Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Jan 1;101(1):86–96. doi: 10.1172/JCI716

Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited. Metabolic studies on offspring of diabetic probands.

I Vauhkonen 1, L Niskanen 1, E Vanninen 1, S Kainulainen 1, M Uusitupa 1, M Laakso 1
PMCID: PMC508544  PMID: 9421470

Abstract

No studies are available that have compared early defects in glucose metabolism in the offspring of insulin-deficient and insulin-resistant probands with non-insulin-dependent diabetes mellitus (NIDDM). To investigate this issue, we evaluated insulin secretion capacity with oral and intravenous glucose tolerance tests and with the hyperglycemic clamp, and insulin action with the euglycemic insulin clamp in 20 offspring of NIDDM patients with low fasting C-peptide (+/-450 pmol/liter), reflecting deficient insulin secretion (IS-group), 18 offspring of NIDDM patients with high fasting C-peptide (>/= 880 pmol/liter), reflecting insulin resistance (IR-group), and 14 healthy control subjects without a family history of NIDDM. The frequency of impaired glucose tolerance was 45.0% in the IS-group and 50% in the IR-group. The IS-group had lower insulin-glucose response at 30 min in the oral glucose tolerance test (85.2+/-10.0 pmol insulin per mmol glucose) than the control group (136.4+/-23.1 pmol insulin per mmol glucose; P < 0.05) and the IR-group (115.6+/-11.8 pmol insulin per mmol glucose; P = 0.05). Furthermore, the acute insulin response during the first 10 min of an intravenous glucose tolerance test was lower in the IS-group than in the IR-group. Maximal insulin secretion capacity evaluated by C-peptide levels during the hyperglycemic clamp did not differ between the groups. The IR-group had lower rates of whole body glucose uptake (60.1+/-4.6 micromol per lean body mass per minute) than did the control group (84.2+/-5.0 micromol per lean body mass per minute; P < 0.001) or the IS-group (82.6+/-5.9 micromol per lean body mass per minute; P < 0.01) and this was due to reduced glucose nonoxidation. To conclude, both impaired insulin secretion and insulin action seem to be inherited and could represent the primary defects in glucose metabolism in the offspring of NIDDM probands.

Full Text

The Full Text of this article is available as a PDF (321.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abate N., Garg A., Peshock R. M., Stray-Gundersen J., Adams-Huet B., Grundy S. M. Relationship of generalized and regional adiposity to insulin sensitivity in men with NIDDM. Diabetes. 1996 Dec;45(12):1684–1693. doi: 10.2337/diab.45.12.1684. [DOI] [PubMed] [Google Scholar]
  2. Abate N., Garg A., Peshock R. M., Stray-Gundersen J., Grundy S. M. Relationships of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest. 1995 Jul;96(1):88–98. doi: 10.1172/JCI118083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arner P., Pollare T., Lithell H. Different aetiologies of type 2 (non-insulin-dependent) diabetes mellitus in obese and non-obese subjects. Diabetologia. 1991 Jul;34(7):483–487. doi: 10.1007/BF00403284. [DOI] [PubMed] [Google Scholar]
  4. Barnett A. H., Eff C., Leslie R. D., Pyke D. A. Diabetes in identical twins. A study of 200 pairs. Diabetologia. 1981 Feb;20(2):87–93. doi: 10.1007/BF00262007. [DOI] [PubMed] [Google Scholar]
