Biomedical subjects
G F Cahill
Publications and source records attributed to G F Cahill.
Needs for animal models of human diseases of the endocrine system.
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Gonadotropin profiles in fed and fasted obese women.
Five obese women were studied before and at the end of a prolonged fast to determine the effect on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and on the response to luteinizing hormone--releasing factor (LRF). Although baseline serum LH values declined from a mean value of 9.1 to 6.5 m.I.U. per milliliter measured at the end of the fast, these changes in mean serum level were not statistically significant. However, the integrated LH secretion did decline when measured at the end of the fasts (p less than 0.05). FSH secretion did not change. LRF-stimulated LH and FSH values showed augmented stimulation at the end of the fast. Pulsatile gonadotropin secretion patterns remained normal. Prolonged fasting appears to alter the baseline LH secretion and the pituitary response to exogenous LRF.
Human evolution and insulin-dependent (IDD) and non-insulin dependent diabetes (NIDD).
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Current concepts of diabetic complications with emphasis on hereditary factors: a brief review.
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Mechanisms of protein sparing in carbohydrate loaded man.
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The redox state and regulation of amino acid metabolism in man.
Traditionally, regulation of amino acid metabolism in both postabsorptive and prolonged-fasted man has been generally regarded as being hormonal in nature. In particular, insulin, and to a lesser extent glucagon, have been nominated for key roles in this process. More recently, however, reconsideration of previous studies involving insulin, glucagon, and protein meals as well as previously unreported studies (cortisol and tri-iodothyronine) from this laboratory, have suggested another means of regulating amino acid metabolism in fasting man. This new hypothesis is centered on the redox state of muscle of fasting man, which is remarkably reduced in both cytosolic and mitochondrial compartments. It was found that insulin, and to a lesser extent glucagon, when infused into fasting subjects (1) rendered muscle significantly more reduced, and (2) resulted in a diminution in urinary nitrogen excretion. In contrast, when either tri-iodothyronine or cortisol were administered to fasting individuals (1) muscle was found to become more oxidized when compared with the control period, and (2) increased urinary nitrogen excretion was observed in both cases. It was noteworthy that the ingestion of a protein meal by a nitrogen-depleted individual was followed by a dramatic change in muscle redox state (the muscle became more reduced), together with marked uptakes of a variety of amino acids. It is therefore proposed that the protein conservation evidenced by fasting man may be dependent on the reduced state of muslce tissue.
Thayer lecture. Diabetes mellitus: a brief overview.
Thus to summarize, there are a number of experimental and critical observations which all tend to support the contention that the hyperglycemia and perhaps to a lesser degree, the insulin deficiency, contribute significantly to the atherosclerosis and more directly initiate and expidite the microangiopathy and neurological abnormalities noted in diabetes. There is little evidence to suggest that the microangiopathy has any direct genetic relationship except via the beta cell and the resulting insulin deficiency.
Diabetes and evolution: some speculations.
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Effects of exogenous glucagon and epinephrine in physiological amounts on the blood levels of free fatty acids and glycerol in dogs.
Exogenous glucagon or epinephrine were infused into normal overnight fasted dogs to raise circulating hormone levels to concentrations within the physiologic range. Plasma levels of glycerol and free fatty acids remained unchanged during the glucagon infusion, but rose significantly during the administration of epinephrine. Plasma insulin in the systemic circulation remained unchanged during the glucagon infusion and increased slightly during the infusion of thecatecholamine. The data suggest that in normal dogs glucagon in physiological amounts has no lipolytic effect. The importance of the sympathetic nervous system in regulating lipolysis in normal mammals is stressed.
Metabolic and endocrine studies in a case of lipoatrophic diabetes.
A 20-yr-old female with congenital lipoatrophic diabetes was studied, with the following findings: (1) Serum insulin levels increased after both oral glucose and intravenous arginine administration; there was no growth hormone response to the latter. (2) The infusion of insulin (0.1 units and 0.5 units/kg) during the fed state and following at 110-hr fast produced only minimal changes of various fuels measured, with the exception of a decrease in the branched-chain amino acids. (3) There was a minimal production of ketones during the 110-hr fast. (4) Matabolic expenditure was markedly increased during the postabsorptive state (65-75 kcal/hr/sg m); it fell into the normal range during the 110-hr fast (31-35 kcal/hr/sq m). (5) Following meals, the patient experienced complaints ranging from cold and shivering to feeling hot with gross diaphoresis. These findings were associated with intermittent lability of her skin temperature, which varied 1 degree - 2 degrees F during a 3-hr period. (6) Progressive increases in doses of regular insulin before each meal resulted in up to a total of 9000 units/day being required before normal blood glucose levels were achieved. (7) A 2-wk therapeutic trial of pimozide provided no significant changes in a variety of hormones and fuels in the basal state or following insulin perturbations. (8) A variety of pituitary hormones and pituitary target organ hormones were studied in both the hypothyroid (Hashimoto's thyroiditis) and euthyroid state (following thyroid replacement). All the hormone responses were normal except that growth hormone did not rise during the slow wave sleep in either thyroid state.
