Robert G. Brodows

Neural Control of Counter-Regulatory Events during Glucopenia in Man

The effect of autonomic denervation on the metabolic and hormonal responses during intracellular glucopenia in man was investigated. 2-Deoxy-d-glucose (2 DG), a competitive inhibitor of glucose metabolism, was administered intravenously to nine normal volunteers and to five patients, three with complete cervical cord transection (C-6) and two with idiopathic orthostatic hypotension. Before, during, and after a 20 min infusion of 2 DG (50 mg/kg) plasma concentrations of glucose, lactate, FFA, total catecholamines, immunoreactive insulin (IRI), human growth hormone (HGH), and cortisol were determined for periods up to 150 min. In control subjects, the initial elevation of FFA, glucose. HGH, and cortisol corresponded with the rise in total catecholamines, with maximal levels attained at 60 min, lactate rose at a slower rate, reaching peak levels at 150 min: although no change in IRI was noted. In contrast, 2 DG-induced glucopenic stress in the autonomic denervated subjects was characterized by no detectable catecholamine release or significant rise in glucose, FFA, lactate, or IRI. However, HGH and cortisol responses in four of the five patients were of a similar or greater magnitude than controls.These studies demonstrate that the integrity of the sympathoadrenomedullary axis is essential for the counter-regulatory response to intracellular glucopenia in man. Cortisol and HGH have no apparent role in these events.

Insulin Action During Acute Starvation: Evidence for Selective Insulin Resistance in Normal Man

The effects of insulin on glucose utilization, lipolysis, and potassium and phosphate metabolism were studied during short-term fasting in six lean subjects using a sequential euglycemic glucose clamp technique (two additional subjects were used in 70 mU/m2/min clamp studies). The subjects were infused with insulin for four hours at four rates ranging from 6 to 442 mU/m2/min before and after a 48-hour fast. Insulin was infused for one hour at each rate in all experiments. Fasting markedly reduced glucose utilization at all insulin infusion rates. On the other hand, the decline in levels of free fatty acids that occurred at insulin concentrations of 30 microU/ml was virtually identical before and after fasting. After insulin was infused for four hours, serum phosphate had decreased in all subjects (P less than 0.001) and strongly correlated with glucose disposal rates (r = 0.76, P less than 0.005). The plasma potassium level also declined in all subjects but did not relate to fasting or glucose disposal. These studies demonstrate that starvation produces selective insulin resistance. The biologic effect of insulin on glucose utilization and plasma phosphate shifts is clearly diminished. Free fatty acid and potassium metabolism are unaffected by starvation.

Counterregulatory Hormonal Responses to Rapid Glucose Lowering in Diabetic Man

To define whether rapid rate of fall in blood glucose stimulates counterregulatory hormonal responses in diabetic man, blood glucose in eight hyperglycemic diabetic subjects was rapidly lowered by intravenous insulin administration. Despite precipitous declines in blood glucose, plasma epinephrine and growth hormone remained virtually unchanged. In contrast, norepinephrine and cortisol increased significantly (P < 0.025) in the face of hyperglycemia or euglycemia, while glucagon was suppressed (P < 0.025). A transient modest fall in mean arterial pressure and a rise in pulse rate were noted. No correlation was observed between glucose disappearance rate or decrement in glucose concentration and the hormonal responses. After sham insulin administration, no change was observed in plasma epinephrine, norepinephrine, and cortisol levels. These findings suggest that rate of fall in blood glucose per se is not a primary signal for counterregulatory hormonal response. Cortisol but not growth hormone release during falling blood glucose in diabetic subjects can occur despite elevated blood glucose levels. The etiology of norepinephrine and cortisol change is unclear.

