalignment leads to metabolic instability. Thus calorie distribution appears to be a more important marker of cardio metabolic health rather than the diet type or amount of total calories consumed daily. ...
... [14] Also due to diurnal secretion of insulin the insulin sensitivity during night hours is similar to that of a diabetic person hence calories consumed during late night could worsen cardio-metabolic health. [8,10] ...
Context:
Coronary artery disease (CAD) is the blockage of coronary arteries, usually consequent to atherosclerosis. CAD is a lifestyle disease with an increasing disease burden in society. Evaluation of risk factors for CAD is crucial for its prevention. Lifestyle components like calorie consumption chronology, saturated fatty acid (SAFA) intake, reclining time, nocturnal eating and intermittent fasting were considered.
Aims:
To correlate calorie distribution, SAFA intake, reclining time, nocturnal eating and intermittent fasting with occurrence of CAD.
Study design/materials and methods:
A case-control study consisting of 235 cases and 185 controls. Questionnaire was self-designed according to NIN guidelines. Study was ICMR funded and data analysis was done using Microsoft Excel and IBM SPSS.
Results:
Across case and control groups, total calorie consumption difference was insignificant (P = 0.42). Calories consumed in breakfast slot (P = 0.001) and dinner slot (P = 0.003) were significantly different possibly due to discrepancy among circadian variation in insulin sensitivity and calorie consumption distribution. Reclining time <1 h in afternoon (odds ratio [OR] = 2.24, 95%, 1.481-3.356) and night (OR = 2.05, 95% confidence limit [CL], 1.233-3.410), SAFA consumption (OR = 2.006, 95% CL, 1.214-3.316), intermittent fasting (OR = 1.748, 95% CL, 0.997-3.067) and nocturnal eating (OR = 1.291, 95% CL, 0.779--2.141) are potential risk factors.
Conclusions:
Calorie consumption chronology, SAFA intake, Reclining time, Nocturnal eating and intermittent fasting emerged as significant risk factors.
... This and similar studies have suggested that there is a moment to moment adjustment of insulin secretory rate as a function of the level of blood glucose, both for somewhat small excursions in blood glucose level and for larger excursions that might be seen following large carbohydrate meals or experimental glucose loads. This parallelism has been examined by many laboratories but this feature of glucose-insulin homeostasis was elegantly emphasized in a study by Hansen et al (18). Figure 6 shows corresponding levels of blood glucose, serum insulin, free fatty acids, growth hormone and glucagon measured frequently over a 24 hour period in healthy males. ...
... Average curves of blood glucose, serum insulin, free fatty acids, growth hormone and glucagon in five healthy males. (From reference18) ...
Diabetes mellitus is a relatively common disease which finds itself entering into the 1970’s with many perplexing problems. Fortunately for a great many diabetic patients, insulin has been available for clinical use for slightly over 50 years. Before the availability of this therapeutic hormone, the young juvenile onset diabetic patient could scarcely anticipate more than 2 years of life after onset of the disease. Prior to 1922, the somewhat older, less severe diabetic patient faced a great many problems with his diabetes but did tend to survive for a considerably longer period of time than the juvenile diabetic, but obviously the quality of life for that patient was far from optimal. The availability of insulin changed the total outlook towards this disease quite markedly.
... Thus, it is not surprising to observe a reduction of pulsatile GH secretion in genetically obese Zucker rats (Tannenbaum et al., 1990). However, opposite to what is seen in patients with type 1 diabetes, where GH levels are usually elevated compared to nondiabetic control patients (Hansen and Johansen, 1970;Bereket et al., 1999), pulsatile GH secretion is dramatically reduced in male streptozotocin (STZ)-induced type 1 diabetic rats (Zhang et al., 2018;Olchovsky et al., 1990). Interestingly, the impact of STZ-induced, insulinopenic diabetes on the GH axis of rats seems to be dose dependent. ...
Evolutionally conserved in all mammalians, the release of GH occurs in a rhythmic pattern, characterized by several dominant surges (pulsatile GH) with tonic low inter-pulse levels (tonic GH). Such pulsatile secretion pattern is essential for many physiological actions of GH on different tissues with defined gender dimorphism. Rhythmic release of pulsatile GH is tightly controlled by hypothalamic neurons as well as peripheral metabolic factors. Changes of GH pattern occur within a range of sophisticated physiological and pathological settings and significantly contribute to growth, ageing, survival and disease predispositions. Precise analysis of GH secretion pattern is vitally important for a comprehensive understanding of the function of GH and the components that regulate GH secretion pattern.
... Indices of this inverse relationship exist across many metabolic states. In humans, fasting (227), malnutrition resulting in anorexia (345), and insulin-dependent type-1 diabetes mellitus (10,19,191,197) are associated with decreased levels of insulin and a rise in GH release, whereas hyperphagia (106,107) and obesity (375,426,548) are associated with elevations in circulating measures of insulin and a fall in GH release. Given this well-established relationship, it comes as a surprise that few observations exist to establish a functional relationship whereby insulin may define GH release. ...
Growth hormone (GH) secretory patterns emerge following birth, and changes in patterning occur throughout life. These secretory patterns are coupled to growth, reproduction and metabolism. Comparing human and animal studies, this review will highlight ultradian patterning of GH release and the mechanisms that contribute to this. Discussions will focus on the emergence in variations in the number and frequency of GH secretory events, and the amounts of GH released (peak and basal). Animal studies have contributed significantly to our understanding of the processes that regulate GH release. However, translation of knowledge from animal models to benefit our understanding of human physiology is sometimes limited. To overcome these limitations, it is critical that we reconcile the cause and consequences of differences in GH release between humans and model organisms. In doing so, we can embrace emerging technologies that will rapidly advance our knowledge of endogenous process that control GH release.
... The SCN influences basal glucose concentrations through autonomic signals to the liver, which indicate time of day, to prepare for activity and anticipate feeding (Abrahamson et al., 2001;Fujii et al., 1989;Kalsbeek et al., 2008). Additionally, the SCN has direct connections to the pancreas, where it regulates rhythmic production of glucagon by alpha cells, enhancing glycogenolysis (Buijs et al., 2001;Gagliardino et al., 1978;Hansen and Johansen, 1970;Ruiter et al., 2003;Tiedgen and Seitz, 1980;Ueyama et al., 1999;Yamamoto et al., 1987). Thus, blood glucose levels are a cumulative output of the circadian clock, food intake, glucagon, corticosterone, and other hormones. ...
PAS domain-containing proteins can act as environmental sensors that capture external stimuli to allow coordination of organismal physiology with the outside world. These proteins permit diverse ligand binding and heterodimeric partnership, allowing for varied combinations of PAS-dependent protein-protein interactions and promoting crosstalk among signaling pathways. Previous studies report crosstalk between circadian clock proteins and the aryl hydrocarbon receptor (AhR). Activated AhR forms a heterodimer with the circadian clock protein Bmal1 and thereby functionally inhibits CLOCK/Bmal1 activity. If physiological activation of AhR through naturally occurring, endogenous ligands inhibits clock function, it seems plausible to hypothesize that decreased AhR expression releases AhR-induced inhibition of circadian rhythms. Because both AhR and the clock are important regulators of glucose metabolism, it follows that decreased AhR will also alter metabolic function. To test this hypothesis, rhythms of behavior, metabolic outputs, and circadian and metabolic gene expression were measured in AhR-deficient mice. Genetic depletion of AhR enhanced behavioral responses to changes in the light-dark cycle, increased rhythmic amplitude of circadian clock genes in the liver, and altered rhythms of glucose and insulin. This study provides evidence of AhR-induced inhibition that influences circadian rhythm amplitude.
... Furthermore, insulin directly down-regulates hepatic synthesis of IGF-binding protein-1 (IGFBP-1), which may increase IGF-1 bioactivity (12). In patients with T1DM, alterations in the GH-IGF-1 axis are present that are characterized by low concentrations of total IGF-1 and IGF-binding protein-3 (IGFBP-3), the main IGFBP in plasma, and high concentrations of IGFBP-1 and GH (13)(14)(15)(16)(17)(18)(19)(20). It is hypothesized that these alterations are due to insulinopenia in the portal system and subsequent insufficient insulinization of the liver. ...
