Nancy V. Bohannon

Risk stratification in coronary artery disease and special populations

In patients with coronary artery disease (CAD), left ventricular (LV) function, the number of diseased vessels, and the severity of myocardial ischemia are important determinants of survival. These factors can be used to identify subsets of high-risk patients who are candidates for aggressive intervention. Among patients with LV dysfunction, those with left main CAD, three-vessel disease, and one- or two-vessel disease with inducible ischemia are at highest risk. High-risk subsets among those with preserved LV function include patients with left main CAD and those with inducible ischemia and either three-vessel disease or two-vessel disease with involvement of the proximal left anterior descending coronary artery. Thus, exercise testing, assessment of ventricular function and, in selected patients, coronary angiography to determine coronary anatomy are valuable tools in risk stratification. In the primary-care setting, patient characteristics such as gender, race, age, and concomitant medical conditions may also be most useful in identifying high-risk patients. Although women in general have some primary protection against premature CAD, especially prior to the menopause, coronary risk in women who have experienced a cardiovascular event is similar to that in men. Coronary mortality is increased in minority populations, and the presence of other risk factors, such as diabetes and hyperlipidemia, can further increase this risk. Up to 80% of diabetic patients die of cardiovascular disease, 75% of which is CAD. The risk in this population is exacerbated by the abnormalities in lipid metabolism associated with the diabetic state. CAD mortality increases with aging, but it is recommended that elderly patients with CAD also receive risk factor intervention, such as cholesterol-lowering therapy. Consideration of the impact of such therapy on quality of life is especially important in initiating such interventions in the older population.

The Effect of Chronic Oral Antidiabetic Therapy on Insulin and Glucagon Responses to a Meal

Nineteen maturity-onset diabetic patients receiving oral hypoglycemic therapy in a university diabetes dinic completed a study to assess the efficacy of the oral agents and to determine their effects on pancreatic islet hormone secretion. All patients were receiving sulfonylureas, and seven were also receiving phenformin. Hie subjects were studied as outpatients in the clinic setting on four different occasions with collections of a baseline blood sample before a standard breakfast and a second sampling two hours postprandially, twice while on their prescribed medication and twice after having been withdrawn from the medication. The values obtained during the two studies on and the two studies off medications were reproducible for each subject. Analysis of the results by paired differences revealed that mean 24-hour urine glucose values deteriorated significantly (p < 0.005) after oral antidiabetic therapy was withdrawn; similarly, mean plasma glucose values, both at baseline and two hours postprandially, rose significantly (p < 0.001) when subjects were off medication. Baseline serum insulin values were not changed, but postprandial levels were significantly higher on oral agents (p <0.005). Plasma immunoreactive glucagon was significantly lower both at baseline (p < 0.02) and postprandially (p < 0.005) when the subjects were on their antidiabetic medications. During the trial off medication, 16 patients became symptomatic, with three of these developing symptoms severe enough to require hospitalization. It is apparent from this study that oral hypoglycemic medications can play a role in controlling symptoms in maturity-onset diabetic patients and that the beneficial effect of these agents on hyperglycemia may, in part, be explained by their stimulation of endogenous insulin secretion and partial suppression of endogenous glucagon.

Dopamine during α- or β-Adrenergic Blockade in Man: HORMONAL, METABOLIC, AND CARDIOVASCULAR EFFECTS

: We studied the contribution of alpha- and beta-adrenergic receptor activation to the cardiovascular, metabolic, and hormonal effects of dopamine. At a concentration of 1.5 mug/kg.min, the infusion of dopamine in 12 normal volunteers was associated with a transient but significant rise in pulse rate, which was prevented by propranolol. Venous plasma glucose did not change throughout the experiments, and a mild increase in plasma free fatty acid levels observed during the administration of dopamine alone was antagonized by propranolol. In contrast, neither the beta-adrenergic blocker, propranolol, nor the alpha-adrenergic blocker, phentolamine, was effective in inhibiting the dopamine-induced rise in plasma glucagon (from 82+/-9 to 128+/-14 pg/ml; P < 0.005) and serum insulin (from 7.5+/-1 to 13+/-1.5 muU/ml; P < 0.005) or its suppression of plasma prolactin (from 8.5+/-1 to 5.2+/-0.8 ng/ml; P < 0.001). Although serum growth hormone levels did not change during the infusion of dopamine alone, an obvious rise occurred in three subjects during the combined infusion of propranolol and dopamine. Whereas some metabolic and cardiovascular effects of dopamine are mediated through adrenergic mechanisms, these observations indicate that this is not the case for the effects of this catecholamine on glucagon, insulin, and prolactin secretion, and thus provide further support for the theory of a specific dopaminergic sensitivity of these hormonal systems in man.

