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.

Pathogenesis of NIDDM: A balanced overview

Background The relation between dietary intake of specific types of fat, particularly trans unsaturated fat, and the risk of coronary disease remains unclear. We therefore studied this relation in women enrolled in the Nurses' Health Study. Methods We prospectively studied 80,082 women who were 34 to 59 years of age and had no known coronary disease, stroke, cancer, hypercholesterolemia, or diabetes in 1980. Information on diet was obtained at base line and updated during follow-up by means of validated questionnaires. During 14 years of follow-up, we documented 939 cases of nonfatal myocardial infarction or death from coronary heart disease. Multivariate analyses included age, smoking status, total energy intake, dietary cholesterol intake, percentages of energy obtained from protein and specific types of fat, and other risk factors. Results Each increase of 5 percent of energy intake from saturated fat, as compared with equivalent energy intake from carbohydrates, was associated with a 17 percent increa...

https://www.nejm.org/doi/pdf/10.1056/NEJM199711203372102

Dietary fat intake and the risk of coronary heart disease in women

Pathogenesis of type 2 diabetes mellitus

Many studies have shown that hyperinsulinemia and/or insulin resistance are related to various metabolic and physiological disorders including hypertension, dyslipidemia, and non-insulin-dependent diabetes mellitus. This syndrome has been termed Syndrome X. An important limitation of previous studies has been that they all have been cross sectional, and thus the presence of insulin resistance could be a consequence of the underlying metabolic disorders rather than its cause. We examined the relationship of fasting insulin concentration (as an indicator of insulin resistance) to the incidence of multiple metabolic abnormalities in the 8-yr follow-up of the cohort enrolled in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease in Mexican Americans and non-Hispanic whites. In univariate analyses, fasting insulin was related to the incidence of the following conditions: hypertension, decreased high-density lipoprotein cholesterol concentration, increased triglyceride concentration, and non-insulin-dependent diabetes mellitus. Hyperinsulinemia was not related to increased low-density lipoprotein or total cholesterol concentration. In multivariate analyses, after adjustment for obesity and body fat distribution, fasting insulin continued to be significantly related to the incidence of decreased high-density lipoprotein cholesterol and increased triglyceride concentrations and to the incidence of non-insulin-dependent diabetes mellitus. Baseline insulin concentrations were higher in subjects who subsequently developed multiple metabolic disorders. These results were not attributable to differences in baseline obesity and were similar in Mexican Americans and non-Hispanic whites. These results support the existence of a metabolic syndrome and the relationship of that syndrome to multiple metabolic disorders by showing that elevations of insulin concentration precede the development of numerous metabolic disorders.

Prospective Analysis of The Insulin-Resistance Syndrome (Syndrome X)

A prospective study of dietary glycemic load, carbohydrate intake, and risk of coronary heart disease in US women

In epidemiologic studies, hyperinsulinemia has been found to be an independent risk factor for coronary heart disease (CHD). However, the mechanisms responsible for its role in atherogenesis remain unclear. We studied the relationship of in vivo insulin action and plasma lipids and lipoproteins in 44 normotriglyceridemic white men (aged 18 to 34 years). The euglycemic, hyperinsulinemic glucose clamp technique was used to quantitate insulin-mediated glucose disposal (MI value) at a plasma insulin concentration of approximately 100 μU/mL. The MI value correlated negatively with plasma triglycerides (r = −0.553, P < .0001), as well as with fasting plasma insulin levels (r = −0.483, P < .001), independent of age, body mass index, and fasting plasma glucose levels. A negative correlation of the MI value was also observed with very low density lipoprotein (VLDL)-cholesterol (r = −0.347, P < .05), VLDL-triglycerides (r = −0.474, P < 0.005), and total cholesterol/high density lipoprotein (HDL)-cholesterol ratio (r = −0.431, P < .01). The relationship between the MI value and the total cholesterol/HDL-cholesterol ratio was independent of VLDL-cholesterol and VLDL-triglycerides, however, not independent of plasma triglycerides. No relationship was observed between insulin-mediated glucose uptake and total cholesterol, low density lipoprotein (LDL)-cholesterol, and HDL-cholesterol values. Individual differences in plasma triglycerides, fasting insulin concentration, and the total cholesterol/HDL-cholesterol ratio accounted for about half the variance observed in the MI value. In conclusion, our findings in normal healthy men support the contention that hyperinsulinemia or insulin resistance may enhance the risk of CHD by adversely affecting lipoprotein levels such as VLDL-cholesterol, VLDL-triglyceride, and the ratio of total cholesterol/HDL-cholesterol.

Relationship between lipoprotein levels and in vivo insulin action in normal young white men

