Hepatic Glucose Uptake During Euglycemic Hyperinsulinemia Associates With Glycemia During Oral Glucose Tolerance Test

: Honka, Miikka-Juhani; Rebelos, Eleni; Pekkarinen, Laura; Tuomola, Nelli; Latva-Rasku, Aino; Koukkari, Leena; Immonen, Heidi; Mari, Andrea; Kalliokoski, Kari K; Hannukainen, Jarna C; Nuutila, Pirjo

Publisher: Oxford University Press

: WASHINGTON

: 2025

: Journal of the Endocrine Society

: J ENDOCR SOC

: bvaf054

: 9

: 5

: 10

: 2472-1972

DOI: https://doi.org/10.1210/jendso/bvaf054

: https://doi.org/10.1210/jendso/bvaf054

: https://research.utu.fi/converis/portal/detail/Publication/491902540

Context:

Postprandial hepatic glycogen synthesis and glycolysis are reduced in hepatic insulin resistance. However, the physiologic interpretation of the reduction in hepatic glucose uptake (GU) during the gold-standard measurement of insulin sensitivity, hyperinsulinemic euglycemic clamp, in insulin resistance is unclear. This is because the peripheral route of glucose and insulin delivery during a clamp study differs greatly from the physiological route.

Objective:

We hypothesized that hepatic GU during hyperinsulinemic euglycemic clamp would predict glycemia during oral glucose tolerance test (OGTT).

Design:

We analyzed cross-sectional data of 120 individuals (70 men and 50 women) who did not have diabetes from the CMgene study cohort. Hepatic GU was measured with [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) and positron emission tomography. Results: In a multiple regression analysis, hepatic GU, endogenous glucose production, insulin secretion capacity, and serum triglycerides predicted OGTT glucose area under the curve (P for all <.05), whereas skeletal muscle GU, the antilipolytic insulin index, and insulin clearance were not statistically significant predictors (P > .05).

Conclusions:

Hepatic GU measured during hyperinsulinemic euglycemic clamp is an independent predictor of OGTT glucose area under the curves even when accounting for well-known other factors affecting glycemic control. This finding supports the idea that insulin-mediated hepatic GU, and more broadly, first-pass glucose extraction, have a meaningful contribution to glycemic control. Thus, this measurement provides useful information about hepatic insulin sensitivity in the more physiologic conditions of the OGTT which may be useful when studying the pathophysiology of impaired glucose tolerance and when evaluating potential treatments for impaired glycemic control.

bvaf054.pdf

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The study was conducted within the Center of Excellence in Cardiovascular and Metabolic Diseases, supported by the Research Council of Finland (grant number 307402 to P.N.), the University of Turku, Turku University Hospital, Åbo Akademi University. M.-J.H. was supported by the Research Council of Finland (grant number 332151), the Finnish Diabetes Research Foundation, the Finnish-Norwegian Medical Foundation, Jalmari and Rauha Ahokas Foundation, the Finnish Cultural Foundation (Varsinais-Suomi Regional fund), and State Research Funding (Turku University Hospital). E.R. reports funding from the Emil Aaltonen Foundation, the Finnish Cultural Foundation, the Paulo Foundation, the Maud Kuistilan Muistosäätiö, the Finnish Diabetes Research Foundation, and from the Finnish Medical Foundation. L.P. was supported by Jalmari and Rauha Ahokas Foundation, Turunmaa Duodecim Society, Turku University Hospital Foundation for Education and Research, and the Finnish Diabetes Research Foundation. N.T. was supported by the Turku University Hospital Foundation for Education and Research and Turunmaa Duodecim Society. J.C.H. received funding from the European Foundation for the Study of Diabetes, the Centre of Excellence in Cardiovascular and Metabolic Diseases, Emil Aaltonen Foundation, the Hospital District of Southwest Finland, Orion Research Foundation, the Finnish Diabetes Research Foundation. The funders did not have any role in designing or conducting the study, in the collection, management, analysis or interpretation of the data, or in the preparation, review, or approval of the manuscript and the decision to submit the manuscript for publication.