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Query: UMLS:C0011860 (type 2 diabetes)
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In one third of patients who suffered an infarction NIDDM and arterial hypertension are present. In the absolute majority of patients with IHD, as apparent from the IRI and C-peptide response after a glucose load, hyperinsulinism is present. The blood sugar response can have the character of diabetes or of impaired glucose tolerance, the curve may be very flat or normal while the IRI and C-peptide response are excessive. Hyperinsulinism has a hypersecretory origin as suggested by the concurrently elevated C-peptide level but also reduced insulin utilization in the liver and peripheral target organs. Hyperinsulinism is thus a regular associated phenomenon of IHD and is a special risk factor independent on hyperglycaemia and associates with the other main risk factors of IHD such as arterial hypertension, HPLP (android obesity), hyperglycaemia (NIDDM) and hirsutism as a manifestation of a hyperandrogenic state in the female organism with the syndrome of polycystic ovaries. Hyperinsulinism plays an indirect role in the pathogenesis of coronary syndrome via the main risk factors (5H syndrome--hyperinsulinism, hypertension, HPLP, hyperglycaemia, hirsutism) and also directly by its action on endothelial paracrine mechanism of the coronary circulation where in the early stage vasoconstrictor factors predominate (endothelin-1, PGF2-alpha) over physiological vasodilatating factors (EDRF-NO, PGE2, PGI2) and this leads then to functional spasms. It seems that also the coronary X syndrome develops very frequently on the background of the hormonal metabolic X syndrome or the 5H syndrome.
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PMID:[Hyperinsulinism and the coronary syndrome]. 149 68

This article is divided into two parts. A retrospective overview summarizes some of the work that provided the framework and tools of the more recent studies. The five novel areas of research are related to the indirect effects of insulin. Regulation of plasma glucose is of central importance in health and diabetes. Understanding this precise regulation requires sensitive isotope dilution methods that can measure the rates at which glucose is produced by the liver and used by the tissues on a minute-to-minute basis. Validation studies indicated that the non-steady-state tracer method yields reasonable results when the specific activity of plasma glucose does not change abruptly. During hyperinsulinemic glucose clamps, the decrease in specific activity of glucose can be prevented by the MSTI. During exercise, the decrease of specific activity can be only in part ameliorated by step-tracer infusion. Depancreatized dogs are used extensively as a model of selective insulin deficiency, because dog stomach secretes physiological amounts of glucagon. This strategy can avoid injections of somatostatin, which can have other affects in addition to the suppression of insulin and glucagon. In human diabetes, in addition to an increase of glucose production, there is also an increase in glucose cycling in the liver. In animal models of diabetes, mild NIDDM, and in glucose intolerance, the percentage of increments of glucose cycling are much larger than those of glucose production. We hypothesize, therefore, that measurements of glucose cycling can be used as an early marker of glucose intolerance. Application of different tracer strategies and use of the depancreatized dog as a model of diabetes, we investigated the importance of the indirect effects of insulin in the pathogenesis of diabetes. 1) Because, in the treatment of IDDM, insulin is administered by the peripheral routes we compared the relative importance of hepatic and peripheral effects of insulin in regulating the rate of glucose production. Experiments were performed in depancreatized dogs that were initially maintained at moderate hyperglycemia (10 mM) with subbasal portal insulin infusion. During the experimental period, insulin was infused either peripherally or portally at 0.9 mU.kg-1.min-1. In addition, peripheral infusions were also given at 0.45 mU.kg-1.min-1. We concluded that when suprabasal insulin levels are provided to moderately hyperglycemic depancreatized dogs, the suppression of glucose production is more dependent on peripheral than portal insulin concentrations. This indirect effect of insulin may be mediated by limitation of the flow of precursors and energy substrates for gluconeogenesis and/or by suppressive effect of insulin on glucagon secretion.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Banting Lecture: glucose turnover. A key to understanding the pathogenesis of diabetes (indirect effects of insulin). 149 70

Insulin resistance (prereceptor, receptor, postreceptor) is a complex phenomenon. It penetrates into the clinical picture via hyperinsulinism as impaired glucose tolerance, or NIDDM, as hyperlipoproteinaemia, arterial hypertension and hirsutism in women (syndrome 5H) associated with the polycystic ovary syndrome or the HAIR-AN syndrome. Based on a group of their 480 patients with NIDDM, 108 women with hirsutism, 320 patients with myocardial infarction and the results of the national cardiovascular programme the authors estimate the prevalence of the 5H syndrome as follows: in the general population 5-10%, in patients with arterial hypertension 15-30%, in NDDM 65-90%, in hirsutic women 10-20% and in patients with myocardial infarction 30-50%. These figures could be, however, substantially higher if as the criterion the IRI response was taken or that of C-peptide in OGTT or the results of the hyperinsulinaemic euglycaemic clamp. The clinical 5H syndrome is a phenomenon of latent insulin resistance perceived late by doctors and patients.
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PMID:[Clinical manifestations of insulin resistance. The hormonal-metabolic syndrome X (5H), its prevalence and impact on cardiovascular morbidity and mortality. I]. 150 12