Context:
In type 1 diabetes mellitus (T1DM), low levels of insulin-like growth factor -1 (IGF-1) and IGF binding protein-3 (IGFBP-3) and high levels of growth hormone (GH) and IGFBP-1 are present, probably due to portal vein insulinopenia.
Objective:
To test the hypothesis that continuous intraperitoneal insulin infusion (CIPII) has a more pronounced effect than subcutaneous (SC) insulin therapy on regulation of the GH-IGF-1 axis.
Design:
Prospective, observational case-control study. Measurements were performed twice at a 26-week interval.
Setting:
Two secondary care hospitals in the Netherlands.
Patients:
A total of 184 patients, age and gender matched, of which 39 used CIPII and 145 SC insulin therapy for the past 4 years.
Outcomes:
Primary endpoint included differences in IGF-1. Secondary outcomes were differences in GH, IGFBP-1 and IGFBP-3.
Results:
IGF-1 was higher with CIPII as compared to SC insulin therapy: 124 μg/l (95% CI 111, 138) versus 108 μg/l (95% CI 102, 115) (p=0.035). Additionally, IGFBP-3 concentrations were higher and IGFBP-1 and GH concentrations were lower with CIPII as compared to SC insulin therapy: 3.78 mg/l (95% CI 3.49, 4.10) versus 3.31 mg/l (95% CI 3.17, 3.47) for IGFBP-3, 50.9 μg/l (95% CI 37.9, 68.2) versus 102.6 μg/l (95% CI 87.8, 119.8) for IGFBP-1 and 0.68 μg/l (95% CI 0.44, 1.06) versus 1.21 μg/l (95% CI 0.95, 1.54) for GH, respectively. In multivariate analysis, IGF-1 had no significant association with HbA1c.
Conclusions:
The GH-IGF-1 axis may be affected by the route of insulin administration with CIPII counteracting dysregulation of the GH-IGF1 axis present during SC insulin therapy.
... Indices of this inverse relationship exist across many metabolic states. In humans, fasting (227), malnutrition resulting in anorexia (345), and insulin-dependent type-1 diabetes mellitus (10,19,191,197) are associated with decreased levels of insulin and a rise in GH release, whereas hyperphagia (106,107) and obesity (375,426,548) are associated with elevations in circulating measures of insulin and a fall in GH release. Given this well-established relationship, it comes as a surprise that few observations exist to establish a functional relationship whereby insulin may define GH release. ...
This article reviews the main findings that emerged in the intervening years since the previous volume on hormonal control of growth in the section on the endocrine system of the Handbook of Physiology concerning the intra-and extrahypothalamic neuronal networks connecting growth hormone releasing hormone (GHRH) and somatostatin hypophysiotropic neurons and the integration between regulators of food intake/metabolism and GH release. Among these findings, the discovery of ghrelin still raises many unanswered questions. One important event was the application of deconvolution analysis to the pulsatile patterns of GH secretion in different mammalian species, including Man, according to gender, hormonal environment and ageing. Concerning this last phenomenon, a great body of evidence now supports the role of an attenuation of the GHRH/GH/Insulin-like growth factor-1 (IGF-1) axis in the control of mammalian aging.
... Indices of this inverse relationship exist across many metabolic states. In humans, fasting (227), malnutrition resulting in anorexia (345), and insulin-dependent type-1 diabetes mellitus (10,19,191,197) are associated with decreased levels of insulin and a rise in GH release, whereas hyperphagia (106,107) and obesity (375,426,548) are associated with elevations in circulating measures of insulin and a fall in GH release. Given this well-established relationship, it comes as a surprise that few observations exist to establish a functional relationship whereby insulin may define GH release. ...
This article reviews the main findings that emerged in the intervening years since the previous volume on hormonal control of growth in the section on the endocrine system of the Handbook of Physiology concerning the intra- and extrahypothalamic neuronal networks connecting growth hormone releasing hormone (GHRH) and somatostatin hypophysiotropic neurons and the integration between regulators of food intake/metabolism and GH release. Among these findings, the discovery of ghrelin still raises many unanswered questions. One important event was the application of deconvolution analysis to the pulsatile patterns of GH secretion in different mammalian species, including Man, according to gender, hormonal environment and ageing. Concerning this last phenomenon, a great body of evidence now supports the role of an attenuation of the GHRH/GH/Insulin-like growth factor-1 (IGF-1) axis in the control of mammalian aging. © 2016 American Physiological Society. Compr Physiol 6:687-735, 2016.
... Hypersecretion of growth hormone (GH) has been demonstrated to impair metabolic control in T1D patients by increasing circulating glucose and lipids (18)(19)(20)(21). The release of GH by the pituitary is predominantly regulated by hypothalamic growth Significance Growth hormone-releasing hormone (GHRH) antagonist MIA-602 reduces hyperlipidemia in rats with type 1 diabetes (T1D). ...
Significance
Growth hormone-releasing hormone (GHRH) antagonist MIA-602 reduces hyperlipidemia in rats with type 1 diabetes (T1D). Elevated triglyceride-rich lipoprotein (TRL) and LDL levels correlate with renal and cardiovascular disease in T1D. Activity of GLP-1 in the intestine to lower TRL, glucagon, and postprandial glucose levels is impaired in T1D subjects. Expression of GHRH receptor was upregulated in the small intestine, involved in chylomicron synthesis in T1D rats. MIA-602 restored GLP-1 actions on hyperlipidemia and hyperglucagonemia in T1D rats and reduced generation of Apo-B48 induced by oleic acid in intestinal epithelial cells in vitro in a GLP-1–dependent manner. MIA-602 significantly improved proteinuria and vasorelaxation capacity in T1D rats. These findings unravel a previously unidentified pathway in T1D mediated by GHRH associated with impaired GLP-1 signaling and hyperlipidemia.
... There is surprisingly little evidence of marked changes in blood glucose concentrations in healthy subjects during their everyday life. Hansen and Johansen (1970) monitored blood glucose throughout ARTICLE IN PRESS acid; R, randomization of subjects; M, matched at baseline on dependent variable; A, all subjects accounted for. the day in five normally fed males; the levels never fell below 71 mg/dl. ...
Although there is a widespread popular assumption that the consumption of refined carbohydrate rapidly increases blood glucose and therefore enhances mood, controlled studies do not support such a view. It is also commonly suggested that a marked increase in blood glucose is followed by a rapid fall, resulting in a hypoglycaemic reaction with associated anxiety-like symptoms. It is, however, uncommon for blood levels to fall to the levels required to diagnose clinical hypoglycaemia. There are, however, several reports of an association between a tendency for blood glucose to fall rapidly, but not to levels necessary to diagnose hypoglycaemia, irritability and aggression. The consumption of meals that are almost entirely carbohydrate can increase the levels of tryptophan in the blood with consequences for the synthesis of serotonin in the brain and hence an improvement in mood. The evidence is, however, that this mechanism is blocked by relatively small amounts of protein in the diet, such that it occurs very rarely when normal meals are consumed. Similarly, there is no support from well-controlled studies for the suggestion that sugar consumption causes hyperactivity in children. There is, however, evidence that pleasant tasting foods, for example chocolate, release endorphins with associated improvements in mood.
... As first pointed out by Hansen and colleagues (Hansen 1970;Hansen and Johansen 1970;Johansen and Hansen 1971), poorly controlled type-1 diabetics demonstrate markedly abnormal patterns of GH secretion, including spontaneous hypersecretion at night, excessive release during exercise (Hansen 1970), resistance to suppression by hyperglycemia (Yde 1969;Press et al. 1984a,b), and increased responsiveness to the a 2 -agonist clonidine (Topper et al. 1985). Many of the patients display GH levels that are in the acromegalic range but do not show signs of acromegaly. ...
