ROLE OF HEPATIC GLUCOSE-PRODUCTION AND GLUCOSE-UPTAKE IN THE PATHOGENESIS OF FASTING HYPERGLYCEMIA IN TYPE-2 DIABETES - NORMALIZATION OF GLUCOSE KINETICS BY SHORT-TERM FASTING

The relative impact of hepatic glucose production (HGP) and peripheral glucose uptake (GU) on plasma glucose concentration was assessed in 5 4 noninsulin-dependent diabetes mellitus (NIDDM) and 50 control subjec ts submitted to a variable period of fasting (14-108 h) with special f ocus on the normal and low hyperglycemic range. Within each population we found a highly significant (P < 0.001) positive correlation betwee n plasma glucose concentration and HGP in the whole range of glycemia, but the slope of the regression line was steeper (P < 0.001) in the d iabetic than in the control group. The two curves intersected at a glu cose level of 4.0 mmol/L. Therefore, for a given HGP rate above the in tersection point, diabetic patients had a higher plasma glucose concen tration than nondiabetic individuals, owing to an approximately 15% re duction (P < 0.025) in the metabolic clearance rate, despite the fact that the plasma insulin level was 2-fold higher (P < 0.05) in the diab etic patients. When diabetic and nondiabetic subjects were compared at a similar low glucose level of 4.0 mmol/L brought about by short-term fasting, all parameters of glucose kinetics were identical in both gr oups. We thus conclude that 1) HGP is the major determinant of plasma glucose concentration in control as well as in diabetic subjects whate ver the nutritional state; 2) the slight hyperglycemia prevailing in m ild NIDDM results from the combination of an impaired insulin-induced inhibition of HGP and stimulation of GU because both parameters are in appropriately normal in the face of elevated plasma glucose and insuli n levels; and 3) the normalization of GU and HGP after short-term fast ing suggests that pathways of noninsulin-mediated GU operate in a norm al way in NIDDM.