Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus.

Abstract

IntroductionSeven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with 13-3HI-and [U-14CIglucose and indirect calorimetry: study I, euglycemic (5.2±0.1 mM) insulin (269±39 pM) clamp; study II, hyperglycemic (14.9±1.2 mM) insulin (259±19 pM) clamp; study III, euglycemic (5.5±0.3 mM) hyperinsulinemic (1650±529 pM) clamp. Seven control subjects received a euglycemic (5.1±0.2 mM) insulin (258±24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H20 and '4CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7±2.1 and 40.7±1.7 gmol/min * kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d)

Effects of hyperglycaemia and hyperinsulinaemia on plasma amino acid levels in obese subjects with normal glucose tolerance

“…In both groups insulin concentrations were in the range known to suppress hepatic glucose production, including amino acids-derived gluconeogenesis. 32,33 On the other hand, hyperglycaemia is also known to contribute to the decline of hepatic glucose production, although with mechanisms still poorly understood. 34 Whether the more pronounced decline in plasma amino acids observed during period A of our study, as compared with the basal period, was entirely due to hyperinsulinaemia or to the combination of hyperinsulinaemia and hyperglycaemia cannot be easily understood.…”

Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance

“…In the diabetic condition, fasting hyperglycaemia provides a compensatory mechanism to maintain glucose metabolism relatively normal in the face of insulin deficiency and/or insulin resistance [8,9,12,25,33]. However, the mass action effect of glucose appears to be greater in normal than in diabetic subjects [8,9,12,25,33], suggesting the existence of a 'glucose resistance'.…”

“…Soskin and Levine in 1937 were the first to study the relationship between the blood glucose level and glucose utilization in pancreatectomized diabetic dogs and suggested that hyperglycaemia provided a compensatory mechanism to maintain normal rates of tissue glucose uptake in the presence of insulin deficiency [11]. We, as well as others, have demonstrated that in both NIDDM and IDDM individuals hyperglycaemia serves a compensatory role to offset the insulin resistance and maintain a normal rate of insulin-mediated glucose disposal [7,8,[12][13][14][15]. Despite the important role of hyperglycaemia in the maintenance of glucose homeostasis in diabetic individuals, few studies have examined the effect of hyperglycaemia on glucose utilization, and these have yielded conflicting results [16][17][18][19].…”

Role of insulin resistance in the pathogenesis of NIDDM

“…To more reliably estimate the contribution of defects in glucose oxidation and storage to decreases in whole body glucose disposal, the fraction of glucose oxidation which is either insulin-independent or not affected by insulin resistance, needs to be estimated. One possibility is to determine glucose oxidation in the basal state, and consider this rate to represent non-insulin-dependent glucose oxidation [63,64]. This approach has two limitations.…”

“…First, a small proportion of basal glucose oxidation is insulin-dependent [65], and second, the presence of insulin-sensitive glucose oxidation, which is not influenced by insulin resistance will be neglected. Even so, by subtracting basal glucose oxidation from glucose oxidation during hyperinsulinaemia, Del Prato et al [63] found that the percent of glucose oxidized and stored of total glucose disposal was similar between patients with NIDDM and control subjects. The best way theoretically is to measure glucose oxidation directly using local indirect calorimetry across muscle tissue, which is the quantitatively most important location for insulin-stimulated glucose utilization [54].…”