Effect of physiological hyperinsulinemia on gluconeogenesis in nondiabeticsubjects and in type 2 diabetic patients

Gluconeogenesis (GNG) is enhanced in type 2 diabetes. In experimental anima ls, insulin at high doses decreases the incorporation of labeled GNG precur sors into plasma glucose. Whether physiological hyperinsulinemia has any ef fect on total GNG in humans has not been determined. We combined the insuli n clamp with the (H2O)-H-2 technique to measure total GNG in 33 subjects wi th type 2 diabetes (BMI 29.0 +/- 0.6 kg/m(2), fasting plasma glucose 8.1 +/ - 0.3 mmol/l) and in 9 nondiabetic BMI-matched subjects after 16 h of fasti ng and after euglycemic hyperinsulinemia. A primed-constant infusion of 6,6 -H-2-glucose was used to monitor endogenous glucose output (EGO); insulin ( 40 mU.min(-1).m(-2)) was then infused while clamping plasma glucose for 2 h (at 5.8 +/- 0.1 and 4.9 +/- 0.2 mmol/l for diabetic and control subjects, respectively). In the fasting state, EGO averaged 15.2 +/- 0.4 mu mol.min(- 1).kg(ffm)(-1) (62% from GNG) in diabetic subjects and 12.2 +/- 0.7 mu mol. min(-1).kg(ffm)(-1) (55% from GNG) in control subjects (P < 0.05 or less fo r both fluxes). Glycogenolysis (EGO - GNG) was similar in the two groups (P = NS). During the last 40 min of the clamp, both EGO and GNG were signific antly (P < 0.01 or less, compared with fasting) inhibited (EGO 7.1 +/- 0.9 and 3.6 +/- 0.5 and GNG 7.9 +/- 0.5 and 4.5 +/- 1.0 mu mol.min(-1).kg(ffm)( -1) in diabetic and control subjects, respectively) but remained significan tly (P < 0.05) higher in diabetic subjects, whereas glycogenolysis was supp ressed completely and equally in both groups. During hyperinsulinemia, GNG was reciprocally related to plasma glucose clearance. In conclusion, physio logical hyperinsulinemia suppresses GNG by similar to 20%, while completely blocking glycogenolysis. Resistance of GNG (to insulin suppression) and re sistance of glucose uptake (to insulin stimulation) are coupled phenomena. In type 2 diabetes, the excess GNG of the fasting state is carried over to the insulinized state, thereby contributing to glucose overproduction under both conditions.