Diabetes / Metabolism Reviews

Published by John Wiley and Sons
Online ISSN: 1099-0895
Publications
Article
Recent advances in the understanding of the pathogenesis of insulin-dependent diabetes mellitus (IDDM) have led to the first trials of disease prevention in susceptible individuals. Two main trials (nicotinamide and insulin) are now running but first results will not be available before the turn of the century. Pilot trials using different approaches, most of them based on the induction of immunotolerance, are also under way and should offer new insight for establishing larger multicentre studies including attempts aimed at primary prevention by removal of diabetogenic components in cow's milk. The field is moving fast and it is expected that intervention for IDDM prevention will be offered to an increasing number of individuals found at risk of developing the disease.
 
Article
Pancreatic islet cell autoantigens associated with insulin-dependent diabetes mellitus (IDDM) include a recently identified family of protein tyrosine phosphatase-like molecules, notably IA-2 and IA-2beta. IA-2 is a 979 amino acid transmembrane protein located on human chromosome 2q35, whereas IA-2beta is 986 amino acids long located on human chromosome 7q36. Comparison of human IA-2 and IA-2beta showed 74% identity within the intercellular domains, but only 27% indentify within the extracellular domains. These IA-2 molecules are expressed predominantly in cells of neuroendocrine origin, particularly pancreatic islets and brain. Radioimmunoprecipitation with recombinant IA-2 and IA-2beta has been used to measure autoantibodies to these molecules and their intracellular fragments. Autoantibodies to IA-2 are detected in the majority (60% to 80%) of newly diagnosed IDDM patients and in less than 2% of controls. The major antigenic determinants of both IA-2 and IA-2beta reside within the C-terminus of their intracellular domains. In first-degree relatives of IDDM patients, the presence of autoantibodies to IA-2 is predictive of IDDM and in combination with autoantibodies to glutamic acid decarboxylase (GAD) the positive predictive value is in the 50% range. The role of IA-2 and IA-2beta in the pathogenesis of IDDM is still unclear. Identification of these antigens has extended our ability to predict the disease and may be valuable in the search for antigen-specific therapies to prevent IDDM.
 
Article
Competition for respiration between substrates in animal tissues has been known for at least 80 years. The most important interaction, quantitatively is between glucose and fatty acids. The starting point in 1963 for the so called Glucose Fatty Acid Cycle was the realisation that the metabolic relationship between glucose and fatty acids is reciprocal and not dependent. Glucose provision promotes glucose oxidation and glucose and lipid storage, and inhibits fatty acid oxidation. Provision of free fatty acids promotes fatty acid oxidation and storage, inhibits glucose oxidation and may promote glucose storage if glycogen reserves are incomplete. This review is concerned predominantly with evidence in man in vivo. In the authors opinion the evidence for inhibitory effects of fatty acids on whole body glucose utilization ad oxidation (predominantly muscles) is decisive and enzyme mechanisms mediating these effects are well established. There is also much evidence that fatty acid oxidation inhibits glucose oxidation and stimulates glucose formation in liver and again enzyme mechanism are known. A permissive role for fatty acids in the insulin secretory response of islet beta-cells has now been firmly established and can be visualised as a mechanism to protect continuing provision of respiratory substrate. Longer term exposure of islet beta-cells to fatty acids impairs the insulin secretory response to glucose and mechanisms are known. There is compelling evidence that fatty acid oxidation may impair glucose oxidation in uncontrolled Type 1 and Type 2 diabetes, but no convincing evidence that fatty acids have a role in diminished glucose storage (glycogen deposition) in Type 2 diabetes. The inhibition of glucose storage which may follow prolonged elevation of plasma FFA in man and experimental animals is associated with glycogen repletion whereas the inhibition of glucose storage in Type 2 diabetes is associated with glycogen depletion. The precise role of fatty acids in disturbed carbohydrate metabolism in Type 2 diabetes is an area where future progress is confidently predicted.
 