Although GH-secreting tumors of the pituitary and the rarer ectopic GHRH-secreting tumors are the most obvious and serious disorders of GH hypersecretion in man, there are a number of pathological states in which excess secretion of GH occurs, due mainly to abnormalities in the normal neuroendocrine basis of GH regulation (Table 1; see Molitch 1986 for review). These GH secretory states differ in their pathobiological implications; the most common and important is diabetes, in which GH hypersecretion aggravates metabolic abnormalities and possibly contributes to the adverse course of retinal microangiopathy. Other metabolic disorders in which GH hypersecretion occurs are starvation (Hintz et al. 1978; Clemons et al. 1981) including anorexia nervosa (Garfinkel 1987), hepatic cirrhosis (Shankar et al. 1986), and renal failure (Bessarione et al. 1987). GH hypersecretion is a cardinal feature of Laron-type dwarfism (Laron et al. 1968), is commonly seen in the diencephalic syndrome (Drop et al. 1980), and occurs in stress (Glick et al. 1965; Reichlin 1968). One rare cause of GH hypersecretion is the syndrome of polyostotic fibrous dysplasia, in which an intrinsic growth-regulatory disorder, expressed in multiple tissues including the pituitary, can lead to the syndrome of acromegaly (Kovacs et al. 1984; Rodman et al. 1988). In this paper I have focused on GH dysregulation in diabetes, because more is known about this disorder than about the other conditions and because it may be the most common form of GH hypersecretion.
... The conflicting results could be explained by the fact that the secretion of GH and cortisol follows a well-defined circadian rhythm [57]. GH secretion is periodic and occurs in a pulsatile fashion where plasma cortisol has a peak in the early day [58]. Hence, ideally, mean 24-h hormone concentrations, based on measurements taken at different intervals, should be used. ...
... In experimental diabetes in rats, GH levels are suppressed with loss of pulsatility (Robinson et al. 1987, Tannenbaum 1981. In contrast, human diabetes is characterised by GH hypersecretion positively correlated to the diabetic aberration (Yde 1969, Hansen & Johansen 1970, Hansen 1972. In concert with this we observed elevated barbital-stimulated GH levels in the present study, which have been demonstrated previously in the same model (Flyvbjerg et al. 1999) and also in NOD mice (Landau et al. 2000). ...
It was recently discovered that the streptozotocin (STZ)-diabetic mouse model is characterised by GH hypersecretion in contrast to the STZ-diabetic rat, the former thus mimicking the changes in GH in human type 1 diabetes. Inhibition of circulating and renal IGF-I by long-acting somatostatin analogues reduces renal and glomerular growth and urinary albumin excretion in diabetic rats. The aim of the present study was to examine renal and glomerular growth in early experimental diabetes in mice along with changes in the GH/IGF-I axis following treatment with the somatostatin analogue octreotide. Balb/C(a) mice were randomised into non-diabetic controls, placebo-treated and octreotide-treated diabetic (50 microg/day) mice and examined 7 and 14 days after induction of diabetes. There was no effect of octreotide treatment on body weight, glycaemic control or food intake. However, octreotide treatment significantly inhibited renal and glomerular growth by the end of the study period when compared with placebo treatment. In addition, octreotide prevented an increase in kidney IGF-I by day 7. GH hypersecretion was observed in the diabetic groups but octreotide treatment reduced GH levels compared with placebo treatment by day 14. No significant differences in serum or kidney IGF-binding protein-3 levels were observed between placebo- and octreotide-treated diabetic mice. In conclusion, this new diabetic mouse model mimicking human type 1 diabetes is characterised by GH hypersecretion and the somatostatin analogue octreotide is able to prevent renal and glomerular growth, probably mediated through changes in circulating GH and local kidney IGF-I levels.
... In diabetic patients, GLU levels are rarely sustained throughout an entire day and they fluctuate according to the fasting state during the night and the successive postprandial states during the day (22). Previous studies have demonstrated that fluctuation in GLU levels during postprandial periods trigger higher levels of oxidative stress, inflammation and a higher risk of heart failure, compared with chronically sustained hyperglycemia (23)(24)(25). ...
Macrophages are involved in the progression of atherosclerosis by releasing pro‑inflammatory cytokines. High levels of interleukin (IL)‑18 are associated with an increased risk of developing diabetes and atherosclerosis. The present study aimed to investigate the association between IL‑18, and high and fluctuating glucose levels in mouse peritoneal macrophages (MPMs), and to assess the involvement of the c‑Jun N‑terminal kinase (JNK) pathway in this association. The MPMs were exposed to 4, 8, 16, 24 and 32 mM glucose for 6 h, which was alternated to either 4/24 mM glucose every 1.5 h for 6 h, or to 32 mM glucose for 3, 6, 12 and 18 h. The expression and secretion levels of IL‑18 were detected using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and ELISA, respectively. High levels of glucose increased the expression and secretion levels of IL‑18 in a dose‑dependent manner (P<0.05, vs. 4 mM glucose). This increase was more important in the cells exposed to fluctuating 4/24 mM glucose every 1.5 h compared with the cells exposed to stable 24 mM glucose (RT‑qPCR, 0.78±0.05, vs. 0.66±0.07; ELISA, 188.23±20.32, vs. 143.16±13.07 pg/ml; P<0.05). The expression and secretion levels of IL‑18 increased 8 and 12 h following exposure to high‑glucose, and then decreased at 18 h (P<0.05, vs. 3 h). Furthermore, SP600125, a JNK inhibitor, decreased the high‑glucose‑induced gene expression of IL‑18 in a dose‑dependent manner. Therefore, high and fluctuating levels of glucose may be associated with inflammation and diabetic atherosclerosis by regulating the expression levels of IL‑18. The present study identified the JNK signaling pathway as one of the mechanisms underlying this association. Targeting IL‑18 may be a novel therapeutic approach against diabetes‑associated atherosclerosis.
... El pico nocturno de GH precede al pico de los ácidos grasos libres y de los cuerpos cetónicos durante aproximadamente dos horas, el mismo tiempo de latencia necesario para la elevación de los ácidos grasos libres después de la infusión de GH en humanos en estado de pos absorción 16 . En un modelo de hipersecreción de GH, como en la diabetes mellitus tipo 1 con control de glucemia precario, ocurre un estado de excesiva lipólisis y cetogénesis, en razón de la incapacidad de secreción compensatoria de insulina por las células β del páncreas 17 . ...
Resumen la hormona de crecimiento (GH), principal regulador del crecimiento postnatal, tiene importantes acciones metabólicas en diversos tejidos, sinérgicas o incluso antagónicas a las del factor de crecimiento, a semejanza de la insulina tipo I (IGF-I) producido, principalmente, en el hígado y después del vínculo del GH con su receptor. Experimentos en modelos animales indican un papel importante del GH en la resistencia a la insulina, mientras que el papel del IGF-I en esa condición, todavía no está completamente elucidado. En los humanos, el GH genera el aumento de la lipólisis y de la oxidación lipídica, mientras que el IGF-I desencadena el aumento de la oxidación lipídica solamente desde el punto de vista crónico. Mientras las acciones sobre el crecimiento son de tiempo limitado, las acciones metabólicas y cardiovasculares del eje GH/ IGF-I duran toda la vida. Los efectos potenciales anabólicos del GH han sido utilizados en condiciones crónicas e hipercatabólicas, aunque las investigaciones sobre los desenlaces clínicos todavía sean escasas. En este artículo, pretendemos revisar las acciones metabólicas del GH provenientes de modelos animales, los estudios en humanos normales y en individuos con deficiencia de GH, diabetes mellitus tipo 1, síndrome metabólico, estados hipercatabólicos y la relación del eje GH/IGF-I con las adipocinas, disfunción endotelial y aterogénesis.
... In type 1 diabetes mellitus (T1DM), with insufficient insulinization of the liver due to lack of endogenous insulin in the portal vein, there appears to be a dysfunction of the GH-IGF1 axis. This is characterized by low concentrations of total IGF1 and IGFBP3 and high concentrations of IGFBP1 and GH (9,10,11,12,13,14). Although these abnormalities have been described in a situation of poor glycaemic control, exogenous s.c. ...