  5. Bonadonna R. C., Groop L., Kraemer N., Ferrannini E., Del Prato S., DeFronzo R. A. Obesity and insulin resistance in humans: a dose-response study. Metabolism. 1990 May;39(5):452–459. doi: 10.1016/0026-0495(90)90002-t. [DOI] [PubMed] [Google Scholar]
  6. Campbell P. J., Carlson M. G. Impact of obesity on insulin action in NIDDM. Diabetes. 1993 Mar;42(3):405–410. [PubMed] [Google Scholar]
  7. DeFronzo R. A. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988 Jun;37(6):667–687. doi: 10.2337/diab.37.6.667. [DOI] [PubMed] [Google Scholar]
  8. DeFronzo R. A., Tobin J. D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. doi: 10.1152/ajpendo.1979.237.3.E214. [DOI] [PubMed] [Google Scholar]
  9. Eriksson J., Franssila-Kallunki A., Ekstrand A., Saloranta C., Widén E., Schalin C., Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med. 1989 Aug 10;321(6):337–343. doi: 10.1056/NEJM198908103210601. [DOI] [PubMed] [Google Scholar]
  10. Ferrannini E. The theoretical bases of indirect calorimetry: a review. Metabolism. 1988 Mar;37(3):287–301. doi: 10.1016/0026-0495(88)90110-2. [DOI] [PubMed] [Google Scholar]
  11. Firth R., Bell P., Rizza R. Insulin action in non-insulin-dependent diabetes mellitus: the relationship between hepatic and extrahepatic insulin resistance and obesity. Metabolism. 1987 Nov;36(11):1091–1095. doi: 10.1016/0026-0495(87)90031-x. [DOI] [PubMed] [Google Scholar]
  12. 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. 1988 Nov;82(5):1503–1509. doi: 10.1172/JCI113758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Froguel P., Zouali H., Vionnet N., Velho G., Vaxillaire M., Sun F., Lesage S., Stoffel M., Takeda J., Passa P. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med. 1993 Mar 11;328(10):697–702. doi: 10.1056/NEJM199303113281005. [DOI] [PubMed] [Google Scholar]
  14. Fuller N. J., Elia M. Potential use of bioelectrical impedance of the 'whole body' and of body segments for the assessment of body composition: comparison with densitometry and anthropometry. Eur J Clin Nutr. 1989 Nov;43(11):779–791. [PubMed] [Google Scholar]
  15. Gulli G., Ferrannini E., Stern M., Haffner S., DeFronzo R. A. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes. 1992 Dec;41(12):1575–1586. doi: 10.2337/diab.41.12.1575. [DOI] [PubMed] [Google Scholar]
  16. Haffner S. M., Stern M. P., Hazuda H. P., Pugh J. A., Patterson J. K. Hyperinsulinemia in a population at high risk for non-insulin-dependent diabetes mellitus. N Engl J Med. 1986 Jul 24;315(4):220–224. doi: 10.1056/NEJM198607243150403. [DOI] [PubMed] [Google Scholar]
  17. Haffner S. M., Stern M. P., Mitchell B. D., Hazuda H. P., Patterson J. K. Incidence of type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity, and body-fat distribution. Diabetes. 1990 Mar;39(3):283–288. doi: 10.2337/diab.39.3.283. [DOI] [PubMed] [Google Scholar]
  18. Henriksen J. E., Alford F., Handberg A., Vaag A., Ward G. M., Kalfas A., Beck-Nielsen H. Increased glucose effectiveness in normoglycemic but insulin-resistant relatives of patients with non-insulin-dependent diabetes mellitus. A novel compensatory mechanism. J Clin Invest. 1994 Sep;94(3):1196–1204. doi: 10.1172/JCI117436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hosker J. P., Rudenski A. S., Burnett M. A., Matthews D. R., Turner R. C. Similar reduction of first- and second-phase B-cell responses at three different glucose levels in type II diabetes and the effect of gliclazide therapy. Metabolism. 1989 Aug;38(8):767–772. doi: 10.1016/0026-0495(89)90064-4. [DOI] [PubMed] [Google Scholar]
