Iatrogenic hypoglycemia is the limiting factor in the management of insulin-dependent diabetes mellitus (IDDM). It causes recurrent physical morbidity, some mortality, and recurrent or even persistent psychosocial morbidity. The principles of glucose counterregulation, the physiological mechanisms that normally very effectively prevent or correct hypoglycemia, are now known. Decrements in insulin, increments in glucagon, and, in the absence of the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors. Iatrogenic hypoglycemia in IDDM is the result of the interplay of absolute or relative therapeutic insulin excess and compromised glucose counterregulation. Syndromes of compromised glucose counterregulation include defective glucose counterregulation (the result of combined deficiencies of the glucagon and epinephrine responses to falling glucose levels), hypoglycemia unawareness (loss of the warning, neurogenic symptoms of developing hypoglycemia), and elevated glycemic thresholds (lower glucose levels required) for autonomic activation and symptoms during effective intensive therapy. These have been conceptualized as examples of hypoglycemiaassociated autonomic failure, a functional disorder distinct from classical diabetic autonomic neuropathy, in IDDM. Recent antecedent iatrogenic hypoglycemia appears to be a major factor in the pathogenesis of hypoglycemia unawareness; there is increasing evidence that this syndrome is reversible with scrupulous avoidance of hypoglycemia. It probably also contributes substantially to the syndrome of elevated glycemic thresholds during intensive therapy. However, factors in addition to recent antecedent hypoglycemia play an important role in the pathogenesis of the syndrome of defective glucose counterregulation. Pending the prevention and cure of IDDM, we need to learn to replace insulin in a much more physiological fashion and/or to prevent, correct, or compensate for compromised glucose counterregulation if we are to eliminate hypoglycemia from the lives of people with IDDM without compromising glycemic control. In the meantime, we must continue to seek better insight into the fundamental mechanisms of compromised glucose counterregulation and to develop practical preventive clinical strategies and practice hypoglycemia risk factor reduction with our patients.

Hypoglycemia: The Limiting Factor in the Management of IDDM

Patients with noninsulin-dependent diabetes mellitus (NIDDM) have both preprandial and postprandial hyperglycemia. To determine the mechanism responsible for the postprandial hyperglycemia insulin secretion, insulin action, and the pattern of carbohydrate metabolism after glucose ingestion were assessed in patients with NIDDM and in matched nondiabetic subjects using the dual isotope and forearm catheterization techniques. Prior to meal ingestion, hepatic glucose release was increased (P< 0.001) in the diabetic patients measured using [2-3Hj or 133HJ glucose. After meal ingestion, patients with NIDDM had excessive rates ofsystemic glucose entry (1,316±56 vs. 1,018±65 mg/kg 7 h, P < 0.01), primarily owing to a failure to suppress adequately endogenous glucose release (680±50 vs. 470±32 mg/kg- 7 h, P < 0.01) from its high preprandial level. Despite impaired suppression of endogenous glucose production during a hyperinsulinemic glucose clamp (P < 0.001) and decreased postprandial C-peptide response (P<0.05) inNIDDM, percent suppression of hepatic glucose release after oral glucose was comparable in the diabetic and nondiabetic subjects (45±3 vs. 39±2%). Although new glucose formation from meal-derived three-carbon precursors (53±3 vs. 40±7 mg/kg 7 h, P < 0.05) was greater in the diabetic patients, it accounted for only a minor part ofthis excessive postprandial hepatic glucose release. Postprandial hyperglycemia was exacerbated by the lack of an appropriate increase in glucose uptake whether measured isotopically or by forearm glucose uptake. Thus as has been proposed for fasting hyperglycemia, excessive hepatic glucose release and impaired glucose uptake are involved in the pathogenesis of postprandial hyperglycemia in patients with NIDDM.

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Postprandial Hyperglycemia in Patients with Noninsulin-dependent Diabetes Mellitus

GLUCOSE is an optional fuel for tissues such as muscle, fat, and liver that can also use fatty acids and other substrates to satisfy their energy needs. However, glucose is an obligate fuel for the central nervous system, since under physiologic conditions, alternative substrates either are excluded by the blood–brain barrier or circulate at concentrations too low to be taken up in substantial quantities.1 Because the brain can neither synthesize nor store more than a few minutes' supply of it, normal cerebral function requires a continuous supply of glucose from the circulation. Consequently, maintenance of the plasma glucose concentration above . . .

Glucose counterregulation, hypoglycemia, and intensive insulin therapy in diabetes mellitus.