In type 1 diabetes mellitus (T1DM), low IGF1 concentrations and high levels of IGF binding protein-1 (IGFBP1) have been reported. It has been suggested that these abnormalities in the GH-IGF1 axis are due to low insulin levels in the portal vein. We hypothesized that the intraperitoneal (IP) route of insulin administration increases IGF-1 concentrations as compared to subcutaneous (SC) insulin. Determination of IGF1 and IGFBP1 concentrations in samples derived from an open-label, randomized cross-over trial comparing the effects of SC and IP insulin delivery on glycaemia. T1DM patients were randomized to receive either 6 months continuous intraperitoneal insulin infusion (CIPII) through an implantable pump (MIP 2007C, Medtronic) followed by 6 months SC insulin or vice versa with a washout phase in between. Data from 16 patients who completed measurements during both treatment phases was analysed. The change in IGF1 during CIPII was 10.4 μg/L (95% confidence interval (CI) -0.94, 21.7 μg/L; p=0.06) and -2.2 μg/L (95% CI -13.5, 9.2 μg/L; p=0.69) during SC insulin. Taking the effect of treatment order in account, the estimated change of IGF1 was 12.6 μg/L (95% CI -3.1, 28.5 μg/L; p=0.11) with CIPII compared to SC insulin. IGFBP1 concentrations decreased with -100.7 μg/L (95% CI -143.0, -58.3 μg/L; p<0.01) with CIPII. During CIPII treatment parts of the growth hormone-IGF1 axis changed compared to SC treatment. This supports the hypothesis that the IP route of insulin administration is of importance in the IGF1 system.
... [46] It has also been shown that blood glucose and insulin concentrations exhibit a circadian rhythm. [44,106] In particular, one's BGC tends to increase during the morning hours before waking up due to an increase in hormones, which is known as the dawn phenomenon. ...
Type 2 diabetes is one of the greatest burdens on the health care industry today. This condition is characterized by poor control of blood glucose concentration (BGC). In order to help those afflicted with type 2 diabetes better control their BGC, the goal of this research is to develop a device that can noninvasively measure BGC. There are several statistical issues that must be addressed before such a device can be developed. The first is to identify inputs that appear to infer BGC and choose a model that can use these inputs to accurately predict BGC. Due to its ability to assign unique dynamics to each input, the Wiener network model is used to predict BGC for each subject. However, there are several challenges to fitting a Wiener network model that can accurately predict BGC, including estimating a large number of parameters, the nonlinearity of the parameters, the stiffness of the least squares objective function for fitting this model, and possible overfitting. Thus an algorithm is designed to fit a Wiener network model where the correlation between predicted and observed BGC is maximized under supervised learning. However, such models were fit with frequent BGC measurements every five minutes. For a non-insulin dependent person, there may only be four BGC measurements per day, which for a week of data or less, implies that there are fewer observations than parameters. Thus, in order to calibrate a noninvasive device, some parameters were held fixed to reduce parameterization, and a novel scheme was devised to estimate the remaining model parameters. Finally, a method of predicting future BGC should be devised that could be used to warn the user if their BGC is going to be too low or too high in the near future. Time series models that use only outputs, such as autoregressive models, to predict BGC into the future performed well in the very near future, but performance degraded quickly as time increased. By utilizing the Wiener network model and previous measurements of BGC, a k-steps ahead prediction model is devised that predicts BGC 5k minutes into the future. This is used to calculate approximate (1-α) 100% forecast intervals for BGC up to one hour into the future.
... The available information on circadian variations in plasma glucagon concentrations is little and inconsistent. In two studies in humans, no daily rhythm in plasma glucagon concentrations was found (25,26). Studies done in mice and rats did show a daily rhythm similar to the one that we show, with peak levels at the end of the dark period (24,27). ...
Despite over a century of insulin therapy and recent advances in glucose monitoring, diabetes and its complications remain a significant burden. Current medications are not durable, with symptoms often returning after treatment ends, and responses vary between patients. Additionally, the effectiveness of many medications diminishes over time, highlighting the need for alternative approaches. Maintaining β-cell mass and promoting β-cell regeneration offer more curable treatments, while cell replacement therapies could be an option if regeneration is not feasible. For both strategies, enhancing β-cell survival is crucial. Growth hormone-releasing hormone (GHRH) was originally discovered for its ability to stimulate the production and release of growth hormone (GH) from the pituitary. Beyond the hypothalamus, GHRH is produced in peripheral tissues, with its receptor, GHRHR, expressed in tissues such as the pituitary, pancreas, adipose tissue, intestine, and liver. Several studies have shown that GHRH and its analogs enhance the survival of insulin-producing pancreatic β-cells both in vitro and in animal models. These beneficial effects strongly support the potential of GHRH agonists and antagonists for the clinical treatment of human metabolic diseases or for enhancing β-cell survival in cells used for transplantation. In the current review, we will discuss the roles of hypothalamic and extrahypothalamic GHRH in metabolism in physiological and pathological contexts, along with the underlying mechanisms. Furthermore, we will discuss the potential beneficial effects of GHRH analogs for the treatment of metabolic diseases.
The aim of this work was to examine the role of Growth Hormone (GH) and tissue growth factors in the pathogenesis of diabetic retinopathy, and to investigate the mechanism of excessive GH secretion in diabetes. Levels of GH and insulin-like growth factor-I (IGF-I) (the principal mediator of the growth promoting activity of GH) were measured in diabetic patients with retinopathy and control subjects. The concentration of basic fibroblast growth factor (bFGF), a potent angiogenic growth factor, was also examined in vitreous and retinal extracts. 24h studies confirmed increased GH and normal IGF-I levels during poor diabetic control suggesting impaired IGF-I production. Serum IGF-I was inversely correlated with HbA1 concentration. Reduced feedback inhibition by IGF-I when control is poor could contribute to excessive GH release. In addition, pretreatment with GH failed to suppress the GH response to GH-releasing hormone (GHRH) in some patients indicating altered GH feedback control. Relative resistance to somatostatin was inferred from the results of treatment with octreotide, a potent somatostatin analogue. GH hypersecretion in diabetes is likely to be a product of several different mechanisms. No correlation was found between the development of background retinopathy and changes in serum IGF-I concentration, in patients commencing continuous subcutaneous insulin infusion. A significant increase in mean serum IGF-I occurred at the onset of proliferative retinopathy in patients treated conventionally (281 ± 54 versus 196 ± 58 micrograms/l; p <0.05). Cultured retinal endothelial cells were demonstrated to release IGF-I but not bFGF into the cell medium. A different release mechanism is likely for bFGF which was abundant in whole retinal extracts. In the diseased diabetic retina, cell damage could release bFGF which would then induce cell competence in surviving endothelial cells and fibroblasts. By allowing the cells to complete the cell cycle, the increase in IGF-I levels could play a crucial role in promoting cell proliferation and neovascularisation.
Glycogen is a branched glucose polymer involved in sustaining blood glucose homeostasis. Liver glycogen comprises α particles (up to 300 nm in diameter) made of joined β particles (∼20 nm in diameter). Glycogen α particles in a mouse model for diabetes are molecularly fragile, breaking down into smaller β particles more readily than in healthy mice. Glycogen phosphorylase (GP), a rate-limiting enzyme in glycogen degradation, is overexpressed in diabetic mice. This study shows that Metformin and Berberine, two common drugs used to treat diabetes, are able to revert the liver glycogen of diabetic mice to the stable structure seen in non-diabetic mice. It is also shown that these drugs reduce the GP level via the cAMP/PKA signaling pathway in diabetic livers and decrease the affinity of GP with the glycogen of db/db mice. These effects of these drugs may slow down the degradation of liver glycogen and improve glucose homeostasis.
Despite decades of study on the contribution of growth hormone (GH) to the development of kidney disease, there remains the question of the relative contribution of elevated levels of GH to kidney damage in humans, particularly in diabetic nephropathy occurring in type 1 patients. In this study, we reviewed several publicly available datasets to examine transcription of twelve genes associated with the GH/IGF1 axis in several types of human and rodent kidney diseases. Our analyses revealed downregulation of renal GHR and IGF1 gene expression in several different chronic human kidney diseases, including diabetic nephropathy, with general upregulation of IGFBP6 in the same tissues and diseases. These findings were generally supported by a review of studies in rodent models. In healthy and diseased human kidneys, increased GHR gene expression was associated with increases in glomerular filtration rate (GFR) and decreases in serum creatinine. IGFBP6 gene expression demonstrated the opposite clinical correlation. Our results suggest the kidney may exhibit GH insensitivity due to low GHR gene expression during most chronic kidney diseases.
