Summary
In seven insulin-deficient (<3 mU/l) pancreatectomised dogs, the direct and glucagon-related indirect effects of intraportal insulin infusion (350 μU/kg-min; 12±1 mU/l) 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-min (323±61 ng/l) for the remaining 150 min. 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.
Article PDF
Similar content being viewed by others
References
Unger RH, Lefebvre PJ (1972) Glucagon physiology. In: Lefebvre PJ, Unger RH (eds) Glucagon, Molecular Physiology, Clinical and Therapeutic Implications. Pergamon Press, London New York, pp 213–244
Unger RH, Orci L (1977) Role of glucagon in diabetes. Arch Intern Med 137: 482–491
Lilavivathana V, Brodows RG, Woolf PD, Campbell RG (1979) Counterregulatory hormonal responses to rapid glucose lowering in diabetic man. Diabetes 28: 873–877
Stevenson RW, Orskov H, Parsons JA, Alberti KGMM (1983) Metabolic responses to intraduodenal glucose loading in insulininfused diabetic dogs. Am J Physiol 245: E200-E208
Stevenson RW, Parsons JA, Alberti KGMM (1981) Comparison of the metabolic responses to portal and peripheral infusions of insulin in diabetic dogs. Metabolism 30: 745–752
Raskin P, Unger RH (1978) Hyperglucagonemia and its suppression: importance in the metabolic control of diabetes. N Engl J Med 299: 433–436
Raskin P, Pietri A, Unger R (1979) Changes in glucagon levels after four to five weeks of glucoregulation by portable insulin infusion pump. Diabetes 28: 1033–1035
Cherrington AD, Steiner KE (1982) The effects of insulin on carbohydrate metabolism in vivo. Clin Endocrinol Metab 11: 307–328
Jennings AS, Cherrington AD, Liljenquist JE, Keller U, Lacy WW, Chiasson JL (1977) The roles of insulin and glucagon in the regulation of gluconeogenesis in the postabsorptive dog. Diabetes 26: 847–856
Rappaport AM, Vranic M, Wrenshall GA (1966) A pedunculated subcutaneous autotransplant of an isolated pancreas remnant, for the temporary deprivation of internal pancreatic secretion in the dog. Surgery 59: 792–798
Chiasson J-L, Liljenquist JE, Sinclair-Smith BC, Lacy WW (1975) Gluconeogenesis from alanine in normal postabsorptive man: intrahepatic stimulatory effect of glucagon. Diabetes 24: 574–584
Goresky CA, Back GG, Nadeau BE (1975) Red cell carriage of label: its limiting effect on the exchange of materials in the liver. Circ Res 36: 328–351
Cherrington AD, Chiasson J-L, Liljenquist JE, Jennings AS, Keller U, Lacy WW (1976) The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog. J Clin Invest 58: 1407–1418
Cherrington AD, Lacy WW, Chiasson J-L (1978) Effect of glucagon on glucose production during insulin deficiency in the dog. J Clin Invest 62: 664–677
Aguilar-Parada E, Eisentraut AM, Unger RH (1969) Pancreatic glucagon secretion in normal and diabetic subjects. Am J Med Sci 257: 415–419
Wide L, Porath J (1966) Radioimmunoassay of proteins with the use of sephadex-coupled antibodies. Biochim Biophys Acta 130: 257–260
Wall JS, Steele R, DeBodo RC, Altszuler N (1957) Effect of insulin on utilization and production of circulating glucose. Am J Physiol 189: 43–50
DeBodo RD, Steele R, Altszuler N, Dunn A, Bishop JS (1963) On the hormonal regulation of carbohydrate metabolism: studies with 14C-glucose. Recent Prog Horm Res 19: 445–448
Cherrington AD, Vranic M (1973) Effect of arginine on glucose turnover and plasma free fatty acids in normal dogs. Diabetes 22: 537–543
Chiasson J-L, Liljenquist JE, Jennings AS, Lacy WW, Cherrington AD (1977) Gluconeogenesis: methodological approaches in vivo. Fed Proc 36: 230–235
Cherrington AD, Williams PE, Shulman GI, Lacy WW (1981) Differential time course of glucagon's effect on glycogenolysis and gluconeogenesis in the conscious dog. Diabetes 30: 180–187
