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

Abstract

Glucose cycling (GC G " G6P) equals 14% of glucose produc- tion in postabsorptive man. Our aim was to determine glucose cycling in six lean and six overweight mild type II diabetics (fasting glycemia: 13910 and 1527 mg/dl), in postabsorp- tive 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-[3Hlglucose) and hepatic glucose produc- tion (HGP) (6-13HJ-glucose). Postabsorptively, GC is a func- tion of glucokinase. With glucose infusion the flux is reversed (net glucose uptake), and GC is a function of glucose 6-phos- phatase. In PA, GC was increased by 100% in lean (from 0.250.07 to 0.43.08 mg/kg per min) and obese (from 0.220.05 to 0.500.07) diabetics. HGP and HTGO in- creased in lean and obese diabetics by 41 and 33%. Glucose infusion suppressed apparent phosphatase activity and gluco- neogenesis much less in diabetics than controls, resulting in marked enhancement (400%) in HTGO and HGP, GC re- mained increased by 100%. Although the absolute responses of C-peptide and insulin were comparable to those of control sub- jects, they were inappropriate for hyperglycemia. Peripheral insulin resistance relates to decreased metabolic glucose clear- ance (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 glu- cose 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 glu- cose-6-phosphatase and kinase may be of importance. 1 .