Oxidation-reduction reactions are essential to life as the core mechanisms of energy transfer. A large body of evidence in recent years presents an extensive and complex network of interactions between the circadian and cellular redox systems. Recent advances show that cellular redox state undergoes a ~24-h (circadian) oscillation in most tissues and is conserved across the domains of life. In nucleated cells, the metabolic oscillation is dependent upon the circadian transcription-translation machinery and, vice versa, redox-active proteins and cofactors feed back into the molecular oscillator. In the suprachiasmatic nucleus (SCN), a hypothalamic region of the brain specialized for circadian timekeeping, redox oscillation was found to modulate neuronal membrane excitability. The SCN redox environment is relatively reduced in daytime when neuronal activity is highest and relatively oxidized in nighttime when activity is at its lowest. There is evidence that the redox environment directly modulates SCN K+ channels, tightly coupling metabolic rhythms to neuronal activity. Application of reducing or oxidizing agents produces rapid changes in membrane excitability in a time-of-day-dependent manner. We propose that this reciprocal interaction may not be unique to the SCN. In this review, we consider the evidence for circadian redox oscillation and its interdependencies with established circadian timekeeping mechanisms. Furthermore, we will investigate the effects of redox on ion-channel gating dynamics and membrane excitability. The susceptibility of many different ion channels to modulation by changes in the redox environment suggests that circadian redox rhythms may play a role in the regulation of all excitable cells.
Die Tatsache, daß dieses Thema an einer Internistentagung diskutiert wird, ist ein Beweis für das zunehmende Interesse der Inneren Medizin für die Angio-logie, und zwar nicht nur für Krankheiten der coronaren, renalen und cerebralen Gefäße, sondern auch für solche der Gliedmassenarterien und -venen, für die bisher in erster Linie die chirurgischen Kliniken zuständig waren. Die z. Z. noch vereinzelten angiologischen Teams medizinischer Kliniken haben sich bereits aufs beste bewährt.
In all mammalian species studied so far, growth hormone (GH) is released in a pulsatile manner which would be crucial for proper somatomedin secretion and normal growth rhythm (Martin 1978; Müller 1987). This is true also in humans beings, in whom a deficiency in spontaneous GH pulsatility isassociated with short stature (Howse et al. 1977; Albertsson-Wikland et al. 1983; Thorner et al. 1986). However, an shown by Spiliotis et al. (1984), a reduced spontaneous GH secretion during the day is not always due to a pituitary secretory inability. In fact, there are many children in whom, in spite of low 24-h GH secretion, a marked somatotroph responsiveness to provocative tests is present. These children have been defined as having GH neurosecretory dysfunction, i.e., an altered GH neuroregulation that leads to a GH deficiency. Therefore, from a clinical viewpoint, the importance of studying the neural control of GH secretion is evident.
Recently, Bauer et al. (1) have reported the synthesis of an octapeptide SMS 201–995 (DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol), found in animal experiments to be about 45 times more potent than native somatostatin (SRIF).
GH is a protein that contains 191 amino acids with two disulfide bonds and four a helices (Abdel-Meguid et al., 1987; de Vos et al., 1992). Its molecular mass is approximately 22 kDa. GH is secreted by the anterior pituitary gland (Theill and Karin, 1993; Ohlsson et al., 1998). GH signal transduction begins with GH binding to a transmembrane GH receptor (Lesniak et al., 1973). GH has two distinct binding domains that bind to two identical GHRs at the cell surface. The initial (high-affinity) binding of the GH binding site I at the GHR is followed by binding at the GH site II, which produces functional receptor dimerization of the two GHRs (de Vos et al., 1992; Carter-Su et al., 2000).
Metabolic control was evaluated under standard conditions in pregnant gestational and insulin-dependent diabetic patients and control subjects from: (1) changes during an 8 hour period in blood glucose, free fatty acids (FFA), glycerol, ketone bodies, chorionic somatomammotropin (HCS), and insulin during the last trimester and (2) changes from weeks 32 to 40 in fasting blood glucose, FFA, glycerol, and ketone bodies. Mean glucose levels calculated from five daily analysis 28 days before delivery were determined in insulin-dependent and gestational diabetic patients (pregnancy glucose level). Group mean 8 hour glucose levels were similar in diabetic patients and control subjects, but glucose swings were greater in diabetic patients. Gestational diabetic patients had delayed insulin response following meals. FFA, glycerol, and ketone bodies varied in parallel with a similar pattern in diabetic patients and control subjects. Insulin-dependent diabetic patients had suppressed lipid mobilization in the afternoon when glucose levels were almost normal. In control subjects, FFA, glycerol, and ketone bodies were not above normal nonpregnant values. Diabetic patients showed great individual variations in all parameters measured. FFA and ketone bodies were significantly above normal; glycerol and glucose were normal. Pregnancy glucose levels were significantly correlated to a mean amplitude of glycemic swings (MAGE) determined from the 8 hour glucose profiles. The glucose value 2 hours after breakfast correlated best to the MAGE value.
This chapter discusses the interactions of growth hormone (GH) with other hormones. GH exerts its multiple effects not on a target organ but on every cell of the organism. Therefore, it is expected that the action of GH depends on the metabolic equilibrium of each cell, which in turn is modified by other hormones. All known hormones have been found to have at least some direct or indirect modifying effect on the production, release, and/or metabolic action of GH. The chapter discusses three types of interaction of GH with other hormones. First interaction includes those of physiological importance such as regulation of blood glucose homeostasis. Second interaction includes those becoming apparent only with disease associated with the over- or underproduction of hormones, such as diabetes mellitus, acromegaly, or GH-suppression in hypothyroidism. Third interaction includes those brought about by the pharmaco-dynamic effects of hormones, such as GH-release induced by high doses of vasopressin. Glucagon may be a stimulus for GH release but only under certain conditions. It is not yet clear whether the effect of glucagon is a direct one on GH release or an indirect one mediated through the falling blood-glucose concentration.
This chapter discusses a family of substances that is called somatomedins. The somatomedins are like insulin in structure and, therefore referred to as insulin-like growth factors (IGFs). It describes the mechanism of action of the IGFs. The somatomedin peptides resemble insulin in both structure and metabolic activity. Insulin's bioactivity—such as stimulation of glucose influx in rat adipose tissue or diaphragm—is not coincident with its immunoreactivity. Antibodies raised against insulin obliterate only about 10% of its effect. The left -over material that is still able to act in insulin's place is termed as nonsuppressible insulin-like activity (NSILA). A spectrum of effects similar to those for somatomedins and IGFs has also been reported for multiplication stimulating activity (MSA). This factor has insulin-like activity and shares with IGFs and somatomedins the ability to support fibroblast proliferation in vitro.
When these studies were initiated late in 1968 the 24-h plasma growth hormone pattern in normal subjects was just discovered. Hunter and Rigal (1) had reported raised plasma growth hormone values during night in children. Quabbe and coworkers (2) had found in adults low day time plasma growth hormone values, intermittent bursts during night with high peaks occurring during times of deeper sleep. Glick and Goldsmith (3) had shown an effect of various feeding procedures on the 24-h plasma growth hormone level. Takahashi et al. (4) and Honda et al. (5) had demonstrated that the release of growth hormone during night coincides with the onset of electroencephalographically determined deep sleep. Experiments in which they had delayed or interrupted sleep provided evidence that the nocturnal growth hormone secretion was related to the onset of sleep and did not reflect a true endogenous circadian rhythm in growth hormone secretion. Extensive studies by Parker and coworkers (6, 7) have amply confirmed and extended these findings
Bei Typ-I-Diabetikern werden in Abhängigkeit von der Güte der Stoffwechseleinstellung erhöhte Wachstumshormonspiegel (STH = Somatotropes Hormon) im Serum gemessen.
Neuere Untersuchungen bezüglich der durch STH regulierten Wachstumsfaktoren weisen auf eine mögliche Bedeutung bei der Entstehung von diabetesbedingten Spätschäden hin.
Ebenso scheint das sog. “Dawn-Phänomen” — ein Anstieg des Nüchtern-Blutzuckers am frühen Morgen — im wesentlichen durch das in der Nacht in Form von Spikes sezernierte STH verursacht zu sein.
In der vorliegenden Untersuchung wurde unter Schlaflaborähnlichen Bedingungen die Sekretion von STH in Abhängigkeit von den Schlafphasen bei Diabetikern im Vergleich zu gesunden, gleichaltrigen Kontrollpersonen erfasst.
