Philip A. Morales

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

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

Lp(a) Concentrations in NIDDM

NIDDM patients have a two- to fourfold increased risk of CHD relative to nondiabetic subjects. This excess risk is explained only partially by increased levels of standard risk factors. We compared the plasma concentrations of Lp(a) in NIDDM patients (n = 260) and nondiabetic subjects (n = 336) who participated in a population-based study (San Antonio Heart Study). Lp(a) was measured using a monoclonal anti-Lp(a) antibody. NIDDM patients and nondiabetic subjects had similar Lp(a) concentrations for both men (13.6 ± 1.5 vs. 16.1 ± 1.4 mg/dl) and women (12.6 ± 0.8 vs. 15.9 ± 1.3 mg/dl) (P = 0.361). Duration of diabetes and level of fasting glycemia were not significantly related to Lp(a) concentrations. Lp(a) levels were significantly higher in patients who had higher total and LDL cholesterol levels. We conclude that in a large population-based study, Lp(a) levels are not increased in NIDDM patients.

Incidence of NIDDM and impaired glucose tolerance in hypertensive subjects: The San Antonio heart study

Hypertension often occurs in association with NIDDM and IGT. We examined the association of hypertension at baseline to the 8-yr incidence of NIDDM and IGT in 1471 subjects who participated in the San Antonio Heart Study. Subjects who were hypertensive at baseline had a higher incidence of NIDDM (8.9 vs. 4.9%, P = 0.041) and IGT (25.2 vs. 10.0%, P < 0.001) than subjects who were normotensive at baseline. After adjusting for age, sex, ethnicity, obesity, body fat distribution, fasting glucose, and insulin, this excess was eliminated for NIDDM, but not for IGT. Specifically, the adjusted OR for NIDDM in hypertensive versus normotensive patients was 0.73 (95% Cl 0.34–1.58), whereas the adjusted OR for IGT was 1.87 (95% Cl 1.08–3.22). The excess risk of NIDDM in hypertensive patients can be explained by their greater age, obesity, more unfavorable body fat distribution, and hyperinsulinemia, whereas the excess risk of IGT is independent of these factors.

Cardiovascular risk factors in non-insulin-dependent diabetic subjects with microalbuminuria.

In subjects with insulin-dependent diabetes mellitus, microalbuminuria has been associated with increased triglyceride and lipoprotein (a) (Lp[a]) concentrations and increased blood pressure. However, few studies have examined whether this association is present in subjects with non-insulin-dependent diabetes mellitus (NIDDM). We measured lipids, lipoproteins, Lp(a), blood pressure, and albumin excretion in 234 subjects with NIDDM from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Seventy-two subjects had microalbuminuria (> or = 30 mg/dl). These subjects had increased systolic and diastolic blood pressures and higher fasting glucose concentrations relative to subjects without microalbuminuria. However, there were no significant differences between subjects with and without microalbuminuria with respect to lipids, lipoproteins, Lp(a), self-reported myocardial infarction, obesity, or body fat distribution. Subjects with diabetic retinopathy had increased microalbuminuria. In multivariate analysis both glycemia and blood pressure continued to be significantly related to the presence of microalbuminuria. We conclude that NIDDM subjects with microalbuminuria have elevated blood pressure and more severe glycemia but do not have a significantly more atherogenic pattern of lipids, lipoproteins, or Lp(a) than subjects without microalbuminuria.

Greater Effect of Glycemia on Incidence of Hypertension in Women Than in Men

OBJECTIVE In subjects with NIDDM, diabetic women have a greater relative excess of CHD relative to nondiabetic women than do diabetic men relative to nondiabetic men. This excess in diabetic women is explained partially by the particularly atherogenic pattern of lipoproteins in this group. We hypothesize that diabetic women also may have a higher incidence of hypertension than diabetic men. RESEARCH DESIGN AND METHODS We examined the effect of NIDDM and IGT relative to NGT on the incidence of hypertension separately in men (n = 844) and women (n = 618) in the 8-yr follow-up of the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. RESULTS Women had a greater risk of hypertension with worsening glucose tolerance (RR NIDDM/NGT = 2.65 and RR IGT/NGT = 1.94) compared with men (RR NIDDM/NGT = 1.61 and RR IGT/NGT = 0.91). Controlling for other possible confounding variables such as age, obesity, body fat distribution, and fasting insulin concentration did not alter the interaction of sex and glycemia on incidence of hypertension. CONCLUSIONS The especially increased risk of hypertension in women with abnormal glucose tolerance may explain partly the high risk of CHD in this group.

