S. M. Haffner

HYPERINSULINAEMIA : THE KEY FEATURE OF A CARDIOVASCULAR AND METABOLIC SYNDROME

SummaryIn a population-based survey of 2,930 subjects, prevalence rates for obesity, Type 2 (non-insulin-dependent) diabetes mellitus, impaired glucose tolerance, hypertension, hypertriglyceridaemia, and hypercholesterolaemia were 54.3, 9.3, 11.1, 9.8, 10.3 and 9.2%, respectively. The prevalence, however, of each of these conditions in its isolated form (free of the other five) was 29.0% for obesity, 1.3% for Type 2 diabetes, 1.8% for impaired glucose tolerance, 1.5% for hypertension, 1.0% for hypertriglyceridaemia, and 1.7% for hypercholesterolaemia. Two-by-two associations were even rarer. The large differences in prevalence between isolated and mixed forms indicate a major overlap among the six disorders in multiple combinations. In the isolated form, each condition was characterized by hyperinsulinaemia (both fasting and 2 h after oral glucose), suggesting the presence of insulin resistance. In addition, in any isolated condition most of the variables categorising other members of the sextet were still significantly altered in comparison with 1,049 normal subjects. In the whole of the subjects who presented with one or another disorder (1,881 of 2,930 or 64%), marked fasting and post-glucose hyperinsulinaemia was associated with higher body mass index, waist:hip ratio, fasting and post-glucose glycaemia, systolic and diastolic blood pressure, serum triglycerides and total cholesterol levels, and with lower HDL-cholesterol concentrations (all p <0.001). We conclude that (1) insulin sensitivity, glucose tolerance, blood pressure, body fat mass and distribution, and serum lipids are a network of mutually interrelated functions; and (2) an insulin resistance syndrome underlies each and all of the six disorders carrying an increased risk of coronary artery disease.

Insulin Sensitivity and Atherosclerosis

Background Reduced insulin sensitivity has been proposed as an important risk factor in the development of atherosclerosis. However, insulin sensitivity is related to many other cardiovascular risk factors, including plasma insulin levels, and it is unclear whether an independent role of insulin sensitivity exists. Large epidemiological studies that measure insulin sensitivity directly have not been conducted. Methods and Results The Insulin Resistance Atherosclerosis Study (IRAS) evaluated insulin sensitivity (SI) by the frequently sampled intravenous glucose tolerance test with analysis by the minimal model of Bergman. IRAS measured intimal-medial thickness (IMT) of the carotid artery as an index of atherosclerosis by use of noninvasive B-mode ultrasonography. These measures, as well as factors that may potentially confound or mediate the relationship between insulin sensitivity and atherosclerosis, were available in relation to 398 black, 457 Hispanic, and 542 non-Hispanic white IRAS participants. Ther...

National Cholesterol Education Program Versus World Health Organization Metabolic Syndrome in Relation to All-Cause and Cardiovascular Mortality in the San Antonio Heart Study

Background—To assess the utility of clinical definitions of the metabolic syndrome (MetS) to identify individuals with increased cardiovascular risk, we examined the relation between the MetS, using both the National Cholesterol Education Program (NCEP) and the World Health Organization definitions, and all-cause and cardiovascular mortality in San Antonio Heart Study participants enrolled between 1984 and 1988. Methods and Results—Among 2815 participants, 25 to 64 years of age at enrollment, 509 met both criteria, 197 met NCEP criteria only, and 199 met WHO criteria only. Over an average of 12.7 years, 229 deaths occurred (117 from cardiovascular disease). Moreover, in the primary prevention population of 2372 participants (ie, those without diabetes or cardiovascular disease at baseline), 132 deaths occurred (50 from cardiovascular disease). In the primary prevention population, the only significant association adjusted for age, gender, and ethnic group was between NCEP-MetS and cardiovascular mortality (hazard ratio [HR], 2.01; 95% CI, 1.13–3.57). In the general population, all-cause mortality HRs were 1.47 (95% CI, 1.13–1.92) for NCEP-MetS and 1.27 (95% CI, 0.97–1.66) for WHO-MetS. Furthermore, for cardiovascular mortality, there was evidence that gender modified the predictive ability of the MetS. For women and men, respectively, HRs for NCEP-MetS were 4.65 (95% CI, 2.35–9.21) and 1.82 (95% CI, 1.14–2.91), whereas HRs for WHO-MetS were 2.83 (95% CI, 1.55–5.17) and 1.15 (95% CI, 0.72–1.86). Conclusions—In summary, although both definitions were predictive in the general population, the simpler NCEP definition tended to be more predictive in lower-risk subjects.

