A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity.

The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. The PPARgamma1 and gamma2 isoforms result from alternative splicing and have ligand-dependent and -independent activation domains. PPARgamma2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5-10-fold more effective than that of PPARgamma1. Insulin stimulates the ligand-independent activation of PPARgamma1 and gamma2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARgamma2 in human adipocytes. Here, we report that a relatively common Pro12Ala substitution in PPARgamma2 is associated with lower body mass index (BMI; P=0.027; 0.015) and improved insulin sensitivity among middle-aged and elderly Finns. A significant odds ratio (4.35, P=0.028) for the association of the Pro/Pro genotype with type 2 diabetes was observed among Japanese Americans. The PPARgamma2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARgamma2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.

Insulin resistance syndrome predicts coronary heart disease events in elderly nondiabetic men.

BACKGROUND: The role of a cluster of risk factors characteristic for the insulin resistance syndrome as a predictor for coronary heart disease (CHD) has not been studied previously. METHODS AND RESULTS: Clustering of cardiovascular risk factors was analyzed by factor analysis to investigate whether these clusters (factors) predict CHD events (CHD death or nonfatal myocardial infarction) in a nondiabetic population of 1069 subjects 65 to 74 years old from eastern Finland followed up for 7 years. There were 151 CHD events (92 for men, 59 for women) during the follow-up period. In men, factor 1 (the insulin resistance factor, which reflected primarily body mass index, waist-to-hip ratio, triglycerides, fasting plasma glucose, and insulin) (hazards ratio [HR] with 95% CI, 1.33, CI 1.08, 1.65, P=0.008), factor 2 (alcohol consumption, high HDL cholesterol, low triglycerides) (HR 0.78, CI 0.63, 0.96, P=0.020), factor 3 (age, systolic blood pressure, urinary albumin/creatinine ratio, left ventricular hypertrophy) (HR 1.52, CI 1.26, 1.83, P<0.001), and factor 4 (high total cholesterol and triglycerides) (HR 1.42, CI 1. 15, 1.77, P=0.002) predicted CHD events in multivariate Cox regression analysis. In women, the insulin resistance factor did not predict CHD events (HR 1.06, CI 0.82, 1.36), but factor 2 (previous stroke, low HDL cholesterol and high triglycerides) (HR 1.34, CI 1. 06, 1.69, P=0.014) and factor 3 (age, systolic blood pressure, urinary albumin/creatinine ratio, left ventricular hypertrophy) (HR 1.44, CI 1.15, 1.82, P=0.002) predicted CHD events. CONCLUSIONS: Our study supports the notion that the insulin resistance syndrome is a risk factor for CHD in elderly men.

Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS).

BACKGROUND: Inflammation has been suggested as a risk factor for the development of atherosclerosis. Recently, some components of the insulin resistance syndrome (IRS) have been related to inflammatory markers. We hypothesized that insulin insensitivity, as directly measured, may be associated with inflammation in nondiabetic subjects. METHODS AND RESULTS: We studied the relation of C-reactive protein (CRP), fibrinogen, and white cell count to components of IRS in the nondiabetic population of the Insulin Resistance Atherosclerosis Study (IRAS) (n=1008; age, 40 to 69 years; 33% with impaired glucose tolerance), a multicenter, population-based study. None of the subjects had clinical coronary artery disease. Insulin sensitivity (S(I)) was measured by a frequently sampled intravenous glucose tolerance test, and CRP was measured by a highly sensitive competitive immunoassay. All 3 inflammatory markers were correlated with several components of the IRS. Strong associations were found between CRP and measures of body fat (body mass index, waist circumference), S(I), and fasting insulin and proinsulin (all correlation coefficients >0.3, P<0.0001). The associations were consistent among the 3 ethnic groups of the IRAS. There was a linear increase in CRP levels with an increase in the number of metabolic disorders. Body mass index, systolic blood pressure, and S(I) were related to CRP levels in a multivariate linear regression model. CONCLUSIONS: We suggest that chronic subclinical inflammation is part of IRS. CRP, a predictor of cardiovascular events in previous reports, was independently related to S(I). These findings suggest potential benefits of anti-inflammatory or insulin-sensitizing treatment strategies in healthy individuals with features of IRS.

Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state.

