Summary
To determine the natural history of the development of Type 2 (non-insulin-dependent) diabetes mellitus, basal plasma insulin and glucose levels and responses to intravenous glucose tolerance tests were determined over a period of 6 years in 42 adult male rhesus monkeys (Macaca mulatta). Among the 28 obese monkeys (percent body fat > 22%) over the age of 10 years, 9 developed overt Type 2 diabetes (fasting plasma glucose, > 7.8 mmol/l; and reduced glucose disappearance rates, KG < 1.5), and 14 monkeys have shown progressive changes which suggest that they may also become diabetic. Application of a highly constant antecedent diet and a consistent 16-h fast minimized experimental variability, and permitted the identification of 8 phases in the progression from normal lean young adult to overt Type 2 diabetes. The earliest changes which could be detected were a slight increase followed by a progressive rise in fasting plasma insulin levels and an increased insulin secretion in response to a glucose stimulus. These events preceded by several years the onset of a gradual deterioration of glucose tolerance. We found that hyper-, normo-, or hypoinsulinaemia could be associated with normoglycaemia or varying degrees of hyperglycaemia; however, the prospective longitudinal study of individual monkeys clearly identified this apparent heterogeneity of plasma insulin and glucose levels as reflecting sequential changes in a continuum of events preceding or accompanying the development of impaired glucose tolerance and Type 2 diabetes mellitus.
Article PDF
Similar content being viewed by others
References
DiGiacomo RE, Myers RE, Baez LR (1971) Diabetes mellitus in a rhesus monkey (Macaca mulatta): a case report and literature review. Lab Anim Sci 21: 572–574
Kirk JH, Casey HW, Harwell JF (1972) Diabetes mellitus in two rhesus monkeys. Lab Anim Sci 22: 245–248
Hamilton CL, Ciaccia P (1978) The course of development of glucose intolerance in the monkey (Macaca mulatta). J Med Primatol 7:165–173
Kemnitz JW, Kraemer GW (1982) Assessment of glucoregulation in rhesus monkeys sedated with ketamine. Am J Primatol 3: 201–210
Brady AG, Koritnik DR (1985) The effects of ketamine anesthesia on glucose clearance in African green monkeys. J Med Primatol 14:99–107
Hansen BC, Pek S, Koerker DJ, Goodner CJ, Wolfe RA, Schielke GP (1981) Neural influences on oscillations in basal plasma levels of insulin in monkeys. Am J Physiol 240 (Endocrinol Metab 3): E5–E11
Hansen BC, Jen K-LC, Pek SB, Wolfe RA (1982) Rapid oscillations in plasma insulin, glucagon, and glucose in obese and normal weight humans. J Clin Endocrinol Metab 54: 785–792
Moore FD (1946) Determination of total body water and solids with isotopes. Science 104: 157–160
Pace N, Kline L, Schachman HK, Harfenist M (1947) Studies on body composition. IV. Use of radioactive hydrogen for measurement in vivo of total body water. J Biol Chem 168: 459–469
Slein MW (1971) D-glucose determination with hexokinase and glucose-6-phosphate dehydrogenase. In: Bergmeyer HV (ed) Methods of enzymatic analysis. Academic, New York, pp 117–123
Hayashi M, Floyd JC Jr, Pek S, Fajans SS (1977) Insulin, proinsulin, glucagon and gastrin in pancreatic tumors in the plasma of patients with organic hyperinsulinism. J Clin Endocrinol Metab 44:681–694
Morgan CR, Lazarow A (1963) Immunoassay of insulin. Two antibody system — plasma insulin levels of normal, subdiabetic and diabetic rats. Diabetes 12: 115–126
Naithani VK, Steffens GJ, Tager HS, Buse G, Rubenstein AH, Steiner DF (1984) Isolation and amino-acid sequence determination of monkey insulin and proinsulin. Hoppe-Seyler's Z Physiol Chem 365: 571–575
National Diabetes Data Group (1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28: 1039–1057
