Mechanism of increased gluconeogenesis in noninsulin-dependent diabetes mellitus. Role of alterations in systemic, hepatic, and muscle lactate and alanine metabolism.

Abstract

IntroductionTo assess the mechanisms responsible for increased gluconeogenesis in noninsulin-dependent diabetes mellitus (NIDDM), we infused 13-14Cjlactate, 13-13Cjalanine, and 16-3Hjglucose in 10 postabsorptive NIDDM subjects and in 9 age-and weightmatched nondiabetic volunteers and measured systemic appearance of alanine and lactate, their release from forearm tissues, and their conversion into plasma glucosq (corrected for Krebs cycle carbon exchange). Systemic appearance of lactate and alanine were both significantly greater in diabetic subjects (18.2±0.9 and 5.8±0.4 ,mol/kg/min, respectively) than in the nondiabetic volunteers (12.6±0.7 and 4.2±0.3 ,umol/kg/min, respectively, P < 0.001 and P < 0.01). Conversions of lactate and alanine to glucose were also both significantly greater in NIDDM subjects (8.6±0.5 and 2.4±0.1 Mmole/kg/min, respectively) than in nondiabetic volunteers (4.2±0.4 and 1.8±0.1 ;mol/kg/min, respectively, P < 0.001 and P < 0.025).The proportion of systemic alanine appearance converted to glucose was not increased in NIDDM subjects (42.7±1.9 vs. 44.2±2.9% in nondiabetic volunteers), whereas the proportion of systemic lactate appearance converted to glucose was increased in NIDDM subjects (48.3±3.8 vs. 34.2±3.8% in nondiabetic volunteers, P < 0.025); the latter increased hepatic efficiency accounted for 40% of the increased lactate conversion to glucose. Neither forearm nor total body muscle lactate and alanine release was significantly different in NIDDM and nondiabetic volunteers. Therefore, we conclude that increased substrate delivery to the liver and increased efficiency of intrahepatic substrate conversion to glucose are both important factors for the increased gluconeogenesis of NIDDM and that tissues other than muscle are responsible for the increased delivery of gluconeogenic precursors to the liver. (J.

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

“…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. In contrast to glycerol, Consoli et al [44] have shown that although gluconeogenesis from alanine is increased, this is entirely due to an increase in the availability of alanine. Interestingly, however, they found evidence for an increased intracellular conversion of lactate to glucose.…”

Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis

“…[6-3 H]glucose specific activities were determined using 4 ml of plasma in duplicate by HPLC (46) with a CV of 0.5%. Plasma [6,6-2 H2]glucose enrichments were determined by gas chromatography-mass spectroscopy (GC-MS) as previously described (14). Plasma lactate, alanine, glycerol, and FFA concentrations were determined by standard microfluorometric assays (36,43,56).…”

Serum Alanine Aminotransferase (ALT) Activity among Diabetic Patients

“…Likewise in the study by Arthur and colleagues (Meltzer et al, 1986) ALT activity at least twice the upper limit of normal of 43IU/L was found to be more common among diabetics. Increased gluconeogenesis, owing to increased conversion of alanine to glucose, is suggested as important mechanism for the up regulation of ALT enzyme activity in diabetic subjects (Consoli et al, 1990). The mean value of Age, BMI, Fasting sugar, Post prandial sugar and Serum ALT activity in Diabetic and Non diabetic subjects (n=208).…”