Iatrogenic hyperinsulinemia, not hyperglycemia, drives insulin resistance in type 1 diabetes as revealed by comparison with GCK-MODY (MODY2)

Justin M. Gregory, T. Jordan Smith, James C. Slaughter, Holly R. Mason, Curtis C. Hughey, Marta S. Smith, Balamurugan Kandasamy, Siri Atma W. Greeley, Louis H. Philipson, Rochelle N. Naylor, Lisa R. Letourneau, Naji N. Abumrad, Alan D. Cherrington, Daniel J. Moore

Research output: Contribution to journalArticle

5 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1565-1576
Number of pages12
Issue number8
StatePublished - Aug 1 2019
Externally publishedYes


PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Gregory, J. M., Smith, T. J., Slaughter, J. C., Mason, H. R., Hughey, C. C., Smith, M. S., Kandasamy, B., Greeley, S. A. W., Philipson, L. H., Naylor, R. N., Letourneau, L. R., Abumrad, N. N., Cherrington, A. D., & Moore, D. J. (2019). Iatrogenic hyperinsulinemia, not hyperglycemia, drives insulin resistance in type 1 diabetes as revealed by comparison with GCK-MODY (MODY2). Diabetes, 68(8), 1565-1576. https://doi.org/10.2337/db19-0324