  20. Inagaki N., Gonoi T., Clement J. P., 4th, Namba N., Inazawa J., Gonzalez G., Aguilar-Bryan L., Seino S., Bryan J. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science. 1995 Nov 17;270(5239):1166–1170. doi: 10.1126/science.270.5239.1166. [DOI] [PubMed] [Google Scholar]
  21. Kahn C. R., Vicent D., Doria A. Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annu Rev Med. 1996;47:509–531. doi: 10.1146/annurev.med.47.1.509. [DOI] [PubMed] [Google Scholar]
  22. Kissebah A. H. Insulin resistance in visceral obesity. Int J Obes. 1991 Sep;15 (Suppl 2):109–115. [PubMed] [Google Scholar]
  23. Klöppel G., Löhr M., Habich K., Oberholzer M., Heitz P. U. Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res. 1985;4(2):110–125. doi: 10.1159/000156969. [DOI] [PubMed] [Google Scholar]
  24. Knowler W. C., Pettitt D. J., Savage P. J., Bennett P. H. Diabetes incidence in Pima indians: contributions of obesity and parental diabetes. Am J Epidemiol. 1981 Feb;113(2):144–156. doi: 10.1093/oxfordjournals.aje.a113079. [DOI] [PubMed] [Google Scholar]
  25. Kvist H., Sjöström L., Tylén U. Adipose tissue volume determinations in women by computed tomography: technical considerations. Int J Obes. 1986;10(1):53–67. [PubMed] [Google Scholar]
  26. Laakso M., Sarlund H., Mykkänen L. Insulin resistance is associated with lipid and lipoprotein abnormalities in subjects with varying degrees of glucose tolerance. Arteriosclerosis. 1990 Mar-Apr;10(2):223–231. doi: 10.1161/01.atv.10.2.223. [DOI] [PubMed] [Google Scholar]
  27. Laakso M., Uusitupa M., Takala J., Majander H., Reijonen T., Penttilä I. Effects of hypocaloric diet and insulin therapy on metabolic control and mechanisms of hyperglycemia in obese non-insulin-dependent diabetic subjects. Metabolism. 1988 Nov;37(11):1092–1100. doi: 10.1016/0026-0495(88)90074-1. [DOI] [PubMed] [Google Scholar]
  28. Larsson H., Ahrén B. Failure to adequately adapt reduced insulin sensitivity with increased insulin secretion in women with impaired glucose tolerance. Diabetologia. 1996 Sep;39(9):1099–1107. doi: 10.1007/BF00400660. [DOI] [PubMed] [Google Scholar]
  29. Laws A., Stefanick M. L., Reaven G. M. Insulin resistance and hypertriglyceridemia in nondiabetic relatives of patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1989 Aug;69(2):343–347. doi: 10.1210/jcem-69-2-343. [DOI] [PubMed] [Google Scholar]
  30. Leahy J. L., Cooper H. E., Weir G. C. Impaired insulin secretion associated with near normoglycemia. Study in normal rats with 96-h in vivo glucose infusions. Diabetes. 1987 Apr;36(4):459–464. doi: 10.2337/diab.36.4.459. [DOI] [PubMed] [Google Scholar]
  31. Lillioja S., Young A. A., Culter C. L., Ivy J. L., Abbott W. G., Zawadzki J. K., Yki-Järvinen H., Christin L., Secomb T. W., Bogardus C. Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J Clin Invest. 1987 Aug;80(2):415–424. doi: 10.1172/JCI113088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lindsten J., Cerasi E., Luft R., Morton N., Ryman N. Significance of genetic factors for the plasma insulin response to glucose in healthy subjects. Clin Genet. 1976 Sep;10(3):125–134. doi: 10.1111/j.1399-0004.1976.tb00024.x. [DOI] [PubMed] [Google Scholar]
  33. MACLEAN N., OGILVIE R. F. Quantitative estimation of the pancreatic islet tissue in diabetic subjects. Diabetes. 1955 Sep-Oct;4(5):367–376. doi: 10.2337/diab.4.5.367. [DOI] [PubMed] [Google Scholar]
