The genetics of human noninsulin-dependent (type 2) diabetes mellitus

Familial aggregation and concordance in monozygotic and dizygotic twins argue strongly for a genetic etiology to noninsulin-dependent diabetes (NIDDM). Nonetheless, studies of pathways implicated by the known physiology have failed to identify gene defects that can explain the genetic susceptibility. In contrast, studies of early onset dominant diabetes have revealed three major loci resulting in diminished insulin secretion. Recently, studies have taken a new approach to map the genes causing typical NIDDM using large numbers of families or sibling pairs. The first reports of these studies have suggested possible loci on chromosomes 1, 2 and 12, but no report has been confirmed. Other studies have examined the quantitative defects that may be precursors of clinical NIDDM such as hyperinsulinemia, hyperglycemia, insulin response to glucose and obesity. These studies have suggested additional loci that may contribute to NIDDM susceptibility, but the genes responsible for most of these loci remain unknown. Studies of NIDDM susceptibility and the role of obesity genes in that susceptibility have entered an exciting new phase, but the challenges of complex disease genetics in humans will have to be conquered to translate this research into preventive or therapeutic benefits.     

Diet, lifestyle, and colorectal cancer: is hyperinsulinemia the missing link?

Several dietary and other lifestyle factors have been implicated in the development of colorectal cancer. However, the precise nature and actual magnitude of the relationship between individual nutrient intakes and other lifestyle factors and colorectal cancer risk are not clear. A unifying hypothesis has recently been proposed that explains why obesity, physical inactivity, alcohol, and consumption of a typical Western diet increase colorectal cancer risk. This hypothesis suggests that these dietary and other lifestyle factors are associated with insulin resistance and hyperinsulinemia and that hyperinsulinemia, in turn, may stimulate growth of colorectal tumors. Two recently published large prospective epidemiologic studies indicate a significant increase in colorectal cancer risk in subjects with diabetes mellitus, thereby supporting this hypothesis.     

Coronary artery disease

Those who have IGT (impaired glucose tolerance) are thought to be highly risky to atherosclerotic coronary artery disease (CAD), probably because of the frequent association with insulin resistance or hyperinsulinemia, obesity or abdominal fat accumulation, hypertriglyceridemia and so on. Whether insulin resistance which is one of the major causes of IGT, following hyperglycemia itself or both is really responsible for CAD is remained to be clarified. Furthermore, IGT is also an apparent candidate for NIDDM in future. Thus, IGT should be intensively treated to prevent or delay the onset of NIDDM and also to minimize the adverse events by atherosclerotic CAD.     

Role of the beta 3-adrenergic receptor locus in obesity and noninsulin-dependent diabetes among members of Caucasian families with a diabetic sibling pair

Obesity and insulin resistance are important risk factors for the development of noninsulin-dependent diabetes (NIDDM) and are prevalent among predisposed first degree relatives of diabetic individuals. Recent molecular screening and analysis of a common missense mutation of the beta 3-adrenergic receptor gene suggested this locus as a strong candidate for increased obesity, earlier age of diabetes onset, and insulin resistance. To test the hypothesis that the beta 3-adrenergic receptor locus affects diabetes susceptibility, obesity as measured by body mass index, and components of the insulin resistance syndrome, we examined the role of this region in families ascertained for two or more NIDDM siblings. Linkage analysis was conducted using both parametric and nonparametric analyses, including multipoint sibling pair analysis. We found no evidence for linkage to NIDDM as a dichotomous trait and no evidence for linkage to body mass index, waist/hip ratio, insulin levels, or glucose levels as quantitative traits or to reported age of onset among NIDDM individuals. The Trp64 Arg missense mutation was present in 11% of the population. The mutation was not associated with NIDDM, and Arg64 carriers did not have earlier NIDDM onset, higher body mass index, or higher waist/hip ratio than Trp64 homozygotes. Among relatives, Arg64 carriers had significantly lower fasting glucose levels and lower waist/hip ratios than Trp64 homozygotes, but no characteristics of the insulin resistance syndrome. We conclude that the beta 3-adrenergic receptor locus does not play an important role in NIDDM susceptibility or in the insulin resistance syndrome among members of families with a strong predisposition to NIDDM.     

Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus

Seven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with [3-3H]- and [U-14C]glucose and indirect calorimetry: study I, euglycemic (5.2 +/- 0.1 mM) insulin (269 +/- 39 pM) clamp; study II, hyperglycemic (14.9 +/- 1.2 mM) insulin (259 +/- 19 pM) clamp; study III, euglycemic (5.5 +/- 0.3 mM) hyperinsulinemic (1650 +/- 529 pM) clamp. Seven control subjects received a euglycemic (5.1 +/- 0.2 mM) insulin (258 +/- 24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H2O and 14CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7 +/- 2.1 and 40.7 +/- 1.7 mumol/min.kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d) hyperglycemia cannot overcome the defects in glucose oxidation and nonoxidative glycolysis; (e) lipid oxidation is elevated and is suppressed only with hyperinsulinemia.     

Laminin-like proteins are differentially regulated during cerebellar development and stimulate granule cell neurite outgrowth in vitro

OBJECTIVE: To review data supporting the hypothesis that syndrome X plays a major role in the pathogenesis of coronary artery disease (CAD), and the effects of lifestyle factors and pharmacologic interventions on insulin, other metabolic parameters, and outcomes. DATA SOURCES: MEDLINE (January 1966-August 1997) and Current Contents database searches identified applicable English-language experimental trials, epidemiologic studies, reviews, and editorials. STUDY SELECTION AND DATA EXTRACTION: Studies that were included addressed the role of insulin resistance and hyperinsulinemia in the pathogenesis of CAD or the effects of lifestyle factors and pharmacologic interventions on metabolic parameters and outcomes. DATA SYNTHESIS: The main characteristics of syndrome X are hyperinsulinemia and insulin resistance. These result in secondary syndrome X features, including hyperglycemia, increased very-low-density lipoprotein concentrations, decreased high-density lipoprotein cholesterol, and hypertension. Insulin resistance is worsened by obesity, and insulin has been shown to contribute to the development of hypertension. Other studies demonstrate that smoking adversely affects glucose and insulin concentrations. Animal studies have linked hyperinsulinemia and atherogenesis. These animal data have been confirmed by several large prospective and population studies that have identified associations between hyperinsulinemia and CAD. CONCLUSIONS: Strong evidence links insulin resistance and hyperinsulinemia to CAD. Lifestyle modifications play an important role in decreasing cardiovascular risk, and clinicians should strongly encourage such changes. Clinicians must also carefully consider the effects of antihypertensive, antihyperglycemic, and antidyslipidemic agents on patients' metabolic profiles when choosing appropriate therapeutic regimens. However, outcome data on many potentially beneficial agents, including calcium antagonists, alpha 1-adrenergic antagonists, angiotensin-converting enzyme inhibitors, metformin, acarbose, and troglitazone, are not yet available.     

Interaction between BTBR and C57BL/6J genomes produces an insulin resistance syndrome in (BTBR x C57BL/6J) F1 mice

Insulin resistance is a common syndrome that often precedes the development of noninsulin-dependent diabetes mellitus (NIDDM). Both diet and genetic factors are associated with insulin resistance. BTBR and C57BL/6J (B6) mice have normal insulin responsiveness and normal fasting plasma insulin levels. However, a cross between these two strains yielded male offspring with severe insulin resistance. Surprisingly, on a basal diet (6.5% fat), the insulin resistance was not associated with fasting hyperinsulinemia. However, a 15% fat diet produced significant hyperinsulinemia in the male mice (twofold at 10 weeks; P < .05). At 10 weeks of age, visceral fat contributed approximately 4.3% of the total body weight in the males versus 1.8% in females. In the males, levels of plasma triacylglycerol and total cholesterol increased 40% and 30%, respectively, compared to females. Plasma free fatty acid concentrations were unchanged. Oral glucose tolerance tests revealed significant levels of hyperglycemia and hyperinsulinemia 15 to 90 minutes after oral glucose administration in the male mice. This was particularly dramatic in males on a 15% fat diet. Glucose transport was examined in skeletal muscles in (BTBR x B6)F1 mice. In the nonhyperinsulinemic animals (females), insulin stimulated 2-deoxyglucose transport 3.5-fold in the soleus and 2.8-fold in the extensor digitorum longus muscles. By contrast, glucose transport was not stimulated in the hyperinsulinemic male mice. Hypoxia stimulates glucose transport through an insulin-independent mechanism. This is known to involve the translocation of GLUT4 from an intracellular pool to the plasma membrane. In the insulin-resistant male mice, hypoxia induced glucose transport as effectively as it did in the insulin-responsive mice. Thus, defective glucose transport in the (BTBR x B6)F1 mice is specific for insulin-stimulated glucose transport. This is similar to what has been observed in muscles taken from obese NIDDM patients. These animals represent an excellent genetic model for studying insulin resistance and investigating the transition from insulin resistance in the absence of hyperinsulinemia to insulin resistance with hyperinsulinemia.     

