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The glucagon response to hypoglycemia, which fulfills a primary role toward restoring the plasma glucose level, is blunted or absent in most patients with type I diabetes. To identify predictive factors for this abnormality and for the capability of glycemic counterregulation, we investigated the relationship between the duration of diabetes and glucagon and glucose responses to insulin-induced hypoglycemia. In 18 type I diabetic patients with 1 through 28 years of disease who had no detectable autonomic neuropathy, individual glucagon increments after insulin hypoglycemia were inversely correlated with the duration of disease (r = -.53, P < .025). Patients with disease for ten or fewer years showed a glucagon rise that was lower than in controls but significantly higher than in patients with a duration of more than ten years. The plasma glucose rise after the nadir correlated with peak glucagon increments (r = .60, P < .01); eight of the nine patients with glycemic increments comparable to normals had had diabetes for ten years or less. Thus, having diabetes for more than ten years implied that not only were glucagon responses to insulin hypoglycemia severely compromised but also that the abrupt restoration of plasma glucose levels was impaired. These findings should be taken into account when establishing goals and modalities for tight metabolic control.

Glycosylated haemoglobin (HbA1) was measured serially by microcolumn chromatography in 38 children with newly diagnosed insulin-dependent diabetes. Initial HbA1 levels of 13.6 +/- 0.5% fell signficiantly from day 0 (prior to therapy) both to day 1 (1.6 +/- 0.2% decrease) and to day 3-5 (2.6 +/- 0.4% decrease) (P < 0.001). This drop correlated closely with changes in blood glucose (P < 0.001), less closely and inversely with plasma bicarbonate levels (P < 0.01), but not with prior duration of symptoms or changes in serum cholesterol and triglyceride concentrations. HbA1 levels reached a nadir of 8.2 +/- 0.3% 3 weeks to 6 months after diagnosis, and correlated with decreasing insulin dosage (P < 0.001). HbA1 levels rose again to 11.4 +/- 0.5% in 21 patients followed for more than 3-6 months. Our results indicate that (1) HbA1 level change rapidly during initial stabilization of insulin-dependent diabetes suggesting that glycosylation may not be entirely irreversible, and (2) HbA1 levels are consistent with clinical assessment of control during remission and postremission phases.

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.

To ascertain if excessive protein catabolism is a feature of uremia, we determined leucine flux and nitrogen balance in 11 stable chronic dialysis patients and in 7 normal subjects. Leucine flux was determined during primed constant infusion of 2H3 and 15N leucine. Nitrogen balance was determined by measurement of nitrogen in the food, dialysate, and urine, and in the dialysis patients by correcting for the changing urea nitrogen pool. To assess if thyroid hormone adversely affects protein metabolism, the above-mentioned studies were done once in the basal state and once after a 7-day course of L-triiodothyronine (T3) treatment. Leucine carbon flux (mumol/kg/min) was 1.22 +/- 0.05 in the controls and 1.40 +/- 0.09 in the renal patients in the basal state (P = NS). Following T3 treatment, leucine carbon flux was increased to 1.40 +/- 0.05 and 1.72 +/- 0.09, respectively, in the controls and the renal patients (P less than .05). Fractional increment of the leucine carbon flux was 14% +/- 3% in the controls and 23% +/- 9% in the renal patients (P less than .05). The leucine nitrogen flux (mumol/kg/min) was 2.10 +/- 0.15 in the controls and 2.54 +/- 0.23 in the renal patients in the basal state (P = NS), and increased to 2.48 +/- 0.14 and 3.44 +/- 0.22, respectively, in controls and renal patients after T3 administration (P less than .05). Fractional increment of leucine nitrogen flux was 19.5% +/- 4.3% in the controls and 36.4% +/- 5.0% in the renal patients (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

The renal clearance of oxipurinol, the major metabolite of allopurinol, was studied in six healthy subjects during normal and restricted (low protein and low calorie) diets. A 600 mg oral dose of allopurinol was administered after 7 days of a normal diet (100 mg protein/day) and again after 2 and 4 weeks of a restricted diet (19 gm protein/day). The renal clearance of oxipurinol was reduced from 19.6 +/- 1.5 ml/min during the normal diet to 10.9 +/- 0.8 and 12.0 +/- 0.9 ml/min (both P less than 0.001) during the restricted diet at 2 and 4 weeks, respectively. These changes in oxipurinol renal clearance paralleled changes in uric acid renal clearance. Furthermore, the plasma oxipurinol half-life was increased from 27.0 +/- 1.7 hours during the normal diet to 51.1 +/- 4.3 and 45.7 +/- 3.7 hours (both P less than 0.001) during the restricted diet at 2 and 4 weeks, respectively. We conclude that dietary protein and calorie restriction cause a sustained reduction in the elimination of oxipurinol.