Summary
Twenty diabetic patients, whose hyperglycaemia had been shown to fail to respond to at least one month's dietary treatment, completed a crossover study in order to: 1) compare the effectiveness of two sulphonylureas, chlorpropamide and glibenclamide, and 2) study the effects of sulphonylureas on insulin secretion and on biochemical indices of glucose intolerance. Fasting blood glucose fell on active treatment from 10.7±0.6 (mean ± SEM) to 6.6+0.7 mmol/l and rose again to 10.6±0.7 after 4 months placebo. A second period of 4 months sulphonylurea therapy resulted in a comparable fall in blood glucose (to 6.9±0.7 mmol/l) and a similar relapse was seen after the second placebo period (to 10.5±0.9 mmol/l). Glucose tolerance and associated insulin secretion improved markedly on active treatment, with ketone bodies, non-esterified fatty acids, and glycerol falling to within the reference range. Sulphonylurea therapy was associated with a small but significant increase in the fasting insulin level. These effects were nearly all reversed 4 months after withdrawal of the sulphonylureas. No marked changes were found in growth hormone, lactate, pyruvate, lactate/pyruvate ratio or fasting cholesterol, triglycerides and lipoproteins. On a weight basis, glibenclamide was 26 times more potent than chlorpropamide and, in the doses used in this study, their biochemical effects were indistinguishable. The effects of these two sulphonylureas seem most likely to be mediated by a direct stimulation of insulin secretion by the B-cell.
Article PDF
Similar content being viewed by others
References
Loubatieres A (1944) Analyse du mecanisme de l'action hypoglycemiante du p-aminobenzenesulfamidoisopropylthiaxiazol (2254 RP). C R Soc Biol (Paris) 138: 766–767
Levine R, Pfeiffer EF (1969) HB 419, a new oral amidiabetic drug. Horm Metab Res 1 (Suppl 1): 1–92
Roth J, Prout TE, Goldfind ID, Wolfe SM, Muenzer J, Grauer LE, Marcus ML (1971) Sulfonylureas: Effects in vivo and in vitro. Ann Intern Med 75: 607–621
Trinder P (1969) Determination of blood glucose using an oxidase-peroxidase system with a noncarcinogenic chromogen. Clin Pathol 22: 158–161
Trinder P (1969) Determination of blood glucose using 4- aminophenazone as oxygen acceptor. J Clin Pathol 22: 246
Sönksen PH (1976) Double-antibody technique for the simultaneous assay of insulin and growth hormone. In: Antoniades HN (ed) Hormones in human blood. Harvard University Press, Cambridge Mass London, p 176–199
Hohorst HJ, Kreutz, FH, Bücher Th (1959) Über Metabolitgehalte und Metabolit-Konzentrationen in der Leber der Ratte. Biochemistry 332: 18–46
Williamson DH, Mellanby J, Krebs HA (1962) Enzymatic determination of D(-)-β-hydroxybutyric acid and acetoacetic acid in blood. Biochem J 82: 90–96
Kreutz FH (1962) Enzymatische Glycerinbestimmung. Klin Wochenschr 40: 362–363
Carruthers M, Young DAB (1973) Free fatty acid estimation by a semi-automated fluroimetric method. Clin Chim Acta 49: 341–348
Kessler G, Lederer H (1966) Fluorometric measurement of triglycerides. In: Automation in analytical chemistry. Technicon Symposia 1965. Medaid Inc, White Plains NY, p 341–344
Levine J, Morgenstern S, Vlastelica D (1968) A direct Lieber- mann-Burchard method for serum cholesterol. In: Automation in analytical chemistry. Technicon Symposia 1967. Medaid Inc, White Plains NY, p 25–28
Perkins JR (1978) in Hormonal and metabolic responses to dietary and sulphonylurea treatments of chronic diabetes. Ph. D. Thesis, University of London, p 47–51
Winer BJ (1970) In: Statistical principles in experimental design. International Student (ed) McGraw Hill, London New York; Mladinska Knjiga, Ljubljana, p 140–224 and 578–618
Abramson E, Arky RA (1967) Treatment of the obese diabetic: A comparative study of placebo, sulfonylurea and phenformin. Metabolism 16: 204–212
Anderson J, Coulson R, Grassick BDM, Morris BA, Thomas WD, Tomlinson RWS, Woodroffe F (1970) Clinical and metabolic study in diabetic patients treated with glibenclamide. Br Med J II: 568–570
Chandalia HB, Hollobaugh SL, Pennington LF, Boshell BR (1969) Use of glibenclamide in maturity onset diabetes: effect of the drug on serum insulin levels. Horm Metab Res 1 (Suppl1): 73–76
Chu P-C, Conway MJ, Krouse HA, Goodner CJ (1968) The pattern of response of plasma insulin and glucose to meals and fasting during chlorpropamide therapy. Ann Intern Med 68: 757–769
Doar JWH, Thompson ME, Wilde CE, Sewell PFJ (1976) Diet and oral antidiabetic drugs and plasma sugar and insulin levels in patients with maturity-onset diabetes mellitus. Br Med J I: 498–500
Lauvaux JP, Mandart G, Heymans G, Ooms HA (1972) Effect of long-term tolbutamide treatment on glucose tolerance and insulin secretion in maturity-onset diabetes without obesity. Horm Metab Res 4: 58–62