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The transition from exogenous glucose delivery to endogenous glucose production late after glucose ingestion is not solely attributable to dissipation of insulin and, therefore, must also involve factors that actively raise the plasma glucose concentration--glucose counterregulatory factors. We have shown that the secretion of two of these, glucagon and epinephrine, is specific for glucose ingestion and temporally related to the glucose counterregulatory process. To determine the physiologic roles of glucagon and epinephrine in postprandial glucose counterregulation, we produced pharmacologic interventions that resulted in endogenous glucagon deficiency with and without exogenous glucagon replacement, adrenergic blockade, and adrenergic blockade coupled with glucagon deficiency starting 225 min after the ingestion of 75 g of glucose in normal subjects. Also, we assessed the effect of endogenous epinephrine deficiency alone and in combination with glucagon deficiency late after glucose ingestion in bilaterally adrenalectomized subjects. Glucagon deficiency resulted in nadir plasma glucose concentrations that were approximately 30% lower (P less than 0.01) than control values, but did not cause hypoglycemia late after glucose ingestion. This effect was prevented by glucagon replacement. Neither adrenergic blockade nor epinephrine deficiency alone impaired the glucose counterregulatory process. However, combined glucagon and epinephrine deficiencies resulted in a progressive fall in mean plasma glucose to a hypoglycemic level late after glucose ingestion; the final glucose concentration was 40% lower (P less than 0.02) than the control (epinephrine deficient) value in these patients, and was nearly 50% lower (P less than 0.001) than the control value and approximately 30% lower (P less than 0.05) than the glucagon-deficient value in normal subjects. We conclude (a) the transition from exogenous glucose delivery to endogenous glucose production late after glucose ingestion is the result of the coordinated diminution of insulin secretion and the resumption of glucagon secretion. (b) Epinephrine does not normally play a critical role in this process, but enhanced epinephrine secretion compensates largely and prevents hypoglycemia when glucagon secretion is deficient.

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Mechanisms of postprandial glucose counterregulation in man. Physiologic roles of glucagon and epinephrine vis-a-vis insulin in the prevention of hypoglycemia late after glucose ingestion.

The mechanisms of postprandial glucose counterregulation—those that blunt late decrements in plasma glucose, prevent hypoglycemia, and restore euglycemia—have not been fully defined. To begin to clarify these mechanisms, we measured neuroendocrine and metabolic responses to the ingestion of glucose (75 g), xylose (62.5 g), mannitol (20 g), and water in ten normal human subjects to determine for each response the magnitude, temporal relationships, and specificity for glucose ingestion. Measurements were made at 10-min intervals over 5 h. By multivariate analysis of variance, the plasma glucose (P < 0.0001), insulin (P < 0.0001), glucagon (P < 0.03), epinephrine (P < 0.0004), and growth hormone (P < 0.01) curves, as well as the blood lactate (P < 0.0001), glycerol (P < 0.001), and β-hydroxybutyrate (P < 0.0001) curves following glucose ingestion differed significantly from those following water ingestion. However, the growth hormone curves did not differ after correction for differences at base line. In contrast, the plasma norepinephrine (P < 0.31) and cortisol (P < 0.24) curves were similar after ingestion of all four test solutions, although early and sustained increments in norepinephrine occurred after all four test solutions. Thus, among the potentially important glucose regulatory factors, only transient increments in insulin, transient decrements in glucagon, and late increments in epinephrine are specific for glucose ingestion. They do not follow ingestion of water, xylose, or mannitol.

Following glucose ingestion, plasma glucose rose to peak levels of 156±6 mg/dl at 46±4 min, returned to base line at 177±4 min, reached nadirs of 63±3 mg/dl at 232±12 min, and rose to levels comparable to base line at 305 min, which was the final sampling point. Plasma insulin rose to peak levels of 150±17 μU/ml (P < 0.001) at 67±8 min. At the time glucose returned to base line, insulin levels (49±12 μU/ml) remained fourfold higher than base line (P < 0.01); thereafter they declined but never fell below base line. Plasma glucagon decreased from 95±14 pg/ml to nadirs of 67±11 pg/ml (P < 0.001) at 84±9 min and then rose progressively to peak levels of 114±17 pg/ml (P < 0.001 vs. nadirs) at 265±12 min. Plasma epinephrine, which was 18±4 pg/ml at base line, did not change initially and then rose to peak levels of 119±20 pg/ml (P < 0.001) at 271±13 min.

These data indicate that the glucose counterregulatory process late after glucose ingestion is not solely due to the dissipation of insulin and that sympathetic neural norepinephrine, growth hormone, and cortisol do not play critical roles. They are consistent with, but do not establish, physiologic roles for the counterregulatory hormones—glucagon, epinephrine, or both—in that process.

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Neuroendocrine responses to glucose ingestion in man. Specificity, temporal relationships, and quantitative aspects

To the extent that they have deficient glucagon secretory responses to plasma glucose decrements, as they commonly do, patients with insulin-dependent diabetes mellitus (IDDM) are dependent on epinephrine-mediated beta-adrenergic mechanisms to promote recovery from hypoglycemia. Thus, they are at increased risk for prolonged hypoglycemia if treated with a nonselective beta-adrenergic antagonist such as propranolol. If the hyperglycemic actions of epinephrine are mediated through beta 2-adrenergic mechanisms, therapeutic efficacy (e.g., for hypertension or ischemic heart disease) could be accomplished without increased risk of hypoglycemia by selective beta 1-adrenergic blockade in such patients. However, oral administration of the relatively selective beta 1-adrenergic antagonist metoprolol (100 mg) and of the nonselective beta-adrenergic antagonist propranolol (80 mg) both impaired recovery from insulin-induced hypoglycemia in patients with IDDM. Thus, at a dose of 100 mg, oral metoprolol is not safer than oral propranolol with respect to recovery from hypoglycemia in patients with IDDM.

Thomas F. Tse

Papers

Mechanisms of postprandial glucose counterregulation in man. Physiologic roles of glucagon and epinephrine vis-a-vis insulin in the prevention of hypoglycemia late after glucose ingestion.

Neuroendocrine responses to glucose ingestion in man. Specificity, temporal relationships, and quantitative aspects

Oral Propranolol and Metoprolol Both Impair Glucose Recovery from Insulin-induced Hypoglycemia in Insulin-dependent Diabetes Mellitus