A human randomized controlled trial comparing metabolic responses to single and repeated hypoglycemia in type 1 diabetes

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AIMS: Hypoglycemia hinders optimal glycemic management in type 1 diabetes (T1D). Long diabetes duration and hypoglycemia impair hormonal counterregulatory responses to hypoglycemia. Our study was designed to test whether i) the metabolic responses and insulin sensitivity are impaired, and ii) affected by short-lived antecedent hypoglycemia in participants with T1D.

MATERIALS AND METHODS: In a randomized, crossover, 2x2-factorial design, nine male participants with T1D and nine comparable control participants underwent 30 min hypoglycemia (p-glucose<2.9mmol/L) followed by a euglycemic clamp on two separate interventions: with and without 30 min hypoglycemia the day before the study day.

RESULTS: During both interventions: insulin sensitivity was consistently lower, while counterregulatory hormones were reduced with 75% lower glucagon and 50% lower epinephrine during hypoglycemia in participants with T1D, who also displayed 40% lower lactate and 5-10-fold increased ketone bodies concentrations following hypoglycemia, whereas palmitate and glucose turnover, forearm glucose uptake and substrate oxidation did not differ between the groups. In participants with T1D, adipose tissue PTEN content, HSL phosphorylation and muscle GLUT4 content were decreased compared with controls. An antecedent hypoglycemic episodes lasting 30 minutes did not affect counter-regulation or insulin sensitivity.

CONCLUSIONS: Participants with T1D displayed insulin resistance, and impaired hormonal counter-regulation during hypoglycemia, whereas glucose and fatty acid fluxes were intact, and ketogenic responses amplified. We observed subtle alterations of intracellular signaling, and no effect of short-lived antecedent hypoglycemia on subsequent counter-regulation. This plausibly reflects the presence of insulin resistance, and implies that T1D is a condition with defective hormonal but preserved metabolic responsiveness to short-lived hypoglycemia.

TidsskriftThe Journal of clinical endocrinology and metabolism
Antal sider13
StatusUdgivet - dec. 2020

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