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Leptin and Body Fat in Type 2 Diabetes and Monodrug Therapy

Department of Internal Medicine, Divisions of Endocrinology and Metabolism and Cardiology, Iowa City Veterans Affairs Medical Center and University of Iowa, and University of Iowa General Clinical Research Center, Iowa City, Iowa 52246

Address all correspondence and requests for reprints to: Dr. William Sivitz, Department of Internal Medicine, University of Iowa Health Care, 3E-17 VA, Iowa City, Iowa 52246. E-mail: william-sivitz{at}uiowa.edu.

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; r² = 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.

This work was supported by Veterans Affairs Medical Research Funds, the Juvenile Diabetes Foundation International, NIH Grant DK-25295, and Grant M01-RR00059 from the National Center for Research Resources, General Clinical Research Centers Program, NIH.

Abbreviations: BMI, Body mass index; DEXA, dual energy x-ray absorptiometry; DM, diabetes mellitus; FFA, free fatty acids; FPG, fasting plasma glucose; FSIVGTT, frequently sampled, iv glucose tolerance test; GCRC, General Clinical Research Center; HbA_1c, hemoglobin A_1c; IFG, impaired fasting glucose; Ins AUC_{0–20 min}, insulin area under the curve for the first 20 min after iv glucose; S_I, sensitivity index; V1, V2, visits 1 and 2.

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