Article
Diabetes is associated with changes in plasma lipids and lipoproteins into atherogenic direction. In IDDM these changes are small or absent if good metabolic control can be maintained. Diabetic nephropathy is, however, associated with the appearance of dyslipoproteinemia. In NIDDM plasma total and VLDL triglyceride levels are elevated, and HDL-cholesterol level is decreased, and this pattern of dyslipoproteinemia does not always respond to improved control of hyperglycemia. Abnormalities of lipoprotein metabolism, not reflected in conventional plasma lipid and lipoprotein level measurements, and glucosylation of lipoproteins and resulting alterations in lipoprotein catabolism may be of importance in the enhanced atherogenesis in diabetes. Both IDDM and NIDDM are associated with an increased frequency of hypertension, but the underlying mechanisms appear to be different. In IDDM hypertension is usually associated with the development of diabetic nephropathy and thus with a long duration of the disease. In NIDDM hypertension is often present already at the time of diagnosis, and also in IGT, the precursor stage of NIDDM, the prevalence of hypertension is already increased. Obesity explains only in part the high prevalence of hypertension in patients with NIDDM. Diabetes is known to be associated with multiple abnormalities in hemostatic factors and, although these abnormalities may contribute importantly to the increased risk of ASVD in diabetic patients, information about their real role is scanty and conflicting. The impact of general major risk factors for ASVD, elevated plasma cholesterol, elevated blood pressure, and smoking, on the risk of ASVD appears to be similar in diabetics and nondiabetics. Only a relatively small proportion of the excessive occurrence of ASVD in diabetics can, however, be explained by the effects of diabetes on the levels of general risk factors for ASVD. This proportion mediated through the effects of diabetes on risk factors is larger in female diabetics than in male diabetics. The major proportion of the excess of ASVD in diabetics remains, however, unexplained and must be due to effects of diabetes itself through mechanisms that are incompletely understood.
 
Article
Maturity-onset diabetes of the young (MODY) is a subtype of non-insulin-dependent diabetes characterized by an early age of onset and an autosomal dominant inheritance. Thus far, two forms of MODY have been identified. One is tightly linked to genetic markers on chromosome 20q and the other is due to various mutations of the glucokinase. gene on chromosome 7p. These two forms of MODY are compared with regard to their phenotypic expression and their differences in insulin secretory defects. Further progress in our understanding of the molecular genetic and pathophysiologic aspects of various forms of MODY may advance our understanding of the nature of more common types of non-insulin-dependent diabetes mellitus.
 
Article
Alcoholic ketoacidosis is a metabolic disorder that occurs in acute-on-chronic ethanol abusers who become acutely starved because of cessation of all caloric intake (including ethanol) owing to gastric intolerance or to an intercurrent acute illness. The precise pathogenesis, and especially the cause of the increased lipolysis, is not known, but several factors known or believed to promote ketogenesis are present in those patients. These are particularly starvation and recent ethanol ingestion. The metabolic disorder responds rapidly to rehydration and administration of glucose intravenously, which stops the ketogenesis. The prognosis in these patients depends on the presence and severity of any underlying illness and the adequacy and effectiveness of treatment for that illness. Patients rarely if ever die from either the ketoacidosis or the lactic acidosis associated with ethanol abuse, but they may succumb to other precipitating or coexisting illnesses.
 
Article
Amino acid availability rapidly regulates protein synthesis and degradation. Increasing amino acid concentrations above the levels found in post-absorptive plasma stimulates protein synthesis in a dose-dependent manner at the level of mRNA translation-initiation and inhibits protein degradation by inhibiting lysosomal autophagy. The anabolic effects of insulin on protein synthesis and protein degradation are exerted at the same sites (i.e., peptide chain initiation and lysosomal stabilization) allowing for a rapid synergistic response when both amino acids and insulin increase after a protein-containing meal. In perfused liver preparations, protein anabolic effects are exerted by a group of amino acids acting in concert. The BCAA are among the amino acids required for stimulation of hepatic protein synthesis, but there is no evidence that BCAA or leucine alone are effective. Leucine alone is an important inhibitor of hepatic protein degradation, but maximal inhibition requires in addition several other regulatory amino acids. In heart and skeletal muscle in vitro, increasing the concentration of the three BCAA or of leucine alone reproduces the effects of increasing the supply of all amino acids in stimulating protein synthesis and inhibiting protein degradation. Skeletal muscle is the largest repository of metabolically active protein and a major contributor to total body nitrogen balance. Supplying energy alone (i.e., carbohydrate and lipids) cannot prevent negative nitrogen balance (net protein catabolism) in animals or humans; only provision of amino acids allows the attainment of nitrogen balance. In rats and in humans nourished parenterally, provision of balanced amino acid solutions or of only the three BCAA cause similar improvements in nitrogen balance for several days. There is some evidence that infusions of leucine alone can stimulate muscle protein synthesis in vivo; the effect may be transitory and was not observed by all investigators; provisions of excess leucine alone does not seem to affect total body or muscle protein degradation in vivo. In postabsorptive rats, in vivo, infusion of the three BCAA together stimulates muscle protein synthesis as much as the infusion of a complete amino acid mixture or of a mixture of essential amino acids; the in vivo effect requires coinfusion of glucose or of small (physiological) doses of insulin, suggesting synergism between insulin and amino acids.(ABSTRACT TRUNCATED AT 400 WORDS)
 