Effects of Acute Insulin Withdrawal and Administration on Plasma Glucagon Responses to Intravenous Arginine in Insulin-dependent Diabetic Subjects

To assess further the role of insulin in the abnormal alpha-cell dysfunction found in human diabetes mellitus, the effects of acute insulin withdrawal and administration on plasma glucagon responses to intravenous arginine were studied in eight insulin-dependent diabetic subjects. Arginine infusions (30 gm. over 30 minutes) were performed during and at one and four hours after discontinuation of a 14-hour insulin infusion (1.5 U. per hour), which had rendered the subjects euglycemic, and on another occasion before and one and four hours into a five-hour infusion of insulin (1.5 U. per hour). During the last hour of the 14-hour infusion, glucagon responses to arginine (area under the curve, nanograms per milliliter per minute) were similar to those found in normal subjects (10.3 ± 0.8 vs. 9.0 ± 0.8, respectively). After discontinuation of the insulin infusions, glucagon responses increased progressively (p < 0.01) to values (16.8 ± 1.2) that exceeded those of normal subjects by four hours (p < 0.01). These were similar to results found in the same subjects studied when their diabetes was in < optimal control (14.9 ± 1.3). Infusion of insulin under these conditions progressively decreased glucagon responses to arginine to values (9.6 ± 0.8; p < 0.01) that, at four hours, were similar to those of normal subjects and to values found at the end of the 14-hour infusion of insulin in the same diabetic individuals. These results demonstrate a rapid effect of insulin on glucagon responses to arginine and suggest that the abnormal responses seen in diabetes mellitus are the immediate result of insulin deficiency. Since abnormal glucagon responses to glucose in diabetes are not as readily corrected by insulin, the mechanisms underlying the abnormal responses to these two stimuli may differ.

Diabetic management by insulin infusion during major surgery

In five insulin-requiring, uremic diabetic patients undergoing renal transplantation, we infused insulin intravenously at a low rate to maintain plasma glucose levels between 100 and 200 mg/100 ml. In those patients receiving 100 mg or more of prednisone per day and 5 per cent dextrose solution, the hourly infusion rate was determined from tthe following equation: insulin (U) = plasma glucose value divided by 100. When prednisone was not given or when the patient was thin, the ratio became: plasma glucose value divided by 150. Results were compared with those of nineteen similar transplant patients treated with conventional subcutaneous insulin therapy during surgery, and significantly better glucose control was achieved with the low dosage, intravenous infusion.

Plasma glucagon suppression by phenformin in man

SummaryIn an attempt to elucidate the mechanism of action of phenformin, eleven juvenile-onset, insulin-requiring diabetic subjects underwent four different treatment regimens during standard breakfast tests. These four treatments were: control (no insulin or phenformin); insulin alone (15 U regular insulin administered subcutaneously one-half hour before breakfast); phenformin alone (50 mg of the timed-release capsule given twice daily for three days before the study and two and one-half hours before breakfast on the day of study); and phenformin plus insulin (in the amounts and at the times stated above). Phenformin was found to decrease postprandial hyperglycaemia significantly when compared with control values, and its addition to insulin further decreased the postprandial glucose rise below that found with insulin alone (p<0.005). These effects were associated with a reduction in early (30-min) postprandial hyperglucagonaemia (p <0.05). Triglyceride levels, gastrin secretion, growth hormone levels, and increments ofα-amino nitrogen were not affected by phenformin. Thus, suppression of postprandial hyperglucagonaemia may be an additional mechanism in the reduction of postprandial hyperglycaemia after phenformin.