Skip to main content

Advertisement

SpringerLink
Log in

Contribution of insulin deficiency and insulin resistance to the development of type 2 diabetes: nature of early stage diabetes

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

At the time of diagnosis of type 2 diabetes (T2D), patients already have varying degrees of beta-cell dysfunction and insulin resistance and the defects continue to deteriorate despite treatment. We examined insulin secretion impairment and insulin resistance in overweight patients with T2D who had metformin failure, with elevated HbA1c at maximal metformin dose. Patients (N = 1,039) were examined at entry to the European Exenatide (EUREXA) clinical trial of add-on exenatide versus sulphonylurea. Mean (±SD) age was 57 ± 10 years, and BMI was 32.4 ± 4.1 kg/m2. All patients underwent an oral glucose tolerance test; HOMA-IR, HOMA-B, ∆I 30/∆G 30, disposition index and pro-insulin/insulin ratio were evaluated in relation to stratified HbA1c levels (≤7.3, >7.3–8.2, >8.2%) and duration of diabetes (<3, ≥3–<6, ≥6 years) using non-parametric analysis of variance. Patients overall had a wide range of impaired insulin secretion (HOMA-B: median 50.4, interquartile range 32.8–78.8) and insulin resistance (HOMA-IR: 4.8, 3.0–7.4). With increasing HbA1c levels, there was a statistically significant decrease in HOMA-B (P < 0.001), ∆I 30/∆G 30 (P = 0.003) and disposition index (P < 0.001), and increase in pro-insulin/insulin (P < 0.001) and HOMA-IR (P < 0.001). With increasing duration since diabetes diagnosis, there was a significant decrease in HOMA-B (P < 0.001), but no significant trend in HOMA-IR, ∆I 30/∆G 30, disposition index or pro-insulin/insulin. Metformin failure in these patients was associated with beta-cell dysfunction to a greater extent than insulin resistance. Loss of the first-phase insulin release, indicated by a low ∆I 30/∆G 30, would indicate that this patient cohort requires add-on therapy that can maintain beta-cell function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Matthews DR (2001) Insulin resistance and β-cell function–a clinical perspective. Diabetes Obes Metab 3(1):S28–S33

    Article  PubMed  Google Scholar 

  2. Polonsky KS, Sturis J, Bell GI (1996) Non-insulin-dependent diabetes mellitus: a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med 334:777–783

    Article  PubMed  CAS  Google Scholar 

  3. Marchetti P, Dotta F, Lauro D, Purrello F (2008) An overview of pancreatic beta-cell defects in human type 2 diabetes: implications for treatment. Regul Pept 146:4–11

    Article  PubMed  CAS  Google Scholar 

  4. Kahn SE (2001) The importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab 86:4047–4058

    Article  PubMed  CAS  Google Scholar 

  5. Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki-Jarvinen H, Evron W, Dailey G, Gerich J (1995) 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 273:1855–1861

    Article  PubMed  CAS  Google Scholar 

  6. UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853

    Article  Google Scholar 

  7. UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865

    Article  Google Scholar 

  8. Jensen CC, Cnop M, Hull RL, Fujimoto WY, Kahn SE, The American Diabetes Association GENNID Study Group (2002) β-Cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic groups in the US. Diabetes 51:2170–2178

    Article  PubMed  CAS  Google Scholar 

  9. Fujimoto WY, Leonetti DL, Bergstrom RW, Kinyoun JL, Stolov WC, Wahl PW (1991) Glucose intolerance and diabetic complications among Japanese-American women. Diabetes Res Clin Pract 13:119–129

    Article  PubMed  CAS  Google Scholar 

  10. Boyko EJ, Keane EM, Marshall JA, Hamman RF (1991) Higher insulin and C-peptide concentrations in Hispanic population at high risk for noninsulin- dependent diabetes mellitus. San Luis Valley Diabetes Study. Diabetes 40:509–515

    Article  PubMed  CAS  Google Scholar 

  11. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH (1988) The natural history of impaired glucose tolerance in the Pima Indians. N Engl J Med 319:1500–1506

    Article  PubMed  CAS  Google Scholar 

  12. Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885

    Article  PubMed  CAS  Google Scholar 

  13. Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL et al (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42:105–116

    Article  PubMed  CAS  Google Scholar 

  14. Staiger H, Machicao F, Stefan N, Tschritter O, Thamer C, Kantartzis K, Schäfer SA, Kirchhoff K, Fritsche A, Häring HU (2007) Polymorphisms within novel risk loci for type 2 diabetes determine beta-cell function. PLoS ONE 2:e832