Sheldon J, Taylor KW, Anderson J (1966) The effects of long-term acetohexamide treatment on pancreatic islet cell function in maturity-onset diabetes. Metabolism 15: 874–883
Tsalikian E, Dunphy TW, Bohannon NV, Lorenzi M, Gerich JE, Forsham PH, Kane JP, Karam JH (1977) The effect of chronic oral antidiabetic therapy on insulin and glucagon responses to a meal. Diabetes 26: 314–321
Barnes AJ, Garbien KJT, Crowley MF, Bloom A (1974) Effect of short and long term chlorpropamide treatment on insulin release and blood glucose. Lancet II: 69–72
Davidson M, Lewis AAG, de Mowbray RR, Boucher BJ, Oakley NW, Nabarro JDN, Ginsberg J, Beaconsfield P (1970) Metabolic and clinical effects of glibenclamide. Lancet I: 57–61
Feldman JM, Lebovitz HE (1971) Endocrine and metabolic effects of glibenclamide. Diabetes 20: 745–755
Hadden DR, Bhatia SK, Rigas A, Weaver JA, Montgomery DAD (1969) Circadian variation of glucose, insulin and free fatty acids during the long-term use of oral hypoglycemic agents in diabetes mellitus with special reference to HB419. Horm Metab Res 1 (Suppl 1): 77–80
Hecht A, Gershberg H, Hulse M (1973) Effect of chlorpropamide on insulin secretion in diabetics: its relationship to the hypoglycemic effect. Metabolism 22: 723–733
Boshell BR, Fox OJ, Roddam RF, Hill PS (1967) The effect of sulphonylurea agents on insulin secretion and insulin reserve. In: Butterfield WJH, Van Westering W (ed) Tolbutamide ... after ten years. International Congress Series No 149. Excerpta Medica Foundation Amsterdam New York London Milan Tokyo Buenos Aires, p 286–297
Fox OJ, McAdams GL, Boshell BR (1967) Effect of sulfonyl- ureas on insulin secretion and insulin reserve. Clin Res 15: 43
Reaven GM, Dray J (1967) Effect on chlorpropamide on serum glucose and immunoreactive insulin concentrations in patients with maturity-onset diabetes mellitus. Diabetes 16: 487–492
Shenfield GM, Logan A, Shirling D, Baird J (1977) Plasma insulin and glucose levels in maturity onset diabetics treated with chlorpropamide. Diabetologia 13: 367–371
Elkeles R, Fraser TR (1970) The effect of short and long term chlorpropamide therapy on glucose tolerance. Diabetologia 6: 148
Perkins JR, West TET, Sönksen PH, Lowy C, Iles C (1977) The effects of energy and carbohydrate restriction in patients with chronic diabetes mellitus. Diabetologia 13: 607–614
Alberti KGMM, Hockaday TDR (1975) The biochemistry of the complications of diabetes. In: Keen H, Jarrett J (ed) Complications of diabetes. Edward Arnold, London, p 221–264
Stone DB, Brown JD (1966) Effect of sulfonylurea drugs on plasma free fatty acid and blood glucose concentrations in man. Diabetes 15: 314–318
Tomkins AM, Bloom A (1972) Assessment of the need for continued oral therapy in diabetics. Br Med J I: 649–651
Feldman JM, Lebovitz HE (1969) Appraisal of the extrapancreatic actions of sulfonylureas. Arch Intern Med 123: 314–322
Williams RH, Tucker BW (1956) Hypoglycemic actions of tolbutamide and carbutamide. Metabolism 5: 801–806
Mirsky IA, Perisutti G, Diengott D (1956) The inhibition of insulinase by hypoglycemic sulfonamides. Metabolism 5: 156–161
Bair JD, Duncan LJP (1957) An analysis of the hypoglycaemic response to tolbutamide. Scott Med J 2: 341–350
Stowers JM, Mahler RF, Hunter RB (1958) Pharmacology and mode of action of the sulphonylureas in man. Lancet I: 278–283
Mariani M-M (1969) The action of sulfonylureas on the insulin secretion of the perfused rat pancreas. Acta Diabetol Lat 6 (Suppl1): 256–270
Loubatieres A (1957) The hypoglycemic sulfonamides: history and development of the problem from 1942 to 1955. Ann NY Acad Sci 71: 4–11
Pfeiffer EF, Pfeiffer M, Ditschuneit H, Ahn C-S (1959) Clinical and experimental studies of insulin secretion following tolbutamide and metahexamide administration. Ann NY Acad Sci 82: 479–495
Feinglos MN, Lebovitz HE (1978) Sulphonylureas increase the number of insulin receptors. Nature 276: 184–185
Greenstein BD (1979) Improved insulin receptor assay: effects of an antidiabetic sulphonylurea on liver membrane insulin receptors from obese hyperglycaemic mice. Br J Pharmacol 66: 317–322
Rabinowitz D, Zierler KL (1965) The action of insulin in man in the postabsorptive and postprandial states. Postgrad Med J 41: 67–72
Clarke BF, Campbell IW (1975) Long-term comparative trial of glibenclamide and chlorpropamide in diet-failed, maturityonset diabetics. Lancet I: 246–248
Bhatia SK, Hadden DR, Montgomery DAD, Weaver JA (1970) Glibenclamide therapy in diabetes mellitus. Br Med J II: 570–572
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sönksen, P.H., Lowy, C., Perkins, J.R. et al. Hormonal and metabolic effects of chlorpropamide, glibenclamide and placebo in a cross-over study in diabetics not controlled by diet alone. Diabetologia 20, 22–30 (1981). https://doi.org/10.1007/BF00253812
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00253812