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Different Mechanisms for Impaired Fasting Glucose and Impaired Postprandial Glucose Tolerance in Humans

¹ Department of Endocrinology, Carl T. Hayden VA Medical Center, Phoenix, Arizona
² Department of Clinical Medicine, Faculdade de Medicina Botucatu, University of Sao Paulo State, Sao Paulo, Brazil
³ Department of Internal Medicine II, Ludwig-Maximilians University of Munich, Munich, Germany
⁴ Department of Internal Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
⁵ Department of Medicine, University of Rochester School of Medicine, Rochester, New York
⁶ Diabetes/Metabolism Unit, Henry Dunant Foundation, Athens, Greece

Address correspondence and reprint requests to Christian Meyer, MD, Carl T. Hayden VA Medical Center, 650 East Indian School Rd., Phoenix, AZ 85012. E-mail: christian.meyer{at}med.a.gov

OBJECTIVE—To compare the pathophysiology of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) in a more comprehensive and standardized fashion than has hitherto been done.

RESEARCH DESIGN AND METHODS—We studied 21 individuals with isolated IFG (IFG/normal glucose tolerance [NGT]), 61 individuals with isolated IGT (normal fasting glucose [NFG]/IGT), and 240 healthy control subjects (NFG/NGT) by hyperglycemic clamps to determine first- and second-phase insulin release and insulin sensitivity. Homeostasis model assessment (HOMA) indexes of ß-cell function (HOMA-%B) and insulin resistance (HOMA-IR) were calculated from fasting plasma insulin and glucose concentrations.

RESULTS—Compared with NFG/NGT, IFG/NGT had similar fasting insulin concentrations despite hyperglycemia; therefore, HOMA-IR was increased 30% (P < 0.05), but clamp-determined insulin sensitivity was normal (P > 0.8). HOMA-%B and first-phase insulin responses were reduced 35% (P < 0.002) and 30% (P < 0.02), respectively, but second-phase insulin responses were normal (P > 0.5). NFG/IGT had normal HOMA-IR but 15% decreased clamp-determined insulin sensitivity (P < 0.03). Furthermore, HOMA-%B was normal but both first-phase (P < 0.0003) and second-phase (P < 0.0001) insulin responses were reduced 30%. IFG/NGT differed from NFG/IGT by having 40% lower HOMA-%B (P < 0.012) and 50% greater second-phase insulin responses (P < 0.005).

CONCLUSIONS—Since first-phase insulin responses were similarly reduced in IFG/NGT and NFG/IGT, we conclude that IFG is due to impaired basal insulin secretion and preferential resistance of glucose production to suppression by insulin, as reflected by fasting hyperglycemia despite normal plasma insulin concentrations and increased HOMA-IR, whereas IGT mainly results from reduced second-phase insulin release and peripheral insulin resistance, as reflected by reduced clamp-determined insulin sensitivity.

Abbreviations: DI, disposition index • EGP, endogenous glucose production • FSIVGTT, frequently sampled intravenous glucose tolerance test • HOMA, homeostasis model assessment • HOMA-%B, HOMA of ß-cell function • HOMA-IR, HOMA of insulin resistance • IFG, impaired fasting glucose • IGT, impaired glucose tolerance • ISI, insulin sensitivity index • NFG, normal fasting glucose • NGT, normal glucose tolerance • OGTT, oral glucose tolerance test • WHR, waist-to-hip ratio

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