Sex and type 2 diabetes: obesity-independent effects on left ventricular substrate metabolism and relaxation in humans

Abstract

Patients with type 2 diabetes (T2DM), particularly women, are at risk for heart failure. Myocardial substrate metabolism derangements contribute to cardiac dysfunction in diabetic animal models. The purpose of this study was to determine the effects of diabetes and sex on myocardial metabolism and diastolic function in humans, separate from those of obesity. Thirty-six diabetic subjects (22 women) and 36 nondiabetic, BMI-matched subjects (21 women) underwent positron emission tomography (myocardial metabolism) and echocardiography (structure, function). Myocardial blood flow and oxygen consumption (MVO(2)) were higher in women than men (P = 0.003 and <0.0001, respectively). Plasma fatty acid (FA) levels were higher in diabetics (vs. obese, P < 0.003) and sex and diabetes status interacted in its prediction (P = 0.03). Myocardial FA utilization, oxidation, and esterification were higher and percent FA oxidation lower in diabetics (vs. obese, P = 0.0004, P = 0.007, P = 0.002, P = 0.02). FA utilization and esterification were higher and percent FA oxidation lower in women (vs. men, P = 0.03, P = 0.01, P = 0.03). Diabetes and sex did not affect myocardial glucose utilization, but myocardial glucose uptake/plasma insulin was lower in the diabetics (P = 0.04). Left ventricular relaxation was lower in diabetics (P < 0.0001) and in men (P = 0.001), and diabetes and sex interacted in its prediction (P = 0.03). Sex, T2DM, or their interaction affect myocardial blood flow, MVO(2), FA metabolism, and relaxation separate from obesity's effects. Sexually dimorphic myocardial metabolic and relaxation responses to diabetes may play a role in the known cardiovascular differences between men and women with diabetes.

Trial registration: ClinicalTrials.gov NCT00572624 NCT00577590.

Figure 1

Effects of sex and diabetes (DM) on left ventricular relaxation. ^aP<0.005 for the subgroup comparison between obese men and women. ^bP=0.03 for the interaction between sex and diabetes status even after adding left ventricular mass index, mean arterial pressure, and rate-pressure product to a multivariate model.

Figure 2

Effects of sex on myocardial blood flow and oxygen consumption (MVO₂). No effect of diabetes (DM). After adjustment for age, ^aP=0.005; ^bP<0.0001. Subgroup analysis: ^cP<0.05 for diabetic men vs. women, ^dP<0.001 for obese men vs. women.

Figure 3

Figure 3A. Effects of sex and diabetes on plasma fatty acid (FA) levels and myocardial FA utilization. No interaction sex & diabetes (DM) on FA utilization. After adjustment for age, ^aP=0.02 and ^bP=0.03, ^cP=0.33, ^dP=0.008. Subgroup analyses: ^eP=0.03 and ^fP<0.06 for diabetic men vs. women, P not significant for obese men vs. women. Figure 3B. Effects of sex and diabetes (DM) on myocardial fatty acid (FA) oxidation, esterification, and %oxidation. After adjustment for age, ^aP=NS, ^bP=0.0060, ^cP=0.03. Subgroup analyses not significantly different for FA oxidation; for FA esterification, ^dP<0.06 for diabetic men vs. women, not significant for obese men vs. women; for %FA oxidation, no significant differences in subgroup analyses.

Figure 3

Figure 3A. Effects of sex and diabetes on plasma fatty acid (FA) levels and myocardial FA utilization. No interaction sex & diabetes (DM) on FA utilization. After adjustment for age, ^aP=0.02 and ^bP=0.03, ^cP=0.33, ^dP=0.008. Subgroup analyses: ^eP=0.03 and ^fP<0.06 for diabetic men vs. women, P not significant for obese men vs. women. Figure 3B. Effects of sex and diabetes (DM) on myocardial fatty acid (FA) oxidation, esterification, and %oxidation. After adjustment for age, ^aP=NS, ^bP=0.0060, ^cP=0.03. Subgroup analyses not significantly different for FA oxidation; for FA esterification, ^dP<0.06 for diabetic men vs. women, not significant for obese men vs. women; for %FA oxidation, no significant differences in subgroup analyses.