David C. Robbins

Impact of Diabetes on Cardiac Structure and Function The Strong Heart Study

BACKGROUND Whether diabetes mellitus (DM) adversely affects left ventricular (LV) structure and function independently of increases in body mass index (BMI) and blood pressure is controversial. METHODS AND RESULTS Echocardiography was used in the Strong Heart Study, a study of cardiovascular disease in American Indians, to compare LV measurements between 1810 participants with DM and 944 with normal glucose tolerance. Participants with DM were older (mean age, 60 versus 59 years), had higher BMI (32.4 versus 28.9 kg/m(2)) and systolic blood pressure (133 versus 124 mm Hg), and were more likely to be female, to be on antihypertensive treatment, and to live in Arizona (all P<0.001). In analyses adjusted for covariates, women and men with DM had higher LV mass and wall thicknesses and lower LV fractional shortening, midwall shortening, and stress-corrected midwall shortening (all P<0.002). Pulse pressure/stroke volume, a measure of arterial stiffness, was higher in participants with DM (P<0.001 independent of confounders). CONCLUSIONS Non-insulin-dependent DM has independent adverse cardiac effects, including increased LV mass and wall thicknesses, reduced LV systolic chamber and myocardial function, and increased arterial stiffness. These findings identify adverse cardiovascular effects of DM, independent of associated increases in BMI and arterial pressure, that may contribute to cardiovascular events in diabetic individuals.

Rising Tide of Cardiovascular Disease in American Indians The Strong Heart Study

BACKGROUND Although cardiovascular disease (CVD) used to be rare among American Indians, Indian Health Service data suggest that CVD mortality rates vary greatly among American Indian communities and appear to be increasing. The Strong Heart Study was initiated to investigate CVD and its risk factors in American Indians in 13 communities in Arizona, Oklahoma, and South/North Dakota. METHODS AND RESULTS A total of 4549 participants (1846 men and 2703 women 45 to 74 years old) who were seen at the baseline (1989 to 1991) examination were subjected to surveillance (average 4.2 years, 1991 to 1995), and 88% of those remaining alive underwent a second examination (1993 to 1995). The medical records of all participants were exhaustively reviewed to ascertain nonfatal cardiovascular events that occurred since the baseline examination or to definitively determine cause of death. CVD morbidity and mortality rates were higher in men than in women and were similar in the 3 geographic areas. Coronary heart disease (CHD) incidence rates among American Indian men and women were almost 2-fold higher than those in the Atherosclerosis Risk in Communities Study. Significant independent predictors of CVD in women were diabetes, age, obesity (inverse), LDL cholesterol, albuminuria, triglycerides, and hypertension. In men, diabetes, age, LDL cholesterol, albuminuria, and hypertension were independent predictors of CVD. CONCLUSIONS At present, CHD rates in American Indians exceed rates in other US populations and may more often be fatal. Unlike other ethnic groups, American Indians appear to have an increasing incidence of CHD, possibly related to the high prevalence of diabetes. In the general US population, the rising prevalence of obesity and diabetes may reverse the decline in CVD death rates. Therefore, aggressive programs to control diabetes and its risk factors are needed.

Effects of Physical Training and Diet Therapy on Carbohydrate Metabolism in Patients with Glucose Intolerance and Non-insulin-dependent Diabetes Mellitus

The effects of 12 wk of physical training in addition to hypocaloric diet (DPT group, N = 10) on body composition, carbohydrate (CHO) tolerance, and insulin secretion and action were compared with the effects of diet therapy alone (D group, N = 8) in CHO-intolerant and non-insulin-dependent diabetic subjects. Fat mass, fat-free mass (FFM), mean fasting plasma glucose, serum C-peptide, and insulin concentrations decreased similarly in both groups. The mean plasma glucose response to a mixed meal decreased approximately 20% in both treatment groups, and, after i.v. glucose, decreased 12% in the D group (P < 0.05), but did not change in the DPT group (NS between groups). The acute serum insulin response (0–6 min) after IG increased significantly in the DPT group only (NS between groups). The mean basal endogenous glucose production (BEGP) decreased 17% (P < 0.025) in the DPT group and by 31% (P < 0.01) in the D group (NS between groups). Hepatic sensitivity to insulin, estimated by BEGP suppression during the euglycemic clamp, increased significantly by 25% in both groups. Total glucose disposal during the euglycemic clamp increased from 3.51 ± 0.04 milligrams of glucose per kilogram of fat-free mass per minute (mg/kg-FFM/min) to 4.45 ± 0.54 mg/kg-FFM/min (P < 0.05) in the DPT group, but no change occurred in the D group (NS between groups). Separation of total glucose disposal rates into CHO oxidative and nonoxidative rates using indirect calorimetry during the euglycemic clamp showed that the mean CHO oxidation rate increased in the D group (P < 0.05), but not in the DPT group (NS between groups). There was, however, a significant difference in the mean CHO nonoxidative rate between the two groups (P < 0.05), increasing in the DPT group but decreasing in the D group. In both groups, the improvements in fasting plasma glucose and meal tolerance appeared to be attributable mostly to decreased BEGP, with increased hepatic sensitivity to insulin. However, glucose disposal was accomplished by different mechanisms in the two groups.