Dabei zeigte sich bei den Typ-I-Diabetikern neben einer erhöhten Grundsekretion ein erhaltenes, an den Delta-Schlaf gebundenes, pulsatiles STH-Sekretionsmuster mit geringeren Sekretionspausen. Zwar waren die Sekretionsmaxima nicht signifikant höher, die STH-Gesamtsekretion (Fläche unter der Kurve) war jedoch bei den Diabetikern signifikant größer als bei den Kontrollpersonen.
Diese Ergebnisse weisen darauf hin, daß trotz Hypersekretion von STH bei Diabetikern das schlafgebundene, pulsatile Sekretionsmuster erhalten bleibt.
Normal nutrient homeostasis depends on the balance between the effects of insulin and those of the counterregulatory hormones.1–4 Classically these hormones have been defined as those that oppose the actions of insulin, and they include glucagon, catecholamines, growth hormone, and cortisol. Of the catecholamines (i.e., epinephrine and norepinephrine), epinephrine is currently considered to act as a circulating hormone, whereas norepinephrine probably acts mainly as a neurotransmitter. Although thyroxine and triiodothyronine affect various aspects of metabolism,5 circulating thyroid hormone levels are not acutely altered by nutrient signals, and fluctuations in their daily secretion do not influence metabolic processes. For these reasons, thyroxine and triiodothyronine are not generally considered among the classic counterregulatory hormones.
Normal nutrient homeostasis depends on the balance between the effects of insulin and those of the so-called contrainsulin or counterregulatory hormones.1”4 These hormones include glucagon, epinephrine, growth hormone, and Cortisol. Although thyroxine and triiodothyronine affect various aspects of metabolism, circulating thyroid hormone levels are not acutely affected by nutrient signals, and fluctuations in their daily secretion do not alter metabolic processes.1 For these reasons, thyroxine and triiodothyronine are not generally considered among the classical contrainsulin hormones. Regulating factors in addition to insulin and the contrainsulin hormones affect metabolic balance. These factors include various neurotransmitters (norepinephrine from sympathetic postganglionic neurons, acetylcholine from parasympathetic neurons and neuropeptides) and substrates including glucose. Detailed discussion of the latter regulatory factors is beyond the scope of this chapter. Their roles have been reviewed elsewhere.1–4
Growth is intrinsically linked with both an increment in cell mass and an acceleration of cellular proliferation. Growing mammalian cells have in common a characteristic set of biochemical phenomena, including an increase in protein synthesis, increased incorporation of nucleic acid precursors into RNA and DNA, and poly-some aggregation (Hershko et al.,1971). These growth-mediating processes are limited by the availability of various nutrients, metabolites, and ions in the extracellular environment, but are also susceptible to regulation by a variety of agents, including hormones. Control points for this hormonal influence upon growth include: membrane-associated processes involved with the transport of amino acids, energy substrates, and ions; transcriptional processes involved in the expression of genetic information through the synthesis of new RNA; and translational processes as reflected in the numbers and efficiency of ribosomal protein-synthesizing units.
Regular physical activity is widely regarded as playing a large role in obesity prevention and treatment efforts. However, current data suggest that men lose more weight with exercise training than women. Thus, in this chapter we review the impact of exercise on weight loss in men and women, and potential homeostatic (appetite hormones) and non-homeostatic (neuronal responses) explanations of sex differences. The evolving story may influence our view on the impact of exercise on weight loss, and whether a true sex difference exists.
This article has no abstract; the first 100 words appear below.
To the Editor: We wish to challenge the conclusions as well as the assertions raised by Raskin and Unger in their article in the August 31 issue of the Journal. First of all, regarding the effect of hyperglucagonemia on glucose regulation in insulin-treated diabetes, the authors cite the studies of Sherwin et al.¹ and Raskin and Unger,² which are in conflict. However, they fail to mention the data of Clarke et al.³ In the latter study, in which physiologic amounts of glucagon were infused in diabetic patients, the authors conclude that "elevated plasma glucagon concentrations seen in most diabetic . . .
The potential for successful automatic control of blood glucose concentration (BGC) has entered a new era due to recent technological advancements in insulin pumps and blood glucose sensors. However, a critical advancement necessary for full automation and long-term use is a control algorithm that can effectively maintain tight control of BGC under extreme variation of important disturbances such as activity, stress, and food consumptions. Since feedforward control (FFC) models disturbances directly it has the potential to eliminate the effects of disturbances completely. A Wiener-type feedforward control law is limited to the inclusion of only input (i.e., modeled disturbances and the manipulated variable) dynamics. Using a semi-coupled modeling network that includes pseudo blood insulin concentration, this work presents a more phenomenological FFC law that includes input dynamics, blood insulin and blood glucose dynamics and blood glucose levels. Modeling results on fifteen adults with type 1 diabetes mellitus for the proposed method are nearly identical to Wiener modeling results.
ZusammenfassungUm Grundlagendaten über Beziehungen zwischen Nahrungsaufnahme und Kohlenhydratstoffwechsel am Miniaturschwein zu erhalten, wurden die zirkadianen Plasmaglucose- und Insulinspiegel bestimmt.Im Gegensatz zu Befunden am Menschen war der maximale Plasmainsulinanstieg nach der Morgenfütterung gleich rasch und gleich hoch wie nach der Nachmittagsfütterung, dagegen fand sich auch beim Schwein ein stark verzögerter Abfall des Plasmainsulins nach der zweiten Fütterung. Nachts blieb der Insulinspiegel konstant, während der Glucosespiegel deutlich abfiel. Der Quotient Insulin/Glucose war nach der zweiten Fütterung — abgesehen von der unmittelbar postprandialen Periode — größer als nach der Morgenfütterung.Für die Assistenz bei den operativen Eingriffen möchten wir Frl. G. Bolz an dieser Stelle danken.SummaryCircadian variations in plasma glucose and insulin in young miniature pigsIn order to establish basic data for the relationships between food intake and carbohydrate metabolism in miniature pigs the variations during the day of plasma glucose and insulin were determined.In contrast to the finding in man, the maximal plasma insulin rise after the morning feed was as rapid and as high as after the afternoon feed, whereas the pig showed, as does man, a markedly slowed fall in plasma insulin after the second feed.During the night the insulin level remained constant, whereas the glucose level fell appreciably. The quotient insulin/glucose was higher, save for the immediate post-prandial period, after the second feed than after the morning feed.RésuméVariations du glucose et de l'insuline plasmatiques dans le courant de la journée chez le porc miniaturePour obtenir des valeurs de base sur les relations entre l'ingestion d'aliments et le métabolisme des hydrates de carbone chez le porc miniature, on a déterminé les taux de glucose et d'insuline plasmatiques dans le courant de la journée.A l'encontre des résultats trouvés chez l'homme, l'augmentation maximum d'insuline plasmatique, après le repas matinal, est aussi rapide et aussi élevée qu'après le repas de l'après-midi; par contre, on observe chez l'homme comme chez le porc, un important retard dans la diminution de l'insuline plasmatique après le deuxième repas. Pendant la nuit, le taux d'insuline reste constant, alors que le taux du glucose diminue nettement. Le quotient insuline/glucose est plus élevé après le deuxième repas qu'après le premier, à l'exception de la période post-prandiale immédiate.ResumenOscilaciones circadianas de la glucosa e insulina plasmáticas en el cerdo miniatura jovenPara obtener datos fundamentales sobre las relaciones entre la ingestión de alimentos y el metabolismo hidrocarbonado en el cerdo miniatura, se valoraron los niveles circadianos de glucosa e insulina plasmáticas. En contraposición a los hallazgos en el hombre, el aumento máximo de insulina plasmática se instauraba rápidamente después de la alimentación matutina y con la misma intensidad que después de la alimentación vespertina, pero en cambio también en el cerdo se halló un descenso muy diferido de la insulina plasmática después de la segunda alimentación. Por la noche permanecía constante el nivel insulínico, mientras que descendía de forma manifiesta el nivel glucémico. El cociente insulina/glucosa era mayor después de la alimentación segunda — prescindiendo del periodo postprandial inmediato — que a continuación de la alimentación matutina.
