Charles J. Goodner

Somatostatin: Hypothalamic Inhibitor of the Endocrine Pancreas

Somatostatin, a hypothalamic peptide that inhibits the secretion of pituitary growth hormone, inhibits basal insulin secretion in fasted cats and rats. In fasted baboons both basal and arginine-stimulated secretion of insulin and glucagon are inhibited. Somatostatin appears to act directly on the endocrine pancreas. The action is dose-related, rapid in onset, and readily reversed.

A (3H)2-Deoxyglucose Method for Comparing Rates of Glucose Metabolism and Insulin Responses Among Rat Tissues In Vivo: Validation of the Model and the Absence of an Insulin Effect on Brain

In 1980 we described an in vivo method for estimating the rate of glucose uptake among selected tissues during an acute insulin response. The method was based upon the same principles as Sokoloffs 2-deoxyglucose (2DG) method. We now report further examination of the basic assumptions of the model and validation of its general applicability by comparing the response of brain and other tissues to prolonged insulin infusion (while glucose is held constant) with their response to a single injection of insulin. The method provides a reproducible estimate of relative insulin response in any tissue that can be anatomically separated at death. Tissues that are minimally sensitive to insulin such as spleen, lung, skin, and gut do not display increments in the calculated value for net rate of tissue uptake of 2DG. Insulin-sensitive tissues display increased rates of uptake that are characteristic for each specific tissue, ranging in magnitude from 1.7- to 17.9-fold over basal among an array of insulin-sensitive tissues. The duration of a unit response to a sub-maximal dose of insulin also varied among the tissues, persisting for 20–30 min after plasma insulin had returned to basal in heart and for 10–20 min in the other insulin-sensitive tissues. The method provides a reproducible measure of glucose metabolism in vivo and has been validated as a means of quantifying relative insulin sensitivity among the peripheral tissues. During steady-state conditions with plasma glucose held constant, brain glucose metabolism was unaffected by a 60-min infusion of insulin.

Somatostatin blockade of acute and chronic stimuli of the endocrine pancreas and the consequences of this blockade on glucose homeostasis.

The nature and extent of somatostatin-induced inhibition of pancreatic endocrine secretion were studied by administration of a number of stimuli of either glucagon or insulin to over night fasted baboons with and without an infusion of linear somatostatin. The stimuli for acute-phase insulin release were intravenous pulses of glucose, tolbutamide, isoproterenol, and secretin. When given 15 min after the start of a somatostatin infusion, these agents were essentially unable to stimulate insulin secretion. Chronic insulin secretion was stimulated by infusions of either glucose or glucagon. Within 10 min of the start of a super-imposed infusion of somatostatin, insulin levels fell to less than 40 percent of prestimulus control and remained suppressed for the duration of the somatostatin infusion. Stimulation of glucagon secretion by insulin-induced hypoglycemia was also blocked by somatostatin. Plasma glucose decreased during somatostatin infusions except when superimposed upon an infusion of glucagon. Somatostatin had no effect on glucose production in a rat liver slice preparation. We conclude: (a) Somatostatin is a potent and so far universally effective inhibitor of both acute and chronic phases of stimulated insulin and glucagon secretion (b) The inhibitory effect is quickly reversible and the pattern of recovery of secretion is appropriate to prevailing signals; (c) Present evidence suggests that the effect of somatostatin on blood glucose is mediated through its effect on blood glucagon; (d) In the overnight-fasted baboon both in the basal state and 45 min into a 4-mg/kg-min glucose infusion, a somatostatin-induced fall in serum insulin levels appears to be unable to prevent a decrease in hepatic glucose production.

The Pattern of Response of Plasma Insulin and Glucose to Meals and Fasting During Chlorpropamide Therapy

Abstract Frequent determinations of insulin and glucose were done in a group of obese diabetics during a 48-hr test period consisting of 24 hr in which normal dietary intake was permitted followed ...

Rapid Reduction and Return of Surface Insulin Receptors After Exposure to Brief Pulses of Insulin in Perifused Rat Hepatocytes

Hepatic receptors are normally exposed to discrete pulses of insulin and glucagon at intervals of 8 to 16 min. Using a multicolumn system for perifusing hepatocytes, we investigated the effect of this pattern on the normal processing of the insulin receptor. Surface-receptor binding was measured in acid-washed cells harvested from individual columns. The number of high-affinity surface receptors fell to a nadir 1 min after the end of a 3-min square-wave pulse of insulin. The maximum reduction reached 45% of baseline at amplitudes of 1000 μU/ml or above. The number of surface binding sites returned to baseline 15 min after the end of the pulse, but the affinity constant of the high-affinity receptor was unchanged. The reduction of surface binding was dose dependent, with an ED50, of 251 ± 34 μU/ml. Prolonging the pulse to 60 min did not affect the nadir or the rate of restoration of the surface-receptor population. The change in surface binding was reduced at 15°C and abolished at 4°C. After a pulse, the pattern of change was a period of rapid decline to a nadir (t1/2 ≤ 1 min) that persisted for 3–5 min, followed by restoration of surface binding that reached baseline in 10–15 min. This same pattern was present after six ED95 pulses delivered at intervals of 15 min. These data indicate that the internalization of hepatocyte surface receptors and their recycling and reinsertion into the plasma membrane can be entrained to pulses at the physiologic pulse frequency.