Non-insulin-dependent diabetes mellitus (NIDDM) results from an imbalance between insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional studies have demonstrated that the earliest detectable abnormality in NIDDM is an impairment in the body's ability to respond to insulin. Because the pancreas is able to appropriately augment its secretion of insulin to offset the insulin resistance, glucose tolerance remains normal. With time, however, the beta-cell fails to maintain its high rate of insulin secretion and the relative insulinopenia (i.e., relative to the degree of insulin resistance) leads to the development of impaired glucose tolerance and eventually overt diabetes mellitus. The cause of pancreatic "exhaustion" remains unknown but may be related to the effect of glucose toxicity in a genetically predisposed beta-cell. Information concerning the loss of first-phase insulin secretion, altered pulsatility of insulin release, and enhanced proinsulin-insulin secretory ratio is discussed as it pertains to altered beta-cell function in NIDDM. Insulin resistance in NIDDM involves both hepatic and peripheral, muscle, tissues. In the postabsorptive state hepatic glucose output is normal or increased, despite the presence of fasting hyperinsulinemia, whereas the efficiency of tissue glucose uptake is reduced. In response to both endogenously secreted or exogenously administered insulin, hepatic glucose production fails to suppress normally and muscle glucose uptake is diminished. The accelerated rate of hepatic glucose output is due entirely to augmented gluconeogenesis. In muscle many cellular defects in insulin action have been described including impaired insulin-receptor tyrosine kinase activity, diminished glucose transport, and reduced glycogen synthase and pyruvate dehydrogenase. The abnormalities account for disturbances in the two major intracellular pathways of glucose disposal, glycogen synthesis, and glucose oxidation. In the earliest stages of NIDDM, the major defect involves the inability of insulin to promote glucose uptake and storage as glycogen. Other potential mechanisms that have been put forward to explain the insulin resistance, include increased lipid oxidation, altered skeletal muscle capillary density/fiber type/blood flow, impaired insulin transport across the vascular endothelium, increased amylin, calcitonin gene-related peptide levels, and glucose toxicity.
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PMID:Pathogenesis of NIDDM. A balanced overview. 153 77

Acanthosis nigricans is a skin lesion characterized by thickening and apparent darkening of the keratin layer of the skin, usually on the neck and axillae. Recent studies reveal that this disorder is directly associated with hyperinsulinemia. A major implication of hyperinsulinemia is insulin resistance--a primary factor in the development of type II diabetes mellitus. Prolonged hypersecretion of insulin presumably leads to pancreatic exhaustion and subsequent glucose intolerance that can progress to type II diabetes. Prospective studies of individuals with acanthosis nigricans have shown very high prevalence rates of type II diabetes. Prevalence studies among adolescents have shown that the lesion appears early in life and is a common finding in some ethnic groups. These data suggest that acanthosis nigricans is an easily detected empirical marker for elevated risk of type II diabetes. The lesion can appear long before the onset of glucose intolerance. Thus, including acanthosis nigricans screening in a comprehensive disease-prevention program can help identify people at risk for type II diabetes prior to the actual onset of glucose intolerance, as well as individuals with undiagnosed diabetes. Interventions that reduce insulin resistance include weight loss and regular physical activity.
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PMID:Assessment of patients with acanthosis nigricans skin lesion for hyperinsulinemia, insulin resistance and diabetes risk. 154 62

Non-insulin-dependent diabetes mellitus (NIDDM) is a major health problem, affecting 5% of the world population. Genetic factors are important in NIDDM, but the mechanisms leading to glucose intolerance are unknown. Genetic linkage has been investigated in multigeneration families to localize, and ultimately identify, the gene(s) predisposing to NIDDM. Here we report linkage between the glucokinase locus on chromosome 7p and diabetes in 16 French families with maturity-onset diabetes of the young, a form of NIDDM characterized by monogenic autosomal dominant transmission and early age of onset. Statistical evidence of genetic heterogeneity was significant, with an estimated 45-95% of the 16 families showing linkage to glucokinase. Because glucokinase is a key enzyme of blood glucose homeostasis, these results are evidence that a gene involved in glucose metabolism could be implicated in the pathogenesis of NIDDM.
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PMID:Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. 154 70

