Increased lipolysis and its consequences on gluconeogenesis in non-insulin-dependent diabetes mellitus.

Abstract

The present studies were undertaken to determine whether Iipolysis was increased in non-insulin-dependent diabetes mellitus (NIDDM) and, if so, to assess the influence of increased glycerol availability on its conversion to glucose and its contribution to the increased gluconeogenesis found in this condition. For this purpose, we infused nine subjects with NIDDM and 16 age-, weight-matched nondiabetic volunteers with 12-3H1 glucose and IU-'4C1 glycerol and measured their rates of glucose and glycerol appearance in plasma and their rates of glycerol incorporation into plasma glucose. The rate of glycerol appearance, an index of lipolysis, was increased 1.5-fold in NIDDM subjects (2.85±0.16 vs. 1.62±0.08 gmol/kg per min, P < 0.001). Glycerol incorporation into plasma glucose was increased threefold in NIDDM subjects (1.13±1.10 vs.036±0.02 ,mol/kg per min, P < 0.01) and accounted for twice as much of hepatic glucose output (6.0±0.5 vs. 3.0±0.2%, P < 0.001). Moreover, the percent of glycerol turnover used for gluconeogenesis (77±6 vs. 44±2, P < 0.001) was increased in NIDDM subjects and, for a given plasma glycerol concentration, glycerol gluconeogenesis was increased more than twofold. The only experimental variable significantly correlated with the increased glycerol gluconeogenesis after taking glycerol availability into consideration was the plasma free fatty acid concentration (r = 0.80, P < 0.01). We, therefore, conclude that lipolysis is increased in NIDDM and, although more glycerol is thus available, increased activity of the intrahepatic pathway for conversion of glycerol into glucose, due at least in part to increased plasma free fatty acids, is the predominant mechanism responsible for enhanced glycerol gluconeogenesis. Finally, although gluconeogenesis from glycerol in NIDDM is comparable to that of alanine and about one-fourth that of lactate in terms of overall flux into glucose, glycerol is probably the most important gluconeogenic precursor in NIDDM in terms of adding new carbons to the glucose pool. (J. Clin. Invest. 1992. 89:169-175.)

The biochemical basis of increased hepatic glucose production in a mouse model of type 2 (non-insulin-dependent) diabetes mellitus

“…For the NZO mice which had a wide range of glycerol concentrations, there was a positive correlation (r --0.81, p < 0.05) between the two parameters. As has been shown in human NIDDM [19], for the same glycerol concentrations, NZO mice converted more of this substrate to glucose than the control mice. This suggests an increase in the intrahepatic conversion of glycerol to glucose in the obese animals.…”

“…Previous studies have shown that in NIDDM elevated NEFA levels are at least partly responsible for impaired suppression of HGP by insulin [14,42,43]. Furthermore, as with the NZO mouse, NIDDM patients have increased conversion of glycerol to glucose [19,20]. Nurjhan et al [19] infused glycerol into control patients to match the levels seen in obese diabetic patients, and found that the control patients still had lower rates of glycerol conversion to glucose than the NIDDM patients.…”

“…Furthermore, as with the NZO mouse, NIDDM patients have increased conversion of glycerol to glucose [19,20]. Nurjhan et al [19] infused glycerol into control patients to match the levels seen in obese diabetic patients, and found that the control patients still had lower rates of glycerol conversion to glucose than the NIDDM patients. They postulated that in obese NIDDM patients there is an intrahepatic mechanism responsible for the increased conversion of glycerol to glucose and suggested that this could be an increase in the levels of fructose 1,6-bisphosphatase.…”

“…More recently it has been shown that there is an increased rate of glycerol conversion to glucose in obese NIDDM patients [19,20]. Nurjhan et al [19] have demonstrated that this is partly due to an increase in substrate supply and partly to an increase in the rate of intrahepatic conversion, and have postulated that the enzyme fructose 1,6-bisphosphatase (FBPase) could be the cause.…”

“…Nurjhan et al [19] have demonstrated that this is partly due to an increase in substrate supply and partly to an increase in the rate of intrahepatic conversion, and have postulated that the enzyme fructose 1,6-bisphosphatase (FBPase) could be the cause.…”