Norman Altszuler

Glucose Uptake and Production During the Oral Glucose Tolerance Test

During the three hours required for absorption of most of a U-C-14-glucose load (1 gm./kg.) given orally to an intact unanesthetized dog in the postabsorptive state, about three quarters of the load reaches the peripheral circulation. The absence of randomization of the label, seen when an equal oral load of 6-C-14-glucose is given, indicates that the glucose reaching the peripheral circulation has not been fragmented, then resynthesized into glucose. During the three-hour period, only 0.34 gm. per kilogram of new (unlabeled) glucose is released by liver instead of the 0.63 gm. per kilogram which would have been produced in the absence of oral glucose; the uptake of the glucose of peripheral circulating blood is 1.03 gm. per kilogram instead of 0.63 gm. per kilogram. Endogenous insulin secreted in response to the oral load exerts a somewhat larger effect to decrease hepatic glucose release (relative to the increase in glucose uptake from peripheral blood) than is the case when insulin is given by peripheral vein.

Effect of Hypophysectomy and Growth Hormone on Glucose Uptake by Rat Epididymal Fat Tissue.

Summary The epididymal fat tissue from hypophysectomized rats took up a significantly smaller amount of glucose than did the normal tissue. A single injection of bovine growth hormone into hypophysectomized rats increased glucose uptake by epidymal fat tissue excised 24 hr later. Sera from hypophysectomized and growth hormone-treated hypophysectomized rats increased glucose uptake by normal fat tissue to the same extent as sera from normal animals. The authors gratefully acknowledge the helpful contributions made by Dr. Richard C. de Bodo.

Interaction of Somatostatin, Glucagon, and Insulin on Hepatic Glucose Output in the Normal Dog

The interaction of insulin and glucagon during infusion of somatostatin (SRIF), which suppresses secretion of these hormones, was investigated in normal, postabsorptive, concious dogs. Hepatic glucose output (production) and over-all glucose uptake by the tissues was measured with 3-3H-glucose, administered by a priming injection along with a constant infusion. Infusion of SRIF (1.5–5.0 μg/min) for 90 minutes resulted in a moderate hypoglycemia associated with a decrease in glucose production. In some animals glucose production and plasma glucose levels returned to normal before the end of SRIF infusion. Glucose uptake tended to follow plasma glucose levels. Upon termination of SRIF infusion, glucose production and uptake and plasma glucose increased sharply. Infusion of glucagon (1 μg./kg./hr.) along with SRIF (3.3 μg./min.) caused an exaggerated increase in glucose production and hyperglycemia over that of glucagon infusion alone. Infusion of a smaller dose of glucagon (0.2 μg./kg./hr.) for two hours produced only small increases in plasma glucose and glucose production; addition of SRIF during the third hour caused a significant increase in glucose production and plasma glucose. Addition of insulin (0.03 U./kg./hr.) to the glucagon infusion had little effect. However the further addition of SRIF failed to produce the marked increase in glucose production and hyperglycemia seen with glucagon-SRIF infusion. It is concluded that acute insulin deficiency produced during SRIF infusion makes the liver more sensitive to the effects of glucagon and that the response of the liver to glucagon and other hyperglycemic agents may be modulated by insulin.

The effects of growth hormone on carbohydrate and lipid metabolism in the dog.

Administration of growth hormone has been shown to influence the metabolism of proteins, fats, and carbohydrates. Despite the large accumulation of data to substantiate these effects, some fundamental questions about the influence of growth hormone on metabolism still remain. The gross and often descriptive effects of growth hormone (e.g. impairment of glucose tolerance, elevation of plasma free fatty acids (FFA), and production of diabetes) need to be studied at a more basic, biochemical level. It is not known a t present whether there is a causal relationship between the various metabolic effects of growth hormone, or whether they reflect separate and independent influences of the hormone. Furthermore, even the gross effects of growth hormone have been questioned in view of the reports that growth hormone administration results in early effects which may differ qualitatively from effects observed a t later periods. Since the growth hormone-induced changes in the plasma concentration of the various metabolic constituents result from changes in either the rates of their production or utilization or both, it was of interest to determine the effect of growth hormone on these parameters. Rates of plasma glucose and FFA production (release into plasma), uptake by tissues, and oxidation were determined in normal dogs at various time periods of a growth hormone regimen. These measurements of glucose and FFA metabolism were made using intravenous (i.v.) infusions of tracer amounts of glucoseC and palmiteteC, respectively. The method of calculation of production and utilization of glucose’” and FFA3 were published earlier. The dogs were maintained on a standard mixed diet fed once a day in the late afternoon, unless indicated otherwise. Bovine growth hormone was injected each day, subcutaneously (s.c.), after completion of the meal. The control experiments were therefore performed about 18 hr following last feeding and hormone injection. *Investigations carried out at New York University School of Medicine were supported by Research grant A-113 (C13, 14, 15) from the National Institute of Arthritis and Metabolic Diseases, Public Health Service, Bethesda, Md., and by grants P-207 E and F from the American Cancer Society, Inc., New York, N.Y. Part of this investigation was supported by Public Health Service Research Career Program Award K3GM-3368-06,07 to N . Altszuler. Part of this research was carried out at Brookhaven National Laboratory under the auspices of the US. Atomic Energy Commission. 14

Oxytocin Infusion Increases Plasma Insulin and Glucagon Levels and Glucose Production and Uptake in the Normal Dog

Infusion of oxytocin (50-500 μU/kg/min) into normal conscious dogs produces a rise in plasma glucose, insulin, and glucagon levels. These changes are accompanied by a prompt increase in glucose production followed by an increase in overall glucose uptake, as determined using 6-3H-glucose infusion.