Predictors of renal and cardiovascular mortality in patients with non-insulin-dependent diabetes: a brief overview of microalbuminuria and insulin resistance

Both microalbuminuria and insulin resistance are present at some stage in the natural history of non-insulin-dependent diabetes mellitus (NIDDM). Microalbuminuria predicts both progression to endstage renal disease and an increase in cardiovascular mortality compared to diabetic patients without microalbuminuria. Conversely, microalbuminuria is not a strong predictor of either renal or cardiovascular mortality in hypertensive nondiabetic subjects. This difference in risk may relate to the presence of glycated albumin in patients with diabetes. Glycation of albumin occurs because of persistent hyperglycemia. Glycated albumin is directly toxic to both renal and vascular tissue through stimulation of reactive oxygen species by both renal and immune protective cells. Blunting the rise in microalbuminuria with either aggressive blood glucose control or angiotensin-converting enzyme (ACE) inhibition, early in the course of the disease, markedly reduces renal mortality. In contrast to microalbuminuria, which is a reflection of renal injury, insulin resistance is a genetically determined problem that directly relates to peripheral glucose utilization. In most cases, insulin resistance is phenotypically expressed as diabetes as a result of environmental factors such as obesity. Insulin resistance is associated with an increased risk for development of both hypertension and NIDDM as well as atherosclerosis. Diabetic or hypertensive subjects with insulin resistance have an increased risk of cardiovascular but not renal mortality. Sustained weight loss is the best way to reduce insulin resistance and arterial pressure. Additionally, alpha blockers, more than other antihypertensive agents reduce insulin resistance. This class of drugs, however, has not been shown to reduce either microalbuminuria or overall cardio-renal mortality.     

Hyperinsulinemia and the risk of stroke in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study

BACKGROUND AND PURPOSE: Several studies have shown that hyperinsulinemia is associated with the risk of coronary heart disease, but information on the association of hyperinsulinemia with the risk of stroke is limited. We investigated the association of hyperinsulinemia with the risk of stroke during a 22-year follow-up of the Helsinki Policemen Study population. METHODS: The study was based on a cohort of 970 men aged 34 to 64 years who were free of cerebrovascular disease, other cardiovascular disease, or diabetes. Risk factor measurements at baseline examination included an oral glucose tolerance test with blood glucose and plasma insulin measurements at 0, 1, and 2 hours. Area under the insulin response curve during oral glucose tolerance test was used as a composite variable reflecting plasma insulin levels. RESULTS: During the 22-year follow-up, 70 men had a fatal or nonfatal stroke. Hyperinsulinemia (highest area under the insulin response curve quintile compared with the combined 4 lower quintiles) was associated with the risk of stroke (age-adjusted hazard ratio, 2.12; 95% CI, 1.28 to 3.49), but not independently of other risk factors (multiple-adjusted hazard ratio, 1.54; 95% CI, 0.90 to 2.62), which was mainly due to the impact of obesity, particularly upper body obesity, with subscapular skinfold thickness used as an index. Of other risk factors, upper body obesity, blood pressure, and smoking were independent predictors of the risk of stroke. CONCLUSIONS: Hyperinsulinemia was associated with the risk of stroke in Helsinki policemen during the 22-year follow-up, but not independently of other risk factors, particularly upper body obesity.     

