1. Six healthy male volunteers received equivalent intravenous beta-blocking doses of propranolol, practolol and betaxolol (SL75212) or saline at weekly intervals Sixty minutes later 0.1 unit/kg insulin was given intravenously. 2. In all studies, maximum hypoglycaemia (mean 1.2 mmol/l) was reached thirty minutes after insulin. Recovery from hypoglycaemia was delayed with propranolol but practolol and betaxolol had no effect. 3. Propranolol blocked the tachycardia and widening of pulse pressure seen in saline treated subjects. It also blocked the rebound rise in free fatty acids (FFA) and glycerol concentrations that followed the nadir of hypoglycaemia. 4. Neither practolol nor betaxolol had significant effects on pulse rate or blood pressure but betaxolol resembled propranolol in blocking the rebound rise in FFA and glycerol, while practolol blocked the rise in glycerol alone. 5. The magnitude of the rise in growth hormone following hypoglycaemia was similar in all groups, but the peak was earlier after practolol and betaxolol

We investigated the effects of alpha and/or beta adrenergic blockade (with phentolamine and/or propranolol) on glucose homeostasis during exercise in six normal subjects and in seven Type I diabetic subjects. The diabetics received a low dose insulin infusion (0.07 mU/kg X min) designed to maintain plasma glucose at approximately 150 mg/dl. In normals, neither alpha, beta, nor combined alpha and beta adrenergic blockade altered glucose production, glucose uptake, or plasma glucose concentration during exercise. In diabetics, exercise alone produced a decline in glucose concentration from 144 to 116 mg/dl. This was due to a slightly diminished rise in hepatic glucose production in association with a normal increase in glucose uptake. When exercise was performed during beta adrenergic blockade, the decline in plasma glucose was accentuated. An exogenous glucose infusion (2.58 mg/kg X min) was required to prevent glucose levels from falling below 90 mg/dl. The effect of beta blockade was accounted for by a blunted rise in hepatic glucose production and an augmented rise in glucose utilization. These alterations were unrelated to changes in plasma insulin and glucagon levels, which were similar in the presence and absence of propranolol. In contrast, when the diabetics exercised during alpha adrenergic blockade, plasma glucose concentration rose from 150 to 164 mg/dl. This was due to a significant increase in hepatic glucose production and a small decline in exercise-induced glucose utilization. These alterations also could not be explained by differences in insulin and glucagon levels. We conclude that the glucose homeostatic response to exercise in insulin-dependent diabetics, in contrast to healthy controls, is critically dependent on the adrenergic nervous system

CONTEXT: Beta-Blockers and angiotensin-converting enzyme (ACE) inhibitors are effective antihypertensive agents for patients with diabetes mellitus. However, beta-blockers attenuate some components of the autonomic response to hypoglycemia and could increase the risk of hypoglycemia. ACE inhibitors may increase insulin sensitivity and predispose users to hypoglycemia. OBJECTIVE: To determine whether use of cardioselective beta-blockers, nonselective beta-blockers, ACE inhibitors, thiazide diuretics, calcium channel blockers, or other antihypertensive drugs alters the risk of developing serious hypoglycemia among older persons prescribed insulin or sulfonylureas. DESIGN: Retrospective cohort study. SETTING: Tennessee Medicaid Program. PATIENTS: A total of 13,559 elderly (mean age, 78+/-7 years) Medicaid enrollees, who were prescribed insulin (n=5171, 38%) or sulfonylureas (n=8368, 62%) from 1985 through 1989. These enrollees contributed a total of 33,107 person-years of insulin or sulfonylurea use for follow-up. MEASUREMENTS: Hospitalization, emergency department admission, or death associated with hypoglycemic symptoms and a concomitant blood glucose determination of less than 2.8 mmol/L (50 mg/dL). RESULTS: We identified 598 persons with an episode of serious hypoglycemia during the study period. The rate of serious hypoglycemia was 2.01 per 100 person-years among those who were not prescribed antihypertensives. Crude rates of serious hypoglycemia were highest among users of ACE inhibitors (2.47 per 100 person-years) and lowest among users of cardioselective beta-blockers (1.23 per 100 person-years). However, when we controlled for demographic characteristics and markers of comorbidity, there was no statistically significant increase or decrease in risk of serious hypoglycemia among users of any class of antihypertensive agents compared with nonusers of antihypertensive drugs. Using nonselective beta-blockers as the reference group, each of these agents was associated with a lower, but not statistically significant, risk of hypoglycemia. CONCLUSIONS: In this population, specific antihypertensive drug therapy had little impact on the risk of hypoglycemia in older diabetic patients. Therapy should be chosen based on other considerations of safety and effectiveness

The effects of atenolol, a new beta1-blocking drug, on pulse rate, sweating, and blood glucose levels during insulin-induced hypoglycaemia were studied in a double-blind crossover trial in eight normal subjects using placebo and propranolol as reference agents. The intensity of induced hypoglycaemia was identical for atenolol, propranolol, and placebo. Propranolol prolonged hypoglycaemia, but atenolol did not. Atenolol may therefore be safe for use in patients receiving insulin

Metoprolol and acebutolol, two supposedly cardio-selective beta-adrenergic recptor blocking agents, were tested in healthy volunteers against propranolol, a non-selective drug, for their effect on blood glucose levels during insulin-induced hypoglycaemia. There was not significant difference between propranolol and metoprolol, which both potentiated the initial hypoglycaemic action of the insulin and delayed the return to normoglycaemia. Acebutolol, even though potentiating the initial hypoglycaemia, did not possess a significant delaying effect. A similar trial should be undertaken in diabetics to determine with certainty the safety of such drugs in diabetes mellitus

