Abstract
We have compared the effects of human proinsulin and insulin on forearm metabolism. Seven normal, non-obese subjects were infused with 386 pmol/kg per hour of proinsulin and 180 pmol/kg per hour of insulin using the euglycaemic clamp technique. Glucose appearance and utilization rates were quantified using a primed continuous infusion of [6′,6′-2H2]glucose. Mean blood glucose was 4.1±0.1 and 4.1±0.2 mmol/l during proinsulin and insulin infusions respectively. Basal insulin concentrations increased from 0.02±0.01 to 0.25±0.03 nmol/l. The proinsulin infusion was chosen to give steady-state levels approximately 20-fold higher on a molar basis than those of insulin, based on previous findings that proinsulin has only 5% the biological potency of insulin. Basal proinsulin concentrations increased from 0.003 to 5.4±0.3 nmol/l. Hepatic glucose production was suppressed similarly during the last hour of each hormone infusion: 0.07±0.16 (proinsulin, P), and 0.01±0.13 (insulin, I) mg/kg per minute. Glucose disposal, however, was significantly increased during the final hour of the insulin infusion: 4.7±0.4 (I) and 3.4±0.2 (P) mg/kg per minute (P=0.025). Net forearm glucose uptake (FGU) increased by a greater amount during insulin compared with proinsulin infusion: 1.44±0.02 (I) and 0.71±0.01 (P) μmol/100 ml forearm per minute (P<0.02). There was a small but significant net drop in arterialized blood lactate and pyruvate concentrations during proinsulin compared with insulin infusion: lactate −43±29 (P) and +63±35 (I) μmol/l (P<0.01); pyruvate −8±3 (P) and +6±2 (I) μmol/l (P<0.02). Arterialized blood alanine concentrations were similar during both series of hormone infusions. Forearm production and arterialized concentrations of glycerol were suppressed by equal amounts during the last hour of each hormone infusion. Despite greater FGU during insulin infusion, forearm production of lactate, pyruvate and alanine were similar during the last hour of each glucose clamp. These results indicate that in overnight fasted normal man: (1) proinsulin may have a preferential effect on the liver compared with muscle in terms of glucose handling; (2) proinsulin is less effective in stimulating FGU than is insulin; (3) from calculation of carbon flux across the forearm, proportionally less glucose was oxidized or stored during infusion of proinsulin compared with insulin; (4) proinsulin has similar effects on forearm lipolysis compared with insulin; (5) proinsulin may have a differential effect on splanchnic lactate metabolism compared with insulin.
Similar content being viewed by others
References
Zuniga-Guajardo S, Zinman B, The metabolic response to the euglycemic insulin clamp in type I diabetes and normal humans. Metabolism 34:926–930, 1985
Taylor R, Agius L, The biochemistry of diabetes. Biochem J 250:625–640, 1988
Radziuk J, Inculet R, The effects of ingested and intravenous glucose on forearm uptake of glucose and glycogen substrate in normal man. Diabetes 32:977–981, 1983
Jackson RA, Hamling JB, Sim BM, Hawa MI, Blix PM, Nabaro JDN, Peripheral lactate and oxygen metabolism in man: the influence of oral glucose loading. Metabolism 36:144–150, 1987
Ruderman NB, Houghton CRS, Hems R, Evaluation of the isolated perfused rat hindquarter for the study of muscle metabolism. Biochem J 124:639–651, 1971
Stevenson RW, Parsons JA, Alberti KGMM, Comparison of the metabolic responses to portal and peripheral infusions of insulin in diabetic dogs. Metabolism 30:745–752, 1981
