Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is uncertain. We therefore determined the relative contributions of hyperglycemia and iatrogenic hyperinsulinemia to insulin resistance using hyperinsulinemic-euglycemic clamps in three participant groups (n = 10/group) with differing insulinemia and glycemia: healthy control subjects (euinsulinemia and euglycemia), glucokinase-maturity-onset diabetes of the young (GCK-MODY; euinsulinemia and hyperglycemia), and type 1 diabetes (hyperinsulinemia and hyperglycemia matching GCK-MODY). We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes. Hemoglobin A1c was normal in control subjects and similarly elevated for type 1 diabetes and GCK-MODY. Basal insulin levels in control subjects and GCK-MODY were nearly equal but were 2.5-fold higher in type 1 diabetes. Low-dose insulin infusion suppressed endogenous glucose production similarly in all groups and suppressed nonesterified fatty acids similarly between control subjects and GCK-MODY, but to a lesser extent for type 1 diabetes. High-dose insulin infusion stimulated glucose disposal similarly in control subjects and GCK-MODY but was 29% and 22% less effective in type 1 diabetes, respectively. Multivariable linear regression showed that insulinemia-but not glycemia-was significantly associated with muscle insulin sensitivity. These data suggest that iatrogenic hyperinsulinemia predominates in driving insulin resistance in type 1 diabetes.
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Acknowledgments. The authors thank Kevin Niswender (Division of Diabetes, Endocrinology, & Metabolism, Vanderbilt University) for serving as this study’s data and safety monitor. The authors are grateful to Lana Howard (nurse manager, Vanderbilt CRC) and the staff of the Vanderbilt CRC and the Vanderbilt Diet, Body Composition, and Human Metabolism Core for their assistance in conducting the studies. Funding. J.M.G. was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (K12-HD-087023). D.J.M. was supported by a JDRF Career Development Award (5-CDA-2014-209-A-N). This study was supported by the Vanderbilt Diabetes Research and Training Center (National Institute of Diabetes and Digestive and Kidney Diseases pilot and feasibility grant P30-DK-020593) and by the National Center for Advancing Translational Sciences (Clinical and Translational Science Award UL1-TR-002243). The Vanderbilt Hormone Assay and Analytical Services Core, which is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (grants DK-059637 and DK-020593), processed hormone assays. The Vanderbilt Mouse Metabolic Phenotyping Core (supported by National Institute of Diabetes and Digestive and Kidney Diseases grant DK-059637) processed isotopic glucose tracer samples. The University of Chicago Monogenic Diabetes Registry is supported by National Institute of Diabetes and Digestive and Kidney Diseases grants R01-DK-104942 and P30-DK-020595.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Duality of Interest. J.M.G. reports consulting fees from InClinica. A.D.C. reports grants, personal fees, and other support from Metavention, Zafgen, and Abvance; grants and personal fees from Boston Scientific, Novo Nordisk, vTv Therapeutics, Merck, Eli Lilly and Company, and Galvani Bioelectronics; personal fees from California Institute for Biomedical Research (Calibr) and MedImmune; and personal fees and other from Fractyl, Thetis Pharmaceuticals, and Sensulin Laboratories. Additionally, A.D.C. has patented a method for treating overweight subjects that is issued to Zafgen, a method for treating diabetes issued to Abvance, and a method for controlling postprandial glucose levels in diabetes issued to Biocon. No other potential conflicts of interest relevant to this article were reported. Author Contributions. J.M.G. designed the study, conducted experiments, gathered and analyzed data, and wrote the manuscript. T.J.S. conducted experiments, gathered data, and analyzed data. J.C.S. assisted with the study design and statistical analysis. H.R.M. conducted experiments. C.C.H. conducted isotopic tracer analyses. M.S.S. performed hormonal and metabolite assays. B.K., S.A.W.G., L.H.P., R.N.N., and L.R.L. facilitated participant recruitment and conducted genotyping. N.N.A., A.D.C., and D.J.M. helped design the study, analyze the data, and write the manuscript. All authors critically reviewed the manuscript. J.M.G. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Data and Resource Availability. The data sets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. No applicable resources were generated or analyzed during the current study. Prior Presentation. Parts of this study were presented in oral form at the 54th Annual Meeting of the European Association for the Study of Diabetes, Berlin, Germany, 1–5 October 2018.