Studies of streptozotocin-induced insulitis and diabetes.
Multiple small injections of streptozotocin produce a delayed, progressive increase in plasma glucose in mice within 5-6 days after the injections, in association with pronounced insulitis and induction of type C viruses within beta cells. Multiple subdiabetogenic doses of streptozotocin in rats and multiple injections of another beta cell toxin, alloxan, in mice did not induce insulitis although hyperglycemia followed the injection of larger quantities of both agents. In mice, the prior injection of 3-O-methyl-D-glucose (3-OMG) or nicotinamide attenuated the diabetic syndrome produced by streptozotocin; however, 3-OMG was more protective. Rabbit antimouse lymphocyte serum, alone, provided partial protection but, when given together with either 3-OMG or nicotinamide, effectively prevented the streptozotocin-induced diabetic syndrome. Cessation of these preventive treatments was followed by the appearance of insulitis and diabetes. These findings suggest that multiple injections of streptozotocin induce, in susceptible hosts, the triad of direct beta cell cytotoxicity, virus induction within beta cells, and cell-mediated autoimmune reaction. These factors, acting separately or in concert, appear to induce a destructive insulitis and severe diabetes. The relative importance of each component and the factors governing host susceptibility remain to be clarified.
Pancreatic beta cell toxicity by streptozotocin anomers.
D-glucose in the pyranose (ring) form exists as two anomers. The alpha-anomer is more effective than the beta-anomer in promoting insulin secretion, suppressing that of glucagon, and protecting beta-cells against alloxan toxicity. Streptozotocin (SZ), a beta cell toxin, is composed of a cytotoxic moiety, 1-methyl 1-nitrosourea, attached to carbon-2 of glucose and exists as either of two anomers in the pyranose form. In 24-hour-fasted male rats, predominantly alpha- or predominantly beta-SZ was injected intravenously and plasma glucose levels were obtained 48 hours later. The alpha-anomer produced significantly greater beta-cell necrosis at doses of 30, 35, and 40 mg./kg. body weight. At higher doses, no differences between the alpha and beta anomers were observed. 3-O-Methyl glucose (3-OMG) protected against both SZ anomers; however, the alpha-SZ remained more toxic. Larger doses of glucose protected against the lower doses of SZ and, under such conditions, the individual glucose anomers appeared equally potent. Finally, mannitol at comparable molar concentrations was ineffective in protecting against the SZ toxicity. This study suggests that streptozotocin's beta cell toxicity is mediated through recognition by the beta cell. In addition, 3-OMG and, to a lesser but significant extent, glucose were shown to protect against the streptozotocin toxicity, whereas mannitol did not.
Memorial. Edgar Stillwell Gordon.
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Editorial: "Control" and diabetes.
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Effects of beta-hydroxybutyrate, glycerol, and free fatty acid infusions on glucagon and epinephrine secretion in dogs during acute hypoglycemia.
The importance of glucagon in the regulation of carbohydrate metabolism is clearly established. However, the role played by this hormone in the regulation of the overall fuel economy is less certain, particularly with respect to such nonglucose fuels as free fatty acids, glycerol, and ketoacids. In order to elucidate glucagon's role with respect to the latter substrates, dogs were infused with solutions of these three fuels, and their A-cell responses to concomitant insulin-induced hypoglycemia were studied. In addition, epinephrine levels were also monitored. It was found that while these infusions failed to suppress glucagon release, the ketoacid infusion did significantly reduce epinephrine secretion during the insulin-induced hypoglycemic period. It was therefore concluded that glucagon secretion under these experimental conditions is not responsive to prevailing non-glucose fuel levels. Indeed, these data suggest that the sympathetic nervous system may play an important role in the regulation of the over-all fuel economy.
Starvation in man.
Starvation entails a progressive selection of fat as body fuel. Soon after a meal glucose utilisation by muscle ceases and fatty acids are used instead. Ketoacid levels in blood become elevated over the first week, and the brain preferentially uses these instead of glucose. The net effect is to spare protein even further, as glucose utilisation by brain is diminished. Nevertheless, there is still net negative nitrogen balance, but this can be nullified by amino acid or protein supplementation. Insulin appears to be the principal regulatory hormone. Recent data suggest that decreased levels of active T3 may play a role by sparing otherwise obligated calories by decreasing metabolic needs.