Impaired stimulation of gluconeogenesis during prolonged hypoglycemia in intensively treated insulin-dependent diabetic subjects

Defective glucose counterregulation commonly seen in intensively treated insulin-dependent diabetes (IDDM) is mediated in part by a failure of compensatory stimulation of hepatic glucose production. Since the response of the liver to insulin-induced hypoglycemia normally involves activation of gluconeogenesis, we measured [14C]alanine conversion to [14C]glucose (a qualitative index of gluconeogenesis) and glucose production (using [3-3H]glucose) in seven intensively treated type I diabetic subjects (hemoglobin-A1, 7.1 +/- 0.4%) during low dose infusion of insulin (0.3 mU/kg.min for 210 min). IDDM patients received insulin overnight to maintain euglycemia before study. Although insulin levels rose to a similar extent as those in normal control subjects (n = 6), the fall in plasma glucose was markedly greater in IDDM (2.5 +/- 0.2 vs. 3.64 +/- 0.2 mM in controls; P < 0.01). The glucagon response was totally lost in IDDM, and epinephrine release was delayed and slightly reduced compared to that in control subjects. In contrast to that in normal subjects, hepatic glucose production in the IDDM subjects remained persistently suppressed by about 60% throughout the study. The conversion of alanine and lactate to glucose remained virtually unchanged in the IDDM, whereas in controls it increased 2-fold above baseline during the last hour of the study. Our data suggest that the failure of gluconeogenesis to increase during hypoglycemia is an important factor contributing to the defective hepatic response observed in the intensively treated type I diabetic subjects

Effect of counterregulatory hormones on kinetic response to ingested glucose in dogs.

The disposal of ingested glucose was quantitated in dogs during individual and combined infusion of glucagon, epinephrine, and cortisol. Initial splanchnic extraction of ingested glucose, endogenous glucose production, and glucose uptake were quantitated using a double-tracer technique. Glucagon or cortisol individually had no effect on the kinetic response to glucose ingestion, whereas epinephrine increased glucose levels by 50-100 mg/dl. Epinephrine caused a reduced suppression of glucose production and a marked inhibition of the initial rise in glucose uptake. Initial splanchnic glucose extraction, plasma insulin, and glucagon were not significantly altered. The addition of glucagon and cortisol to epinephrine did not accentuate hyperglycemia, except after 150 min when glucose production increased. We conclude that a) epinephrine produces glucose intolerance when infused individually, b) this effect is primarily dependent on inhibition of glucose uptake and, to a lesser extent, on a reduction in suppression of endogenous glucose output, and c) addition of glucagon and cortisol has only a minor effect on epinephrine-induced changes in glucose disposal. Our data suggest an important role of epinephrine in stress-induced glucose intolerance

Role of gluconeogenesis in epinephrine-stimulated hepatic glucose production in humans.

To evaluate the contribution of gluconeogenesis to epinephrine-stimulated glucose production, we infused epinephrine (0.06 micrograms X kg-1 X min-1) for 90 min into normal humans during combined hepatic vein catheterization and [U-14C]alanine infusion. Epinephrine infusion produced a rise in blood glucose (50-60%) and plasma insulin (30-40%), whereas glucagon levels increased only at 30 min (19%, P less than 0.05). Net splanchnic glucose output transiently increased by 150% and then returned to base line by 60 min. In contrast, the conversion of labeled alanine and lactate into glucose increased fourfold and remained elevated throughout the epinephrine infusion. Similarly, epinephrine produced a sustained increase in the net splanchnic uptake of cold lactate (four- to fivefold) and alanine (50-80%) although the fractional extraction of both substrates by splanchnic tissues was unchanged. We conclude that a) epinephrine is a potent stimulator of gluconeogenesis in humans, and b) this effect is primarily mediated by mobilization of lactate and alanine from extrasplanchnic tissues. Our data suggest that the initial epinephrine-induced rise in glucose production is largely due to activation of glycogenolysis. Thereafter, the effect of epinephrine on glycogenolysis (but not gluconeogenesis) wanes, and epinephrine-stimulated gluconeogenesis becomes the major factor maintaining hepatic glucose production