Hetenyi G Jr (1981) Calculation of the rate of gluconeogenesis in vivo. In: Cobelli C, Bergman RN (eds) Carbohydrate Metabolism. John Wiley and Sons Ltd, pp 201–219
Leevy CM, Mendenhall CL, Lesko W, Howard MM (1962) Estimation of hepatic blood flow with indocyanine green. J Clin Invest 71: 1169–1179
Greenway CV, Stark RD (1971) Hepatic vascular bed. Physiol Rev 51: 23–65
Chan T, Exton J (1976) A rapid method for the determination of glycogen content and radioactivity in small quantities of tissue or isolated hepatocytes. Anal Biochem 71: 96–105
Ferez G, Kemmer FW, Lickley HLA, Vranic M (1981) Importance of glucagon in mediating epinephrine-induced hyperglycemia in alloxan-diabetic dogs. Am J Physiol 241: E328-E335
Stevenson RW, Parsons JA, Alberti KGMM (1983) Effect of intraportal and peripheral insulin on glucose turnover and recycling in diabetic dogs. Am J Physiol 244: E190-E195
Cahill GF Jr (1971) Physiology of insulin in man. Diabetes 20: 785–799
Davis MA, Williams PE, Cherrington AD (1985) Effect of glucagon on hepatic lactate metabolism in the conscious dog. Am J Physiol 248: E463-E470
Brockman RP, Bergman EN, Joo PK, Manns JG (1975) Effect of glucagon and insulin on net hepatic metabolism of glucose precursors in sheep. Am J Physiol 229: 1344–1350
Le Cam A, Freychet P (1976) Glucagon stimulates the A system for neutral amino acid transport in isolated hepatocytes of adult rat. Biochem Biophys Res Commun 72: 893–901
Kilberg MS, Neuhaus OW (1977) Hormonal regulation of hepatic amino acid transport. J Supramol Struct 6: 191–204
Kilberg MS, Handlogten ME, Christensen HN (1980) Characteristics of an amino acid transport system in rat liver for glutamine, asparagine, histidine, and closely related analogs. J Biol Chem 255: 4011–4019
Cherrington AD (1982) Gluconeogenesis: its regulation by insulin and glucagon. In: Brownlee M (ed) Handbook of Diabetes Mellitus, Ch 2. Garland STPM Press, New York, pp 45–119
Shulman GI, Lacy WW, Liljenquist JE, Keller U, Williams PE, Cherrington AD (1980) Effect of glucose, independent of changes in insulin and glucagon secretion, on alanine metabolism in the conscious dog. J Clin Invest 65: 496–505
Katz J, Rognstad R (1976) Futile cycles in the metabolism of glucose. Curr Top Cell Regul 10: 237–289
Diamond MP, Rollings RC, Erlendson L, Williams PE, Lacy WW, Rabin D, Cherrington AD (1980) Dichloroacetate — its in vivo effects on carbohydrate metabolism in the conscious dog. Diabetes 29: 702–710
Lloyd B, Burrin J, Smythe P, Alberti KGMM (1978) Enzymic fluorometric continuous-flow assays for blood glucose, lactate, pyruvate, alanine, glycerol, and 3-hydroxybutyrate. Clin Chem 24: 1724–1729
Ho RJ (1970) Radiochemical assay of long chain fatty acids using 63Ni as tracer. Anal Biochem 26: 105–113
Gottesman I, Mandarino L, Gerich J (1984) Review: use of glucose uptake and glucose clearance for the evaluation of insulin action in vivo. Diabetes 33: 184–191
Cherrington AD, Williams PE, Harris MS (1978) Relationship between the plasma glucose level and glucose uptake in the conscious dog. Metabolism 27: 787–791
Unger, RH, Groi L (1975) The essential role of glucagon in the pathogenesis of the endogenous hypoglycaemia of diabetes mellitus. Lancet 1: 14–16
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Stevenson, R.W., Williams, P.E. & Cherrington, A.D. Role of glucagon suppression on gluconeogenesis during insulin treatment of the conscious diabetic dog. Diabetologia 30, 782–790 (1987). https://doi.org/10.1007/BF00275744
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00275744