Risk factors for the development of NIDDM in Yonchon County, Korea

OBJECTIVE: To determine the risk factors for the development of NIDDM in Yonchon County of Korea. RESEARCH DESIGN AND METHODS: We studied 1,193 Korean nondiabetic subjects at baseline who participated in a 2-year follow-up study on diabetes in Yonchon County. A 75-g oral glucose tolerance test was performed 2 years after the baseline examination. Age, sex, and anthropometric and metabolic characteristics at baseline were analyzed simultaneously as potential predictors of conversion to NIDDM. We also designed a nested case-control study to determine the role of hyperinsulinemia and/or hyperproinsulinemia in the conversion to NIDDM in patients with newly developed diabetes and control subjects matched for age, sex, BMI, and waist-to-hip-ratio. RESULTS: At 2 years, 67 subjects developed diabetes, as defined by World Health Organization criteria. The age-adjusted incidence was significantly higher in men (6.4%) than in women (3.0%), and the incidence increased as age increased in both sexes. Multiple logistic regression analysis revealed age, male sex, and fasting and 2-h glucose levels to be significant risk factors for the development of NIDDM, whereas waist-to-hip ratio and BMI were not. In a nested case-control study, baseline proinsulin but not insulin levels were significantly higher in subjects who progressed to NIDDM than in those who did not. CONCLUSIONS: In the Korean population, beta-cell dysfunction, as measured by high proinsulin levels, seems to be associated with subsequent development of NIDDM, whereas regional and general obesity and fasting insulin levels, which may be a surrogate for insulin resistance, were not.     

Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects

A definitive assessment of the relative roles of insulin resistance and insulin deficiency in the etiology of NIDDM is hampered by several problems. 1) Due to better methodology, data on insulin resistance are generally more accurate and consistent than data on insulin deficiency. 2) In source data, case-control studies are prone to selection bias, while epidemiological associations, whether cross-sectional or longitudinal, are liable to misinterpretation. 3) Insulin secretion and action are physiologically interconnected at multiple levels, so that an initial defect in either is likely to lead with time to a deficit in the companion function. The fact that both insulin resistance and impaired insulin release have been found to precede and predict NIDDM in prospective studies may be in part a reflection of just such relatedness. 4) Direct genetic analysis is effective in rarer forms of glucose intolerance (MODY, mitochondrial mutations, etc.) but encounters serious difficulties with typical late-onset NIDDM. Despite these uncertainties, the weight of current evidence supports the view that insulin resistance is very important in the etiology of typical NIDDM for the following reasons: 1) it is found in the majority of patients with the manifest disease; 2) it is only partially reversible by any form of treatment (117); 3) it can be traced back through earlier stages of IGT and high-risk conditions; and 4) it predicts subsequent development of the disease with remarkable consistency in both prediabetic and normoglycemic states. Of conceptual importance is also the fact that the key cellular mechanisms of skeletal muscle insulin resistance (defective stimulation of glucose transport, phosphorylation, and storage into glycogen) have been confirmed in NIDDM subjects by a variety of in vivo techniques [ranging from catheter balance (118) to multiple tracer kinetics (119) to 13C nuclear magnetic resonance spectroscopy (120)], and have been detected also in normoglycemic NIDDM offspring (121). If insulin resistance is a characteristic finding in many cases of NIDDM, insulin-sensitive NIDDM does exist. On the other hand, given the tight homeostatic control of plasma glucose levels in humans, beta-cell dysfunction, relative or absolute, is a sine qua non for the development of diabetes. If insulin deficiency must be present whereas insulin resistance may be present, is this proof that the former is etiologically primary to the latter? If so, do we have convincing evidence that the primacy of insulin deficiency is genetic in nature? The answer to both questions is negative on several accounts. The defect in insulin secretion in overt NIDDM is functionally severe but anatomically modest: beta-cell mass is reduced by 20-40% in patients with long-standing NIDDM (122). Moreover, the insulin secretory deficit is progressively worse with more severe hyperglycemia (123) and recovers considerably upon improving glycemic control (124). These observations indicate that part of the insulin deficiency is acquired (through glucose toxicity, lipotoxicity, or both). In addition, although insulin deficiency is necessary for diabetes, it may not always be sufficient to cause NIDDM. In fact, subtle defects in the beta-cell response to glucose may be widespread in the population (108, 125) and only cause frank hyperglycemia when obesity/insulin resistance stress the secretory machinery. Conceivably, there could be beta-cell dysfunction without NIDDM just as there is insulin resistance without diabetes. Incidentally, any defect in insulin secretion, whether in normoglycemic or hyperglycemic persons, could be due to other factors than primary beta-cell dysfunction: amyloid deposits in the pancreas (126), changes in insulin secretagogues (amylin, GLP-1, GIP, galanin) (127-130), early intrauterine malnutrition (131). Finally, the predictive power of early changes in insulin secretion for the development of typical NIDDM is generally lower than that of insulin     

Plasma PAF acetylhydrolase in non-insulin dependent diabetes mellitus and obesity: effect of hyperinsulinemia and lovastatin treatment