Article
Ketone body concentrations fluctuate markedly during physiological and pathological conditions. Tracer techniques have been developed in recent years to study production, utilization, and the metabolic clearance rate of ketone bodies. This review describes data on the roles of insulin, catecholamines, and thyroid hormones in the regulation of ketone body kinetics. The data indicate that insulin lowers ketone body concentrations by three independent mechanisms: first, it inhibits lipolysis, and thus lowers free fatty acid availability for ketogenesis; second, it restrains ketone body production within the liver; third, it enhances peripheral ketone body utilization. To assess these effects in humans in vivo, experimental models were developed to study insulin effects with controlled concentrations of free fatty acids, insulin, glucagon, and ketone bodies. Presently available data also support an important role of catecholamines in increasing ketone body concentrations. Evidence was presented that norepinephrine increases ketogenesis not only by stimulating lipolysis, and thus releasing free fatty acids, but also by increasing intrahepatic ketogenesis. Thyroid hormone availability was associated with lipolysis and ketogenesis. Ketone body concentrations after an overnight fast were only modestly elevated in hyperthyroidism resulting from increased peripheral ketone body clearance. There was a significant correlation between serum triiodothyronine levels and the ketone body metabolic clearance rate. Thus, ketone body homeostasis in human subjects resulted from the interaction of hormones such as insulin, catecholamines, and thyroid hormones regulating lipolysis, intrahepatic ketogenesis, and peripheral ketone body utilization.
 
Article
Obesity is associated with in vitro insulin resistance in adipocytes; this sensitivity defect is not explained by insulin binding; it might be explained by a defect in the insulin receptor. The capacity of glucose transport changes marginally in obesity. In addition, lipolysis changes in obesity, but is dependent upon changes in adipocyte cell size. In NIDDM the capacity for glucose transport and lipolysis are affected by the degree of hyperglycemia associated with changes in metabolic control and these changes are reversible. The sensitivity of antilipolysis and insulin binding is unaffected by NIDDM while the sensitivity of the glucose transport system is altered in NIDDM. This altered sensitivity of glucose transport presumably occurs at a step in coupling beyond the point where transport and lipolysis diverge, actually precedes diabetes, is not improved with treatment of the hyperglycemia associated with NIDDM, and may be inherent. The conclusions from the adipocyte mechanism studies in the Pima Indians reported in this review are in almost all cases the same as those derived from studies in Caucasian subjects; and any differences that do exist can be explained by differences in study design. Thus, the Pima Indians have been shown to be a suitable model for the study of the mechanisms of impaired insulin action in isolated adipocytes from obese and diabetic subjects. A longitudinal study of NIDDM is ongoing in the Pima Indians. Such a study cannot be undertaken in the general population; thus, it is important to document the similarities in mechanisms where the Pima Indians can be compared to the Caucasian population. The logical extension of the studies presented here will be the results of the Pima longitudinal study.
 