Jimenez JT, Walford S, Home PD, Haning I, Alberti KGMM, Free insulin levels and metabolic effects of meal-time bolus and square-wave intraperitoneal insulin infusion in insulin-dependent diabetic patients. Diabetologia 28:728–733, 1985
Davis SN, Butler PC, Brown M, Beer S, Sobey W, Hanning I, Home PD, Hales CN, Alberti KGMM, The effects of human proinsulin on glucose turnover and intermediary metabolism. Metabolism 40:953–961, 1991
Revers RR, Henry R, Schmeiser L, Kolterman O, Cohen R, Bergenstal R, Polonsky K, Jaspan J, Olefsky JM, The effects of biosynthetic human proinsulin on carbohydrate metabolism. Diabetes 33:762–770, 1984
Glauber HS, Revers R, Henry R, Schmeiser L, Wallace P, Kolterman O, Cohen R, Rubenstein AH, Galloway JA, Frank B, Olefsky JM, In vivo deactivation of proinsulin: action on glucose disposal and hepatic glucose production in normal man. Diabetes 35:311–317, 1986
Lavelle-Jones M, Scott MH, Holterman O, Rubenstein AH, Olefsky JM, Moosa AR, Selective suppression of hepatic glucose output by human proinsulin in the dog. Am J Physiol 252:E233-E236, 1987
Cohen RM, Licinio J, Polonsky KS, Galloway J, Frank B, Cherrington A, Rubenstein AH, The effect of biosynthetic human proinsulin on the hepatic response to glucagon in insulin-deficient diabetes. J Clin Endocrinol Metab 64:476–481, 1987
DeFronzo RA, Jacob E, Jequier E, Maeder E, Wahren J, Felber JP, The effect of insulin on the disposal of intravenous glucose. Diabetes 30:1000–1007, 1981
Frank BH, Pettee JM, Zimmerman RE, Burck PJ, The production of human proinsulin and its transformation to human insulin and C-peptide. In: Rich DH, Gross E (eds) Peptides: structure and biological function. Rockford, IL, Rockford Piece Chemical Co., pp 729–738, 1981
Defronzo RA, Tobin JD, Andres R, Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214-E223, 1979
Whitney RJ, The measurement of volume changes in human limbs. J Physiol (Lond) 121:1–27, 1953
Cooper KE, Edholm OG, Moltram RF, The blood flow in skin and muscle of the human forearm. J Physiol (Lond) 128:258–267, 1955
Zierler KL, Theory of the use of arteriovenous concentration differences for measuring metabolism in steady and non-steady state. J Clin Invest 40:2111–2125, 1961
Norwich KH, Measuring rates of appearance in systems which are not in steady state. Can J Physiol Pharmacol 51:91–101, 1973
Steele R, Influence of glucose loading and of injected insulin on hepatic glucose output. Ann NY Acad Sci 82:420–431, 1959
Bier DM, Arnold KJ, Sherman WR, Holland WH, Holmes WF, Kipnis DM, In vivo measurement of glucose and alanine metabolism with stable isotopic tracers. Diabetes 26:1005–1015, 1977
Ferrannini E, Smith JD, Cobelli C, Toffolo G, Pilo A, Defronzo RA, Effect of insulin on the distribution and disposition of glucose in man. J Clin Invest 76:357–367, 1985
Bell PM, Firth RG, Rizza RA, Assessment of insulin action in insulin-dependent diabetes mellitus using [6-14C]glucose, [3-3H]glucose, and [2-3H]glucose. J Clin Invest 78:1479–1486, 1986
Bergenstal RM, Cohen RM, Lever E, Polonsky K, Jaspan J, Blu PM, Revers R, Olefsky JM, Holterman O, Steiner K, Cherrington A, Frank B, Galloway J, Rubenstein AH, The metabolic effects of biosynthetic human proinsulin in individuals with type I diabetes. J Clin Endocrinol Metab 58:973–979, 1984
Soeldner JS, Slone D, Critical variables in the RIA of serum insulin using the double antibody system. Diabetes 14:771–779, 1965
Heding LG, Radioimmunological determination of human C-peptide in serum. Diabetologia 11:541–548, 1975