Sympathetic control of hepatic glycogenolysis during glucopenia in man

Liver glycogen stores may be mobilized during hypoglycemia by release of adrenomedullary catecholamines, by release of norepinephrine from sympathetic nerve endings and by release of glucagon. To clarify the nature of peripheral sympathetic control of hepatic glycogenolysis during glucopenia in man, 2-deoxy-d-glucose (2 DG), a competitive inhibitor of glucose metabolism, was infused intravenously (50 mg/kg) to nine normal volunteers and four adrenalectomized patients for 20 min. In normal volunteers, the initial elevation of free fatty acids (FFA) and growth hormone (HGH) correspond with the rise in total catecholamines, with maximal levels attained at 60 min; lactate and cortisol rose at a slower rate, no change in IRI was noted. Plasma glucose levels were 148 percent of preinfusion values by 120 min and remained elevated. In adrenalectomized subjects, despite no change in plasma FFA, lactate, catecholamines and glucagon, glucose rose 20 percent by 150 min; the growth hormone and insulin responses were similar to normals; A significant increase in glucose response from 60 min onward was found in the 2 DG infusion studies when compared to cortisone administration, alone. Thus, during glucopenia, plasma glucose rose in spite of unchanged adrenomedullary catecholamine and glucagon levels. The findings indicate that the sympathetic neurotransmitter, norepinephrine, contributes to counter-regulatory events during 2 DG-induced glucopenia presumably via its release from hepatic sympathetic nerve endings,

Control of insulin secretion during fasting in man

During early starvation, declines in blood glucose and insulin levels occur concomitantly. To determine whether extracellular glucopenia is the primary signal for decreased insulin secretion, i.v. glucose was given as a continuous infusion to 7 lean male subjects throughout a 72-hr fast at the rate needed to maintain plasma glucose at the normal postabsorptive levels. Five lean male control subjects were fasted without glucose infusion. The acute insulin response to 5 g of i.v. glucose was determined after the fast in both groups. Significant glucopenia and concomitant insulinopenia were observed by 24 hr of fasting alone. In contrast, despite constant plasma glucose concentration of 86 ± 3 mg/dl (±SEM) in the subjects receiving glucose infusion, significant insulinopenia was observed by 48 hr (p < 0.01) and there was essentially no difference in the mean insulin levels of the two groups. Significant free fatty acid increments were observed and comparable in both groups; however, the ketogenic response was significantly blunted by continuous glucose infusion (p < 0.001 at 72 hr). Plasma glucagon increased significantly (p < 0.001) by 48 hr in fasting alone and remained unchanged in the group receiving glucose. There was no significant change in urinary catecholamine excretion in the subjects receiving glucose. The acute insulin response to i.v. glucose was similar in both the starved and infused groups when compared to postabsorptive subjects. These data suggest extracellular glucopenia is not a prerequisite for insulin-openia in starvation.

Mechanism of plasma cyclic AMP response to hypoglycemia in man

The effect of insulin-induced hypoglycemia on plasma cyclic AMP levels was studied in normal volunteers, adrenalectomized, and sympathectomized subjects. Significant increases in plasma glucagon were observed in all groups. Normal subjects all had two- to threefold rises in plasma cAMP while no response was seen in any adrenalectomized or sympathectomized subject. These findings suggest that the mechanism for enhanced plasma cAMP release during insulin-induced hypoglycemia is catecholamine dependent. Glucagon does not contribute significantly to this response.

Starvation enhances the ability of insulin to inhibit its own secretion.

To examine whether decreased insulin secretion during starvation is related to a change in the ability of insulin to inhibit its own secretion, plasma C-peptide was measured after plasma insulin levels were acutely raised by intravenous (IV) insulin infusion in a dose of 40 and 80 mU/M2/min in obese subjects before and after a 72 hour fast. Plasma glucose concentration was maintained +/- 4% of basal levels by a variable glucose infusion. During the 80 mU infusion, at plasma insulin levels of 200 microU/mL, plasma C-peptide fell by 0.17 pmol/mL in the fed state. In the fasted state, despite basal levels that were 36% lower, C-peptide decreased by 0.21 pmol/mL. Highly significant increases in percent suppression after fasting were noted during both 40 mU and 80 mU studies. The plasma C-peptide response was related to the insulin infusion dose in both the fed and fasted state. In contrast, alpha cell suppression by insulin, as determined by plasma glucagon levels, was not altered by fasting. It is concluded that enhanced inhibitory influences of insulin on the beta cell during starvation may be a physiologically important mechanism for diminished insulin secretion during the transition from the fed to the fasting state.