Many of the prevalence studies of diabetes in Asian populations are reviewed. When compared to Whites, Asians have an even greater predominance of non-insulin-dependent (NIDDM) over insulin-dependent diabetes (IDDM). Diabetes prevalence is higher among migrant Asians than in their homelands, and is often higher than in the majority population of their new homes. It is hypothesized that when a vulnerable population experiences environmental influences accompanying 'westernization', insulin resistance and eventually glucose intolerance develop. Asians are postulated to be a vulnerable ethnic group. Since many portions of Asia are also becoming westernized, it is postulated that insulin resistance and glucose intolerance will become more common in Asia. If this prediction is correct, then NIDDM will be a major health problem in Asia in the near future.
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PMID:The growing prevalence of non-insulin-dependent diabetes in migrant Asian populations and its implications for Asia. 156 34

In a cross-sectional study, we evaluated the metabolic profiles of lean (Fa/?) and obese (fa/fa) Zucker male rats at 4 to 8 months of age. Although all of the obese rats (N = 108) demonstrated glucose intolerance, most of the obese rats exhibited only mild elevations of fasted and fed plasma glucose. Only 14 of the obese rats were severely hyperglycemic, which resulted in substantial elevations of glycohemoglobin (GHb) levels. The nerve and lens levels of glucose, sorbitol, and fructose were elevated, and the myo-inositol was depleted in all hyperglycemic obese rats, but not in the euglycemic obese rats. With increasing duration of hyperglycemia, the neural myo-inositol level approached normal, while the lenses became cataractous. All obese rats had increased urinary albumin excretion (UAE), which was dependent on age (r = .45, P less than .02) and independent of hyperglycemia, glucosuria, and polyuria. In conclusion, although the euglycemic obese rats exhibited some diabetic abnormalities, the hyperglycemic obese Zucker rat more closely resembled the altered metabolic profile associated with type II diabetes mellitus.
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PMID:Metabolic abnormalities of the hyperglycemic obese Zucker rat. 158 32

Coronary heart disease risk factor levels were studied in 184 first-degree relatives (sisters and brothers) of non-insulin-dependent diabetic subjects (124 relatives with normoglycemia, 34 relatives with impaired glucose tolerance [IGT], and 26 relatives with non-insulin-dependent diabetes mellitus [NIDDM]) and in 215 relatives of nondiabetic subjects (194 relatives with normoglycemia and 21 relatives with IGT). Subjects with IGT exhibited the highest insulin responses to an oral glucose load. Systolic blood pressure was significantly higher; serum high density lipoprotein cholesterol level was significantly lower; and total, low density lipoprotein, and very low density lipoprotein triglyceride levels were higher in the relatives with a family history of diabetes who had IGT or NIDDM than in the normoglycemic relatives without a family history of diabetes. These abnormal changes were not seen in normoglycemic relatives or relatives with IGT who had no family history of NIDDM. Thus, in relatives of diabetics, abnormal glucose tolerance seems to induce changes in cardiovascular heart disease risk factor levels that are similar to those observed in NIDDM. Therefore, a family history of diabetes adds substantially to the risk for atherosclerosis, particularly in subjects with IGT.
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PMID:Early abnormalities in coronary heart disease risk factors in relatives of subjects with non-insulin-dependent diabetes. 159 Dec 29

Recent research has demonstrated that reduced insulin-stimulated glucose metabolism in skeletal muscle (insulin resistance) and hyperinsulinism are common features in widespread diseases such as essential hypertension, android obesity, non-insulin dependent diabetes mellitus, dyslipidemia (in the form of raised serum triglyceride and reduced serum high-density lipoprotein (HDL) cholesterol) and arteriosclerosis. Simultaneously, investigations in a comprehensive group of healthy middle-aged men have revealed insulin resistance in one fourth. On the basis of these observations, a working hypothesis is suggested which postulates that genetic abnormalities in one or more of the candidate genes in the modes of action of insulin occur in a great proportion of the population. These may result in insulin resistance (primary genetic insulin resistance). Primary insulin resistance may be potentiated by a series of circumstances such as ageing, high-fat diet, lack of physical activity, hormonal and metabolic abnormalities or drugs (secondary insulin resistance). As a consequence of the reduced effect of insulin on muscle tissue, compensatory hyperinsulinism develops. Depending on the remaining vulnerability of the individual the hyperinsulinism is presumed to result in development of one or more phenotypes. For example if the beta-cells of the pancreas are unable to secrete sufficient insulin to compensate the insulin resistance on account of genetic defects, glucose intolerance will develop. In a similar manner, hyperinsulinism in insulin-resistant individuals who are predisposed to essential hypertension is presumed to reveal genetic defects in the blood pressure regulating mechanisms and thus contribute to development of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Insulin resistance--a physiopathological condition with numerous sequelae: non-insulin-dependent diabetes mellitus (NIDDM), android obesity, essential hypertension, dyslipidemia and atherosclerosis]. 163 67


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