Hormone-independent activation of EGP during hypoglycemia is absent in type 1 diabetes mellitus

Michèle Mevorach, Jonathan Kaplan, Chee Jen Chang, Luciano Rossetti, Harry Shamoon

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Abstract

It has been suggested that insulin-induced suppression of endogenous glucose production (EGP) may be counteracted independently of increased epinephrine (Epi) or glucagon during moderate hypoglycemia. We examined EGP in nondiabetic (n = 12) and type 1 diabetic (DM1, n = 8) subjects while lowering plasma glucose (PG) from clamped euglycemia (5.6 mmol/l) to values just above the threshold for Epi and glucagon secretion (3.9 mmol/l). Individualized doses of insulin were infused to maintain euglycemia during pancreatic clamps by use of somatostatin (250 μg/h), glucagon (1.0 ng · kg-1 · min-1), and growth hormone (GH) (3.0 ng · kg-1 · min-1) infusions without need for exogenons glucose. Then, to achieve physiological hyperinsulinemia (HIns), insulin infusions were fixed at 20% above the rate previously determined for each subject. In nondiabetic subjects, PG was reduced from 5.4 ± 0.1 mmol/l to 3.9 ± 0.1 mmol/l in the experimental protocol, whereas it was held constant (5.3 ± 0.2 mmol/l and 5.5 mmol/l) in control studies. In the latter, EGP (estimated by [3-3H]glucose) fell to values 40% of basal (P < 0.01). In contrast, in the experimental protocol, at comparable HIns but with PG at 3.9 ± 0.1 mmol/l, EGP was activated to values about twofold higher than in the euglycemic control (P < 0.01). In DM1 subjects, EGP failed to increase in the face of HIns and PG = 3.9 ± 0.1 mmol/l. The decrease from basal EGP in DM1 subjects (4.4 ± 1.0 μmol · kg- 1 · min-1) was nearly twofold that in nondiabetics (2.5 ± 0.8 μmol · kg-1 · min-1, P < 0.02). When PG was lowered further to flank hypoglycemia (~3.1 mmol/l), the failure of EGP activation in DM1 subjects was even more profound but associated with a 50% lower plasma Epi response (P < 0.02) compared with nondiabetics. We conclude that glucagon- or epinephrine-independent activation of EGP may accompany other counterregulatory mechanisms during mild hypoglycemia in humans and is impaired or absent in DM1.

Original languageEnglish (US)
Pages (from-to)E421-E429
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume278
Issue number3 41-3
Publication statusPublished - Mar 1 2000

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Keywords

  • Counterregulation
  • Endogenous glucose production
  • Glucose turnover

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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