The relationship between peripheral glucose utilisation and insulin sensitivity in the regulation of hepatic glucose production: studies in normal and alloxan-diabetic dogs.

BACKGROUND: Hepatic glucose overproduction (HGP) of diabetes could be primary or could occur in response to the metabolic needs of peripheral (skeletal muscle (SkM)) tissues. This question was tested in normal and diabetic dogs.

METHODS: HGP, SkM glucose uptake (Rd(tissue)), metabolic clearance of glucose (MCRg) and glycolytic flux (GF(exog)), and SkM biopsies were measured in the same dogs before and after alloxan-induced diabetes. Normal dogs were exposed to (1) an extended 20-h fast, (2) low- and high-dose glucose infusions (GINF) at basal insulinaemia, and chronic diabetic dogs were exposed to (3) hyperglycaemia, (4) phlorizin-induced normoglycaemia, and (5) poor and good diabetic control.

RESULTS: (1) Prolonged fast: HGP, Rd(tissue), and GF(exog) fell in parallel (p < 0.05). (2) Low-dose GINF: plasma glucose, insulin, Rd(tissue), MCRg, and GF(exog) were unchanged, but HGP fell by approximately 40%, paralleling the supplemental GINF. (3) High-dose GINF at basal insulin: plasma glucose doubled and synchronous changes in HGP, Rd(tissue), MCRg, and GF(exog) occurred; IC(glucose), G6P, and glycogen were unchanged. (4) Hyperglycaemic diabetes: HGP was raised (p < 0.05), matching urinary glucose loss (UGL) and decreased MCR(g), and maintaining normal basal Rd(tissue) and GF(exog). SkM IC(glucose) was increased and glycogen decreased (both p < 0.05). (5) Phlorizin-induced normoglycaemia in diabetic dogs: HGP rose, matching the increased UGL, while maintaining normal Rd(tissue) and GF(exog). Intramuscular substrates normalised. (6) Whole body and SkM metabolism normalised with correction of the insulin resistance and good diabetic control.

CONCLUSION: HGP reflects whether SkM is in a state of relative glucose 'excess' or absolute/relative glucose 'deprivation'.