Insulin resistance is characterized principally by impaired insulin-mediated glucose uptake which provokes a compensatory increase in pancreatic beta-cell secretory activity. For a time this may produce well-controlled plasma glucose levels but as the insulin resistance worsens the augmented insulin production becomes inadequate to keep plasma glucose at euglycemia leading to the development of non-insulin dependent diabetes mellitus (NIDDM), accompanied by hyperinsulinemia and hyperglycemia. A number of metabolic defects are associated with NIDDM including obesity, hypercoagulability, cardiovascular disease risk factors such as hypertension and dyslipidemia and these constitute the insulin resistance syndrome. The identity of the biochemical factor that might link all these defects is not yet known. We have hypothesized that platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) may be such a link. In this study, we measured plasma acetylhydrolase (EC.1.1.48), which degrades PAF to the inactive metabolise lyso-PAF, as a surrogate for PAF activity in three groups of hypercholesterolemic subjects: lean controls (n = 9), non-diabetic obese (n = 6) and NIDDM subjects (n = 6). The ages and body mass indices of the subjects were 46 +/- 3.1 and 24.2 +/- 2.2 for the lean controls, 52 +/- 2.5 and 28.7 +/- 0.9 for the NIDDM subjects and 60 +/- 2 and 27.6 +/- 2.1 for the obese, non-diabetic subjects (mean +/- S.E.M.). The measurements were made before and after therapy with the cholesterol-lowering drug lovastatin, a 3-hydroxy 3 methylglutaryl (HMG) coenzyme. A reductase inhibitor (40 mg/day) for 3 months. Fasting plasma glucose (FPG) levels were 91 +/- 11, 96 +/- 3 and 146 +/- 11 mg/dl, for the lean, obese and NIDDM subjects, respectively, before therapy began. Lovastatin did not affect FPG in any of the three subject groups. Before treatment, the fasting plasma insulin (FPI) levels were 6.1 +/- 0.92, 10.83 +/- 2.03 and 14.68 +/- 3.64 mU/l for the lean, non-diabetic obese and NIDDM subjects, respectively. After lovastatin therapy only the obese group exhibited a significant change in FPI (15.35 +/- 2.47 mU/l) (P < 0.05). Total cholesterol levels were similar in all three groups both before and after lovastatin therapy but within each group lovastatin therapy significantly reduced the total cholesterol by 32, 29 and 34% in the lean, obese and NIDDM subject groups respectively (P < 0.0001). Lovastatin therapy reduced LDL-cholesterol levels by 40, 32 and 46% in the lean, obese and NIDDM subjects, respectively, but produced no significant effect on HDL or triglyceride levels. Before therapy, the plasma acetylyhydrolase activities were 104 +/- 7, 164 +/- 7 and 179 +/- 7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Lovastatin therapy reduced plasma acetylhydrolase levels to 70 +/- 7, 87 +/- 6 and 86 +/- 7 nmol/ml per min in the lean, obese and NIDDM subjects, respectively. Plasma acetylhydrolase activity was predominantly (> 80%) associated with LDL cholesterol both before and after lovastatin treatment. Also, plasma acetylhydrolase activity significantly correlated with fasting plasma insulin levels before lovastatin therapy but not after. Taken together, this study clearly implicates PAF metabolism in three defects associated with the insulin resistance syndrome: hypercholesterolemia, obesity and NIDDM. Additionally, we conclude that chronic hyperinsulinemia may play a significant role in the production of plasma acetylhydrolase.     

The insulin resistance syndrome in native Hawaiians. Native Hawaiian Health Research (NHHR) Project