Lack of Effect of Lovastatin on Restenosis after Coronary Angioplasty

BACKGROUND Experimental and clinical observations suggest that lowering serum lipid levels may reduce the risk of restenosis after coronary angioplasty. We report the results of a prospective, randomized, double-blind trial evaluating whether lowering lipid levels with lovastatin can prevent or delay restenosis after angioplasty. METHODS Seven to 10 days before angioplasty, we randomly assigned eligible patients to receive lovastatin (40 mg orally twice daily) or placebo. Patients who underwent successful, complication-free, first-time angioplasty of a native vessel (the index lesion) continued to receive therapy for six months, when a second coronary angiogram was obtained. The primary end point was the extent of restenosis of the index lesion, as assessed by quantitative coronary arteriography. Of 404 patients randomly assigned to study groups, 384 underwent angioplasty; 354 of the procedures were successful, and 321 patients underwent angiographic restudy at six months. RESULTS At base line, the patients in the lovastatin group (n = 203) and the placebo group (n = 201) were similar with respect to demographic clinical, angiographic, and laboratory characteristics. At base line the mean (+/- SD) degree of stenosis, expressed as a percentage of the diameter of the vessel, was 64 +/- 11 percent in the lovastatin group, as compared with 63 +/- 11 percent in the placebo group (P = 0.22). Despite a 42 percent reduction in the serum level of low-density lipoprotein cholesterol in the lovastatin group, after six months of treatment the amount of stenosis seen in the second angiogram was 46 +/- 20 percent in the placebo group, as compared with 44 +/- 21 percent in the lovastatin group (P = 0.50). Similarly, there were no significant differences in minimal luminal diameter or other measures of restenosis. A trend was noted toward more myocardial infarctions in the lovastatin group, as a result of acute vessel closure or restenosis at the site of angioplasty, but there were no other important differences between the two groups in the frequency of fatal or nonfatal events at six months. CONCLUSIONS Treatment with high-dose lovastatin initiated before coronary angioplasty does not prevent or delay the process of restenosis in the first six months after the procedure.

Adverse Effects of Diabetes on Multiple Cardiovascular Disease Risk Factors in Women: The Strong Heart Study

OBJECTIVE Many studies have shown that diabetes increases the risk of cardiovascular disease (CVD) in women to a greater extent than in men. One explanation could be that diabetes has more adverse effects on CVD risk factors in women than in men. We compared diabetes-associated differences in CVD risk factors in men and women in the Strong Heart Study, a population-based study of CVD and its risk factors in American Indians. RESEARCH DESIGN AND METHODS A total of 1,846 men and 2,703 women between the ages of 45 and 74 years from 13 American Indian communities in three geographic areas underwent an examination that included a medical history; an electrocardiogram; anthropometric and blood pressure measurements; an oral glucose tolerance test; and measurements of fasting plasma lipoproteins, fibrinogen, insulin, HbA1c, and urinary albumin. RESULTS Statistically significantly greater adverse differences in those with diabetes versus those without diabetes were observed in women than in men for waist-to-hip ratio, HDL cholesterol, apolipoprotein (apo)B, apoA1, fibrinogen, and LDL size. In multiple linear regression models adjusting for age, center, sex, and diabetes, the diabetes by sex interaction terms were statistically significant for waist-to-hip ratio, LDL cholesterol, HDL cholesterol, apoB, apoA1, fibrinogen, and LDL size. CONCLUSIONS Compared with diabetes-associated differences in men, diabetes in women was related to greater adverse differences in levels of several CVD risk factors. Although the magnitude of the individual diabetes-related differences between men and women was not large, the combined effects of these risk factor differences in diabetic women may be substantial. The apparent greater negative impact of diabetes on CVD risk factors in women may explain, in part, the greater risk for CVD in diabetic women.