Article
In this article we have described the hypothesis that insulin stimulates glucose transport through glucose transporter translocation from an intracellular pool to the plasma membrane. In addition, we have shown that changes in the numbers and subcellular distributions of glucose transporters correlate with alterations in insulin-stimulated glucose transport activity in several experimental models of insulin resistance and hyperresponsiveness. However, in experiments with counterregulatory hormones and with hyperresponsive states induced by nutritional repletion following deprivation, changes in insulin responsiveness cannot be fully explained by such alterations in the numbers and/or subcellular distribution of glucose transporters. Thus, evidence has been presented for changes in glucose transporter intrinsic activity that both inhibit and augment insulin-stimulated glucose transport rates. Finally, we have discussed data suggesting that the translocation process is applicable to human tissue and that significant changes in adipose cell glucose transport activity have been correlated with total glucose disposal in various metabolic states in humans. Determining the physiologic factors involved in modulating these events at the cellular level is an important area for further investigation.
 
Article
Benfluorex is a hypolipidaemic agent with biguanide-like properties. To evaluate its blood glucose lowering action, a single-blind study protocol was designed. Two groups of seven type II (non-insulin-dependent) diabetic patients matched for age (50 +/- 4 vs. 53 +/- 1 years), sex, body mass index (27.8 +/- 0.6 vs. 26.5 +/- 0.7 kg/m2), and duration of diabetes were studied before and after 1 month of treatment with benfluorex 150 mg tid (= tres in die = three times a day), PO (= per os = by mouth) or a placebo, respectively. All patients had previously been treated by diet alone. In all patients, parameters of glucose and lipid metabolism were obtained. Insulin sensitivity was assessed by means of a euglycaemic (5.1 +/- 0.1 mM) hyperinsulinaemic (516 +/- 28 pM) clamp performed in combination with [3(-3)H]glucose infusion and indirect calorimetry. In no case was there a significant change in body mass index (27.6 +/- 0.5 vs. 26.4 +/- 0.7 kg/m2). After 1 month of treatment, fasting plasma glucose (6.8 +/- 0.2 vs. 8.1 +/- 0.6 mM) and HbA1C (glycated haemoglobin; 6.5 +/- 0.2 vs. 8.0 +/- 0.7%) were lower in the benfluorex group than in the placebo-treated patients (both p < 0.05). No change was observed in hepatic glucose production (HGP) (13.5 +/- 1.4 vs. 13.9 +/- 1.1 mumol/min per kg), the basal rate of glucose, and lipid oxidation and non-oxidative glucose metabolism, or in plasma triglyceride and total cholesterol concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Article
We have examined the effect of chronic (20 days) oral administration of benfluorex (35 mg/kg) in a rat model of non-insulin-dependent diabetes mellitus (NIDDM), as induced by injection of streptozotocin 5 days after birth and characterized by frank hyperglycaemia, hypoinsulinaemia, and hepatic and peripheral insulin resistance. In the benfluorex-treated diabetic rats, basal plasma glucose levels were decreased (7.9 +/- 0.2 mM as compared with 17.2 +/- 1.1 mM in the pair-fed untreated diabetic and 6.7 +/- 0.2 mM in the benfluorex-treated non-diabetic rats) while the basal and the glucose-stimulated (IVGTT) plasma insulin levels were not improved. The lack of improvement of glucose-induced insulin release after benfluorex treatment was confirmed under in vitro conditions (perfused pancreas). In the benfluorex-treated diabetic rats, basal glucose production and overall glucose utilization were normalized. Following hyperinsulinaemia (euglycaemic clamp), glucose production was normally suppressed while overall glucose utilization was not significantly improved. Since benfluorex exerts a predominant action on the liver in the present rat model of diabetes, and since increased basal hepatic glucose output is a major metabolic abnormality and is responsible for much of the elevated fasting blood glucose levels in NIDDM, the use of such a compound in NIDDM may be potentially relevant.
 
Article
Gestational diabetes mellitus (GDM) is associated with increased risk of poor outcomes for the pregnancy. It is a strong risk factor for subsequent diabetes. The epidemiology of GDM in African-American women is not well known. It has not been demonstrated that their risk factors are similar in character and weight to those among White women. There is considerable multicollinearity among GDM risk factors such as age, parity, obesity, hypertension, and family history of diabetes, and this needs to be sorted out.
 
Top-cited authors
Matti I J Uusitupa
  • University of Eastern Finland
Markku Laakso
  • University of Eastern Finland
Jaakko Tuomilehto
  • Danube University Krems
Soroku Yagihashi
  • Hirosaki University
Walter J Pories
  • East Carolina University