The Korean journal of internal medicine

  • 제34권5호
  • /
  • Pages.1068-1077
  • /
  • 2019
  • /
  • 1226-3303(pISSN)
  • /
  • 2005-6648(eISSN)
대한내과학회 (The Korean Association of Internal Medicine)
권호 표지
DOI QR코드

DOI QR Code

Higher glucagon-to-insulin ratio is associated with elevated glycated hemoglobin levels in type 2 diabetes patients

  • Lee, Minyoung (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Kim, Minkyung (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Park, Jong Suk (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Lee, Sangbae (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • You, Jihong (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Ahn, Chul Woo (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Kim, Kyung Rae (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine) ;
  • Kang, Shinae (Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine)
  • 투고 : 2016.07.23
  • 심사 : 2017.06.26
  • 발행 : 2019.09.01
⟨ 이전 논문 다음 논문 ⟩

초록

Background/Aims: The importance of α-cell dysfunction in the pathogenesis of type 2 diabetes has re-emerged recently. However, data on whether relative glucagon excess is present in clinical settings are scarce. We aimed to investigate associations between glucagon-to-insulin ratio and various metabolic parameters. Methods: A total of 451 patients with type 2 diabetes naïve to insulin treatment were recruited. Using glucagon-to-insulin ratio, we divided subjects into quartiles according to both fasting and postprandial glucagon-to-insulin ratios. Results: The mean age of the subjects was 58 years, with a mean body mass index of 25 kg/m2. The patients in the highest quartile of glucagon-to-insulin ratio had higher glycated hemoglobin (HbA1c) levels. HbA1c levels were positively correlated with both fasting and postprandial glucagon-to-insulin ratios. Subjects in the highest quartile of postprandial glucagon-to-insulin ratio were more likely to exhibit uncontrolled hyperglycemia, even after adjusting for confounding factors (odds ratio, 2.730; 95% confidence interval, 1.236 to 6.028; p for trend < 0.01). Conclusions: Hyperglucagonemia relative to insulin could contribute to uncontrolled hyperglycemia in type 2 diabetes patients.

키워드

과제정보

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI14C0336). The authors are grateful to Dr. Lee and Ms. Hong (the Biostatistics Collaboration Units of Yonsei University College of Medicine) for their advice on the statistical analyses.

