Mild type II diabetes markedly increases glucose cycling in the postabsorptive state and during glucose infusion irrespective of obesity.

Glucose cycling (GC; G in equilibrium G6P) equals 14% of glucose production in postabsorptive man. Our aim was to determine glucose cycling in six lean and six overweight mild type II diabetics (fasting glycemia: 139 +/- 10 and 152 +/- 7 mg/dl), in postabsorptive state (PA) and during glucose infusion (2 mg/kg per min). 14 control subjects were weight and age matched. GC is a function of the enzyme that catalyzes the reaction opposite the net flux and is the difference between hepatic total glucose output (HTGO) (2-[3H]glucose) and hepatic glucose production (HGP) (6-[3H]-glucose). Postabsorptively, GC is a function of glucokinase. With glucose infusion the flux is reversed (net glucose uptake), and GC is a function of glucose 6-phosphatase. In PA, GC was increased by 100% in lean (from 0.25 +/- 0.07 to 0.43 +/- .08 mg/kg per min) and obese (from 0.22 +/- 0.05 to 0.50 +/- 0.07) diabetics. HGP and HTGO increased in lean and obese diabetics by 41 and 33%. Glucose infusion suppressed apparent phosphatase activity and gluconeogenesis much less in diabetics than controls, resulting in marked enhancement (400%) in HTGO and HGP, GC remained increased by 100%. Although the absolute responses of C-peptide and insulin were comparable to those of control subjects, they were inappropriate for hyperglycemia. Peripheral insulin resistance relates to decreased metabolic glucose clearance (MCR) and inadequate increase of uptake during glucose infusion. We conclude that increases in HGP and HTGO and a decrease of MCR are characteristic features of mild type II diabetes and are more pronounced during glucose infusion. There is also an increase in hepatic GC, a stopgap that controls changes from glucose production to uptake. Postabsorptively, this limits the increase of HGP and glycemia. In contrast, during glucose infusion, increased GC decreases hepatic glucose uptake and thus contributes to hyperglycemia. Obesity per se did not affect GC. An increase in glucose cycling and turnover indicate hepatic insulin resistance that is observed in addition to peripheral resistance. It is hypothesized that in pathogenesis of type II diabetes, augmented activity of glucose-6-phosphatase and kinase may be of importance.