The response to intravenous insulin was studied in seven diabetics after a dose of placebo, propranolol (40 mg), or metoprolol (50 mg). Two of the seven subjects also had a week´s course of each of the same agents taken three times daily. Neither of the beta-blockers potentiated the effect of insulin as judged by the rate of reduction in blood-glucose. However, blood-glucose recovery was reduced significantly by propranolol, but not significantly by metoprolol. Propranolol caused severe bradycardia and raised diastolic blood-pressure during hypoglycaemia; these effects were milder with metoprolol. Propranolol inhibited the free-fatty-acid levels after hypoglycaemia to a greater extent than did metoprolol. The results strongly suggest that propranolol (and presumably other non-selective beta-blockers) is hazardous in subjects prone to hypoglycaemia. When diabetics require beta-blockade a cardioselective beta 1-blocker should be used

In order to evaluate the influence of beta-adrenergic blockade on recovery from insulin-induced hypoglycemia, we compared the effect of saline or propranolol infusion during concomitant hypoglycemia in normal and type I diabetic persons. The diabetic subjects were initially rendered euglycemic with a basal insulin infusion. Glucose turnover was measured using [3-3H]glucose tracer. Propranolol caused a small but significant delay in glucose recovery in normal subjects, with plasma glucose only 80% of the values seen during saline infusion 1 h after hypoglycemia (P less than 0.005). This delay was caused by a 70% reduction in the rebound glucose output, which was responsible for posthypoglycemic recovery. In the diabetic subjects, glucose recovery was significantly delayed as compared with that in normal persons, even in the absence of propranolol, and associated with reduced secretion of epinephrine and glucagon. Moreover, the addition of propranolol caused a further 50% reduction in glucose recovery such that plasma glucose remained below 50 mg/dl for 3 h. In contrast to normals, propranolol did not inhibit the already blunted rebound in glucose output. However, propranolol prevented the decline in glucose utilization that occurred when saline alone was infused. During saline infusion, glucose uptake was at basal rates by 60 min whereas, during propranolol administration, glucose uptake remained above baseline until 180 min (P less than 0.01). Thus, propranolol may interfere with glucose recovery after insulin-induced hypoglycemia in diabetic patients by blocking epinephrine´s inhibition of glucose utilization whereas, in normals, propranolol´s effect is largely accounted for by blockade of epinephrine-induced hepatic glucose production

To assess the relative roles of growth-hormone and the adrenergic hormoncs, adrenalinc and noradrenaline, in the recovery of plasma-glucosce and plasma-free-fatty-acids from acute hypoglycæmia, intravenous insulin-tolerance tests were carried out in six healthy men with and withoutthe concurrent intravenous administration of propranolol, an adrenergic beta-receptor antagonist. Propranolol affected neither the rate nor the extent of fall of plasma-glucose during the insulin-tolerance tests, but dampened its subsequent rebound. In the case of plasma-free-fatty-acids, however, the rebound was virtually abolished, even though plasma-growth-hormone was greatly increased. Propranolol also abolished the rebound of plasma-glycerol.We conclude that: (l) growth-hormone either plays little part in mediating the rebound of plasma-free-fatty acids during acute hypoglycærnia or requires a certain permissive level of adrenergic activity; and (2) that the rebound of plasma-glucose during acute hypoglycæmiamay depend partly on the availability of glycerol for gluconeogenesis. Our findings indicate that propranolol should be used with caution in patients receiving insulin or oral hypoglycæmic agents.

We tested the hypotheses that nonselective beta-adrenergic blockade does not cause absolute hypoglycemia unawareness but shifts the glycemic thresholds for symptoms to lower plasma glucose concentrations and that neither neuroglycopenic symptoms nor cognitive impairments during hypoglycemia are altered by beta-adrenergic blockade. To do so, we applied the euglycemic and stepped hypoglycemic clamp techniques to patients with moderately controlled insulin-dependent diabetes mellitus (IDDM) in the absence (n = 8) and presence (n = 9) of the nonselective beta-adrenergic antagonist propranolol. Compared with the corresponding euglycemic clamps, total symptom scores first increased at the 4.4-mM plasma glucose step (a higher level than that of 2.8 mM in nondiabetic subjects studied previously) in the absence of propranolol. Beta-adrenergic blockade did not produce absolute hypoglycemia unawareness. Indeed, at the frankly hypoglycemic step of 2.8 mM, total symptom scores tended to be higher in the presence than in the absence of propranolol. This was largely the result of greater (P less than 0.01) perception of diaphoresis. However, symptom scores did not increase until the 3.3-mM plasma glucose step during beta-adrenergic blockade. The perception of hunger, and perhaps that of tremulousness, was reduced by propranolol at the higher glucose steps. Neuroglycopenic symptoms were not reduced by propranolol. The cognitive function of memory, but not that of attention, was impaired, also starting at the 4.4-mM glucose step. This was not impaired further by propranolol. Thus, we formed the following conclusions. 1) Nonselective beta-adrenergic blockade does not cause absolute hypoglycemia unawareness but shifts the glycemic thresholds for symptoms to lower plasma glucose concentrations in patients with IDDM. 2) Beta-adrenergic blockade does not reduce neuroglycopenic symptoms, and it does not further impair cognitive function during hypoglycemia in IDDM patients