OBJECTIVE: To investigate whether fasting hyperinsulinemia is associated with a clustering of cardiovascular disease (CVD) risk factors, manifesting as the insulin resistance syndrome (IRS), in a population of native Hawaiians. RESEARCH DESIGN AND METHODS: A total of 574 native Hawaiians > or = 30 years of age were examined for blood pressure, waist-to-hip ratio (WHR), BMI, oral glucose tolerance, and fasting lipid, insulin, and C-peptide concentrations. All statistical analyses (n = 384) excluded 190 individuals who had NIDDM or who were taking hypertension medication. Using logistic regression analysis, fasting insulin and C-peptide levels were compared with CVD risk factors (glucose intolerance, hypertension, central adiposity, elevated triglyceride levels, and low HDL cholesterol levels) after adjusting for age and obesity. RESULTS: Sixty-six percent of native Hawaiians were overweight or obese, and 70% were found to have central adiposity. Fasting insulin concentrations were correlated with BMI, WHR, blood pressure, and triglyceride, HDL cholesterol, and glucose concentrations. Fasting insulin was also significantly associated with an increasing number of CVD risk factors in each participant (P < 0.001). Fasting insulin and C-peptide concentrations were independently associated with glucose intolerance, high triglyceride levels, and low HDL cholesterol levels. However, only fasting C-peptide concentrations were independently associated with hypertension and central adiposity. Apparent differences in the correlates of fasting insulin and C-peptide may be related to multiple factors and warrant further evaluation. CONCLUSIONS: This study provides cross-sectional data confirming the existence of the IRS in native Hawaiians. However, further longitudinal studies are needed to examine the relationship of insulin resistance and/or surrogate markers to increased rates of NIDDM and CVD mortality in native Hawaiians.     

Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus

Recent epidemiological studies indicate that individuals who maintain a physically active lifestyle are much less likely to develop impaired glucose tolerance and non-insulin-dependent diabetes mellitus (NIDDM). Moreover, it was found that the protective effect of physical activity was strongest for individuals at highest risk of developing NIDDM. Reducing the risk of insulin resistance and NIDDM by regularly performed exercise is also supported by several aging studies. It has been found that older individuals who vigorously train on a regular basis exhibit a greater glucose tolerance and a lower insulin response to a glucose challenge than sedentary individuals of similar age and weight. While the evidence is substantial that aerobic exercise training can reduce the risk of impaired glucose tolerance and NIDDM, the evidence that exercise training is beneficial in the treatment of NIDDM is not particularly strong. Many of the early studies investigating the effects of exercise training on NIDDM could not demonstrate improvements in fasting plasma glucose and insulin levels, or glucose tolerance. The adequacy of the training programmes in many of these studies, however, is questionable. More recent studies using prolonged, vigorous exercise-training protocols have produced more favourable results. There are several important adaptations to exercise training that may be beneficial in the prevention and treatment of insulin resistance, impaired glucose tolerance and NIDDM. An increase in abdominal fat accumulation and loss of muscle mass are highly associated with the development of insulin resistance. Exercise training results in preferential loss of fat from the central regions of the body and should therefore contribute significantly in preventing or alleviating insulin resistance due to its development. Likewise, exercise training can prevent muscle atrophy and stimulate muscle development. Several months of weight training has been found to significantly lower the insulin response to a glucose challenge without affecting glucose tolerance, and to increase the rate of glucose clearance during a euglycaemic clamp. Muscle glucose uptake is equal to the product of the arteriovenous glucose difference and the rate of glucose delivery or muscle blood flow. While it has been known for many years that insulin will accelerate blood glucose extraction by insulin-sensitive peripheral tissues, recent evidence suggests that it can also acutely vasodilate skeletal muscle and increase muscle blood flow in a dose-dependent manner. A reduced ability of insulin to stimulate muscle blood flow is a characteristic of insulin-resistant obese individuals and individuals with NIDDM. Exercise training, however, has been found to help alleviate this problem, and substantially improve the control of insulin over blood glucose. Improvements in insulin resistance and glucose tolerance with exercise training are highly related to an increased skeletal muscle insulin action. This increased insulin action is associated with an increase in the insulin-regulatable glucose transporters, GLUT4, and enzymes responsible for the phosphorylation, storage and oxidation of glucose. Changes in muscle morphology may also be important following training. With exercise training there is an increase in the conversion of fast twitch glycolytic IIb fibres to fast twitch oxidative IIa fibres, as well as an increase in capillary density. IIa fibres have a greater capillary density and are more insulin-sensitive and -responsive than IIb fibres. Evidence has been provided that morphological changes in muscle, particularly the capillary density of the muscle, are associated with changes in fasting insulin levels and glucose tolerance. Furthermore, significant correlations between glucose clearance, muscle capillary density and fibre type have been found in humans during a euglycaemic clamp. Exercise training may also improve control over hepatic glucose production by increasin     

