Acute and long-term effects of octreotide in patients with ACTH-dependent Cushing's syndrome.

PURPOSE: Octreotide is of proven efficacy in the management of patients with acromegaly, thyrotropin-secreting pituitary adenomas, and certain gastrointestinal tumors, but its effect in Cushing's syndrome is less clear. PATIENTS AND METHODS: We studied 10 patients who presented with adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, 3 of whom were previously adrenalectomized. Serum cortisol or ACTH levels were measured before and during the administration of octreotide 50 to 500 micrograms every 8 hours for 24 to 72 hours. RESULTS: Treatment was effective in four patients: serum cortisol levels decreased to within or below the normal range in Patients 1, 2, and 3, and ACTH levels were substantially lowered in Patient 4, who had previously been adrenalectomized for a metastatic islet cell tumor. These responses were sustained during long-term treatment for 2 to 72 weeks. All four patients showed no evidence of a pituitary tumor on computed tomographic or magnetic resonance imaging and had proven (Patients 3 and 4) or presumed ectopic disease. Of the six patients who did not respond, four had pituitary tumors and two had presumed ectopic ACTH production. CONCLUSION: We conclude that a short trial of octreotide is warranted in patients with ACTH-dependent Cushing's syndrome who have no demonstrable pituitary tumor. A response to treatment should alert the physician to the possibility of an ectopic ACTH source and will identify patients whose disease may be controllable using octreotide.

Addison's disease, hypertension, renal and hepatic microthrombosis in 'primary' antiphospholipid syndrome.

We describe a 14 year old boy with antiphospholipid syndrome who initially presented at the age of 10 with recurrent loin pain, fever, weight loss, leucocytosis, thrombocytopenia, hypertension and haematuria. He had primary adrenal insufficiency with bilaterally enlarged adrenals on computed tomographic (CT) scan consistent with adrenal infarction. Renal and liver biopsies showed microthrombi in the glomerular capillaries and hepatic sinusoids respectively. The case is unusual in that hypertension rather than hypotension was dominant and a CT scan was consistent with bilateral adrenal infarction without haemorrhage. He represented with evidence of persistent hypertension with glomerulosclerosis and glomerular microthrombi on repeat renal biopsy. He continues to have permanent adrenal insufficiency with complete atrophy of his adrenals.

Acute and chronic effects of sulfonylurea drugs on pancreatic islet function in man.

The pancreatic islet can be viewed as an integrator of nutrient, neural, and hormonal signals. In normal people, glucose directly stimulates insulin release and also plays a key role as a potentiator of nonglucose stimulants of the B-cells. In patients with non-insulin-dependent diabetes mellitus (NIDDM), the direct effect of glucose on insulin secretion is markedly impaired. However, as hyperglycemia develops, basal insulin levels and insulin responses to nonglucose signals are maintained in many NIDD patients by the potentiating effect of hyperglycemia. Both acute and chronic administration of sulfonylurea drugs results in enhanced B-cell sensitivity to the potentiating effect of glucose. During sulfonylurea therapy this effect initially causes an increase in insulin level. However, as the glucose level falls during therapy the insulin level may tend to return toward pretreatment values, thereby masking the improvement of B-cell function. In NIDD patients with mild to moderate hyperglycemia (fasting plasma glucose less than 200 mg/dl), chronic sulfonylurea therapy results in the maintenance of near-normal insulin levels, but at a lower plasma glucose level. In patients with more severely impaired B-cell function, whose insulin levels before therapy are subnormal despite marked hyperglycemia, there is a net absolute increase in insulin levels during chronic sulfonylurea administration. Thus, some NIDD patients may show an increase in basal insulin levels during chronic sulfonylurea therapy while others may not; however, all patients who respond to sulfonylureas demonstrate increased B-cell sensitivity to glucose. Acute and chronic sulfonylurea treatment also results in a suppression of glucagon levels, an effect that may be secondary to the enhancement of B-cell function. The fall of plasma glucose during chronic sulfonylurea therapy is associated with a decrease in hepatic glucose production in NIDD patients. The magnitude of this effect is correlated with the degree of enhancement of basal insulin secretion. Thus, chronic sulfonylurea therapy clearly enhances pancreatic islet function in patients with NIDDM. We postulate that the major antihyperglycemic action of sulfonylurea therapy is mediated by this pancreatic effect.

The response of plasma triglyceride, cholesterol, and lipoprotein lipase to treatment in non-insulin-dependent diabetic subjects without familial hypertriglyceridemia.

