Despite the effects of hyperinsulinemia and hyperglycemia, 2 factors known
to inhibit endogenous glucose production (EGP) in nondiabetic subjects, inc
reased EGP is a consistent feature of type 2 diabetes. Recent studies have
suggested that increased glucose-6-phosphatase (G6Pase) and/or decreased gl
ucokinase (GK) may explain the increase in EGP. However, no studies to date
have clearly established this relationship in type 2 diabetes. The present
studies were designed to determine rates of EGP and the activities of G6Pa
se and GK in obese patients scheduled for gastric bypass surgery. The study
group consisted of 14 obese nondiabetic subjects and 13 patients with type
2 diabetes (BMI 53.7 +/- 2.4 vs. 50.1 +/- 1.6 kg/m(2)). Rates of EGP were
determined after an overnight fast with a 4-h infusion of [6,6]-D-glucose,
and they were significantly higher in the type 2 diabetic patients (85.9 +/
- 10.0 vs. 137.8 +/- 14.4 mg . m(-2) . min(-1), P < 0.001) despite greater
plasma glucose (5.1 +/- 0.1 vs. 12.0 +/- 1.1 mmol/l) and similar insulin co
ncentrations (130.8 +/- 19.8 vs. 112.8 +/- 16.2 pmol/l, NS). Moreover, resi
stance to insulin-induced suppression of EGP was observed in the patients w
ith type 2 diabetes when insulin concentrations were increased from similar
to 120 to 180 pmol/l. Hepatic G6Pase activity determined from freshly isol
ated microsomes was significantly increased in the type 2 diabetic patients
compared with the obese control subjects (0.16 +/- 0.02 vs, 0.09 +/- 0.01
mu mol . min(-1) . mg(-1) protein, P < 0.02), whereas levels of GK were dec
reased (1.20 +/- 0.16 vs. 2.01 +/- 0.01 mu mol . min(-1) . mg(-1) protein,
P < 0.01). Net flux through G6Pase was significantly increased in type 2 di
abetic patients (P < 0.01). We conclude that increased EGP is mediated in p
art by increased G6Pase flux in type 2 diabetes.