Role of glucagon in the development of T2D in participants with prediabetes: a post-hoc analysis

Introduction: Prediabetes is a heterogeneous condition characterized by elevated fasting glucose and/or abnormal 2-hour glucose and/or increased HbA1c levels which still do not meet the criteria for Type 2 Diabetes (T2D). Lifestyle modifications stand as the primary preventive measure for T2D in individuals with prediabetes.

Glucagon increases hepatic glucose production in humans. Elevated glucagon levels, insufficient secretion of insulin and insulin resistance are distinctive characteristics of diabetes. The dysregulation of glucagon has been studied, but still its role in the progression from prediabetes to T2D has not been investigated. In our study we want to gain more insight into the interplay between glucagon and the development of T2D in diabetes prevention studies.

Methods: We conducted a post-hoc analysis on a group of 548 participants with prediabetes (36% male and 64% female) enrolled in two randomized controlled trials: Diabetes Nutrition Algorithm Study in Prediabetes (DiNA-P) and the Optimal Fibre Trial (OptiFiT). Both used a lifestyle intervention of one year to prevent the development of T2D and an additional year of follow up. Oral glucose tolerance tests were used to assess glycemic state; MR spectroscopy was used to measure liver fat content. Glucagon was assessed with ELISAs (Mercodia). In this study, we performed correlations, comparative tests and a regression analysis to investigate the modulating effects of glucagon on T2D development. [1] [2] [3] [4] [5]

Results: We see significantly higher baseline fasting glucagon levels in patients who develop diabetes after one year compared to those who did not (p<0,036). Males exhibited higher glucagon levels than females at baseline, after one year and two years. However, this gender difference does not explain glucagon-dependent diabetes onset.

Baseline glucagon values significantly correlated with liver fat content and one-year changes of liver fat content (p= 0,000, r²= 0,377). However, changes in glucagon secretion and changes in intrahepatic liver fat did not show a significant correlation. Furthermore, glucagon baseline correlated with HOMA-IR (p= 0,000, r²= 0,242) and Matsuda Index (p= 0,000, r²= 0,157), but not with HOMA-β. Changes in HOMA-IR correlated with changes in liver fat (p= 0,005; r²= 0,034).

Finally, we performed a binary logistic regression model, where HOMA-IR and HOMA-β emerged as independent predictors of the development of T2D, while glucagon did not.

Conclusion: This study suggests that glucagon is associated with the development of T2D in prediabetic individuals, but HOMA-IR and HOMA-β are predictors that are more consistent. Unexpectedly, glucagon is primarily related to (hepatic) insulin resistance rather than beta-cell function despite the strong alpha- to beta-cell crosstalk. These findings contribute valuable insights into the interplay of glucagon, insulin resistance, and beta-cell function in the progression to T2D in participants with prediabetes

Interessenkonflikt

I,Marta Csanalosi declare to have no conflicts of interest.

• References

• 1 Fritsche A., Wagner R., Heni M., Kantartzis K., Machann J., Schick F., Lehmann R., Peter A., Dannecker C., Fritsche L., Valenta V., Schick R., Nawroth P.P., Kopf S., Pfeiffer A.F.H., Kabisch S., Dambeck U., Stumvoll M., Blüher M., Birkenfeld A.L., Häring H.U.. Different Effects of Lifestyle Intervention in High- and Low-Risk Prediabetes: Results of the Randomized Controlled Prediabetes Lifestyle Intervention Study (PLIS). Diabetes 2021; 70 (12) 2785-2795
• 2 Sandforth A., von Schwartzenberg R.J., Arreola E.V., Hanson R.L., Sancar G., Katzenstein S., Lange K., Preißl H., Dreher S.I., Weigert C., Wagner R., Kantartzis K., Machann J., Schick F., Lehmann R., Peter A., Katsouli N., Ntziachristos V., Dannecker C., Fritsche L., Birkenfeld A.L.. Mechanisms of weight loss-induced remission in people with prediabetes: a post-hoc analysis of the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS). The lancet. Diabetes & endocrinology 2023; 11 (11) 798-810
• 3 Finan B., Capozzi M.E., Campbell J.E.. Repositioning Glucagon Action in the Physiology and Pharmacology of Diabetes. Diabetes 2020; 69 (04) 532-541
• 4 Capozzi M.E., Wait J.B., Koech J., Gordon A.N., Coch R.W., Svendsen B., Finan B., D'Alessio D.A., Campbell J.E.. Glucagon lowers glycemia when β-cells are active. JCI insight 2019; 5 (16) e129954
• 5 Wewer Albrechtsen N.J., Kuhre R.E., Pedersen J., Knop F.K., Holst J.J.. The biology of glucagon and the consequences of hyperglucagonemia. Biomarkers in medicine 2016; 10 (11) 1141-1151

Publication History

Article published online:
18 April 2024