Effects of secretin on insulin secretion and glucose tolerance.

Effects of intravenous (IV) infusion of secretin during IV infusion of glucose were examined in normal men. Secretin was administered according to three schedules: with each schedule a comparable priming dose was delivered in the first minute, but this was followed by a maintained (120 min) infusion of secretin at a relatively high rate, or by maintained infusion at one-third that rate, or by brief (15 min) infusion at the lower rate. The lower infusion rate produced increments in secretin in the blood within the range attainable during endogenous secretion. By comparison with effects of glucose alone each secretin infusion enhanced the increments of immunoreactive insulin in the blood. Enhancement of the early release (0-5 min) of insulin was similar with each type of secretin infusion, but the integrated changes in insulin levels through the total infusion period were related to the total doses of secretin. With each dose of secretin glucose tolerance was improved but the three mean glucose curves observed during infusions of secretin were not distinguishable from one another in spite of widely different integrated insulin responses. Secretin did not modify suppression of immunoreactive glucagon or free fatty acids in the blood during hyperglycemia. The results suggest that the effect of continuous administration of secretin on glucose tolerance is not simply related to its integrated insulinotropic action. It is suggested that the effect may be highly dependent on enhancement of insulin secretion early in the response to glycemia, or that it may be due to effects of secretin on glucose production or disposal which are not mediated by insulin.     

Effects of isoflurane anesthesia on glucose tolerance and insulin secretion in Yucatan minipigs.

Isoflurane's effect on intravenous glucose tolerance and insulin secretion was studied in six Yucatan minipigs. Unanesthetized animals, with previously placed indwelling venous catheters, were tested while resting comfortably in slings. The same animals were then retested during isoflurane anesthesia. Serum glucose and insulin concentrations were measured at predetermined times in response to an intravenous bolus of dextrose. The glucose disappearance rate (k), baseline plasma insulin concentration, the area under the insulin response curve, and the insulinogenic index were significantly lower in the anesthetized animals than in controls. The results of this study indicate that anesthesia with isoflurane significantly alters the glucose/insulin response to an intravenous glucose tolerance test and, therefore, is unsuitable for studies when glucose tolerance is to be assessed.     

Effect of short-term clofibrate on glucose metabolism and insulin secretion in patients with mild maturity-onset diabetes mellitus

The effect of 1 week clofibrate administration on glucose and insulin responses to oral glucose and to intravenous tolbutamide was evaluated in 21 patients with mild maturity-onset diabetes (fasting plasma glucose 108-152 mg/100 ml). After treatment, oral glucose tolerance and hypoglycaemic effect of tolbutamide were significantly improved; plasma insulin response was reduced after glucose and unmodified after tolbutamide; fasting plasma glucose was also significantly reduced. These findings did not correlate with the observed fall in serum lipids. Short-term clofibrate improves glucose metabolism in mild diabetes irrespective of its effects on lipid metabolism. It is suggested that the drug's action may be mediated by reduced insulin resistance.     

Hyperbolic relationship between insulin secretion and sensitivity on oral glucose tolerance test

The utility of the disposition index as a measure of beta-cell compensatory capacity rests on the established hyperbolic relationship between its component insulin secretion and sensitivity measures as derived from the intravenous glucose tolerance test (IVGTT). If one is to derive an analogous measure of beta-cell compensation from the oral glucose tolerance test (OGTT), it is thus necessary to first establish the existence of this hyperbolic relationship between OGTT-based measures of insulin secretion and insulin sensitivity. In this context, we tested five OGTT-based measures of secretion (insulinogenic index, Stumvoll first phase, Stumvoll second phase, ratio of total area-under-the-insulin-curve to area-under-the-glucose-curve (AUC(ins/gluc)), and incremental AUC(ins/gluc)) with two measures of sensitivity (Matsuda index and 1/Homeostasis Model of Assessment for insulin resistance (HOMA-IR)). Using a model of log(secretion measure) = constant + beta x log(sensitivity measure), a hyperbolic relationship can be established if beta is approximately equal to -1, with 95% confidence interval (CI) excluding 0. In 277 women with normal glucose tolerance (NGT), the pairing of total AUC(ins/gluc) and Matsuda index was the only combination that satisfied these criteria (beta = -0.99, 95% CI (-1.66, -0.33)). This pairing also satisfied hyperbolic criteria in 53 women with impaired glucose tolerance (IGT) (beta = -1.02, (-1.72, -0.32)). In a separate data set, this pairing yielded distinct hyperbolae for NGT (n = 245) (beta = -0.99, (-1.67, -0.32)), IGT (n = 116) (beta = -1.18, (-1.84, -0.53)), and diabetes (n = 43) (beta = -1.37, (-2.46, -0.29)). Moreover, the product of AUC(ins/gluc) and Matsuda index progressively decreased from NGT (212) to IGT (193) to diabetes (104) (P < 0.001), consistent with declining beta-cell function. In summary, a hyperbolic relationship can be demonstrated between OGTT-derived AUC(ins/gluc) and Matsuda index across a range of glucose tolerance. Based on these findings, the product of these two indices emerges as a potential OGTT-based measure of beta-cell function.     