참고문헌

  1. Defronzo RA. Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-795. https://doi.org/10.2337/db09-9028
  2. Fonseca VA. Defining and characterizing the progression of type 2 diabetes. Diabetes Care 2009;32 Suppl 2:S151-S156. https://doi.org/10.2337/dc09-S301
  3. Edgerton DS, Cherrington AD. Glucagon as a critical factor in the pathology of diabetes. Diabetes 2011;60:377-380. https://doi.org/10.2337/db10-1594
  4. Li XC, Zhuo JL. Current insights and new perspectives on the roles of hyperglucagonemia in non-insulin-dependent type 2 diabetes. Curr Hypertens Rep 2013;15:522-530. https://doi.org/10.1007/s11906-013-0383-y
  5. Quesada I, Tuduri E, Ripoll C, Nadal A. Physiology of the pancreatic alpha-cell and glucagon secretion: role in glucose homeostasis and diabetes. J Endocrinol 2008;199:5-19. https://doi.org/10.1677/JOE-08-0290
  6. Liljenquist JE, Mueller GL, Cherrington AD, et al. Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man. J Clin Invest 1977;59:369-374. https://doi.org/10.1172/JCI108649
  7. Ramnanan CJ, Edgerton DS, Kraft G, Cherrington AD. Physiologic action of glucagon on liver glucose metabolism. Diabetes Obes Metab 2011;13 Suppl 1:118-125.
  8. Tappy L. Regulation of hepatic glucose production in healthy subjects and patients with non-insulin-dependent diabetes mellitus. Diabete Metab 1995;21:233-240.
  9. Franklin I, Gromada J, Gjinovci A, Theander S, Wollheim CB. Beta-cell secretory products activate alpha-cell ATP-dependent potassium channels to inhibit glucagon release. Diabetes 2005;54:1808-1815. https://doi.org/10.2337/diabetes.54.6.1808
  10. Leung YM, Ahmed I, Sheu L, et al. Insulin regulates islet alpha-cell function by reducing KATP channel sensitivity to adenosine 5'-triphosphate inhibition. Endocrinology 2006;147:2155-2162. https://doi.org/10.1210/en.2005-1249
  11. Ahren B, Larsson H. Impaired glucose tolerance (IGT) is associated with reduced insulin-induced suppression of glucagon concentrations. Diabetologia 2001;44:1998-2003. https://doi.org/10.1007/s001250100003
  12. Shah P, Basu A, Basu R, Rizza R. Impact of lack of suppression of glucagon on glucose tolerance in humans. Am J Physiol 1999;277:E283-E290.
  13. Shah P, Vella A, Basu A, Basu R, Schwenk WF, Rizza RA. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 2000;85:4053-4059.
  14. Ipp E. Impaired glucose tolerance: the irrepressible alpha-cell? Diabetes Care 2000;23:569-570. https://doi.org/10.2337/diacare.23.5.569
  15. Larsson H, Ahren B. Islet dysfunction in insulin resistance involves impaired insulin secretion and increased glucagon secretion in postmenopausal women with impaired glucose tolerance. Diabetes Care 2000;23:650-657. https://doi.org/10.2337/diacare.23.5.650
  16. Ahren B. Beta- and alpha-cell dysfunction in subjects developing impaired glucose tolerance: outcome of a 12-year prospective study in postmenopausal Caucasian women. Diabetes 2009;58:726-731. https://doi.org/10.2337/db08-1158
  17. Unger RH. Role of glucagon in the pathogenesis of diabetes: the status of the controversy. Metabolism 1978;27:1691-1709. https://doi.org/10.1016/0026-0495(78)90291-3
  18. Charron MJ, Vuguin PM. Lack of glucagon receptor signaling and its implications beyond glucose homeostasis. J Endocrinol 2015;224:R123-R130. https://doi.org/10.1530/JOE-14-0614
  19. Cho YM, Merchant CE, Kieffer TJ. Targeting the glucagon receptor family for diabetes and obesity therapy. Pharmacol Ther 2012;135:247-278. https://doi.org/10.1016/j.pharmthera.2012.05.009
  20. Dunning BE, Foley JE, Ahren B. Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia 2005;48:1700-1713. https://doi.org/10.1007/s00125-005-1878-0
  21. Rohrer S, Menge BA, Gruber L, et al. Impaired crosstalk between pulsatile insulin and glucagon secretion in prediabetic individuals. J Clin Endocrinol Metab 2012;97:E791-E795. https://doi.org/10.1210/jc.2011-3439
  22. Jin SM, Choi SH, Choi DW, et al. Glucagon/insulin ratio in preoperative screening before pancreatic surgery: correlation with hemoglobin A1C in subjects with and without pancreatic cancer. Endocrine 2014;47:493-499. https://doi.org/10.1007/s12020-013-0159-9
  23. Moon JS, Won KC. Pancreatic α-cell dysfunction in type 2 diabetes: old kids on the block. Diabetes Metab J 2015;39:1-9. https://doi.org/10.4093/dmj.2015.39.1.1
  24. Rivera N, Everett-Grueter CA, Edgerton DS, et al. A novel glucagon receptor antagonist, NNC 25-0926, blunts hepatic glucose production in the conscious dog. J Pharmacol Exp Ther 2007;321:743-752. https://doi.org/10.1124/jpet.106.115717
  25. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502. https://doi.org/10.1093/clinchem/18.6.499
  26. Abdul-Ghani M, DeFronzo RA. Fasting hyperglycemia impairs glucose- but not insulin-mediated suppression of glucagon secretion. J Clin Endocrinol Metab 2007;92:1778-1784. https://doi.org/10.1210/jc.2006-1515
  27. Ahlkvist L, Omar B, Valeur A, Fosgerau K, Ahren B. Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice. J Endocrinol 2016;228:171-178.
  28. Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 1987;36:274-283. https://doi.org/10.2337/diab.36.3.274
  29. Consoli A, Nurjhan N, Capani F, Gerich J. Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM. Diabetes 1989;38:550-557. https://doi.org/10.2337/diab.38.5.550
  30. Yoon KH, Ko SH, Cho JH, et al. Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab 2003;88:2300-2308. https://doi.org/10.1210/jc.2002-020735
  31. Reaven GM, Chen YD, Golay A, Swislocki AL, Jaspan JB. Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1987;64:106-110. https://doi.org/10.1210/jcem-64-1-106
  32. Umpaichitra V, Bastian W, Taha D, Banerji MA, AvRuskin TW, Castells S. C-peptide and glucagon profiles in minority children with type 2 diabetes mellitus. J Clin Endocrinol Metab 2001;86:1605-1609. https://doi.org/10.1210/jcem.86.4.7415
  33. Ferrannini E, Muscelli E, Natali A, et al. Association of fasting glucagon and proinsulin concentrations with insulin resistance. Diabetologia 2007;50:2342-2347. https://doi.org/10.1007/s00125-007-0806-x
  34. Liu Z, Kim W, Chen Z, et al. Insulin and glucagon regulate pancreatic α-cell proliferation. PLoS One 2011;6:e16096. https://doi.org/10.1371/journal.pone.0016096
  35. Ohn JH, Kwak SH, Cho YM, et al. 10-Year trajectory of β-cell function and insulin sensitivity in the development of type 2 diabetes: a community-based prospective cohort study. Lancet Diabetes Endocrinol 2016;4:27-34. https://doi.org/10.1016/S2213-8587(15)00336-8
  36. Mohan V, Vijayaprabha R, Rema M, et al. Clinical profile of lean NIDDM in South India. Diabetes Res Clin Pract 1997;38:101-108. https://doi.org/10.1016/S0168-8227(97)00088-0
  37. Chang SA, Kim HS, Yoon KH, et al. Body mass index is the most important determining factor for the degree of insulin resistance in non-obese type 2 diabetic patients in Korea. Metabolism 2004;53:142-146. https://doi.org/10.1016/S0026-0495(03)00314-7
  38. Kim DJ, Lee MS, Kim KW, Lee MK. Insulin secretory dysfunction and insulin resistance in the pathogenesis of Korean type 2 diabetes mellitus. Metabolism 2001;50:590-593. https://doi.org/10.1053/meta.2001.22558
  39. Bessho M, Murase-Mishiba Y, Tsutsumi C, et al. Glycaemic instability correlates with a hyperglucagonaemic response in patients with type 1 diabetes without residual beta-cell function. Diabetes Res Clin Pract 2013;102:e38-e40. https://doi.org/10.1016/j.diabres.2013.09.003
  40. Dinneen S, Alzaid A, Turk D, Rizza R. Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM. Diabetologia 1995;38:337-343. https://doi.org/10.1007/BF00400639