Obesity and dyslipidemia

The primary dyslipidemia related to obesity is characterized by increased triglycerides, decreased HDL levels, and abnormal LDL composition. Much work has been done to elucidate the pathogenesis of the dyslipidemia of obesity, which seems to be closely related to insulin resistance in obese individuals; however, more studies in humans are needed to further understand the metabolic mechanisms underlying the changes, and to distinguish between the roles of insulin resistance and body fat in the lipoprotein changes. The dyslipidemia associated with obesity no doubt plays a major role in the development of atherosclerosis and CVD in obese individuals. All of the components of the dyslipidemia, including higher triglycerides, decreased HDL levels, and increased small, dense LDL particles, have been shown to be atherogenic. Weight loss and exercise, even if they do not result in normalization of body weight, can improve this dyslipidemia and thus reduce CVD risk. In addition, obese individuals should be targeted for intense lipid-lowering therapy, when necessary.

LDL Cholesterol as a Strong Predictor of Coronary Heart Disease in Diabetic Individuals With Insulin Resistance and Low LDL The Strong Heart Study

Diabetes has been shown to increase the risk of coronary heart disease in all populations studied. However, there is a lack of information on the relative importance of diabetes-associated risk factors for cardiovascular disease (CVD), especially the role of lipid levels, because low density lipoprotein (LDL) cholesterol often is not elevated in diabetic individuals. The objective of this analysis was to evaluate CVD risk factors in a large cohort of diabetic individuals and to compare the importance of dyslipidemia (ie, elevated triglycerides and low levels of high density lipoprotein [HDL] cholesterol) and LDL cholesterol in determining CVD risk in diabetic individuals. The Strong Heart Study assesses coronary heart disease and its risk factors in American Indians in Arizona, Oklahoma, and South/North Dakota. The baseline clinical examinations (July 1989 to January 1992) consisted of a personal interview, physical examination, and drawing of blood samples for 4549 study participants (2034 with diabetes), 45 to 74 years of age. Follow-up averaged 4.8 years. Fatal and nonfatal CVD events were confirmed by standardized record review. Participants with diabetes, compared with those with normal glucose tolerance, had lower LDL cholesterol levels but significantly elevated triglyceride levels, lower HDL cholesterol levels, and smaller LDL particle size. Significant independent predictors of CVD in those with diabetes included age, albuminuria, LDL cholesterol, HDL cholesterol (inverse), fibrinogen, and percent body fat (inverse). A 10-mg/dL increase in LDL cholesterol was associated with a 12% increase in CVD risk. Thus, even at concentrations well below the National Cholesterol Education Program target of 130 mg/dL, LDL cholesterol is a strong independent predictor of coronary heart disease in individuals with diabetes, even when components of diabetic dyslipidemia are present. These results support recent recommendations for aggressive control of LDL cholesterol in diabetic individuals, with a target level of <100 mg/dL.

Loss of Early Phase of Insulin Release in Humans Impairs Glucose Tolerance and Blunts Thermic Effect of Glucose

Loss of the early phase of insulin release has been documented in both type I (insulin-dependent) and type II (non-insulin-dependent) diabetes; however, the physiological importanceof this loss is unsettled. We created a model of loss of the early phase of insulin release in normal volunteers. Somatostatin (SRIF) was briefly infused (from −5 to 15 min) during intravenous (IVGTT) and oral (OGTT) glucose tolerance tests. The thermic response to oral glucose was determined under these conditions by indirect calorimetry. Early insulin release was totally blocked during IVGTT and OGTT by SRIF infusion. During the IVGTT, glucose tolerance was deteriorated in association with loss of the early phase of insulin release as indicated by a decrease in the K value (control 1.9 ± 0.36 vs. SRIF 1.1 ± 0.27, P < .001). Higher plasma glucose concentrations were observed during SRIF tests in the OGTT at 60, 90, 120, 150, and 180 min; total glycemic excursion was larger during the SRIF test (9473 ± 3089 mg · dl−1 · 5 h−1) when compared with the control condition (6583 ± 2329 mg dl−1 5 h−1). During the OGTT the total amount of glucose oxidized (control 56 ± 4.2 vs. SRIF 55 ± 3.4 g/5 h) was similar in both conditions, suggesting that nonoxidative pathways of glucose disposal were responsible for the deterioration in glucose tolerance. Surprisingly, we found that glucose-induced thermogenesis was reduced in association with loss of the early phase of insulin release (control 102 ± 21.3 vs. SRIF 72 ± 27.8 J/5 h, P < .001). Thus, loss of the early phase of insulin release is associated with deterioration of glucose tolerance and blunted glucose-induced thermogenesis. These data underscore the key role of the early phase of insulin release in glucose homeostasis and provide a possible mechanism that could lead eventually to obesity and diabetes.