The effects of treatment on plasma total triglyceride, total cholesterol, and plasma postheparin lipase activities have not been evaluated in non-insulin-dependent diabetic (NIDD) subjects without a coexisting familial lipid disorder. In 49 untreated NIDD subjects, there was a linear relationship between glycosylated hemoglobin (GHb) and triglyceride (r = 0.35, P less than 0.02). This correlation was improved after adjusting for the effects of obesity by a partial correlation analysis. After therapy, there was a significant relationship between the change in GHb and the change in triglyceride. To determine whether changes in lipid removal from plasma may contribute to the decrease in plasma lipid concentrations during treatment, the plasma postheparin lipoprotein lipase and hepatic lipase activities were evaluated in a subgroup (N = 8) of these NIDD subjects before and after 1 and 3 mo of therapy. Plasma postheparin hepatic lipase activity in the NIDD subjects was not different from that observed in six normal control subjects and did not change during therapy. In contrast, plasma postheparin lipoprotein lipase activity was lower in the untreated NIDD subjects than in the control subjects. Analysis of the two phases (early and late) of the postheparin lipoprotein lipase activity in plasma showed that the abnormal early phase in untreated NIDD corrected to normal values in less than a month, but the late phase was not corrected until the 3-mo measurement. These findings suggest that some NIDD subjects have a defect in heparin releasable lipoprotein lipase activity, which is reversed with improved glycemic control.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of glucagon secretion during a tolbutamide infusion in normal and noninsulin-dependent diabetic subjects.

To determine the effect of tolbutamide on glucagon release in noninsulin-dependent diabetic and normal subjects and how plasma glucose levels may modulate this effect, the acute glucagon response (AGR) to a 5-g iv arginine pulse was determined before and during a tolbutamide infusion. There was a decrease in plasma glucose concentration in both normal and diabetic subjects (both P less than 0.001); there tended to be a suppression of the AGR (4 of 6 normals and 8 of 11 diabetics), but this suppression was not statistically significant. In separate studies, when the plasma glucose level was clamped at baseline values by a variable rate of glucose infusion, the AGR was suppressed during the tolbutamide infusion in all 7 normal [change in AGR (delta AGR) = -35 +/- 12 pg/ml; P less than 0.05] and all 6 noninsulin-dependent diabetic subjects (delta AGR = -14 +/- 5 pg/ml, p less than .05). In 6 insulin-dependent diabetic subjects, there was no evidence of glucagon suppression by tolbutamide (delta AGR = +2 +/- 2 pg/ml). These results are consistent with the hypothesis that sulfonylureas suppress glucagon secretion by augmenting insulin secretion, an effect that falling glucose levels can mask. Consideration of this observation is necessary when interpreting the effects of a sulfonylurea on islet cell responses.

Aldose reductase inhibition improves nerve conduction velocity in diabetic patients.

To assess the potential role of polyol-pathway activity in diabetic neuropathy, we measured the effects of sorbinil--a potent inhibitor of the key polyol-pathway enzyme aldose reductase--on nerve conduction velocity in 39 stable diabetics in a randomized, double-blind, cross-over trial. During nine weeks of treatment with sorbinil (250 mg per day), nerve conduction velocity was greater than during a nine-week placebo period for all three nerves tested: the peroneal motor nerve (mean increase [+/- S.E.M.], 0.70 +/- 0.24 m per second, P less than 0.008), the median motor nerve (mean increase, 0.66 +/- 0.27, P less than 0.005), and the median sensory nerve (mean increase, 1.16 +/- 0.50, P less than 0.035). Conduction velocity for all three nerves declined significantly within three weeks after cessation of the drug. These effects of sorbinil were not related to glycemic control, which was constant during the study. Although the effect of sorbinil in improving nerve conduction velocity in diabetics was small, the findings suggest that polyol-pathway activity contributes to slowed nerve conduction in diabetics. The clinical applicability of these observations remains to be determined, but they encourage further exploration of this approach to the treatment or prevention of diabetic neuropathy.

Chronic chlorpropamide therapy of noninsulin-dependent diabetes augments basal and stimulated insulin secretion by increasing islet sensitivity to glucose.

