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- Title
Iatrogenic Hyperinsulinemia, Not Hyperglycemia, Drives Insulin Resistance in Type 1 Diabetes as Revealed by Comparison With GCK-MODY (MODY2).
- Authors
Gregory, Justin M.; Smith, T. Jordan; Slaughter, James C.; Mason, Holly R.; Hughey, Curtis C.; Smith, Marta S.; Kandasamy, Balamurugan; Greeley, Siri Atma W.; Philipson, Louis H.; Naylor, Rochelle N.; Letourneau, Lisa R.; Abumrad, Naji N.; Cherrington, Alan D.; Moore, Daniel J.
- 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 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.
- Subjects
TYPE 1 diabetes; INSULIN resistance; FREE fatty acids; HYPERINSULINISM; HYPERGLYCEMIA
- Publication
Diabetes, 2019, Vol 68, Issue 8, p1565
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db19-0324