    Article  PubMed  Google Scholar 

  15. Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G et al (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40:638–645

    Article  PubMed  CAS  Google Scholar 

  16. DeFronzo RA, Tripathy D (2009) Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32(2):S157–S163

    Article  PubMed  CAS  Google Scholar 

  17. Bi Y, Zhu D, Jing Y, Hu Y, Feng W, Shen S, Tong G, Shen X, Yu T, Song D, Yang D (2011) Decreased beta cell function and insulin sensitivity contributed to increasing fasting glucose in Chinese. Acta Diabetol. doi:10.1007/s00592-010-0194-4

  18. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110

    Article  PubMed  CAS  Google Scholar 

  19. UK Prospective Diabetes Study (UKPDS) Group (1995) Overview of 6 years’ therapy of type II diabetes: a progressive disease (UKPDS 16). Diabetes 44:1249–1258

    Article  Google Scholar 

  20. Östgren CJ, Lindblad U, Ramstam J, Melander A, Rastam L (2002) Glycaemic control, disease duration and β-cell function in patients with type 2 diabetes in a Swedish community; Skaraborg Hypertension and Diabetes Project. Diabet Med 19:125–129

    Article  PubMed  Google Scholar 

  21. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B, American Diabetes Association, European Association for the Study of Diabetes (2009) Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32:193–203

    Article  PubMed  CAS  Google Scholar 

  22. Consoli A, Gomis R, Halimi S, Home PD, Mehnert H, Strojek K, Van Gaal LF (2004) Initiating oral glucose-lowering therapy with metformin in type 2 diabetic patients: an evidence-based strategy to reduce the burden of late-developing diabetes complications. Diabetes Metab 30:509–516

    Article  PubMed  CAS  Google Scholar 

  23. Cook MN, Girman CJ, Stein PP, Alexander CM, Holman RR (2005) Glycemic control continues to deteriorate after sulfonylureas are added to metformin among patients with type 2 diabetes. Diabetes Care 28:995–1000

    Article  PubMed  CAS  Google Scholar 

  24. Kazda C, Gallwitz B, Simó R, Guzmán JR, Kraus P, Nicolay C, Rose L, Schernthaner G (2009) The European Exenatide study of long-term exenatide vs. glimepiride for type 2 diabetes: rationale and patient characteristics. Diabetes Obes Metab 11:1131–1137

    Article  PubMed  CAS  Google Scholar 

  25. Abdul-Ghani MA, Tripathy D, DeFronzo RA (2006) Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care 29:1130–1139

    Article  PubMed  CAS  Google Scholar 

  26. Eklund M, Shaat N, Almgren P, Groop L, Berntorp K (2010) Prediction of postpartum diabetes in women with gestational diabetes mellitus. Diabetologia 53:452–457

    Article  Google Scholar 

  27. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419

    Article  PubMed  CAS  Google Scholar 

  28. Keskin M, Kurtoglu S, Kendirci M, Atabek ME, Yazici C (2005) Homeostasis model assessment is more reliable than the fasting glucose/insulin ratio and quantitative insulin sensitivity check index for assessing insulin resistance among obese children and adolescents. Pediatrics 115:e500–e503

    Article  PubMed  Google Scholar 

  29. Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462–1470

    Article  PubMed  CAS  Google Scholar 

  30. Tan MH, Baksi A, Krahulec B, Kubalski P, Stankiewicz A, Urquhart R, Edwards G, Johns D, GLAL Study Group (2005) Comparison of pioglitazone and gliclazide in sustaining glycemic control over 2 years in patients with type 2 diabetes. Diabetes Care 28:544–550

    Article  PubMed  CAS  Google Scholar 

  31. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD (2005) Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin treated patients with type 2 diabetes. Diabetes Care 28:1092–1100

    Article  PubMed  CAS  Google Scholar 

  32. Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, Baron AD (2005) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 28:1083–1091

    Article  PubMed  CAS  Google Scholar 

  33. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD, Exenatide-113 Clinical Study Group (2004) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27:2628–2635

    Article  PubMed  CAS  Google Scholar 

  34. Festa A, Williams K, D’Agostino R Jr, Wagenknecht LE, Haffner SM (2006) The natural course of beta-cell function in nondiabetic and diabetic individuals: the Insulin Resistance Atherosclerosis Study. Diabetes 55:1114–1120

    Article  PubMed  CAS  Google Scholar 

  35. Røder ME, Porte D Jr, Schwartz RS, Kahn SE (1998) Disproportionately elevated proinsulin levels reflect the degree of impaired B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 83:604–608