Determinants of diabetes mellitus in the Pima Indians

OBJECTIVE: To review the research findings on the determinants of diabetes mellitus in Pima Indians. RESEARCH DESIGN AND METHODS: Pima Indians in Arizona have participated in a longitudinal diabetes study that has provided data on and hypotheses about the development of NIDDM. Findings from this study are reviewed and updated. RESULTS: Frequency distributions of plasma glucose and HbA1 are bimodal in Pima adults, and substantial risk of the specific vascular complications of diabetes is confined to those in the higher components of these distributions. These findings contributed to the adoption of internationally recognized criteria for classification of glucose tolerance. Diabetes in the Pimas is strongly familial, and probably of genetic origin, although the precise nature of the gene or genes involved remains unknown. Obesity, which is at least in part environmentally determined, is a major factor interacting with the presumed genetic susceptibility to result in diabetes. The incidence of diabetes in the Pimas has increased during the last several decades, providing further evidence for environmental-genetic interaction. Longitudinal studies suggest that the progression from normal to diabetes can be considered to involve two stages. The first, primarily attributable to insulin resistance, leads to impaired glucose tolerance, and the second, which depends on insulin secretory failure, leads to worsening hyperglycemia and overt diabetes. CONCLUSIONS: The Pimas and many other American Indian populations suffer from a high incidence of diabetes and its characteristic disabling or fatal complications, and would benefit from continued research on the pathogenesis and prevention of the disease.     

Hypertension and insulin resistance

Non insulin dependent diabetes mellitus (NIDDM) and obesity are defined as classical insulin resistant states. Essential hypertension is now also considered to be an insulin resistant state, even in absence of NIDDM or obesity, as shown in epidemiological, clinical and experimental studies. Neither the underlying mechanism nor a direct causality between the two phenomena has been detected as yet, but different hypotheses have been postulated where, on the one hand, insulin resistance and hypertension are considered to be causally related and, on the other hand, they are considered to be parallel phenomena due to genetic and acquired factors. The clarification of the connection between hypertension and insulin resistance seems to be of great clinical importance, since they are both independent risk factors for cardiovascular disease and mortality from cardiovascular complications. This paper gives an overview of the results of recent research on the possible underlying pathogenetic mechanisms linking hypertension and insulin resistance.     

Abnormalities of insulin pulsatility and glucose oscillations during meals in obese noninsulin-dependent diabetic patients: effects of weight reduction

Twenty-seven obese patients, including 8 with normal glucose tolerance, 10 with subclinical NIDDM, and 9 with overt noninsulin-dependent diabetes mellitus (NIDDM), were studied before and after prolonged weight loss to assess the effects of the underlying defects of diabetes per se from those of obesity and chronic hyperglycemia on the regulation of pulsatile insulin secretion. Serial measurements of insulin secretion and plasma glucose were obtained during 3 standardized mixed meals consumed over 12 h. Insulin secretion rates were calculated by deconvoluting plasma C peptide levels using a mathematical model for C peptide clearance and kinetic parameters derived individually in each subject. Absolute (nadir to peak) and relative (fold increase above nadir) amplitudes of each insulin secretory pulse and glucose oscillation were calculated. Compared to the obese controls, the subclinical and overt NIDDM patients manifested the following abnormal responses: 1) decreased relative amplitudes of insulin pulses, 2) reduced frequency of glucose oscillations, 3) increased absolute amplitudes of glucose oscillations, 4) decreased temporal concomitance between peaks of insulin pulses and glucose oscillations, 5) reduced correlation between the relative amplitudes of glucose oscillations concomitant with insulin pulses, and 6) temporal disorganization of the insulin pulse profiles. These defects were more severe in the overt NIDDM patients, and weight loss only partially reversed these abnormalities in both NIDDM groups. These findings indicate that beta-cell responsiveness is reduced, and the regulation of insulin secretion is abnormal under physiological conditions in all patients with NIDDM, including those without clinical manifestations of the disease. These abnormalities are not completely normalized with weight loss, even in patients who achieve metabolic control comparable to that in obese controls. The results are consistent with the presence of an inherent beta-cell defect that contributes to secretory derangements in subclinical NIDDM patients. This abnormality precedes frank hyperglycemia and may ultimately contribute to the development of overt NIDDM.     

The distribution of cartilage degeneration of the human patella in relation to individual subchondral mineralization

OBJECTIVE--To evaluate androgen concentrations in relation to insulin resistance in men and women with and without NIDDM. Recent studies have indicated the potential importance of the regulation of insulin sensitivity by androgens in both women and men. Low sex hormone binding globulin (SHBG) concentration is an independent risk factor for the development of non-insulin-dependent diabetes mellitus (NIDDM) in women and is strongly associated statistically with signs of insulin resistance. RESEARCH DESIGN AND METHODS--We compared measurements of anthropometric variables and SHBG, steroid hormone, and insulin concentrations of women and men who have NIDDM with those of control subjects. RESULTS--Women with NIDDM had somewhat higher plasma insulin concentrations, lower SHBG, and higher free testosterone values than did control subjects with similar body mass index (BMI). Women with NIDDM had marginally higher waist-to-hip ratios (WHR). Plasma insulin concentrations correlated positively with BMI, WHR, and free testosterone and negatively with SHBG. In multivariate analyses, insulin concentrations remained positively associated with BMI and free testosterone. Men with NIDDM had higher fasting plasma insulin concentrations than did the nondiabetic control subjects. Testosterone and SHBG were lower in the diabetic men than in both control groups. The derived value of free testosterone was not different between groups. Univariate correlation analyses revealed tight statistical couplings between plasma insulin on the one hand and SHBG and testosterone concentrations (negative) on the other. In multivariate analyses, only the insulin-testosterone association remained. CONCLUSIONS: Women with NIDDM have high levels of free testosterone and low levels of SHBG. Insulin resistance is closely correlated with these signs of hyperandrogenicity as well as with obesity. Men with NIDDM also have low levels of SHBG and, in contrast to women, low testosterone values. Insulin values correlate negatively with these hormonal factors. Based on the results of experimental work and intervention studies, we suggest that these androgen abnormalities might be causally related to insulin resistance in NIDDM.     

Diagnosis and classification of diabetes mellitus: new criteria

New recommendations for the classification and diagnosis of diabetes mellitus include the preferred use of the terms "type 1" and "type 2" instead of "IDDM" and "NIDDM" to designate the two major types of diabetes mellitus; simplification of the diagnostic criteria for diabetes mellitus to two abnormal fasting plasma determinations; and a lower cutoff for fasting plasma glucose (126 mg per dL [7 mmol per L] or higher) to confirm the diagnosis of diabetes mellitus. These changes provide an easier and more reliable means of diagnosing persons at risk of complications from hyperglycemia. Currently, only one half of the people who have diabetes mellitus have been diagnosed. Screening for diabetes mellitus should begin at 45 years of age and should be repeated every three years in persons without risk factors, and should begin earlier and be repeated more often in those with risk factors. Risk factors include obesity, first-degree relatives with diabetes mellitus, hypertension, hypertriglyceridemia or previous evidence of impaired glucose homeostasis. Earlier detection of diabetes mellitus may lead to tighter control of blood glucose levels and a reduction in the severity of complications associated with this disease.     

Insulin resistance implications for type II diabetes mellitus and coronary heart disease

PURPOSE: To review information on the implications of insulin resistance for type II diabetes mellitus (non-insulin-dependent diabetes mellitus) and coronary heart disease, and to derive guidance from this information for the management of these conditions. DATA SOURCES: A MEDLINE search of English-language articles published between 1985 and July 1996, and review of the bibliographies of articles obtained through the MEDLINE search and textbooks. STUDY SELECTION: Primary research articles, reviews and perspectives on the epidemiology of diabetes and cardiovascular diseases and on intervention outcomes in these diseases. DATA EXTRACTION: Study design and quality were assessed, with particular attention to methods, study population size and other characteristics. Conclusions of review articles and perspectives were analyzed critically. DATA SYNTHESIS: Type II diabetes is associated with a two- to fourfold excess of coronary heart disease, compared to nondiabetic populations. In most studies, glycemia and duration of clinical diabetes were found to be only weak risk factors for coronary heart disease. Conventional coronary heart disease risk factors such as dyslipidemia and hypertension have been associated with coronary heart disease in type II diabetes subjects. Hyperinsulinemia and insulin resistance have been predictive of the development of type II diabetes and, in some studies, of coronary heart disease. CONCLUSION: Strategies to prevent the development of coronary heart disease in diabetic and possibly prediabetic subjects should emphasize a multifactorial approach, including: a) improved glycemic control; b) aggressive treatment of risk factors for coronary heart disease, including insulin resistance; c) primary prevention of NIDDM; and d) use of glucose lowering agents that improve insulin sensitivity and cardiovascular risk factors.