Role of glucagon suppression on gluconeogenesis during insulin treatment of the conscious diabetic dog

Abstract

Summary. In seven insulin-deficient (< 3 mU/1) pancreatectomised dogs, the direct and glucagon-related indirect effects of intraportal insulin infusion (350 ~U/kg-min; 12 + 1 mU/1) on glucose production were determined. Insulin was infused for 300 min during which time the plasma glucagon concentration was allowed to fall (314+94 to 180+63 ng/l) for 150 min before being replaced by an infusion intraportally at 2.6ng/kg-rnin (323+61ng/1) for the remaining 150min. Glucose production and gluconeogenesis were determined using arterio-venous difference and tracer techniques. Insulin infusion shut off net hepatic glucose output and caused the plasma glucose, blood glycerol and plasma non-esterified fatty acid levels to fall. It caused the hepatic fractional extraction of alanine (0.41 +0.10 to 0.21 +0.06) and lactate (0.32__+0.09 to 0.04___0.03) to fall which increased their concentrations. When glucagon was replaced, all of these changes were fully or partly reversed with the exception of the changes in glycerol and nonesterified fatty acids. Indeed, 70% of the fall in hepatic glucose production and virtually 100% of the changes in lactate and alanine metabolism produced by basal insulin infusion were mediated by a fall in glucagon. However, the fall in hepatic uptake of glycerol was unaffected by changes in glucagon and thus gluconeogenesis from this substrate was inhibited by insulin per se probably as a result of reduced lipolysis. The latter effect of insulin may explain the incomplete restoration of hepatic glucose production when hyperglucagonaemia was re-established during insulin infusion.Key words: Diabetes, insulin, glucagon, glycogenolysis, gluconeogenesis, dog.Fasting hyperglycaemia is associated with insulin-deficient diabetes and is accompanied by inappropriately raised plasma glucagon concentrations [1][2][3][4]. However, insulin treatment can reduce or even nonnalise glucagon levels in the diabetic dog [4,5] and man [6,7]. Since both elevations in plasma insulin [8] and reductions in plasma glucagon [9] can reduce hepatic glucose production and gluconeogenesis, the aim of the present study was to determine the relative roles of the changes in insulin and glucagon which result from insulin infusion in reducing the hyperglycaemia and elevated gluconeogenesis apparent in overnight-fasted diabetic (pancreatectomised) dogs. This was accomplished by administering insulin alone via the portal circulation at a low infusion rate then re-establishing the starting glucagon levels in the second half of the study by intraportal infusion of glucagon coincident with the insulin infusion. Since the dogs were prepared with indwelling catheters in the left common hepatic vein, the portal vein and in the femoral artery, net hepatic balances of glucose and gluconeogenic substrates could be calculated using the arteriovenous difference technique. Materials and methods Animals and surgical proceduresEleven mongrel dogs (15-23 kg) of either sex were fed a normal diet (Kal Kan meat and Wayne Dog Chow, Wayne Meat Ration, Alli...

Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.

“…Lactate was slightly higher from 90 to 180 min in the peripheral infusion group, but the baseline value was also higher. After the peak that occurred at 30 min, lactate decreased by 2 60 AM more with equimolar peripheral than with portal infusion, which for a liver fractional extraction of0.3 (2) would add another 0.3 gmol * kg-' * min -'. Ifwe omit this last calculation as it results from a nonsignificant difference, the measured changes in precursors could account for a rate ofGP of -0.7 Mmol * kg`* min1 .…”

“…This glucagon is indistinguishable from pancreatic glucagon ( 18) and normally is suppressible by insulin (2). With intraportal insulin infusion downstream from the site of glucagon production, insulin reaches the glucagon-producing cells at peripheral concentrations.…”

“…However, insulin could inhibit GP not only through a direct hepatic action, but also indirectly by reducing the availability of substrates and energy for gluconeogenesis. This mechanism might be of particular importance in diabetes where gluconeogenesis is substantially increased ( 1,2). Also, peripheral insulin levels may control glucose production by their inhibitory effect on glucagon secretion.…”

“…In brief, carrier glucose was added to an aliquot of eluate from ion-exchange chromatography. Glucose was then oxidized with periodate to five molecules of formic acid (derived from carbons [1][2][3][4][5] and one molecule of formaldehyde (derived from carbon 6). After the addition of dimedone, formaldehyde precipitates as formaldimedone.…”

Insulin signaling is required for insulin’s direct and indirect action on hepatic glucose production

“…These mechanisms may be particularly important in the diabetic state, in which gluconeogenesis is considerably increased (11)(12)(13)(14), and in which hyperglycemia per se has been shown to potentiate the indirect actions of insulin (15). Furthermore, since up to 75% of basal HGP is driven by glucagon (16), insulin-induced suppression of glucagon release may be another indirect mechanism by which insulin suppresses HGP (2,3,17,18).…”