MECHANISM OF INCREASED GLUCONEOGENESIS IN NONINSULIN-DEPENDENT DIABETES-MELLITUS - ROLE OF ALTERATIONS IN SYSTEMIC, HEPATIC, AND MUSCLE LACTATE AND ALANINE METABOLISM

To assess the mechanisms responsible for increased gluconeogenesis in noninsulin-dependent diabetes mellitus (NIDDM), we infused [3-14]lactate, [3-13C]alanine, and [6-3H]glucose in 10 postabsorptive NIDDM subjects and in 9 age- and weight-matched nondiabetic volunteers and measured systemic appearance of alanine and lactate, their release from forearm tissues, and their conversion into plasma glucose (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 μmol/kg/min, respectively) than in the nondiabetic volunteers (12.6 ± 0.7 and 4.2 ± 0.3 μmol/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 μmole/kg/min, respectively) than in nondiabetic volunteers (4.2 ± 0.4 and 1.8 ± 0.1 μmol/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 incfeased 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 non-diabetic 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 gluconeogenesi of NIDDM and that tissues other than muscle are responsible for the increased delivery of gluconeogenic precursors to the liver.