Evidence for a causative relationship between prolonged tissue hypoxia and diabetic retinopathy and glomerulosclerosis are presented. Based on the assumption that one of the most fundamental requirements for optimal cellular metabolism is a constant cellular oxygen tension, the “three-in-one concept” for the development of diabetic microangiopathy is formulated. The term “three-in-one” is employed because this concept partly or completely includes “the glycoprotein-”, “the hypoxia-”, and “the growth hormone hypothesis”. Diabetics show evidence of variability in the tissue oxygen availability/demand ratio which is compensated by three self-regulating factors: 1) an increase in local flow, 2) an increase in red cell 2,3-DPG leading to a shift to the right of the oxyhaemoglobin dissociation curve, and 3) an increase in the oxygen-binding capacity or the haemoglobin concentration. The level of plasma inorganic phosphate (Pi) is of importance in maintaining high 2,3-DPG levels. However, since Pi fluctuates depending upon changes in the control of diabetes, the regulatory mechanism of the 2,3-DPG modulated unloading of oxygen from the erythrocytes often becomes insufficient, and therefore in poorly regulated diabetics with less than optimal 2,3-DPG levels, the main load of compensation against tissue hypoxia is placed on an adjustment in the microcirculation of the organ involved. However, in order for the microvascular dilatation to occur, the cells must experience a hypoxic stimulus. The summation of the infinite number of discrete and occasionally pronounced hypoxic injuries to the tissue cells in association with the adverse effect of local vasodilatation with increased plasma permeation through the vessel walls might over the years lead to diabetic microangiopathy.
It is suggested that excessive secretion of growth hormone (G.H.) may be the cause of diabetic capillary disease. G.H. hypersecretion inhibits glucose metabolism and results in an accumulation of sorbitol. This in turn causes an osmotic imbalance resulting in damage to tissues.
Pegvisomant is a GH analogue that includes a single amino acid substitution at position 120 that generates the GHR antagonist. Additional changes include amino acid substitutions within binding site 1 and a further modification by the addition of polyethylene glycol moieties that increase the half-life and reduce the immunogenicity of the molecule. In acromegalics, pegvisomant is the most effective treatment for normalizing the IGF-I, and pegvisomant significantly improves insulin sensitivity in patients suffering from acromegaly. However, there are simply no data available that might support a role for pegvisomant treatment in disorders in which glucose metabolism is disturbed and in which reducing GH action would be theoretically beneficial.
The development of the concept of homeostasis began in the mid 19th century, when Claude Bernard (1813–1878) claimed that ‘la fixeté du milieu interieur' is essential for higher organisms to
survive in an ever changing environment. “Standing or staying the same” is the literal meaning of the term homeostasis, which
was introduced later by Walter B. Cannon (1871-1945) and derived from the Greek words homeios (the same) and stasis (staying). However, as Cannon emphasized, homeostasis does not mean something set and immobile that stays exactly the same
all the time. In his words, homeostasis “means a condition that may vary, but which is relatively constant”. This definition
was refined by Donald C. Jackson (1987): “Homeostasis is znot a single optimal control condition but rather a variety or continuum
that varies with the animal's circumstances. Set points or regulated values are not fixed, but may change depending on ambient
conditions or because of changing physiological conditions or demands.”
IN A SERIES OF EXPERIMENTS ON THE HUMAN FOREARM, PREPARATION DESIGNED TO EXAMINE THE EFFECTS OF VARIATIONS IN IMMUNOLOGICALLY DETERMINED ENDOGENOUS SERUM INSULIN LEVELS AND OF BLOOD GLUCOSE CONCENTRATIONS ON MUSCULAR GLUCOSE UPTAKE, THE FOLLOWING RESULTS WERE OBTAINED: (a) A highly significant correlation between muscular glucose uptake and simultaneous arterial serum insulin concentration. (b) No correlation between glucose uptake and simultaneous arterial blood glucose concentration during hyperglycemia. (c) A maximal insulin effect on muscular glucose uptake at arterial serum insulin concentrations at about 200 muU/ml. This observation is, however, based on only a few experiments.
Plasma growth hormone (GH) levels were measured during arginine infusion in normal subjects, insulin-dependent diabetic patients, and obese maturity-onset diabetic patients under conditions of normoglycemia and hyperglycemia; GH secretory response to insulin-induced hypoglycemia was also evaluated. When acutely hyperglycemic normal subjects showed a markedly diminished peak GH response to arginine infusion (4.1 ± 2.4 mμg per milliliter) as compared to the GH response for the normoglycemic state (12.5 ± 2.6 mμg per milliliter). The peak GH response in insulin-dependent diabetic patients was not significantly different when hyperglycemic (12.5 ± 2.5 mμg per milliliter) or normoglycemic (18.7 ± 3.7 mμg per milliliter), while that of the maturity-onset diabetic patients was blunted both when hyperglycemic (4.1 ± 1.6 mμg per milliliter) and normoglycemic (5.4 ± 1.0 mμg per milliliter). The difference between normal subjects and diabetic patients could not be explained by differences in the plasma levels of arginine achieved during the infusions. Insulin-induced hypoglycemia was a more potent stimulus to GH release than arginine infusion in all groups, though the GH response was significantly (p < 0.005) less in the obese maturity-onset diabetic patients than in the other two groups. The peak levels for normal (29.6 ± 9.2 mμg per milliliter), insulin-dependent diabetic patients (39.1 ± 4.2 mμg per milliliter), and obese maturity-onset diabetic patients (9.2 ± 1.4 mμg per milliliter) were all higher than GH levels achieved following arginine infusion. The observation that acutely induced hyperglycemia blocks arginine stimulated GH release in the majority of normal subjects would indicate that glucose is a regulator of GH secretion in situations other than hypoglycemia. The failure of hyperglycemia to block arginine-induced GH release in chronically hyperglycemic diabetic patients suggests an altered relationship of GH releasing mechanisms in this disease.
Plasma insulin and growth hormone were measured by radioimmunoassay in healthy adults during the latter part of 22 hr. fasts and after graded glucose loads. The insulin concentration was less than 8 μ-u./ml. in all fasting samples and in samples taken after the blood glucose had returned to fasting levels. Insulin levels increased with increasing glucose loads.
During fasting, growth hormone showed intermittently raised secretion; in some subjects high values were reached at times which could not be related to external events or to stress. Growth hormone levels were consistently low during the absorption of glucose but rose immediately thereafter. This rise occurred increasingly late and reached increasing levels as the glucose loads were made progressively larger.
Insulin had almost invariably returned to fasting levels before the growth hormone concentrations began to rise.
The Introduction of sensitive radioimmunological techniques for the determination of human growth hormone (GH) (1,2) has made it possible to study its concentration in plasma under various physiological and pathological conditions. Secretion of GH has been shown to respond to different stimuli, e.g., hypoglycemia (3), infusion of certain amino acids (4) and physical activity (5), but the relative importance of these factors for the release of hormone under physiological conditions has not yet been fully established. Considerable variations in the hormone level of an individual have been observed when repeated determinations were done on a single day. This and the occasional finding of unexpectedly high concentrations after an overnight fast have complicated our understanding of the normal regulation of GH concentration in plasma. Very little is known about the physiological variations of GH release during a 24-hour period. We report determinations of GH during a 24-hour fast in normal adults. These studies show a pattern of intermittent bursts of GH secretion during the night and a part of the day, with concentrations varying from undetectable to very high values. Some of the implications of this finding are discussed.
RECENT methodological improvements in radio-immunoassays for growth
hormone1,2 have led to increasing use of these techniques in
clinical and physiological research. We have found a large and
apparently previously unreported difference in the fasting growth
hormone level of normal males and females.
EEG, pulse rate, respiration and eye movement were polygraphically recorded throughout the night in 10 normal adult male subjects. Blood was collected every 20 min throughout the night by means of an indwelling venous catheter without disturbing the natural course of sleep. Human growth hormone (HGH) and blood sugar were measured in these plasma samples. Depth of sleep was classified into 5 stages by EEG. A marked elevation of plasma HGH was constantly observed coincident with the onset of sleep. Following the initial large HGH peak, additional peaks of HGH, with a decrease in the size of subsequent peaks, were observed. Shifting the time of the onset of sleep by 3 hr before or after the usual bedtime did not change the elevation of plasma HGH coincident with the onset of sleep. When a state of full wakefulness was maintained at night, plasma HGH did not rise. The secretion of plasma HGH was inhibited during paradoxical sleep. It is concluded that nocturnal sleep is a potent stimulator for the se...