To determine the effect of chronic sulfonylurea therapy on islet function in noninsulin-dependent diabetes mellitus (NIDDM), studies were performed in 18 untreated NIDDM patients before and after 12-16 weeks of chlorpropamide therapy. Fasting plasma glucose (FPG) fell with chlorpropamide therapy from 249 +/- 16 to 157 +/- 8 mg/dl (mean +/- SEM; P less than 0.001), and basal insulin increased from 17 +/- 2 to 24 +/- 3 microU/ml (P less than 0.001). The percent change in basal insulin correlated with the pretreatment FPG (r = 0.62; P less than 0.01) and inversely with the change in FPG during chlorpropamide (r = -0.57; P less than 0.025). Thus, patients with the highest pretreatment FPG showed the largest relative increase in basal insulin and the largest fall of FPG with chlorpropamide therapy. In nine patients, arginine-stimulated acute insulin responses (AIR) were studied at each of three plasma glucose (PG) levels both before and during chlorpropamide treatment. AIR at FPG was not different before and during treatment. However, when PG during treatment was matched by glucose infusion to the pretreatment FPG, the AIR was clearly increased during chlorpropamide therapy (176 +/- 65 vs. 49 +/- 11 microU/ml; P less than 0.02). When AIR is plotted against PG for each individual, the slope of the regression line generated (slope of glucose potentiation) is a measure of that patient's islet sensitivity to glucose. The logarithm of the slope of glucose potentiation correlated inversely with FPG (r = -0.92; P less than 0.001). Chlorpropamide treatment increased the slopes of potentiation from 0.26 +/- 0.11 to 1.47 +/- 0.70 (P less than 0.01). We conclude that chronic chlorpropamide therapy augments both basal and stimulated insulin secretion in NIDDM and that this may be an important mechanism of the drug's hypoglycemic effect. The data support the hypothesis that the hyperglycemia of NIDDM is related to islet insensitivity to glucose and that chlorpropamide treatment improves this impairment.

The effect of chronic sulfonylurea therapy on hepatic glucose production in non-insulin-dependent diabetes.

In 20 patients with untreated non-insulin-dependent diabetes mellitus (NIDDM), there was a positive relationship between fasting plasma glucose (FPG) and glucose production rate, calculated by the isotope dilution technique (r = 0.72, P less than 0.001). This suggests that glucose production rate is an important determinant of FPG in untreated NIDDM. Fifteen patients were also studied during therapy with chlorpropamide for 3-6 mo. During therapy, FPG was lower (133 +/- 9 vs. 216 +/- 20 mg/dl, mean +/- SEM; P less than 0.001), glucose production was lower (59.5 +/- 2.0 vs 77.6 +/- 4.9 mg/m2/min; P less than 0.005), and there was a significant correlation between the fall in glucose production and the fall in FPG (r = 0.59, P less than 0.05). Fasting IRI levels increased in some, but not all, patients during chlorpropamide (untreated 18 +/- 2, treated 21 +/- 2 muU/ml; P= NS). However, there was a significant relationship between the percent rise in IRI and the fall in glucose production during treatment (r = 0.75, P less than 0.001). Patients with a rise in fasting insulin during therapy had a greater fall in glucose production than those whose insulin did not rise (25.4 +/- 8.1 vs. 7.8 +/- 2.4 mg/m2/min; P less than 0.005). When a low-dose insulin infusion was given to approximate the increases of portal venous insulin during therapy, similar falls of glucose production occurred. We conclude that inhibition of endogenous glucose production during chronic chlorpropamide therapy is an important mechanism for the lowering of FPG and that enhanced insulin secretion is the reason for the major part of this inhibition. The small fall in glucose production in those patients whose insulin level did not rise during therapy suggests an additional contribution by some other mechanism.

Insulin responses to nonglucose stimuli in non-insulin-dependent diabetes mellitus during a tolbutamide infusion.

To determine the effect of tolbutamide on insulin release to nonglucose stimuli in non-insulin-dependent diabetes mellitus and how plasma glucose levels may modulate this effect, the acute insulin response (AIR) to an isoproterenol (12 Micrograms) or an arginine (5 g) i.v. pulse was determined before and during a tolbutamide infusion (7.5 mg/m2/min) in 25 male subjects. During the tolbutamide infusion, there was an increase in the AIR to both isoproterenol (% delta AIR = +49 +/- 21%, N = 11, P less than 0.05) and arginine (% delta AIR = +52 +/- 15%, N = 12, P less than 0.005) and a decrease in plasma glucose (delta plasma glucose for isoproterenol = -24 +/- 6 mg/dl, P less than 0.005; for arginine = -26 +/- 3 mg/dl, P less than 0.001). In separate studies, when the plasma glucose was clamped at baseline values by a variable rate of glucose infusion, there was a greater effect of tolbutamide on AIR when compared with the unclamped tolbutamide studies (isoproterenol: % delta AIR = +132 +/- 25%, P less than 0.025; arginine: % delta AIR = +95 +/- 12%, P less than 0.05). Thus, tolbutamide increases the AIR of nonglucose stimuli, but this augmentation by tolbutamide is blunted by the concomitant decrease in plasma glucose. Consideration of this observation is necessary when interpretating the effects of a sulfonylurea on islet cell responses.