Thermic effect of infused glucose and insulin in man. Decreased response with increased insulin resistance in obesity and noninsulin-dependent diabetes mellitus.

The thermic effect of infused glucose and insulin was measured by combining the hyperinsulinemic euglycemic clamp technique with indirect calorimetry, in 10 normal weight volunteers (group I), 7 obese subjects with normal glucose tolerance (group II), and 13 obese subjects with abnormal glucose tolerance or noninsulin-dependent diabetes mellitus before (group IIIa) and after weight loss of 10.8 +/- 0.4 kg (group IIIb). During hyperinsulinemia (760-1,100 pmol/liter), total glucose disposal from combined endogenous production and glucose infusion was 545 +/- 49, 441 +/- 70, 233 +/- 35, 231 +/- 31 mg/min and energy expenditure changed by + 0.476 +/- 0.080, +0.293 +/- 0.095, -0.114 +/- 0.063, and +0.135 +/- 0.082 kJ/min in group I, II, IIIa, and IIIb, respectively. The increased energy expenditure correlated with glucose storage (measured cost of processing the glucose: 1.33 kJ/g). In group IIIa there was no increase in energy expenditure in response to glucose and insulin infusions. After therapy (group IIIb) there was a significant recovery (P less than 0.05) of the thermic effect of infused glucose although total glucose disposal was unchanged. It is proposed that the recovered thermic effect of infused insulin/glucose is due to the different contributions of gluconeogenesis in the fasting state and during the glucose clamp before and after weight loss. In addition we hypothesize that some of the lower thermic effect of food reported in obese noninsulin-dependent diabetics may be explained by decreased energy expenditure due to a greater suppression of hepatic gluconeogenesis as well as by lower storage rate.

Reduction of Glycosylated Hemoglobin and Postprandial Hyperglycemia by Acarbose in Patients With NIDDM: A placebo-controlled dose-comparison study

OBJECTIVE To compare the safety and efficacy of three doses of acarbose (100, 200, and 300 mg three times daily) with placebo for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) in patients maintained on dietary therapy alone. RESEARCH DESIGN AND METHODS This multicenter double-blind placebo-controlled trial was 22 weeks in duration. The trial consisted of a 2-week screening period, a 4-week placebo run-in period, and a 16-week double-blind treatment period. The primary measure of drug efficacy was the mean change from baseline in HbA1c levels. Additional efficacy variables included the mean change from baseline in fasting and postprandial plasma glucose and serum insulin levels. RESULTS After 16 weeks of treatment, acarbose-treated patients had statistically significant reductions in mean HbA1c levels of 0.78, 0.73, and 1.10% (relative to placebo) in the 100-, 200-, and 300-mg t.i.d. groups, respectively. Significant reductions in fasting and postprandial plasma glucose levels, glucose area under the time-concentration curve, and maximum glucose concentration were also observed in acarbose-treated patients. Although there were no statistically significant differences among the 100-, 200-, and 300-mg treatment groups, there was a trend toward a dose-response relationship for most plasma glucose variables that were measured. Gastrointestinal side effects (e.g., abdominal pain, flatulence, and diarrhea) and serum transaminase elevations (e.g., aspartate aminotransferase [AST] and alanine aminotransferase [ALT] were more frequently reported in the acarbose-treated patients than in the placebo-treated control patients. Transaminase elevations occurred only at the 200-, and 300-mg dosages and were readily reversible on discontinuation of treatment. CONCLUSIONS Acarbose at doses of 100, 200, and 300 mg administered three times daily for 16 weeks significantly reduced HbA1c levels and postprandial hyperglycemia. Treatment with acarbose is a safe and effective adjunct to dietary therapy for the treatment of NIDDM.