The effects of non-insulin-dependent diabetes mellitus on the kinetics of onset of insulin action in hepatic and extrahepatic tissues.

Abstract

The mechanism(s) of insulin resistance in non-insulin-dependent diabetes mellitus remains ill defined. The current studies sought to determine whether non-insulin-dependent diabetes mellitus is associated with (a) a delay in the rate of onset of insulin action, (b) impaired hepatic and extrahepatic kinetic responses to insulin, and (c) an alteration in the contribution of gluconeogenesis to hepatic glucose release. To answer these questions, glucose disappearance, glucose release, and the rate of incorporation of '4CO2 into glucose were measured during 0.5 and 1.0 mU/kg-' per min-' insulin infusions while glucose was clamped at -95 mg/dI in diabetic and nondiabetic subjects. The absolute rate of disappearance was lower (P < 0.05) and the rate of increase slower (P < 0.05) in diabetic than nondiabetic subjects during both insulin infusions. In contrast, the rate of suppression of glucose release in response to a change in insulin did not differ in the diabetic and nondiabetic subjects during either the low (slope 30-240 min:0.02±0.01 vs 0.02±0.01) or high (0.02±0.00 vs 0.02±0.00) insulin infusions. However, the hepatic response to insulin was not entirely normal in the diabetic subjects. Both glucose release and the proportion of systemic glucose being derived from "4CO2 (an index of gluconeogenesis) was inappropriately high for the prevailing insulin concentration in the diabetic subjects. Thus non-insulin-dependent diabetes mellitus slows the rate-limiting step in insulin action in muscle but not liver and alters the relative contribution of gluconeogenesis and glycogenolysis to hepatic glucose release. (J. Clin. Invests 1995. 95:755-762.) Key words: insulin resistance . gluconeogenesis * glucose turnover * rate of onset of insulin action

Synthesis Rate of Muscle Proteins, Muscle Functions, and Amino Acid Kinetics in Type 2 Diabetes

“…Increased gluconeogenesis is consistent with the current observation. Although gluconeogenesis has not been measured in the current study, increased glucose production and increased gluconeogenesis are reported to occur in type 2 diabetic patients when they are not treated (16). In the current study, the circulating amino acid concentrations remained unchanged, including alanine and glutamine.…”

“…It is possible that leucine oxidation may not truly reflect net urinary nitrogen loss in all physiological and pathological states (14,15). For example, there is an increased gluconeogenesis in type 2 diabetic subjects (16) when the circulating glucose levels are high, although their leucine flux is usually normal in this situation (7). Increased gluconeogenesis involves consumption of glucogenic amino acids that could theoretically increase urinary nitrogen loss.…”

“…Table 1, were studied. Average diabetes duration was 8.5 years (range [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Six of the diabetic patients were on oral hypoglycemic agents, whereas the other two were on diet therapy alone.…”

Tissue-Specific Regulation of Mitochondrial and Cytoplasmic Protein Synthesis Rates by Insulin

“…1), responded differently to insulin than the muscle. During insulin infusion, the flux of substrates such as nonesterified fatty acids and amino acids decreases, thus reducing the overall liver substrate metabolism (48). However, replacement of amino acids alone failed to reverse the inhibitory effect of insulin on liver mitochondrial protein synthesis.…”

“…However, replacement of amino acids alone failed to reverse the inhibitory effect of insulin on liver mitochondrial protein synthesis. Other potential factors that affect liver energetics include a suppression of gluconeogenesis in liver by insulin (48). At the postreceptor level, the insulin signaling pathway has been demonstrated to differ between the muscle and the liver.…”