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Iatrogenic Hyperinsulinemia, Not Hyperglycemia, Drives Insulin Resistance in
Type 1 Diabetes as Revealed by Comparison to GCK-MODY (MODY2).
Authors Gregory JM, Smith TJ, Slaughter JC, Mason HR, Hughey CC, Smith MS, Kandasamy B,
Greeley SAW, Philipson LH, Naylor RN, Letourneau LR, Abumrad NN, Cherrington AD,
Moore DJ
Submitted By Submitted Externally on 6/24/2019
Status Published
Journal Diabetes
Year 2019
Date Published 5/1/2019
Volume : Pages Not Specified : Not Specified
PubMed Reference 31092478
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.


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