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Diabetes. 2019 May 15. pii: db190324. doi: 10.2337/db19-0324. [Epub ahead of print]

Iatrogenic Hyperinsulinemia, Not Hyperglycemia, Drives Insulin Resistance in Type 1 Diabetes as Revealed by Comparison to GCK-MODY (MODY2).

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Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN
Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN.
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN.
Diet, Body Composition, and Human Metabolism Core, Vanderbilt University, Nashville, TN.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism and the Kovler Diabetes Center, University of Chicago, Chicago, IL.
Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN.


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 controls (euinsulinemia, euglycemia), glucokinase maturity-onset of the young (GCK-MODY; euinsulinemia, hyperglycemia), and type 1 diabetes (hyperinsulinemia, 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. HbA1c was normal in controls and similarly elevated for type 1 diabetes and GCK-MODY. Basal insulin levels in control 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 and GCK-MODY, but to a lesser extent for type 1 diabetes. High-dose insulin infusion stimulated glucose disposal similarly in control and GCK-MODY, but was 29% and 22% less effective in type 1 diabetes, respectively. Multivariable linear regression showed insulinemia-but not glycemia-was significantly associated with muscle insulin sensitivity. These data suggest iatrogenic hyperinsulinemia predominates in driving insulin resistance in type 1 diabetes.


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