Individuals with long-standing
type 1 diabetes (T1D) are at increased risk of severe
hypoglycemia secondary to impairments in normal
glucose counterregulatory responses (CRRs). Strategies to prevent
hypoglycemia are often ineffective, highlighting the need for novel
therapies.
ATP-sensitive
potassium (
KATP) channels within the hypothalamus are thought to be integral to
hypoglycemia detection and initiation of CRRs; however, to date this has not been confirmed in human subjects. In this study, we examined whether the
KATP channel-activator
diazoxide was able to amplify the CRR to
hypoglycemia in T1D subjects with long-duration diabetes. A randomized, double-blind, placebo-controlled cross-over trial using a stepped hyperinsulinemic
hypoglycemia clamp was performed in 12 T1D subjects with prior ingestion of
diazoxide (7 mg/kg) or placebo.
Diazoxide resulted in a 37% increase in plasma levels of
epinephrine and a 44% increase in plasma
norepinephrine during
hypoglycemia compared with placebo. In addition, a subgroup analysis revealed that the response to oral
diazoxide was blunted in participants with E23K polymorphism in the
KATP channel. This study has therefore shown for the first time the potential utility of
KATP channel activators to improve CRRs to
hypoglycemia in individuals with T1D and, moreover, that it may be possible to stratify therapeutic approaches by genotype.