Effect of short- and long-term chlorpropamide therapy on oral glucose tolerance and erythrocyte insulin receptors in non-obese non-insulin dependent diabetes mellitus

Erythrocyte (RBC) insulin receptors and the insulin response to glucose load (oGTT) were evaluated in ten male, non-obese, non-insulin dependent diabetic patients (NIDDM) before and after 14 and 90 days of 250 mg/day of chlorpropamide administration. In addition, as a control group, twelve healthy non-obese subjects were studied. Diabetic patients with fasting plasma glucose level higher than 14 mmol/l (group A), presented a significant improvement in the incremental glucose area only after 90 days of therapy. There was an evident reduction in insulin secretion, in comparison to normals, which however increased progressively during drug administration. No alterations in insulin binding to RBC receptors were observed either before or after the use of chlorpropamide, but the normalization of the initially low number of receptors per cell (N) and an increased high affinity constant (Ke) were achieved. In group B with fasting glucose less than 14 mmol/l there was a significant reduction in plasma glucose levels during oGTT without changes in glucose areas and a significant improvement of the insulin secretion was noted only in the early samples. Except for transient alterations in N and Ke no significant changes were observed in insulin-RBC binding parameters. We conclude that the improvement in the glucose tolerance in NIDDM is associated both to a greater insulin secretion and to the correction of the alterations in receptor parameters which could be related, at least partially, to proportionate changes in reticulocyte count.     

Concentrated loss of insulin secretion in Wistar rats with normal glucose tolerance

Rats with decreased insulin response and with normal glucose tolerance were concentrated by repeated selective breeding of normal Wistar rats with low insulinogenic index. In general, the mean insulinogenic index of the inbred offsprings showed a tendency to decrease more than their parents generation. Thus mean insulinogenic indices in second (F2), third (F3) and fourth (F4) generations were significantly reduced more than the normal rats without glucose intolerance. Pancreatic islets from the F3 and F4 rats lost partially their ability to release insulin at 20 mM glucose in vitro. It is suggested that a defect responsible for the decreased insulin response in the F2, F3 and F4 rats resulted from a loss of the ability to secrete insulin in each islet, and that this defect was concentrated by repeated selective breeding of normal Wistar rats.     

Gestational diabetes mellitus and impaired glucose tolerance in an aged Macaca mulatta

Gestational diabetes mellitus was diagnosed in an aged (21-year-old) pregnant rhesus monkey (Macaca mulatta); she was hyperglycemic and had minimal glucose clearance in an intravenous glucose tolerance test (iv-GTT). An overweight (840 g) dead full-term fetus was delivered by cesarean section. A second iv-GTT conducted 3 months later revealed impaired glucose tolerance. While pregnant, the monkey was hyperinsulinemic and showed minimal secretory response to the glucose load. When tested postpartum, the fasting insulin was only slightly elevated, but the insulin response to glucose was still lacking.     

Effects of propranolol and metoprolol on the peripheral circulation.

The effects of single doses of propranolol and metoprolol on skin temperature and skin and muscle blood flow were compared in 10 normal subjects and four patients with essential hypertension. In normal subjects the mean skin temperature fell by 1.30 +/- 0.62 degrees C 90 minutes after 80 mg propranolol and 0.15 +/- 0.05 degrees C after 100 mg metoprolol. Skin blood flow and resting muscle blood flow were not affected by metoprolol but fell significantly after propranolol. Both drugs reduced post-exercise muscle hyperaemia, propranolol by more than metoprolol. Similar changes were seen in the hypertensive patients. Propranolol should be used with care in patients with known vascular disease.     

Changes in insulin secretion after secretin administration and the implications in diabetes mellitus

Secrepan (Eisai Co. Tokyo, Japan) was administered to 9 healthy volunteers and 36 patients with non-insulin dependent diabetes mellitus (NIDDM) to clarify the effect of secretin on the pancreatic B-cell, by determining the changes in blood of insulin (IRI). Whereas IRI in healthy subjects showed a monophasic change, reaching a peak (delta IRI = 43 +/- 7.3 microunits/ml, M +/- SE) 5 min after secretin loading and returning to the basal level in 15 min, NIDDM patients on diet therapy (delta IRI = 40.2 +/- 7.6 microunits/ml) showed no significant difference from the control group, but NIDDM patients on sulfonylurea (SU) (15.5 +/- 2.4 microunits/ml) and those on insulin therapy (5.3 +/- 1.4 microunits/ml), both showed a significant depression in responsiveness. Further, the changes in insulin secretion after atropine administration in healthy subjects and the changes in IRI response to Secrepan in vagotomized patients were also determined. As a result, data which preclude the possibility of association of the vagus nerve and cholinergic nerve with the stimulation of insulin secretion by secretin were obtained, and a direct action of secretin on the cell of islets of Langerhans was suggested. The maximum IRI response after a secretin load had a significant positive correlation with the IRI response after a 75-gm GTT and the content of C-peptide immunoreactivity in 24-hour urine. Therefore, insulin response to a secretin load can be useful in assessing endogenous insulin secretion and provides a pertinent clinical guide for the selection of an appropriate therapy for diabetes mellitus.     

Effects of prostaglandin synthesis inhibitors on human insulin secretion and carbohydrate tolerance

Prostaglandin E (PGE) has been hypothesized to be an endogenous regulator of carbohydrate metabolism because it decreases human insulin secretion and carbohydrate tolerance. This report compares the effects of four inhibitors of PGE synthesis on the acute insulin response to glucose and subsequent glucose disappearance rates. Ibuprofen, acetylsalicylic acid and sodium salicylate treatments in normal volunteers were associated with augmented insulin secretion and improved glucose tolerance while indomethacin had the opposite effects. In view of these findings and the known effects of PGE on carbohydrate metabolism, we suggest that the effects of indomethacin may have been due to an action of the drug other than inhibiting PGE synthesis.