The relation of body fat mass and distribution to markers of chronic inflammation

OBJECTIVE: To study the relation of fibrinogen and C-reactive protein (CRP) to various measures of body fat and body fat distribution and to investigate whether these relations were explained by differences in insulin sensitivity.DESIGN AND SUBJECTS: Cross-sectional analysis of the IRAS (Insulin Resistance Atherosclerosis Study), a large (n=1559) tri-ethnic population (non-Hispanic whites, African-Americans and Mexican-Americans) across different states of glucose tolerance.MEASUREMENTS: Glucose tolerance (oral glucose tolerance test), insulin sensitivity (frequently sampled intravenous glucose tolerance test and minimal model analysis), assessment of body fat mass and distribution (weight, girths, bioelectrical impedance), subclinical atherosclerosis (B-mode ultrasonography of carotid artery intima-media thickness, IMT), CRP (highly sensitive immunoassay), fibrinogen (standard assay).RESULTS: Both CRP and fibrinogen were related to all measures of body fat. Strong correlations (correlation coefficient r≥0.35) were found between CRP and body mass index (BMI), waist circumference and adipose body mass, respectively. The associations were consistent in non-diabetic and type-2 diabetic subjects, were generally stronger in women, and were only moderately attenuated by the prevailing insulin sensitivity (SI). In a multivariate linear regression model waist circumference explained 14.5% of the variability of circulating CRP levels (P=0.0001), BMI 0.4% (P=0.0067), and SI 1.7% (P=0.0001). Common carotid artery IMT was related to CRP and fibrinogen in men, but not in women, and was attenuated after adjusting for BMI or waist.CONCLUSION: Our findings show that measures of body fat are strongly associated with circulating levels of CRP and fibrinogen. These associations were not explained by lower SI in obese subjects. Chronic, subclinical inflammation may be one pathophysiological mechanism explaining the increased risk of atherosclerotic disease associated with adiposity.

Dyslipidemia and Hyperglycemia Predict Coronary Heart Disease Events in Middle-Aged Patients With NIDDM

Patients with NIDDM are at increased risk for coronary heart disease (CHD). However, information on the predictive value of cardiovascular risk factors and the degree of hyperglycemia with respect to the risk for CHD in diabetic patients is still limited. Therefore, we carried out a prospective study on risk factors for CHD, including a large number of NIDDM patients. At baseline, risk factor levels of CHD were determined in 1,059 NIDDM patients (581 men and 478 women), aged from 45 to 64 years. These patients were followed up to 7 years with respect to CHD events. Altogether, 158 NIDDM patients (97 men [16.7%] and 61 women [12.8%]) died of CHD and 256 NIDDM patients (156 men [26.8%] and 100 women [20.9%]) had a serious CHD event (death from CHD or nonfatal myocardial infarction). A previous history of myocardial infarction, low HDL cholesterol level (<1.0 mmol/l), high non-HDL cholesterol (>5.2 mmol/l), high total triglyceride level (>2.3 mmol/l), and high fasting plasma glucose (>13.4 mmol/l) were associated with a twofold increase in the risk of CHD mortality or morbidity, independently of other cardiovascular risk factors. High calculated LDL cholesterol level (≥4.1 mmol/l) was significantly associated with all CHD events. The simultaneous presence of high fasting glucose (>13.4 mmol/l) with low HDL cholesterol, low HDL–to–total cholesterol ratio, or high total triglycerides further increased the risk for CHD events up to threefold. Our 7-year follow-up study provides evidence that dyslipidemia and poor glycemic control predict CHD mortality and morbidity in patients with NIDDM.

Hyperinsulinemia in a Population at High Risk for Non-Insulin-Dependent Diabetes Mellitus

The prevalence of non-insulin-dependent diabetes mellitus (NIDDM) is higher in Mexican Americans than in non-Hispanic white Americans, even after adjustment for the formers greater overall and more centralized adiposity. We postulated that this excess risk of NIDDM could be due to resistance to insulin. We performed oral glucose-tolerance tests with measurements of serum insulin concentrations in 225 Mexican Americans and 180 non-Hispanic whites without diabetes as part of the San Antonio Heart Study, a population-based study of risk factors for diabetes. Changes in serum insulin concentrations in response to the glucose challenge were quantified by the area under the serum insulin curve. Overall adiposity was characterized by body-mass index, and regional body-fat distribution by the ratio of subscapular to triceps skinfolds and the ratio of waist to hip circumference. After adjustment for these indicators of adiposity and also for differences in glucose tolerance, Mexican Americans were found to have significantly greater areas under the serum insulin curve than non-Hispanic whites. These data suggest that, like other populations at high risk for NIDDM such as Pima Indians and Micronesians, Mexican Americans have more hyperinsulinemia than can be accounted for by their adiposity.

Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance. The Insulin Resistance Atherosclerosis Study (IRAS).

Hyperinsulinemia is associated with the development of coronary heart disease. However, the underlying mechanisms are still poorly understood. Hypercoagulability and impaired fibrinolysis are possible candidates linking hyperinsulinism with atherosclerotic disease, and it has been suggested that proinsulin rather than insulin is the crucial pathophysiological agent. The aim of this study was to investigate the relationship of insulin and its precursors to markers of coagulation and fibrinolysis in a large triethnic population. A strong and independent relationship between plasminogen activator inhibitor-1 (PAI-1) antigen and insulin and its precursors (proinsulin, 32-33 split proinsulin) was found consistently across varying states of glucose tolerance (PAI-1 versus fasting insulin [proinsulin], r=0.38 [r=0.34] in normal glucose tolerance; r=0.42 [r=0.43] in impaired glucose tolerance; and r=0.38 [r=0.26] in type 2 diabetes; all P<0.001). The relationship remained highly significant even after accounting for insulin sensitivity as measured by a frequently sampled intravenous glucose tolerance test. In a stepwise multiple regression model after adjusting for age, sex, ethnicity, and clinic, both insulin and its precursors were significantly associated with PAI-1 levels. The relationship between fibrinogen and insulin and its precursors was significant in the overall population (r=0.20 for insulin and proinsulin; each P<0.001) but showed a more inconsistent pattern in subgroup analysis and after adjustments for demographic and metabolic variables. Stepwise multiple regression analysis showed that proinsulin (split products) but not fasting insulin significantly contributed to fibrinogen levels after adjustment for age, sex, clinic, and ethnicity. Decreased insulin sensitivity was independently associated with higher PAI-1 and fibrinogen levels. In summary, we were able to demonstrate an independent relationship of 2 crucial factors of hemostasis, fibrinogen and PAI-1, to insulin and its precursors. These findings may have important clinical implications in the risk assessment and prevention of macrovascular disease, not only in patients with overt diabetes but also in nondiabetic subjects who are hyperinsulinemic.

Microalbuminuria. Potential marker for increased cardiovascular risk factors in nondiabetic subjects

Microalbuminuria is associated with progression to renal disease in insulin-dependent diabetes and with increased mortality in noninsulin-dependent diabetes. In contrast, few studies have addressed the effect of microalbuminuria on cardiovascular risk in nondiabetics. We, therefore, determined the level of microalbuminuria in 316 nondiabetic subjects from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular risk factors. Microalbuminuria (greater than or equal to 30 mg/l) was found in 42 of these 316 subjects (13%). Subjects with microalbuminuria had significantly higher blood pressure, triglyceride concentration, sum of insulin concentrations during a glucose tolerance test, and prevalence of hypertension and of self-reported myocardial infarction than subjects without microalbuminuria. When subjects with hypertension were excluded (n = 27), normotensive subjects with microalbuminuria (n = 31) still had significantly higher triglyceride concentrations and insulin sum than normotensive subjects without microalbuminuria (n = 258), suggesting that an increased atherogenic risk factor pattern exists even in normotensive subjects with microalbuminuria. Microalbuminuria may be a marker for cardiovascular risk, although it is not certain whether microalbuminuria causes these metabolic changes or results from some metabolic disturbance such as insulin resistance.

Microalbuminuria and Carotid Artery Intima-Media Thickness in Nondiabetic and NIDDM Subjects The Insulin Resistance Atherosclerosis Study (IRAS)

BACKGROUND AND PURPOSE Microalbuminuria is associated with cardiovascular mortality in subjects with non-insulin-dependent diabetes mellitus (NIDDM). However, little is known about this association in nondiabetic subjects. Specifically, it is not known whether microalbuminuria is related to an early stage of atherosclerosis manifested as increased intima-media thickness (IMT) of carotid arteries. We investigated the relationship between microalbuminuria and carotid artery IMT in 991 nondiabetic and 450 NIDDM subjects aged 40 to 69 years. METHODS Microalbuminuria was defined as albumin-to-creatinine ratio > or = 2 mg/mmol in a morning spot urine sample. B-mode ultrasound was used to assess the IMT of the common and internal carotid arteries. RESULTS Altogether 13.9% of nondiabetic and 27.6% of NIDDM subjects had microalbuminuria, and 31.1% of nondiabetic and 50.8% of NIDDM subjects had hypertension. Subjects with microalbuminuria had greater common carotid artery (CCA) IMT than those without microalbuminuria (nondiabetic: 0.84 +/- 0.02 versus 0.80 +/- 0.01 mm, P = .010; NIDDM: 0.89 +/- 0.02 versus 0.86 +/- 0.01 mm, P = .152; combined: 0.86 +/- 0.01 versus 0.82 +/- 0.01, P = .005). The association of microalbuminuria and CCA IMT was independent of age, sex, ethnicity, smoking, and lipoprotein levels. Although further adjustment for hypertension in the multivariate linear regression analysis attenuated the difference in CCA IMT between subjects with and without microalbuminuria, this difference continued to be significant (combined: 0.86 +/- 0.01 versus 0.83 +/- 0.01, P = .015). In contrast to CCA IMT, microalbuminuria was not related to ICA IMT. CONCLUSIONS Microalbuminuria was associated with increased CCA IMT. This relationship was only partly mediated by hypertension. Thus, microalbuminuria is related to atherosclerosis at an early stage of the disease process.

Role of Obesity and Fat Distribution in Non-insulin-dependent Diabetes Mellitus in Mexican Americans and Non-Hispanic Whites

Recent data have suggested that central obesity is related positively to the prevalence of non-insulindependent diabetes mellitus (NIDDM). We examined whether central obesity (measured by the ratio of subscapular to triceps skinfold) was predictive of NIDDM prevalence independently of overall obesity (measured by body mass index, BMI) in 1231 Mexican Americans and 939 non-Hispanic whites who participated in the San Antonio Heart Study, a population-based survey of diabetes and cardiovascular risk factors. Mexican Americans are characterized by higher rates of NIDDM, greater overall obesity, and more central body fat distribution than age-matched non-Hispanic whites. Using multiple logistic regression with age, ethnicity, BMI, and central obesity as covariates, overall obesity was positively associated with NIDDM prevalence in both sexes (P < 0.001) but central obesity was related to NIDDM prevalence only in women. Our data suggest that the effect of centrality decreases at higher levels of centrality. While both BMI and centrality narrow the ethnic difference in NIDDM prevalence, Mexican Americans still have an increased risk of NIDDM (odds ratio = 2.33 in men and 1.80 in women), suggesting that other factors, possibly genetic, may also be important determinants of the ethnic differences in NIDDM prevalence.