BACKGROUND: Subjects who convert to type 2 diabetes mellitus have increased cardiovascular risk factors relative to nonconverters. However, it is not known whether these atherogenic changes in the prediabetic state are predominantly due to insulin resistance, decreased insulin secretion, or both. METHODS AND RESULTS: We examined this issue in the 7-year follow-up of the San Antonio Heart Study, in which 195 of 1734 subjects converted to type 2 diabetes. At baseline, converters had significantly higher body mass index, waist circumference, triglyceride concentration, and blood pressure and lower HDL cholesterol than nonconverters. Atherogenic changes in converters were markedly attenuated (and no longer significant) after adjustment for the homeostasis model assessment of insulin resistance (HOMA IR, a surrogate for insulin resistance); in contrast, the differences in risk factors between converters and nonconverters increased after adjustment for the ratio of early insulin increment to early glucose increment (DeltaI(30-0)/DeltaG(30-0)) during an oral glucose tolerance test (a surrogate for insulin secretion). We also compared converters who had a predominant insulin resistance (high HOMA IR and high DeltaI(30-0)/DeltaG(30-0)) (n=56) and converters who had a predominant decrease in insulin secretion (low HOMA IR and low DeltaI(30-0)/DeltaG(30-0)) (n=31) with nonconverters (n=1539). Only the converters who were insulin resistant had higher blood pressure and triglyceride levels and lower HDL cholesterol levels than nonconverters. CONCLUSIONS: Our data suggest that atherogenic changes in the prediabetic state are mainly seen in insulin-resistant subjects and that strategies to prevent type 2 diabetes might focus on insulin-sensitizing interventions rather than interventions that increase insulin secretion because of potential effects on cardiovascular risk.

NIDDM and its metabolic control predict coronary heart disease in elderly subjects.

The aim of this study was to evaluate whether noninsulin-dependent diabetes (NIDDM) and its metabolic control and duration predict coronary heart disease (CHD) events during a 3.5-year follow-up in a randomly selected Finnish population sample 65-74 years of age at baseline. Of 1,298 subjects participating in the baseline study, 1,069 were nondiabetic and 229 had NIDDM. During the follow-up, 3.4% of nondiabetic and 14.8% of NIDDM subjects died from CHD or had a nonfatal myocardial infarction (MI). The impact of NIDDM on CHD mortality and morbidity was more marked in women than in men. Odds ratios (ORs) and their 95% confidence intervals for CHD death and nonfatal MI in women with NIDDM compared with women with normal glucose tolerance were 11.7 (3.8-36.4) and 4.7 (3.6-6.1). In men, the corresponding ORs were 0.43 (0.1-1.9) and 1.4 (0.6-3.2). In multiple logistic regression analyses including all study subjects, NIDDM (P < 0.01), male sex (P < 0.05), and previous MI (P < 0.01) predicted CHD death (n = 45). NIDDM (P < 0.01), male sex (P < 0.05), previous MI (P < 0.05), current smoking (P < 0.001), systolic blood pressure (P < 0.001), and low high-density lipoprotein cholesterol (P < 0.01) predicted all CHD events (CHD death or nonfatal MI) (n = 107). In NIDDM subjects, only glycated hemoglobin A1c (GHbA1c) at baseline (P < 0.01) and duration of diabetes (P < 0.05) predicted CHD death (n = 15) and all CHD events (n = 33). There was a significant increase in the risk of CHD death and all CHD events in NIDDM subjects with GHbA1c levels higher than 7.0% compared with diabetic subjects with lower GHbA1c (ORs 4.3 [1.1-16.7] and 2.2 [1.0-5.1]). In conclusion, NIDDM and its metabolic control and the duration of diabetes are important predictors of CHD in elderly subjects, particularly in women.

The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin sensitivity and acute insulin response in normoglycemic subjects.