Chronic clamping of plasma glucose levels at ≥250 mg/dl in four partially depancreatized but previously nondiabetic dogs was followed within 2 wk by persistent hyperglycemia and glycosuria of ≤500 g/day, ketonuria, and weight loss. Three of the four dogs required daily insulin injections to control these catabolic manifestations. There was no evidence of spontaneous improvement of the severe diabetic state during the 39–69 days of observation after discontinuation of intravenous glucose infusion. Impairment of intravenous glucose tolerance, loss of the insulin response to glucose and arginine, fasting hyperglucagonemia, exaggerated glucagon responsiveness to arginine, and a significant reduction in sensitivity to insulin were characteristic of all diabetic dogs. Morphometric analysis of the endocrine pancreas revealed a profound reduction in the number and size of identifiable islets of the hyperglycemic dogs compared with islets from their own pancreases resected months earlier and with those from pancreatic remnants of eight subtotally depancreatized control dogs that had not been subjected to chronic hyperglycemic clamping. The reduction in number and size of islets of the hyperglycemic dogs was largely the consequence of depletion of insulin-containing cells and was similar to that of dogs with long-standing alloxan-induced diabetes. In the eight control dogs, clinical evidence of diabetes did not develop during a follow-up period of 193–296 days. In this group, there was no evidence of diminution of intravenous glucose tolerance, of the insulin response to glucose or arginine, or of insulin sensitivity as determined by an acute hyperinsulinemic hyperglycemic clamp. The number and size of islets and number of β-cells in pancreatic remnants from these dogs did not differ morphometrically from those of the pancreatic segment that had been resected. We conclude that in subtotally depancreatized but nondiabetic dogs, maintenance of constant hyperglycemia of ≥ 250 mg/dl by means of intravenous glucose infusion causes a severe, persistent, and often insulin-requiring diabetic state that does not occur in the absence of the hyperglycemia.

Severe Diabetes Induced in Subtotally Depancreatized Dogs by Sustained Hyperglycemia

OBJECTIVE To study effects of high carbohydrate intake on hyperglycemia, islet functions, and plasma lipoproteins in patients with NIDDM. RESEARCH DESIGN AND METHODS An attempt was made to induce hyperglycemia in 10 men with NIDDM by feeding them an isocaloric high-carbohydrate diet (65% of energy as simple carbohydrates [31% as glucose] and 20% as fat) for 28 days in a metabolic ward. Response to the high-carbohydrate diet was compared with that of feeding a diet rich in monounsaturated fat (45% of energy as fat [31% as monounsaturated fat] and 38% as carbohydrates) for 28 days in a cross-over manner. Islet functions were assessed by evaluating plasma glucose, insulin, C-peptide and glucagon responses to standard meal tolerance tests on days 0, 14, 21, and 28 of each dietary period. Fasting plasma lipoproteins were determined during the last week of each dietary period. RESULTS The high-carbohydrate diet caused significant but modest accentuation of hyperglycemia, particularly in patients with moderately severe diabetes mellitus, whereas no change was observed with the high-monounsaturated fatty-acid diet. Accentuation of hyperglycemia was accompanied by an increase in plasma glucagon levels, but no significant change in insulin and C-peptide responses. In 1 patient, feeding the high-carbohydrate diet for 68 days produced marked hyperglycemia and caused definite suppression of insulin and C-peptide responses along with an increase in glucagon levels. Compared with the high-monounsaturated fat diet, the high-carbohydrate diet also raised plasma triglyceride and VLDL cholesterol concentrations. CONCLUSIONS High-carbohydrate diets may cause accentuation of hyperglycemia and a rise in plasma glucagon levels in NIDDM patients. High-carbohydrate diets also adversely affect lipoproteins and therefore may not be desirable in all NIDDM patients.

Effect of High Carbohydrate Intake on Hyperglycemia, Islet Function, and Plasma Lipoproteins in NIDDM

Acute manipulations of insulin in vivo regulate the display of insulin receptors induced on activated T lymphocytes after presentation of alloantigen. This study explored the immunobiological consequences of regulation of insulin-receptor display by acute manipulations of insulin achieved during the hyperinsulinemic-euglycemic clamp in healthy normal individuals and obese subjects. T lymphocytes were isolated at 0, 1, and 4 h of hyperinsulinemia from seven normal volunteers and seven obese individuals and studied for their capacity to 1 ) synthesize a complement of insulin receptors on cell membrane, 2 ) respond to alloantigen in the mixed-lymphocyte culture (an immunologic activity unrelated to manipulations in insulin concentrations in complete medium), and 3 ) respond to the lymphocyte-mediated cytotoxicity reaction (an immunologic activity known to be modulated by insulin). In the face of a reduction in receptor numbers to 25% of baseline in normal individuals, alloreactivity in the mixed-lymphocyte culture was not affected (95 ± 9% of time 0 after 4 h of hyperinsulinemia), whereas lymphocyte-mediated cytotoxicity fell from 14 ± 4 at time 0 to 2 ± 2% sp Cr release ( P < 0.02). Hyperinsulinemia achieved by the clamp in seven obese subjects did not alter the synthesis of insulin receptors on cell membrane after presentation of alloantigen. In the absence of further reduction of insulin-receptor membrane display, neither the mixed-lymphocyte culture nor lymphocyte-mediated cytotoxicity reaction was affected. It is concluded that those immunologic activities of lymphocytes that can be modulated by insulin are affected by regulation of insulin-receptor display on activated lymphocytes. Therefore, receptor regulation is not effete but carries significant immunologic consequence. This study supports the hypothesis that insulin-directed immunologic activity is regulated at the site of receptor display rather than at the locus of regulation of the ligand itself.

Michael Koffler

Papers

Relationship between lipoprotein levels and in vivo insulin action in normal young white men

Severe Diabetes Induced in Subtotally Depancreatized Dogs by Sustained Hyperglycemia

Effect of High Carbohydrate Intake on Hyperglycemia, Islet Function, and Plasma Lipoproteins in NIDDM

Immunobiological Consequence of Regulation of Insulin Receptor on Alloactivated Lymphocytes in Normal and Obese Subjects

The effects of many commonly used drugs on diabetic control