Ervin Szoke

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

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 β-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.

Effect of Aging on Glucose Homeostasis: Accelerated Deterioration of Beta Cell Function in Individuals with Impaired Glucose Tolerance

OBJECTIVE—To examine the effect of aging on insulin secretion (first- and second-phase insulin release) and insulin sensitivity in people with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS—First- and second-phase insulin secretion and insulin sensitivity were assessed in hyperglycemic clamp experiments in 266 individuals with NGT and 130 individuals with IGT, ranging in age from ∼20 to ∼70 years. Changes in β-cell function were compared using the disposition index to adjust for differences in insulin sensitivity. RESULTS—As expected, both phases of insulin release and insulin sensitivity were reduced in individuals with IGT (all P < 0.01). Insulin sensitivity was not independently correlated with age in either group. In people with NGT, the disposition index for first- and second-phase insulin release decreased similarly at a rate of ∼0.7% per year. In people with IGT, the disposition indexes for first- and second-phase insulin release decreased at greater rates (∼2.2 and 1.4% per year, P = 0.002 and 0.009, respectively, vs. NGT), with the decrease in first phase being greater than that of second phase (P = 0.025). CONCLUSIONS—Insulin secretion (both first and second phase) normally decreases at a rate of ∼0.7% per year with aging; this decrease in β-cell function is accelerated about two-fold in people with impaired glucose tolerance—first phase to a greater extent than second phase. Finally, aging per se has no effect on insulin sensitivity independent of changes in body composition.

Different pathophysiology of impaired glucose tolerance in first-degree relatives of individuals with type 2 diabetes mellitus

To assess whether an increased genetic predisposition for type 2 diabetes mellitus (T2DM) influences the contributions of insulin resistance and impaired insulin secretion to impaired glucose tolerance (IGT), 437 subjects not known to have T2DM underwent an oral glucose tolerance test and a 3-hour hyperglycemic clamp. Plasma insulin responses and insulin sensitivity were compared between all subjects (unselected for demographic or anthropometric characteristics) who had normal glucose homeostasis and no first-degree T2DM relative (n = 133), IGT with a first-degree T2DM relative (IGT/FH+, n = 74), or IGT without a first-degree T2DM relative (IGT/FH-, n = 50). Compared with those with normal glucose homeostasis, first- and second-phase plasma insulin responses were reduced approximately 45% and 30%, respectively (both P < .001), in IGT/FH+, whereas insulin sensitivity was only approximately 20% reduced (P = .011). In contrast, in IGT/FH-, first-phase plasma insulin responses were only approximately 20% reduced (P = .016), second-phase plasma insulin responses were not reduced, but insulin sensitivity was approximately 40% reduced (P < .001). The IGT/FH+ group differed significantly from the IGT/FH- group by having 25% to 30% lower first-phase plasma insulin responses (P = .026) and 25% to 30% greater insulin sensitivity (P = .027). Adjustment for obesity abolished the differences in insulin resistance but not plasma insulin responses. However, when the IGT groups were stratified into subgroups based on body mass index (BMI), first-phase plasma insulin responses were approximately 30% lower in IGT/FH+ with a BMI of at least 27 kg/m(2) (P = .018) but similar in IGT/FH+ with a BMI less than 27 kg/m(2) compared with the corresponding IGT/FH- subgroups. We conclude that, in IGT, an increased genetic predisposition for T2DM increases the contribution of impaired insulin secretion to its pathophysiology. This effect is enhanced by obesity.