  34. Matsuda A., Kuzuya T. The prevalence of low insulin responders to oral glucose load among groups with various patterns of family history of diabetes. Diabet Med. 1996 Sep;13(9 Suppl 6):S59–S62. [PubMed] [Google Scholar]
  35. Migdalis I. N., Zachariadis D., Kalogeropoulou K., Nounopoulos C., Bouloukos A., Samartzis M. Metabolic abnormalities in offspring of NIDDM patients with a family history of diabetes mellitus. Diabet Med. 1996 May;13(5):434–440. doi: 10.1002/(SICI)1096-9136(199605)13:5<434::AID-DIA102>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  36. Newman B., Selby J. V., King M. C., Slemenda C., Fabsitz R., Friedman G. D. Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia. 1987 Oct;30(10):763–768. doi: 10.1007/BF00275741. [DOI] [PubMed] [Google Scholar]
  37. Niskanen L. K., Tuomi T., Karjalainen J., Groop L. C., Uusitupa M. I. GAD antibodies in NIDDM. Ten-year follow-up from the diagnosis. Diabetes Care. 1995 Dec;18(12):1557–1565. doi: 10.2337/diacare.18.12.1557. [DOI] [PubMed] [Google Scholar]
  38. Niskanen L. K., Uusitupa M. I., Sarlund H., Siitonen O., Pyörälä K. Five-year follow-up study on plasma insulin levels in newly diagnosed NIDDM patients and nondiabetic subjects. Diabetes Care. 1990 Jan;13(1):41–48. doi: 10.2337/diacare.13.1.41. [DOI] [PubMed] [Google Scholar]
  39. Niskanen L., Karjalainen J., Sarlund H., Siitonen O., Uusitupa M. Five-year follow-up of islet cell antibodies in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1991 Jun;34(6):402–408. doi: 10.1007/BF00403178. [DOI] [PubMed] [Google Scholar]
  40. Niskanen L., Karjalainen J., Siitonen O., Uusitupa M. Metabolic evolution of type 2 diabetes: a 10-year follow-up from the time of diagnosis. J Intern Med. 1994 Sep;236(3):263–270. doi: 10.1111/j.1365-2796.1994.tb00794.x. [DOI] [PubMed] [Google Scholar]
  41. Nyholm B., Mengel A., Nielsen S., Skjaerbaek C., Møller N., Alberti K. G., Schmitz O. Insulin resistance in relatives of NIDDM patients: the role of physical fitness and muscle metabolism. Diabetologia. 1996 Jul;39(7):813–822. doi: 10.1007/s001250050515. [DOI] [PubMed] [Google Scholar]
  42. O'Rahilly S., Turner R. C., Matthews D. R. Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N Engl J Med. 1988 May 12;318(19):1225–1230. doi: 10.1056/NEJM198805123181902. [DOI] [PubMed] [Google Scholar]
  43. Penttilä I. M., Voutilainen E., Laitinen P., Juutilainen P. Comparison of different analytical and precipitation methods for direct estimation of serum high-density lipoprotein cholesterol. Scand J Clin Lab Invest. 1981 Jun;41(4):353–360. doi: 10.3109/00365518109092057. [DOI] [PubMed] [Google Scholar]
  44. Pimenta W., Korytkowski M., Mitrakou A., Jenssen T., Yki-Jarvinen H., Evron W., Dailey G., Gerich J. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative. JAMA. 1995 Jun 21;273(23):1855–1861. [PubMed] [Google Scholar]
  45. Rossetti L., Giaccari A., DeFronzo R. A. Glucose toxicity. Diabetes Care. 1990 Jun;13(6):610–630. doi: 10.2337/diacare.13.6.610. [DOI] [PubMed] [Google Scholar]
  46. Schalin-Jäntti C., Härkonen M., Groop L. C. Impaired activation of glycogen synthase in people at increased risk for developing NIDDM. Diabetes. 1992 May;41(5):598–604. doi: 10.2337/diab.41.5.598. [DOI] [PubMed] [Google Scholar]