Serum human growth hormone (HGH), serum immunoreactive insulin (IRI), plasma free fatty acids, and blood glucose were measured during intravenous glucose and intravenous tolbutamide tolerance tests in 13 normal and 13 prediabetic (offspring of two diabetic parents) males, closely matched for weight and age. Only prediabetics with normal glucose tolerance during oral, intravenous, and cortisone-primed glucose tolerance tests were evaluated. Mean serum HGH levels were significantly higher in prediabetics in response to intravenous tolbutamide and at the end of the 3-hr intravenous glucose tolerance tests (IVGTT). This is interpreted as a hyperresponsiveness of the growth hormone-releasing mechanisms in prediabetic subjects. The insulin response during the first 10 min of an IVGTT was significantly reduced in prediabetic males as compared to normal controls, whereas the insulin response to intravenous tolbutamide was not significantly different at the same time intervals in the same subjects.It appears, therefore, that measuring IRI during an IVGTT can be valuable in detecting the earliest signs of diabetes even before any disturbance of blood glucose homeostasis is seen. The possibility that growth hormone hypersecretion in prediabetics might play a role in the pathogenesis of human diabetes mellitus is discussed.
THE essential principle of competition for a given amount of anti-hormone between standard or unknown quantities of hormone and a fixed amount of labelled hormone in Yalow and Berson's1 radio-immunoassay has been maintained in all modifications. The modifications have simplified the apparatus and have achieved a more rapid and complete separation of free and antibody-bound radioactive hormone after the immunological reaction has taken place. This has been achieved best by double-antibody techniques2,3. The introduction of a second antibody has made these immunoassays sensitive to factors in serum and plasma4,5 which may give rise to spuriously high, or spuriously low, or even ``negative'' plasma values6. Another drawback is the difficulty in evaluating and correcting for the increased denaturation in serum or plasma of labelled hormone. This is inherent in modifications where free radioactive hormone cannot easily be isolated. Yalow and Berson1 called this phenomenon ``incubation damage'' and estimated the percentage breakdown in individual sera by incubation without anti-hormone. Their chromato-electrophoresis, as does all paper chromatography, allows for a correction, because free polypeptide hormone is isolated at the site of application. The evaluation of breakdown is important in assay of peptide hormones, particularly glucagon, because pancreatic glucagon is very rapidly destroyed in serum or plasma unless special precautions are taken.
Plasma growth hormone (GH), insulin, cortisol, and glucose were measured during sleep on 38 nights in eight young adults. Blood was drawn from an indwelling catheter at 30-min intervals; EEG and electrooculogram were recorded throughout the night. In seven subjects, a plasma GH peak (13-72 mmug/ml) lasting 1.5-3.5 hr appeared with the onset of deep sleep. Smaller GH peaks (6-14 mmug/ml) occasionally appeared during subsequent deep sleep phases. Peak GH secretion was delayed if the onset of sleep was delayed. Subjects who were awakened for 2-3 hr and allowed to return to sleep exhibited another peak of GH secretion (14-46 mmug/ml). Peak GH secretion was not correlated with changes in plasma glucose, insulin, and cortisol. The effects of 6-CNS-active drugs on sleep-related GH secretion were investigated. Imipramine (50 mg) completely abolished GH peaks in two of four subjects, whereas chlorpromazine (30 mg), phenobarbital (97 mg), diphenylhydantoin (90 mg), chlordiazepoxide (20 mg), and isocarboxazid (30 mg) did not inhibit GH peaks. Altered hypothalamic activity associated with initiation of sleep results in a major peak of growth hormone secretion unrelated to hypoglycemia or changes in cortisol and insulin secretion.
Summary Human growth hormone (HGH) has recently been shown to play a prominent role in the control of blood glucose homeostasis. Furthermore, it has long been known that administration of growth hormone in animals can induce a diabetes-like state. In human subjects, exogenous administration of HGH or hypersecretion of the endogenous hormone in acromegaly is accompanied by glucose intolerance in only about 25 per cent of the cases. — In this paper, data are presented which give a more diversified picture of the so-called diabetogenic action of HGH. It is suggested that HGH, although decreasing the peripheral utilization of glucose, is not a primary diabetogenic factor, since its insulinogenic action causes a compensatory hyperinsulinism, with normal glucose tolerance as the result. HGH is diabetogenic only in prediabetic subjects whose pancreas is unable to respond to the insulinogenic effect of the hormone. In such subjects, the diabetogenic action of HGH not being counterbalanced by a compensatory hyperinsulinism, glucose intolerance may result. Thus, HGH may be regarded as anadditional factor for the development of diabetes, the major prerequisite being a preëxisting prediabetic state.
Human growth hormone (HGH) has been measured in the plasma of fasting subjects at the moment of awaking and 1–3 hr later after normal activity. Basal levels of men and women were not different and were usually less than 1 mμg/ml. A marked rise in the later (“ambulatory”) specimens occurred in women, to a mean level of 6.5 mμg/ml. This rise was not seen in men, whose basal and ambulatory values were indistinguishable. Administration of estrogen to men resulted in a reproduction of the normal female pattern of HGH increase after activity. Variations of ambulatory but not basal HGH were noted in women followed throughout the menstrual cycle, with a distinct luteal phase rise beginning shortly after ovulation. It is postulated (a) that estrogens act to enhance pituitary sensitivity, or that of higher centers, to the HGH-releasing effects of physical activity and possibly other stimuli; and (b) that this effect may be at least partly responsible for the differences in plasma HGH noted between men and women, and in women during the menstrual cycle. It is also suggested that the increased HGH secretion following estrogen administration has a mammotropic action, and that the higher levels in normal women may play a physiologic role in the development and maintenance of the breast.
The diurnal pattern of plasma growth hormone levels has been investigated in nine children, without endocrinopathy, aged 8–15 yr., from whom blood samples were taken hourly during the day and 2-hourly at night.
Growth hormone was undetectable (< 1 μmg./ml.) during the first 2 hr. after meals but the levels rose thereafter to values many times higher than those found in adults. High values were consistently encountered during the night.
Plasma growth hormone (GH) levels were measured at intervals throughout the day in various subjects. Several healthy men showed increased levels 3–4 hr. after a meal. Plasma GH was generally low in obese subjects with or without diabetes. Four acromegalic patients had consistently and markedly raised levels which were unaffected by food. In two thyrotoxic patients GH values were not different from normal.
A colorimetric micromethod, based on the formation of FFA-Cu soaps, was developed for determining free fatty acids (FFA) in 50 μl of plasma. FFA was extracted with chloroform-heptane-methanol. Silicic acid was used to eliminate interference by the phospholipids. Diphenylcarbazide was chosen for the colorimetric determination of copper. These modifications render the method more sensitive than other available colorimetric methods. The method requires only capillary samples and is therefore suitable for repeated registration of the concentration of FFA during experimental conditions.
This is a report of some methodological studies on the enzymatic determination of blood sugar, in particular concerning the composition of the enzyme mixture, the non-specific oxidation, the precipitation media, the effect of added heparin, fluoride, and benzoic acid, and the glutathione problem. On the basis of the results, the author describes a procedure of enzymatic blood sugar determination which affords considerable accuracy. © 1967 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.
Apparent growth hormone hyperresponsiveness in prediabetes
- R H Unger
- M D Siperstein
- L L Madison
- A M Eisentraut
- N Whissen
- R.H. Unger
Unger, 1%.]-I., Siperstein, M.D., Madison, L.L., Eisentraut, A.M., Whissen, N.: Apparent growth hormone hyperresponsiveness in prediabetes. J. Lab. clin. Med. 64, 1013 (1964) (Abstract).
The relationship of the anterior
- F G Young
Young, F.G.: The relationship of the anterior
Growth hormone secretion in response to arginine infusion in normal and diabetic subjects: Relationship to blood glucose levels
- S Z Burday
- P H Fine
- D S Shalch
- S.Z. Burday