Gray IP, Siddle K, Frank BH, Hales CN, Characterization and use in immunoradiometric assay of monoclonal antibodies directed against human proinsulin. Diabetes 36:684–688, 1987
Lloyd B, Burrin J, Smythe P, Alberti KGMM, Enzymatic fluorimetric continuous flow assays for blood glucose, lactate, pyruvate, alanine, glycerol and 3-hydroxybutyrate. Clin Chem 24:1724–1729, 1978
Orskov H, Thomsen HG, Yale H, Wick chromatography for the rapid and reliable immunoassay of insulin, glucagon and growth hormone. Nature 219:193–195, 1968
Davis SN, Monti L, Piatti P, Brown M, Hetherington C, Orskov H, Sobey W, Hales N, Alberti KGMM, Dose-response characteristics of human proinsulin and insulin in non-insulin-dependent diabetic humans. Am J Physiol 263:E28-E35, 1992
Dillon RS, Importance of haematocrit in interpretation of blood sugar. Diabetes 14:672–674, 1965
Waldhausl WK, Bratusch-Marrain P, Gasic S, Komjati M, Heding L, Inhibition by proinsulin of endogenous C-peptide release in healthy man. Am J Physiol 251:E139-E145, 1986
Argoud G, Schade D, Eaton P, Underestimation of hepatic glucose production by radioactive and stable tracers. Am J Physiol 252:E606-E615, 1987
McMahon M, Schwenk F, Haymond M, Rizza R, Underestimation of glucose turnover measured with [6-3H] and [6,6-2H2] but not [6-14C]glucose during hyperinsulinemia in humans. Diabetes 38:97–108, 1989
Yki-Jarvinen H, Consoli A, Narjhan N, Young A, Gerich JE, Mechanism for underestimation of isotopically determined glucose disposal. Diabetes 38:744–751, 1989
Fineberg E, Merimee TJ, Effects of comparative perfusions of equimolar, single component insulin and proinsulin in the human forearm. Diabetes 22:676–686, 1973
Kelley D, Reilly J, Veneman T, Mandarino L, Effects of insulin on skeletal muscle glucose storage, oxidation and glycolysis in humans. Am J Physiol 258:E923-E929, 1990
Yki-Jarvinen H, Molt D, Young A, Stone K, Bogardus C, Regulation of glycogen synthase and phosphorylase activities by glucose and insulin in human skeletal muscle. J Clin Invest 80:95–100, 1987
Freymond D, Bogardus C, Okubo M, Stone K, Mott D, Impaired insulin-stimulated muscle glycogen synthase activation in vivo in man is related to low fasting glycogen synthase phosphatase activity. J Clin Invest 81:1503–1509, 1988
Young A, Bogardus C, Stone K, Mott D, Insulin response of components of whole body and muscle carbohydrate metabolism in humans. Am J Physiol 254:E231-E236, 1988
Mandarino J, Wright KS, Verity LS, Nichols J, Bell J, Kolterman O, Beck-Nielsen H, Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase, phosphofructokinase, and glycogen synthase. J Clin Invest 80:655–663, 1987
Gelfand RA, Barrett EJ, Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man. J Clin Invest 80:1–6, 1987
Katz J, McGarry JD, The glucose paradox: is glucose a substrate for liver metabolism? J Clin Invest 74:1901–1909, 1984
Nurjhan N, Campbell P, Kennedy F, Miles J, Gerich JE, Insulin dose-response characteristics for suppression of glycerol release and conversion to glucose in humans. Diabetes 5:1320–1331, 1986
Bakir S, Jarrett R, The effects of low dose intravenous insulin infusion upon plasma glucose and non-esterified fatty acid levels in very obese and non-obese human subjects. Diabetologia 20:592–596, 1991
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Davis, S.N., Monti, L., Piatti, P.M. et al. Assessment of proinsulin's effects on intermediary metabolism using the forearm technique in normal man. Acta Diabetol 30, 29–35 (1993). https://doi.org/10.1007/BF00572871
Issue Date:
DOI: https://doi.org/10.1007/BF00572871