  47. Sjöström L., Kvist H., Cederblad A., Tylén U. Determination of total adipose tissue and body fat in women by computed tomography, 40K, and tritium. Am J Physiol. 1986 Jun;250(6 Pt 1):E736–E745. doi: 10.1152/ajpendo.1986.250.6.E736. [DOI] [PubMed] [Google Scholar]
  48. Turner R. C., McCarthy S. T., Holman R. R., Harris E. Beta-cell function improved by supplementing basal insulin secretion in mild diabetes. Br Med J. 1976 May 22;1(6020):1252–1254. doi: 10.1136/bmj.1.6020.1252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Uusitupa M. I., Niskanen L. K., Siitonen O., Voutilainen E., Pyörälä K. Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in type 2 (non-insulin-dependent) diabetic and non-diabetic subjects. Diabetologia. 1993 Nov;36(11):1175–1184. doi: 10.1007/BF00401063. [DOI] [PubMed] [Google Scholar]
  50. Uusitupa M., Siitonen O., Aro A., Pyörälä K. Prevalence of coronary heart disease, left ventricular failure and hypertension in middle-aged, newly diagnosed type 2 (non-insulin-dependent) diabetic subjects. Diabetologia. 1985 Jan;28(1):22–27. doi: 10.1007/BF00276995. [DOI] [PubMed] [Google Scholar]
  51. Vaag A., Henriksen J. E., Madsbad S., Holm N., Beck-Nielsen H. Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus. J Clin Invest. 1995 Feb;95(2):690–698. doi: 10.1172/JCI117715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Walker M. Obesity, insulin resistance, and its link to non-insulin-dependent diabetes mellitus. Metabolism. 1995 Sep;44(9 Suppl 3):18–20. doi: 10.1016/0026-0495(95)90314-3. [DOI] [PubMed] [Google Scholar]
  53. Ward W. K., Bolgiano D. C., McKnight B., Halter J. B., Porte D., Jr Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest. 1984 Oct;74(4):1318–1328. doi: 10.1172/JCI111542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Ward W. K., Halter J. B., Best J. D., Beard J. C., Porte D., Jr Hyperglycemia and beta-cell adaptation during prolonged somatostatin infusion with glucagon replacement in man. Diabetes. 1983 Oct;32(10):943–947. doi: 10.2337/diab.32.10.943. [DOI] [PubMed] [Google Scholar]
  55. Warram J. H., Martin B. C., Krolewski A. S., Soeldner J. S., Kahn C. R. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med. 1990 Dec 15;113(12):909–915. doi: 10.7326/0003-4819-113-12-909. [DOI] [PubMed] [Google Scholar]
  56. Whipp B. J., Davis J. A., Torres F., Wasserman K. A test to determine parameters of aerobic function during exercise. J Appl Physiol Respir Environ Exerc Physiol. 1981 Jan;50(1):217–221. doi: 10.1152/jappl.1981.50.1.217. [DOI] [PubMed] [Google Scholar]
  57. Yamagata K., Furuta H., Oda N., Kaisaki P. J., Menzel S., Cox N. J., Fajans S. S., Signorini S., Stoffel M., Bell G. I. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Nature. 1996 Dec 5;384(6608):458–460. doi: 10.1038/384458a0. [DOI] [PubMed] [Google Scholar]
  58. Yamagata K., Oda N., Kaisaki P. J., Menzel S., Furuta H., Vaxillaire M., Southam L., Cox R. D., Lathrop G. M., Boriraj V. V. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Nature. 1996 Dec 5;384(6608):455–458. doi: 10.1038/384455a0. [DOI] [PubMed] [Google Scholar]
  59. van den Ouweland J. M., Lemkes H. H., Ruitenbeek W., Sandkuijl L. A., de Vijlder M. F., Struyvenberg P. A., van de Kamp J. J., Maassen J. A. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet. 1992 Aug;1(5):368–371. doi: 10.1038/ng0892-368. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES