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.

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