    Article  PubMed  Google Scholar 

  36. Kirchhoff K, Machicao F, Haupt A, Schäfer SA, Tschritter O, Staiger H, Stefan N, Häring HU, Fritsche A (2008) Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia 51:597–601

    Article  PubMed  CAS  Google Scholar 

  37. Røder ME, Dinesen B, Hartling SG, Houssa P, Vestergaard H, Sodoyez-Goffaux F, Binder C (1999) Intact proinsulin and β-cell function in lean and obese subjects with and without type 2 diabetes. Diabetes Care 22:609–614

    Article  PubMed  Google Scholar 

  38. Utzschneider KM, Van de Lagemaat A, Faulenbach MV, Goedecke JH, Carr DB, Boyko EJ, Fujimoto WY, Kahn SE (2010) Insulin resistance is the best predictor of the metabolic syndrome in subjects with a first-degree relative with type 2 diabetes. Obesity (Silver Spring) 18(9):1781–1787

    Google Scholar 

  39. Pivatto I, Bustos P, Amigo H, Acosta AM, Arteaga A (2007) Association between proinsulin, insulin, proinsulin/insulin ratio, and insulin resistance status with the metabolic syndrome. Arq Bras Endocrinol Metabol 51:1128–1133

    Article  PubMed  Google Scholar 

  40. Atabek ME, Pirgon O (2008) Use of metformin in obese adolescents with hyperinsulinemia: a 6-month, randomized, double-blind, placebo-controlled clinical trial. J Pediatr Endocrinol Metab 21:339–348

    PubMed  CAS  Google Scholar 

  41. Del Prato S, Tiengo A (2001) The importance of first-phase insulin secretion: implications for the therapy of type 2 diabetes mellitus. Diabetes Metab Res Rev 17:164–174

    Article  PubMed  CAS  Google Scholar 

  42. Kanat M, Norton L, Winnier D, Jenkinson C, DeFronzo RA, Abdul-Ghani MA (2011) Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose. Acta Diabetol. doi:10.1007/s00592-011-0285-x

  43. Xu G, Stoffers DA, Habener JF, Bonner-Weir S (1999) Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 48:2270–2276

    Article  PubMed  CAS  Google Scholar 

  44. Fehse F, Trautmann M, Holst JJ, Halseth AE, Nanayakkara N, Nielsen LL, Fineman MS, Kim DD, Nauck MA (2005) Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 90:5991–5997

    Article  PubMed  CAS  Google Scholar 

  45. Marchetti P, Lupi R, Guerra SD, Bugliani M, D’Aleo V, Occhipinti M, Boggi U, Marselli L, Masini M (2009) Goals of treatment for type 2 diabetes: beta-cell preservation for glycemic control. Diabetes Care 32(2):S178–S183

    Article  PubMed  CAS  Google Scholar 

  46. Bunck MC, Diamant M, Cornér A, Eliasson B, Malloy JL, Shaginian RM, Deng W, Kendall DM, Taskinen M-R, Smith U, Yki-Järvinen H, Heine RJ (2009) One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients. Diabetes Care 32:762–768

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr Peter Bates, Cambridge Medical Writing Services, UK, for help in preparation of the manuscript. The authors are also grateful to all of the investigators involved in the EUREXA clinical trial. This study was supported by Eli Lilly and Company and Amylin Pharmaceuticals Inc. Duality of Interest: CK, PK and CN are employees of Eli Lilly and Company; BG and GS have received travel grants and remuneration as members of the EUREXA study advisory board.

Author information

Authors and Affiliations

  1. Department of Medicine IV, Eberhard-Karls-University, Otfried-Müller-Street 10, 72076, Tübingen, Germany

    Baptist Gallwitz

  2. Lilly Deutschland GmbH, Werner-Reimers-Strasse 2-4, 61352, Bad Homburg, Germany

    Christof Kazda, Petra Kraus & Claudia Nicolay

  3. Department of Medicine I, Rudolfstiftung Hospital, 1030, Vienna, Austria

    Guntram Schernthaner

Authors
  1. Baptist Gallwitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christof Kazda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Petra Kraus
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claudia Nicolay
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guntram Schernthaner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Baptist Gallwitz.

Additional information

Clinical trial registration: EudraCT 2005-005448-21.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gallwitz, B., Kazda, C., Kraus, P. et al. Contribution of insulin deficiency and insulin resistance to the development of type 2 diabetes: nature of early stage diabetes. Acta Diabetol 50, 39–45 (2013). https://doi.org/10.1007/s00592-011-0319-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-011-0319-4

Keywords

Search

Navigation