Plasma levels of proinsulin and its conversion intermediates are elevated in NIDDM patients. Recent studies have suggested that proinsulin levels are also increased relative to insulin levels in subjects who subsequently develop NIDDM. This may be due to insulin resistance or a defect in proinsulin processing or insulin secretion. If insulin resistance is the trigger, the proinsulin-to-insulin ratio would be higher in insulin-resistant subjects than in insulin-sensitive subjects. We examined the association of fasting proinsulin, 32,33 split proinsulin, and the proinsulin-to-insulin ratio with insulin sensitivity (SI), estimated by a frequently sampled intravenous glucose tolerance test and the minimal model in 138 normoglycemic subjects ages 53-61 years. We also investigated the relation of proinsulins and the proinsulin-to-insulin ratio to acute insulin response (AIR). Fasting specific insulin (r = -0.64), intact proinsulin (r = -0.43), and 32,33 split proinsulin (r = -0.54) concentrations were inversely correlated and the proinsulin-to-insulin ratio positively (r = 0.31) correlated with SI (P < 0.001). Fasting specific insulin (r = 0.64), intact proinsulin (r = 0.35), and 32,33 split proinsulin (r = 0.45) concentrations were positively correlated and proinsulin-to-insulin ratio (r = -0.40) inversely correlated with AIR (P < 0.001). The proinsulin-to-insulin ratio increased by increasing levels of SI (quartiles of SI from low to high: 0.048, 0.078, 0.078, 0.068; P = 0.012) and decreased by increasing AIR (quartiles of AIR from low to high: 0.088, 0.068, 0.058, 0.058; P = 0.005). These associations were independent of age, sex, BMI, and waist-to-hip ratio. Furthermore, the relation between the proinsulin-to-insulin ratio and AIR was independent of SI. In conclusion, in normoglycemic subjects, insulin resistance (low SI) was associated with a low rather than a high proinsulin-to-insulin ratio. Subjects who maintained normoglycemia with a low AIR had an increased proinsulin-to-insulin ratio compared with those who needed high AIR to maintain normoglycemia. These results suggest that, in subjects with normal glucose tolerance, insulin resistance does not induce increased proinsulin relative to insulin secretion, but rather is associated with enhanced processing of proinsulin.

Insulin resistance, body fat distribution, and sex hormones in men.

Although many studies have suggested that increased androgenicity is associated with insulin resistance and hyperinsulinemia in both pre- and postmenopausal women, relatively few data are available on this relationship in men. We examined the association of body mass index (BMI), waist-to-hip ratio (WHR), sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol with insulin concentrations and whole-body glucose disposal in 87 men from a population-based study in Kuopio, Finland. BMI was significantly correlated with fasting insulin (r = 0.46), total whole-body glucose disposal (r = -0.30), glucose oxidation (r = -0.21), and nonoxidative glucose disposal (r = -0.25). WHR also was significantly associated with fasting insulin (r = 0.61), total whole-body glucose disposal (r = -0.54), glucose oxidation (r = -0.23), and nonoxidative whole-body glucose disposal (r = -0.50). SHBG and total and free testosterone were significantly associated with insulin concentrations and total and nonoxidative glucose disposal but not with glucose oxidation. DHEA-SO4 and estradiol were not associated with insulin, glucose concentrations, or whole-body glucose disposal in univariate analysis. In multivariate analysis, total whole-body glucose disposal was associated negatively with WHR and positively associated with total testosterone and SHBG; nonoxidative whole-body glucose disposal was associated negatively with WHR and positively associated with total and free testosterone. Glucose oxidation was significantly associated only with WHR. In conclusion, higher WHR and lower testosterone were strongly associated with a decrease in total and nonoxidative whole-body glucose disposal in men.

Microalbuminuria precedes the development of NIDDM.

Several studies have indicated that insulin resistance, elevated blood pressure (BP), and dyslipidemia precede the onset of non-insulin-dependent diabetes mellitus (NIDDM). Little data, however, exist on the presence of renal disease in prediabetic subjects. We measured albumin excretion in a cross-sectional population study in subjects 65-74 years of age living in eastern Finland in relation to the risk of developing diabetes 3.5 years later. The prevalence of microalbuminuria (urinary albumin-to-urinary creatinine ratio > or = 2 mg/mmol) was 1.3-, 1.8-, and 2.0-fold higher among subjects with impaired glucose tolerance (n = 242), newly diagnosed NIDDM subjects (n = 92), and previously diagnosed NIDDM subjects (n = 136), respectively, compared with subjects with normal glucose tolerance (n = 826). Nondiabetic subjects with microalbuminuria had multiple abnormalities in cardiovascular risk factors including elevated BP, high triglyceride concentration, high insulin concentration, and a low high-density lipoprotein cholesterol concentration, a cluster of risk factors typical for prediabetic individuals. The relationship between microalbuminuria and the incidence of NIDDM over the 3.5-year follow-up was studied in 891 subjects who were free of diabetes at baseline. Converters to diabetes (n = 69) had a higher prevalence of hypertension (68.1 vs. 54.4%, P < 0.05) and a higher prevalence of microalbuminuria (43.5 vs. 30.4%, P < 0.05) than nonconverters (n = 822). In logistic regression analysis, microalbuminuria predicted the development of NIDDM independently of BP level.(ABSTRACT TRUNCATED AT 250 WORDS)

Microalbuminuria is associated with insulin resistance in nondiabetic subjects: the insulin resistance atherosclerosis study.

Microalbuminuria is associated with excess cardiovascular mortality in both diabetic and nondiabetic subjects. Patients with NIDDM and microalbuminuria are more insulin resistant than those without microalbuminuria. However, the relationship between insulin resistance and microalbuminuria in patients with NIDDM could be due to hyperglycemia, which can cause both insulin resistance and an increase in albumin excretion rate. Little is known about microalbuminuria and insulin resistance in nondiabetic subjects. Therefore, we examined, cross-sectionally, the relationship of insulin sensitivity (S(I) x 10(-4) min x microU(-1) x ml(-1)), estimated by a frequently sampled intravenous glucose tolerance test and the minimal model and fasting plasma insulin concentration, to microalbuminuria (albumin-to-creatinine ratio > or = 2 mg/mmol) in 982 nondiabetic subjects aged 40-69 years. Altogether, 15% of the subjects had microalbuminuria, and 32% had hypertension. Subjects with microalbuminuria had a lower degree of insulin sensitivity (means +/- SE, 1.70 +/- 0.11 vs. 2.25 +/- 0.07, P = 0.003) and higher fasting insulin concentrations (17.4 +/- 1.1 vs. 15.7 +/- 0.5 mU/l, P = 0.059) compared with subjects without microalbuminuria. In logistic regression analysis, an increasing degree of insulin sensitivity was related to a decreasing prevalence of microalbuminuria (odds ratio = 0.86, 95% CI: 0.79-0.94, P < 0.001). Although this relationship attenuated after adjustment for age, sex, ethnicity, hypertension, fasting glucose, and BMI, it still remained significant. The association between insulin sensitivity and microalbuminuria was shown not to be different between normotensive and hypertensive subjects. Our results suggest a relationship between insulin resistance and microalbuminuria in nondiabetic subjects that is partially dependent on blood pressure, glucose levels, and obesity.

Relationship of proinsulin and insulin to cardiovascular risk factors in nondiabetic subjects.

Recent data suggest that proinsulin is strongly associated with cardiovascular risk factors in diabetic subjects. However, this relationship has not been examined in nondiabetic subjects. Therefore, we examined the relation of proinsulin to lipids, obesity (body mass index), and waist-to-hip ratio in 260 nondiabetic individuals from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Proinsulin was measured by radioimmunoassay, and insulin was measured by a Linco radioimmunoassay that does not cross-react with proinsulin. Fasting insulin was significantly associated with body mass index (0.42), waist-to-hip ratio (r = 0.30), triglyceride (r = 0.29), high-density lipoprotein cholesterol (r = -0.20), and systolic blood pressure (r = 0.16) but not significantly related to diastolic blood pressure (r = 0.11). Fasting proinsulin was significantly associated with body mass index (r = 0.19), waist-to-hip ratio (r = 0.25), triglyceride (r = 0.41), systolic blood pressure (r = 0.19), and diastolic blood pressure (r = 0.15). Proinsulin was more strongly related to increased triglyceride than insulin despite its weaker relationship to obesity. In multivariate analyses, proinsulin continued to be significantly related to triglyceride concentrations (explaining 23.1% of the variance) and to systolic blood pressure (explaining 4.0% of the variance), even after adjusting for insulin. These observations suggest that proinsulin should be measured in addition to insulin in epidemiological studies. Proinsulin may be a marker for metabolic decompensation in prediabetic subjects.

Insulin sensitivity and acute insulin response in African-Americans, non-Hispanic whites, and Hispanics with NIDDM: the Insulin Resistance Atherosclerosis Study.