Predicting Diabetes: Moving Beyond Impaired Glucose Tolerance

We developed predictive models for type II diabetes using stepwise multiple logistic regression analyses of a cohort of 844 Mexican Americans and 641 non-Hispanic whites who were nondiabetic at baseline and who were then followed for 8 yr. Models were developed for the overall population and separately for each sex and ethnic group. For optimal models, the multiple logistic regression program selected potential risk factors from a panel of 5 categorical and 14 continuous demographic, anthropometric, metabolic, and hemodynamic variables. For reduced models, the list of candidate variables was restricted to those commonly used in ordinary clinical practice, i.e., skinfolds, and serum insulin and postural glucose load variables were excluded. For all models, the stepwise process selected a mixture of anthropometric, glucose, lipid, and hemodynamic variables. The top 15% of the risk continuum for each model was defined as high risk to compare the performance of the models with the performance of impaired glucose tolerance (15% prevalence) as a predictor of diabetes. The relative risk of being high risk ranged from 12.16 to 35.29, whereas the relative risk of having impaired glucose tolerance ranged from 7.11 to 10.0. The sensitivity of the multiple logistic regression models ranged from 67.7 to 83.3% compared with 56.5 to 62.1% for impaired glucose tolerance. The results indicate that multivariate predictive models perform at least as well, if not better than impaired glucose tolerance in predicting type II diabetes but need not require an oral glucose load. Moreover, the models highlight the complex metabolic and hemodynamic syndrome that precedes diabetes.

Level of control of hypertension in Mexican Americans and non-Hispanic whites.

Compared with non-Hispanic whites, Mexican Americans have a higher prevalence of diabetes, greater adiposity, and an unfavorable body fat distribution. The prevalence of hypertension, however, is similar or lower in Mexican Americans than in non-Hispanic whites. There is little information on the level of blood pressure control in Mexican Americans. We compared the mean blood pressure levels of Mexican American and non-Hispanic white hypertensive subjects in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Hypertension was defined as one or more of a systolic blood pressure > or = 160 mm Hg, a diastolic blood pressure > or = 95 mm Hg, and current use of antihypertensive medications. Three hundred and fifty-eight Mexican Americans and 241 non-Hispanic whites met these criteria. Poor hypertension control was defined as a systolic blood pressure > or = 160, a diastolic blood pressure > or = 95 mm Hg, or both. After adjustment for age, gender, obesity, body fat distribution, and level of educational attainment, Mexican American hypertensive subjects were in significantly poorer control than non-Hispanic white hypertensive subjects. The reasons for their poorer control are unknown, but our findings emphasize the importance of hypertension in this ethnic group.

Clinical Gallbladder Disease in NIDDM Subjects: Relationship to duration of diabetes and severity of glycemia

Objective— To examine the relationship between the prevalence of gallbladder disease and severity of glycemia among diabetic individuals and to provide insight into whether the diabetes-gallstone association is a causal one, because NIDDM patients have an increased prevalence of clinical gallbladder disease. Research Design and Methods— We examined 462 diabetic individuals identified during the San Antonio Heart Study, a population-based survey of diabetes and cardiovascular disease in Mexican Americans and non-Hispanic whites. Diabetes was diagnosed according to National Diabetes Data Group criteria. Results— The prevalence of self-reported gallbladder disease was 34.2% in diabetic women and 7.2% in diabetic men. Although duration of diabetes was positively related to the prevalence of gallbladder disease (P < 0.01), type of therapy was not associated, and fasting glucose concentration was inversely associated with gallbladder disease. Conclusions— Factors other than hyperglycemia may account for the increased prevalence of gallbladder disease in diabetic subjects.