Obesity impairs vascular relaxation in human subjects: hyperglycemia exaggerates adrenergic vasoconstriction arterial dysfunction in obesity and diabetes.

OBJECTIVES: Arterial dysfunction occurs in obesity and diabetes. However, there is uncertainty about the relative contribution of endothelial dysfunction, smooth muscle dysfunction, or adrenergic hyperresponsiveness. METHODS AND RESULTS: We examined forearm resistance vessel responses to intra-arterial vasoactive agents in matched subjects on no antihyperglycemic medications classified as (1) Type 2 diabetes, (2) impaired fasting glucose (IFG), (3) obese, and (4) nonobese. Responses to both acetylcholine and nitroprusside were impaired in obese, IFG, and diabetic subjects compared to nonobese. However, diabetic and IFG subjects had no further impairment than normoglycemic obese subjects. Gender-specific data revealed that obese, IFG, and diabetic males compared to nonobese males demonstrated impaired responses to nitroprusside. However, among females, obese, IFG, and diabetic subjects demonstrated impaired acetylcholine-mediated responses. Multivariate analyses revealed that gender and adiposity, but not glycemia, were strongly related to acetylcholine and nitroprusside responses. Vasoconstriction to norepinephrine was greater in subjects with diabetes and IFG compared to nondiabetic obese controls. CONCLUSIONS: Microvascular vasodilator function is impaired in obesity, with little further impairment in IFG and Type 2 diabetes. Females appear more sensitive to the deleterious effect of obesity on endothelium-mediated resistance vessel function, and males to smooth muscle-mediated function. There is a specific increase in adrenergic vasoconstrictor responses in IFG and Type 2 diabetes independent of obesity.

Leptin and body fat in type 2 diabetes and monodrug therapy.

To better understand the relations among leptin, insulin, and body fat during the metabolic progression to diabetes and during drug monotherapy, metabolic parameters were examined in subjects classified as 1) type 2 diabetes; 2) impaired fasting glucose or mild diabetes mellitus; 3) nondiabetic, matched for body mass index (BMI); and 4) nonobese, nondiabetic. Diabetic subjects were also studied during no pharmacological treatment, after 3 months of randomization to metformin or glyburide, and after 3 months of cross-over to the opposite drug. Log leptin correlated more with percent body fat (slope, 0.042; confidence interval, 0.036-0.047; r(2) = 0.826; P < 0.0001) than with total fat mass, percent truncal or nontruncal fat, or BMI. When normalized to percent fat, leptin did not differ by gender. Leptin normalized to percent fat was 35% less in untreated diabetes than that in BMI-matched controls (P < 0.001). Leptin normalized to percent fat was increased by 25% (P < 0.01) as a result of glyburide therapy compared with pretreatment values, but was unchanged by therapy with metformin. Across a spectrum of subjects with diabetes, impaired fasting glucose/mild diabetes, or BMI-matched nondiabetic controls, normalized leptin significantly correlated with glucose-induced insulin release, but not with insulin sensitivity. Our data suggest that plasma leptin is reduced in untreated type 2 diabetes probably as a consequence of reduced insulin secretion and that circulating leptin concentrations are differentially affected by monodrug therapy.