NIDDM is usually characterized by beta-cell failure and decreased insulin sensitivity. It has been reported that a high proportion of African-American NIDDM subjects are insulin sensitive. To examine this issue, we determined insulin sensitivity (S(I)) in 479 NIDDM subjects by minimal model analyses of frequently sampled intravenous glucose tolerance (FSIGT) from the Insulin Resistance Atherosclerosis Study (IRAS), a large multicenter study of insulin sensitivity and cardiovascular risk in African-Americans, Hispanics, and non-Hispanic whites. The African-Americans and non-Hispanic whites were sampled in Los Angeles and Oakland, California. The non-Hispanic whites and Hispanics were sampled in San Antonio, Texas, and San Luis Valley, Colorado. We defined the proportion of insulin-sensitive (S(I)) subjects as > or =1.61 min-1 x microU-1 x ml-1, which is above the median for nondiabetic subjects of all ethnic groups in the IRAS. Using this definition, the proportion of insulin-sensitive diabetic subjects was very low in all ethnic groups (non-Hispanic whites [14.3%] vs. African-Americans [6.5%], P = 0.039 in Los Angeles and Oakland; non-Hispanic whites [6.8%] vs. Hispanics [4.9%], P = 0.737 in San Luis Valley and San Antonio). These results were also similar in newly diagnosed mildly hyperglycemic diabetic subjects. In addition, these results were not affected by the adjustment for differences in obesity, body fat distribution, and severity of hyperglycemia. Even in nonobese subjects (with BMI <30 kg/m2), the proportion of insulin-sensitive subjects (S(I) > or =1.61 min-1 x microU-1 x ml-1) was low (3.6-9.7%). The acute insulin response (AIR) was significantly higher in African-Americans than in non-Hispanic whites; there were no ethnic differences in AIR between Hispanics and non-Hispanic whites. There were no significant ethnic differences for non-insulin-mediated glucose disposal (S(G)). We conclude that the number of insulin-sensitive NIDDM subjects is low and similar among non-Hispanic whites, Hispanics, and African-Americans in the U.S.

Increased insulin resistance and insulin secretion in nondiabetic African-Americans and Hispanics compared with non-Hispanic whites. The Insulin Resistance Atherosclerosis Study.

The etiology of NIDDM is still controversial, with both insulin resistance and decreased insulin secretion postulated as potential important factors. African-Americans and Hispanics have a two- to threefold excess risk of developing NIDDM compared with non-Hispanic whites. Yet little is known concerning the prevalence of insulin resistance and secretion defects in minorities, especially in African-Americans in population-based studies. Fasting and 2-h post-glucose load glucose and insulin levels, insulin-mediated glucose disposal (insulin sensitivity index) (S(I)), glucose effectiveness (S(G)), and first-phase insulin response (acute insulin response [AIR]) were determined in nondiabetic African-Americans (n= 288), Hispanics (n= 363), and non-Hispanic whites (n= 435) as part of the Insulin Resistance Atherosclerosis Study. Subjects received a standard 2-h oral glucose tolerance test on the first day and an insulin-modified frequently sampled intravenous glucose tolerance test on the second day. African-Americans and Hispanics were more obese than non-Hispanic whites. Both African-Americans and Hispanics had higher fasting and 2-h insulin concentrations and AIR but lower S(I) than non-Hispanic whites. No ethnic difference was observed in S(G). After further adjustments for obesity, body fat distribution, and behavioral factors, African-Americans continued to have higher fasting and 2-h insulin levels and AIR, but lower S(I) than non-Hispanic whites. In contrast, after adjustment for these covariates, no significant ethnic differences in S(I) or fasting insulin levels were observed between Hispanics and non-Hispanic whites. Hispanics continued to have higher 2-h insulin levels and AIRs than those in non-Hispanic whites. In this report, the association between S(I) and upper body adiposity (waist-to-hip, ratio) was similar in each ethnic group. Both nondiabetic African-Americans and Hispanics have increased insulin resistance and higher AIR than nondiabetic non-Hispanic whites, suggesting that greater insulin resistance may be in large part responsible for the higher prevalence of NIDDM in these minority groups. However, in Hispanics. the greater insulin resistance may be due to greater adiposity and other behavioral factors.

Proinsulin and specific insulin concentration in high- and low-risk populations for NIDDM.

Hyperinsulinemia and insulin resistance have been implicated as risk factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). Recent data suggest that proinsulin may comprise a large proportion of immunoreactive insulin in subjects with NIDDM and possibly in those with impaired glucose tolerance (IGT) as well. Increased proinsulin concentrations are thought to be an early indicator of a failing pancreas. We examined proinsulin, insulin (using an assay that does not display appreciable cross-reactivity with proinsulin), and the fasting proinsulin:insulin ratio in 206 nondiabetic Mexican-American (a high-risk population for NIDDM) and 123 nondiabetic non-Hispanic white (a low-risk population for NIDDM) participants in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Mexican-Americans had significantly higher fasting and 2-h proinsulin and insulin levels but similar fasting proinsulin:insulin ratios compared with non-Hispanic whites. After statistical adjustment for age, body mass index, waist-to-hip ratio, and glucose tolerance status, Mexican-Americans continued to have higher fasting and 2-h insulin and fasting and 2-h proinsulin concentrations but similar proinsulin:insulin ratios compared with non-Hispanic whites. The fasting proinsulin:insulin ratio was higher in 85 subjects with NIDDM compared with subjects with IGT or normal glucose tolerance (0.31, 0.09, and 0.07, respectively). Thus, nondiabetic subjects from a high-risk population for NIDDM are hyperinsulinemic (using an assay that does not cross-react with proinsulin) and, further, do not secrete more proinsulin relative to insulin itself than do nondiabetic subjects from a low-risk population.

New amino acid substitutions in the IRS-2 gene in Finnish and Chinese subjects with late-onset type 2 diabetes.

We investigated the significance of the variants of the IRS-2 gene in patients with type 2 diabetes. The entire coding part of the IRS-2 gene was screened by single-strand conformation polymorphism analysis in 40 Chinese and 40 Finnish patients with late-onset type 2 diabetes. The association of the variants of the IRS-2 gene with type 2 diabetes was studied in 85 Finnish diabetic patients and 82 Finnish control subjects and in 100 Chinese diabetic patients and 85 Chinese control subjects. The four variants predicting structural changes in the insulin receptor substrate (IRS)-2 protein included an insertion of AAC (Asn) in the Asn repeat sequence centered around codons 29-36 (allele frequencies of 0 vs. 0.6% and 1.5 vs. 0%), the Ala157Thr substitution (0 vs. 0% and 0.5 vs. 0%), the Leu647Val substitution (0.6 vs. 0% and 0 vs. 0%), and the Gly1057Asp polymorphism (31 vs. 31% and 35 vs. 30%) (P = NS for all comparisons). Furthermore, six silent variants were observed (CGC147CGG, CCC155CCG, GCC156GCT, AGT723AGC, TGT816TGC, and CCC829CCT). The Gly1057Asp polymorphism was not associated with insulin resistance or impaired insulin secretion in Finnish subjects with normal glucose tolerance (n = 295) or impaired glucose tolerance (n = 38). These data indicate that structural variants of the IRS-2 gene were uncommon in Finnish and Chinese patients with type 2 diabetes. Thus, the variants in the coding part of the IRS-2 gene are unlikely to have a major role in the development of type 2 diabetes in Finnish or Chinese subjects.

Asymptomatic hyperglycemia and atherosclerotic vascular disease in the elderly.

OBJECTIVE--To investigate the relationship between asymptomatic hyperglycemia (IGT or newly diagnosed NIDDM) and atherosclerotic vascular disease. RESEARCH DESIGN AND METHODS--A representative cross-sectional population sample of 1431 subjects (511 men, 920 women; 65-74 yr old). Altogether, 312 men and 515 women had NGT, 84 men and 158 women had IGT, 33 men and 59 women had newly diagnosed NIDDM, and 82 men and 188 women had previously diagnosed NIDDM. Participation rate was 71%. Main outcome measures were prevalence rates of CHD, stroke, and intermittent claudication. RESULTS--There was no difference in the prevalence of definite or possible MI verified at hospital between subjects with asymptomatic hyperglycemia and NGT (15.5 vs. 13.3% in men, 6.3 vs. 5.3% in women). Men with asymptomatic hyperglycemia had 1.5 x higher prevalence of angina pectoris (29.4 vs. 19.3%, P less than 0.05), major Q-QS changes (21.1 vs. 12.0%, P less than 0.05), ischemic ECG changes (59 vs. 45%, P less than 0.05), and silent MI on ECG (14.8 vs. 7.9%, P less than 0.05) compared to men with NGT. Women with asymptomatic hyperglycemia had more often ischemic ECG changes compared to women with NGT (48.3 vs. 39.7%, P less than 0.05). There was no difference (NS) in the prevalence of verified stroke (3.5 vs. 4.6% in men, 2.7 vs. 2.5% in women) or claudication (7.0 vs. 7.7% in men, 4.6 vs. 4.3% in women) between subjects with asymptomatic hyperglycemia and NGT. In multiple logistic regression analyses, the association between risk factors and MI or ischemic ECG changes in subjects with asymptomatic hyperglycemia was not consistent. CONCLUSION--Elderly subjects with asymptomatic hyperglycemia (particularly men) tended to have an increased prevalence of CHD. Thus, asymptomatic hyperglycemia in the elderly is not a benign phenomenon but is associated with cardiovascular morbidity.

Prevalence of diabetes and impaired glucose tolerance in elderly subjects and their association with obesity and family history of diabetes.

The goal of this study was to investigate the prevalence of impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) in elderly subjects and their association with obesity, central obesity, and a family history of diabetes. A representative population sample of 1300 subjects (471 men, 829 women) aged 65-74 yr participated in the study. The participation rate was 71%. The prevalence rates of previously and newly diagnosed NIDDM and IGT, based on a history of diabetes and an oral glucose tolerance test, were 8.7, 7.0, and 17.8% in men and 11.7, 7.1, and 19.1% in women. Thus, 33.8% of men and 37.9% of women had abnormal glucose tolerance according to World Health Organization criteria. Obesity (body mass index greater than or equal to 27 kg/m2 in men and greater than or equal to 25 kg/m2 in women) and central obesity (waist-hip ratio greater than or equal to 0.98 in men and greater than or equal to 0.89 in women) doubled the prevalence of IGT or NIDDM. The combination of obesity and a family history of diabetes was associated with a more marked increase in the prevalence of IGT or NIDDM in men than in women. Simultaneous presence of obesity, central obesity, and a family history of diabetes was associated with a threefold increase in the prevalence of IGT or NIDDM (65.4 vs. 24.1% in men, 52.8 vs. 19.6% in women, P less than 0.001). The major risk factors for NIDDM, e.g., obesity, central fat distribution, and a family history of diabetes, explained 10% of the variance in 2-h glucose values in multiple regression analysis. In conclusion, the prevalence of IGT and NIDDM was high in elderly subjects. Although obesity, central fat distribution, and a family history of diabetes were significantly associated with the increased prevalence of IGT or NIDDM, they explained only a minor proportion of the variance in 2-h glucose values.

Insulin resistance syndrome predicts coronary heart disease events in elderly type 2 diabetic men.

OBJECTIVE: To investigate whether cardiovascular risk factors cluster with hyperinsulinemia in elderly type 2 diabetic subjects and, if so, whether this clustering predicts coronary heart disease (CHD) events during a 7-year follow-up. RESEARCH DESIGN AND METHODS: Clustering of cardiovascular risk factors was analyzed by factor analysis. Cox regression models were used to investigate whether these clusters (factors) predict CHD events (CHD death or nonfatal myocardial infarction) during a 7-year follow-up in 229 type 2 diabetic subjects aged 65-74 years. RESULTS: There were 70 CHD events (21 in men and 49 in women) during the follow-up period. In diabetic men, components of the insulin resistance syndrome (IRS) loaded on Factor 1 (the insulin resistance factor), which reflected high fasting insulin, obesity (high BMI), central obesity (high waist-to-hip ratio), high total triglycerides, and a short duration of diabetes. Only this IRS factor predicted CHD events in multivariate Cox regression analysis (hazard ratio [HR] 1.71, 95% CI 1.08-2.71, P = 0.022). In diabetic women, components of IRS loaded on two factors, none of which predicted CHD events. In women, only Factor 4, characterized by advanced age, left ventricular hypertrophy on electrocardiogram, high alcohol consumption, high systolic blood pressure, and albuminuria, predicted CHD events in multivariate Cox regression analysis (1.34, 1.03-1.74, P = 0.03). CONCLUSIONS: IRS is a risk factor for CHD in elderly type 2 diabetic men.

Heart rate in relation to insulin sensitivity and insulin secretion in nondiabetic subjects.

OBJECTIVE: Elevated heart rate has been predictive of cardiovascular disease and has been proposed as a global index of the autonomic nervous system influence on the heart. Hyperinsulinism has been shown to trigger sympathetic activity experimentally; however, the clinical and epidemiological data on the association of heart rate with hyperinsulinism and insulin resistance are conflicting. RESEARCH DESIGN AND METHODS: Insulin sensitivity (S(I)) and the acute insulin response (AIR) to glucose were assessed by a frequently sampled intravenous glucose tolerance test and related to resting heart rate in the tri-ethnic nondiabetic population (n = 1,000) of the Insulin Resistance Atherosclerosis Study. RESULTS: Heart rate was related to fasting insulin (r = 0.20), intact proinsulin (r = 0.15), split proinsulin (r = 0.17), and AIR (r = 0.18), and an inverse relation was found between heart rate and S(I) (r = -0.19) (all P values <0.0001, adjusted for age, sex, ethnicity, glucose tolerance status, and smoking). In a multiple linear regression analysis (adjusting for age, sex, ethnicity, clinical center, glucose tolerance status, and smoking), heart rate was significantly and independently associated with AIR, proinsulin, and S(I). CONCLUSIONS: Proinsulin, acute insulin secretion, and S(I) are associated with heart rate in nondiabetic subjects.

Glucokinase gene variants in subjects with late-onset NIDDM and impaired glucose tolerance.

OBJECTIVE: To investigate the frequency of variants of the glucokinase (GCK) gene in subjects with late-onset non-insulin-dependent diabetes mellitus (NIDDM) and in subjects with late-onset impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: The study population included 36 Finnish patients with late-onset NIDDM who were treated with diet for > 8 years or who were newly diagnosed and 40 subjects with late-onset IGT who had low or normal insulin levels when tested by an oral glucose tolerance test. All exons, exon-intron junctions, and islet and liver promotor regions of the GCK gene were amplified with the polymerase chain reaction and screened for mutations using single-strand conformation polymorphism analysis. RESULTS: A silent third-base substitution (TAC: >TAT) in codon 215 of exon 6 was found in 2.8% of NIDDM patients and in 5.0% of IGT subjects. Polymorphisms were found in islet exon 1 at nucleotide 403 (C-->G) in 16.7% of NIDDM patients and in 17.5% of IGT subjects and in the noncoding region of the islet promotor at nucleotide -30 (G-->A) in 13.9% of NIDDM patients and in 25.0% of IGT subjects. Furthermore, in liver intron 1 a variant (C-->T), 12 base pairs upstream from the splice acceptor site, was found in 5.6% of NIDDM patients and in 7.5% of IGT subjects. CONCLUSIONS: These results indicate that the mutations in the coding region of the GCK gene are not likely to play a major role the pathogenesis of late-onset NIDDM or IGT in the Finnish population.

Plasma oxidizability in subjects with normal glucose tolerance, impaired glucose tolerance, and NIDDM.

OBJECTIVE: Several lines of evidence support an atherogenic role for oxidized low-density lipoprotein (LDL). Studies on LDL oxidation in diabetes to date have examined LDL isolated from plasma, but have failed to evaluate the other pro- and antioxidant factors present in vivo, the balance of which could be crucial in determining the susceptibility of LDL to lipid peroxidation. RESEARCH DESIGN AND METHODS: We examined the oxidizability of plasma from Mexican-Americans in the San Antonio Heart Study. The oxidizability of plasma in 75 subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and non-insulin-dependent diabetes mellitus (NIDDM) was studied after co-incubation with a free radical initiator, 2,2'-azobis-2-amidinopropane hydrochloride (AAPH). Lipid peroxide (LPO) levels were measured by a modified fluorimetric assay. RESULTS: Baseline LPO levels (mumol/l; means +/- SE) were similar in the three glucose tolerance categories (NGT, 1.99 +/- 0.07; IGT, 1.88 +/- 0.07; NIDDM, 1.97 +/- 0.07; P = 0.521). However, after incubation with AAPH (NGT, 4.30 +/- 0.20; IGT, 4.45 +/- 0.20; NIDDM, 5.35 +/- 0.20; P = 0.003), the diabetic plasma had significantly greater amounts of LPOs compared with the other two groups. There was no significant difference in LPOs between the NGT and IGT groups. The statistical significance of increased oxidizability of the diabetic plasma persisted after exclusion of patients who smoked cigarettes (n = 15) or who had vascular disease (n = 4). CONCLUSIONS: In conclusion, this study shows that the plasma of Mexican-American subjects with NIDDM is more prone to lipid peroxidation than that of non-Hispanic whites.