피인용 문헌

  1. Postprandial Lipemia Modulates Pancreatic Alpha-Cell Function in the Prediction of Type 2 Diabetes Development: The CORDIOPREV Study vol.68, pp.5, 2019, https://doi.org/10.1021/acs.jafc.9b06801
  2. GLP1 receptor agonism protects against acute olanzapine-induced hyperglycemia vol.319, pp.6, 2019, https://doi.org/10.1152/ajpendo.00309.2020
  3. Bihormonal dysregulation of insulin and glucagon contributes to glucose intolerance development at one year post-delivery in women with gestational diabetes: a prospective cohort study using an early vol.68, pp.8, 2021, https://doi.org/10.1507/endocrj.ej20-0795
  4. Functional Status of Pancreatic α and β Cells in Type 2 Diabetes Mellitus Patients with Different Plasma Triglyceride Levels: A Retrospective Analysis vol.2021, 2021, https://doi.org/10.1155/2021/9976067
  5. Voluntary physical activity protects against olanzapine-induced hyperglycemia vol.130, pp.2, 2019, https://doi.org/10.1152/japplphysiol.00876.2020
  6. The Change in Glucagon Following Meal Ingestion Is Associated with Glycemic Control, but Not with Incretin, in People with Diabetes vol.10, pp.11, 2019, https://doi.org/10.3390/jcm10112487