WHO Technical Report Series, No 646. (1980) Who Chronicle 34: 361
Scheffe H (1959) The analysis of variance. Wiley, New York
Jen K-LC, Hansen BC, Metzger BL (1985) Adiposity, anthropometric measures, and plasma insulin levels of rhesus monkeys. International J Obesity 9: 213–224
Metzger BL, Hansen BC, Speegle LM, Jen K-LC (1985) Characterization of glucose intolerance in obese monkeys. J Obes Wt Reg 4:153–167
Vague J, Vague Ph, Tramoni M, Vialettes B (1983) Clinical features of diabetogenic and atherogenic obesity. Tohoku J Exp Med 141 (Suppl):145–159
Reaven GM, Moore J, Greenfield M (1983) Quantification of insulin secretion and in vivo insulin action in nonobese and moderately obese individuals with normal glucose tolerance. Diabetes 32:600–604
Bogardus C, Lillioja S, Mott D, Reaven GR, Kashiwagi A, Foley JE (1984) Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians. J Clin Invest 73: 800–805
Bogardus C, Lillioja S, Mott DM, Hollenbeck C, Reaven G (1985) Relationship between degree of obesity and insulin action in man. Am J of Physiol 248 (Endocrinol Metab 11) E286–291
Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D (1984) Relationships between insulin secretion, insulin action and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. J Clin Invest 74: 1238–1246
Bennett PH, Knowler WC, Pettitt DJ, Carraher MJ, Vasquez B (1982) Longitudinal studies of the development of diabetes in the Pima Indians. In: Eschwege E (ed) Advances in diabetes epidemiology. Elsevier, Amsterdam Oxford New York, pp 65–74
Reaven GM, Olefsky JM (1977) Relationship between heterogeneity of insulin responses and insulin resistance in normal subjects and patients with chemical diabetes. Diabetologia 13: 201–206
Savage PJ, Dippe SE, Bennett PH, Gordon P, Roth J, Rushforth NB, Miller M (1975) Hyperinsulinemia and hypoinsulinemia — insulin responses to oral carbohydrate over a wide spectrum of glucose tolerance. Diabetes 24: 362–368
Zimmett P, Whitehouse S, Alford F, Chisholm D (1978) The relationship of insulin response to a glucose stimulus over a wide range of glucose tolerance. Diabetologia 15: 23–27
Liu G, Coulston A, ChenY-DI, Reaven GM (1983) Does day-long absolute hypoinsulinemia characterize the patient with non-insulin-dependent diabetes mellitus? Metabolism 32: 754–756
Weir GC (1982) Noninsulin-dependent diabetes mellitus: interplay between B-cell inadequacy and insulin resistance. Am J Med 73:461–464
Kosaka K, Hagura R, Kuzuya T (1977) Insulin response in equivocal and definite diabetes, with special reference to subjects who had mild glucose intolerance but later developed definite diabetes. Diabetes 26: 944–952
Keen H, Jarrett RJ, McCartney P (1982) The ten-year follow-up of the Bedford Survey (1962–1972): glucose tolerance and diabetes. Diabetologia 22: 73–78
Kadowaki T, Miyake Y, Hagura R, Kajinuma H, Kuzuya N, Akanuma Y, Kosaka K (1983) On the pathogenesis of Type II diabetes with special reference to diminished insulin response and obesity: a 5–12 year follow-up study of subjects with borderline glucose tolerance. Tohoku J Exp Med 141 (Suppl): 141–146
Sasaki A, Suzuki T, Horiuchi N (1982) Development of diabetes in Japanese subjects with impaired glucose tolerance: a seven year follow-up study. Diabetologia 22:154–157
Reaven GM (1984) Insulin secretion and insulin action in noninsulin-dependent diabetes mellitus: which defect is primary? Diabetes Care 7 (Suppl 1): 17–24
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hansen, B.C., Bodkin, N.L. Heterogeneity of insulin responses: phases leading to Type 2 (non-insulin-dependent) diabetes mellitus in the rhesus monkey. Diabetologia 29, 713–719 (1986). https://doi.org/10.1007/BF00870281
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00870281