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1 Division of Endocrinology, Mayo Clinic, Rochester, MN, USA
* To whom correspondence should be addressed. E-mail: rizza.robert{at}mayo.edu.
To determine whether regulation of fasting endogenous glucose production (EGP) and glucose disappearance (Rd) are both abnormal in people with type 2 diabetes, EGP and Rd were measured in 7 "severe"(SD), 9 "mild" (MD) and 12 nondiabetic (ND) subjects (12.7±0.6 vs. 8.1±0.4 vs. 5.1±0.4 mmol/L) following an overnight fast when glucose, insulin and glucagon concentrations differed and during a clamp when glucose, insulin and glucagon concentrations were matched. Fasting insulin was higher in both the SD and MD than nondiabetic subjects whereas fasting glucagon only was increased (p<0.05) in SD. Fasting EGP, glycogenolysis, gluconeogenesis (measured with the 2H2O method) and Rd all were increased (p<0.05) in SD but did not differ in MD or ND. On the other hand, when glucose (~11 mmol/L), insulin (~72 pmol/L), and glucagon (~140 pg/ml) concentrations were raised to values similar to those observed in the "severe" diabetic subjects during the clamp, EGP was higher (14.1±1.3 vs. 14.1±0.8 vs. 8.6±1.0 µmol/kg/min; p<0.001) and Rd lower (16.6±1.8 vs. 16.5±0.7 vs. 38.2±4.2 µmol/kg/min; p<0.01) in both SD and MD than in ND. The higher EGP in the SD and MD than ND during the clamps was due to increased (p<0.05) rates of glycogenolysis (4.2 ± 1.7 vs. 3.5 ± 1.0 vs. 0.0 ± 0.8 µmol/kg/min) since gluconeogenesis did not differ amongst groups (9.9 ± 0.9 vs. 9.1 ± 0.8 vs. 8.2 ± 0.9 µmol/kg/min). Free fatty acids were elevated in the "severe" diabetic subjects before (p<0.02) and in both diabetic groups during the clamp (p<0.001), lending further support to the concept that alterations in fat metabolism contribute to inappropriately elevated rates of glucose production in people with type 2 diabetes mellitus. We conclude that neither glucose production nor glucose disappearance is appropriate for the prevailing glucose, insulin and glucagon concentrations in people with "mild" or "severe" diabetes. Both increased rates of gluconeogenesis (likely due to higher glucagon concentrations) and lack of suppression of glycogenolysis contribute to excessive glucose production in the type 2 diabetics.
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