Insulin dose-response characteristics among individual muscle and adipose tissues measured in the rat in vivo with 3[H]2-deoxyglucose.

The dose-response characteristics of three skeletal muscles, three adipose tissue beds, and heart muscle to single i.v. injection of insulin were compared in vivo. Comparisons were made at 8 dose levels spanning the entire range for response by all tissues and for the integrated whole body response as reflected in the rate of disappearance of 3H-2-deoxyglucose from plasma. The insulin-sensitive tissues varied widely with respect to the magnitude of the maximal response and the sensitivity to insulin as judged by the effective dose 50% (ED 50). Among the muscles, a slow-twitch oxidative muscle, soleus, was more sensitive than the fast-twitch glycolytic muscle, extensor digitorum longus (EDL), while a mixed muscle, quadriceps femoris, displayed even lower sensitivity. Heart muscle sensitivity was comparable to EDL. Among the adipose sites, the rank order of sensitivity was subcutaneous > epididymal ≫ omental. The threshold for a detectable response to insulin was 0.013 U/kg rat.

Effects of Somatostatin on Hemostasis in Baboons

Because some baboons repeatedly infused with somatostatin died we reviewed available autopsy material. All six animals chronically treated with somatostatin displayed gross or microscopical pulmonary hemorrhage and increased hemosiderin in lung and liver whereas only one of six untreated animals had a similar abnormality. We therefore examined the hemostatic system in living baboons. Thrombocytopenia (mean platelet count of 84,000 per microliter) was noted in six of seven baboons chronically treated with somatostatin; platelet survival was normal. Clotting factors were unaffected. Fibrinogen concentration and survival were unchanged. The acute effects of intravenous somatostatin (0.8 micrograms per kilogram per minute for two hours) in previously untreated animals transiently decreased platelet count, reduced retention of platelets on glass-bead columns and inhibited aggregation induced by ADP, collagen and epinephrine. Bleeding times were not prolonged. Somatostatin added to platelet-rich plasma in vitro was without effect. These data suggest that prolonged administration of somatostatin should be undertaken with caution.

Central α-Adrenergic Regulation of Growth Hormone and Insulin

Serum growth hormone (GH) fell and serum insulin (IRI) rose within 30 min following infusion of phentolamine, an α-adrenergic blocking agent, into the anterior hypothalamus or third ventricle of conscious, fasted baboons. GH and IRI were unchanged following intravenous infusion systemically of phentolamine at doses 2 to 4 times greater than given centrally, indicating that the reciprocal changes in GH and IRI did not result from direct action of phentolamine on the adenohypophysis and pancreatic islets. Rather, these data suggest that the phentolamine blocked hypothalamic adrenergic mechanisms participating in the normal regulation of GH and IRI. Plasma glucose and 17-OHCS rose and plasma glycerol fell in association with changes in GH and IRI, but blood pressure, heart rate and internal temperature were not altered.

Decreased Insulin- and Glucagon-Pulse Amplitude Accompanying β-Cell Deficiency Induced by Streptozocin in Baboons

The effect of β-cell deficiency on the spontaneous pulsatile secretory pattern of the islets of Langerhans was studied in the baboon. Measures of β-cell function were correlated with the secretory pattern before and at intervals after streptozocin administration. The degree of insulin deficiency was variable and ranged from mild to moderate. Highly regular pulses were less prevalent in baboons compared with rhesus monkeys and humans, but the mean frequency was similar and was not affected by treatment. The principal effect of β-cell destruction was to proportionately reduce the pulse amplitude of insulin (−39%, P < .003) without detectable change in pulse frequency, interhormonal phase relationship, or the regularity of pulses. Glucagon-pulse amplitude also fell (−19%, P < .09), but not significantly. However, glucagon-pulse amplitude was strongly correlated with insulin-pulse amplitude (r = −.59, P < .002), whereas mean fasting plasma concentrations of insulin and glucagon were not significantly changed after treatment. Because streptozocin affects only the β-cell, the data indicate a major influence of the insulin pulse on the α-cell secretory pulse. The data do not support the presence of a separate pacemaker for the α-cell but do not eliminate this possibility. The strong correlation of reduction in insulin-pulse amplitude with increasing fasting glucose and decreasing glucose disappearance lends support to growing evidence that the pattern of insulin secretion is an important determinant of normal glucose homeostasis.

Assessment of obesity in pigtailed monkeys (Macaca nemestrina).

Obesity was studied in a colony of 873 Macaca nemestrina to establish tools for epidemiologic studies, to examine a genetic form of obesity, to document age/sex relationships to obesity, and to compare metabolic profiles of obese and normal monkeys. Age/weight growth curves were analyzed to select the most obese monkeys and age- and sex-matched normal controls. Degree of adiposity was determined using tritiated water for estimation of lean body mass. Body weight, anterior trunk height, and abdominal and triceps skinfolds were measured. Fasting insulin, fasting free fatty acids, and glucose disappearance rate were determined. The results give evidence of similarities between macaque and human obestiy.