On the Mechanism of Diazoxide-induced Hyperglycemia

Infusion of diazoxide (16.5 mg./kg. in 10 minutes) into normal unanesthetized dogs resulted in a prompt hyperglycemia due to increased hepatic glucose production as measured with a 3-3H-glucose primer-infusion technique. Plasma insulin and gtucagon were decreased. Glucose uptake failed to increase. Diazoxide administration during period of alpha adrenergic receptor blockade with phentolamine still caused hyperglycemia and increased glucose production. Glucose uptake was inhibited despite adequate plasma insulin. Infusion of somatostatin along with insulin prevented the effects of diazoxide on plasma glucose and glucose production. It is concluded that diazoxide hyperglycemia is not due solely to decreased insulin secretion or increased epinephrine secretion and that gtucagon is not a contributory factor. Diazoxide may act directly to increase glucose production and inhibit glucose uptake. Somatostatin appears capable of blocking the effect of diazoxide on glucose production by an unknown mechanism.

Fat mobilization and plasma hormone levels in fasted dogs

Abstract The aim of this work was to study the regulation of ketone body metabolism in the dog during prolonged fasting. In nine nonobese dogs, which were starved for 2 wk, free fatty acids, triglycerides, glycerol, ketone bodies, and glucose were measured as well as insulin, glucagon, growth hormone, T 4 and T 3 , and reverse-T 3 . Free fatty acids and glycerol concentrations rose gradually during the whole period. Acetoacetate and β-hydroxybutyrate reached levels of 130 ± 50 and 350 ± 125 μmol/liter, respectively. Glucose levels remained constant initially but declined significantly by the end of the starvation period. Insulin levels declined moderately. Glucagon and growth hormone values were not influenced by fasting. T 4 concentrations remained in the normal range, T 3 levels declined significantly, but reverse-T 3 levels did not rise during starvation. The results are compared with data from the literature on human starvation. From the data on the lipid parameters it is concluded that fat mobilization progresses at a slower rate in the dog than in man. The absence of a pronounced hypoglycaemia results in a hormonal setting (unchanged glucagon and growth hormone concentrations, together with an only slightly decreased insulin concentration) which protects the dog from the development of severe ketosis.

Tolbutamide and glyburide differ in effectiveness to displace α- and β-adrenergic radioligands in pancreatic islet cells and membranes

Previous in vivo findings indicated that α-adrenergic blocking agents enhanced tolbutamide-induced insulin secretion, whereas β-blockade attenuated it. In the present study, the interaction of tolbutamide and glyburide with the rat islet adrenergic receptors is examined directly by determining the effectiveness of these drugs to displace the specific α- and β-adrenergic radioligands, [3H]-clonidine and [3H]-dihydroalprenolol (DHA). It was found that both tolbutamide and glyburide had affinity constants for the adrenergic receptors that were similar to those for the natural receptor ligands and powerful antagonists. Tolbutamide displaced both α- and β-radioligands but had a higher affinity at the β-receptor. Glyburide also displaced radioligands from both types of receptors but had a higher affinity for the α-receptor. This study suggests that these two sulfonylurea hypoglycemic agents may affect insulin secretion by different mechanisms.

Displacement of alpha- and beta-radioligands by specific adrenergic agonists in rat pancreatic islets.

Secretion of insulin is increased by beta-adrenergic agonists and inhibited by alpha-adrenergic agonists. However, administration of epinephrine, which acts on both types of receptors, inhibits insulin secretion. A preliminary study using [3H]-dihydroergocryptine and [3H]-dihydroalprenolol as the respective alpha- and beta-receptor binding ligands, surprisingly revealed a preponderance of beta-binding sites in normal rat pancreatic islets. The present study, using displacement by epinephrine, norepinephrine, isoproterenol and clonidine validated the use of these radioligands as appropriate for specific receptor binding in pancreatic islet cells. The islets were found to have 55 fmol/mg protein of alpha-adrenergic receptor sites and 170 fmol/mg protein of beta-receptor sites. The affinity of both alpha- and beta-receptors for epinephrine was similar, as judged by the displacement of either radioligand, thus ruling out a preferential affinity of alpha-receptor binding as an explanation for the alpha-inhibition of insulin secretion. The data on radioligand displacement by clonidine indicate that the alpha-receptor is of the alpha 2-type.

Inositol production by the brain in normal and alloxan-diabetic dogs

Abstract It was found that there was no net uptake of inositol by CSF from plasma, indicating that the high concentration of inositol in the CSF relative to that in plasma of normal and diabetic dogs originates from inositol synthesized by brain. The inositol concentration and rate of efflux from the CSF were used to measure inositol turnover in CSF, and from this was calculated a minimum rate of inositol production by dog brainin vivo. There was no significant difference in the rate of inositol production by the brain (88 μmoles/kg brain/h) between the normal and alloxan-diabetic dog.