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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).

Author information

1
Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN justin.m.gregory.1@vumc.edu.
2
Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN.
3
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN.
4
Diet, Body Composition, and Human Metabolism Core, Vanderbilt University, Nashville, TN.
5
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
6
Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism and the Kovler Diabetes Center, University of Chicago, Chicago, IL.
7
Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN.

Abstract

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. Clinicaltrials.gov:NCT02971202.

PMID:
31092478
DOI:
10.2337/db19-0324

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