of Endocrinology and Metabolism, Karolinska Hospital, and Department of Clinical Physiology, Huddinge Hospital, Stockholm
Department
INFLUENCE OF GROWTH HORMONE ON SPLANCHNIC GLUCOSE PRODUCTION IN MAN
By
Ulf Adamson, John Wahren
and Erol Cerasi
ABSTRACT The influence of growth hormone (GH) on splanchnic exchange of glucose and glucogenic precursors was investigated in 11 healthy subjects using the hepatic venous catheter technique. GH was infused intravenously at the rate of 40 \g=m\g/kgbody weight over 30 min. A peak plasma GH level of 219 \m=+-\25 ng/ml was obtained. During GH infusion the blood glucose concentration fell slightly but significantly. In addition, the splanchnic glucose output decreased by approximately 35\p=n-\40 % during and immediately after GH infusion. The splanchnic uptake of the glucogenic precursors lactate, pyruvate, alanine and glycerol was not significantly influenced by GH infusion. The arterial concentration of insulin fell slightly, while the glucagon level remained unchanged during the infusion but decreased 20\p=n-\30 min after the end of GH infusion. Indirect estimates of the peripheral glucose utilization indicated that GH infusion was accompanied by a 25 % reduction in peripheral glucose uptake. The influence of GH on the inhibition of splanchnic glucose output induced by endogenous insulin in connection with intravenous glucose infusion (2 mg/kg/min) was studied in 6 subjects. GH infusion, given 60 min before the onset of glucose administration, did not significantly modify the splanchnic glucose output response to glucose infusion. It is concluded that a) GH may exert a direct inhibitory influence on splanchnic glucose output which is independent of changes in insulin and glucagon, b) hepatic glycogenolysis, but probably not gluconeogenesis is influenced by GH, and c) GH infusion is accompanied by decreased peripheral utilization of glucose.
(GH) exerts complex effects on carbohydrate metabolism. Its diabetogenic action has been documented in detail by several investigators, and constitutes the classical action of GH on glucose homoeostasis (for reviews, see Kipnis 1965; Adamson 1975). However, it has been known since many decades that GH may also induced hypoglycaemia and thus mimic the action of insulin (Marx et al. 1944; Kurtz et al. 1951; Westermeyer 8c Raben 1954; Zahnd et al. 1960; Pearsson et al. 1960; Frohman et al. 1967; Cheng 8c Kulant 1970; Fineberg 8c Merimee 1974). We have recently shown that even moderate to small doses of GH, infused over 30 min, may acutely lower the blood glucose level in normal man (Adamson 8c Cerasi 1975a). Neither the metabolic significance, nor the underlying mechanism of this insulin-like action of GH are well understood (for review see Merimee 8c Rabin 1973). Since the liver is the major site of regulation of the glucose homoeostasis, the present series of experiments have been performed in order to evaluate the influence of GH on glucose output and precursor uptake of the splanchnic area in man. Growth hormone
MATERIAL AND METHODS Eleven healthy men, mostly blood donors, with a mean age of 34 years (range 26-45) were studied. All had normal iv glucose tolerance, with a K value of 2.66 ± 0.31 % min-1 (range 1.19-4.08) (Ikkos 8c Luft 1957), and normal insulin response to glucose infusion (high insulin responders) (Cerasi Se Luft 1967). The mean body weight of the subjects was 90.2 ± 2.0 °/o (range 80-101 °/o) of the ideal weight, taking into account sex, age and height (Documenta Geigy 1960). Hepatic vein catheterizations were performed in the morning after an overnight fast. Teflon catheters were inserted into a brachial artery and an antecubital vein. A Ccurnand catheter was inserted percutaneously into an antecubital vein, and advanced under fluoroscopic control to a right-sided hepatic vein. The tip of the catheter was positioned 3-4 cm from the wedge position, and its location checked repeatedly by fluoroscopy during the study. When the catheters were in place, simultaneous arterial and hepatic venous blood samples were collected at 7.5-15 min intervals before, during and up to 30 min (60 min in 6 subjects) after the infusion of GH (Crescormon®, Kabi Stockholm), which was given as a 30 min constant rate infusion (40 jig/kg). In 6 of the subjects, the GH infusion was followed after 60 min by a glucose infusion (2 mg/kg/min for 45 min). These subjects were studied a second time without GH infusion, thus serving as their own controls. The hepatic blood flow was measured by the continuous infusion technique (Bradley 1948) using indocyanine green dye (Rowell et al. 1966). The splanchnic output of glucose was calculated as the product of the difference between the arterial and hepatic venous concentrations and the estimated hepatic blood flow. Blood glucose was measured in whole blood by the glucose oxidase procedure (Huggett Se Nixon 1957). Lactate (Wahren 1966), pyruvate (Segal et al. 1956), glycerol (Wieland 1962), and alanine (Karl et al. 1972) by enzymatic techniques. A commercially available kit (the Radiochemical Centre, Amersham, England) was used for insulin assay. Plasma GH was measured by a double antibody radioimmunoassay technique
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Department
INFLUENCE OF GROWTH HORMONE ON SPLANCHNIC GLUCOSE PRODUCTION IN MAN
By
Ulf Adamson, John Wahren
and Erol Cerasi
ABSTRACT The influence of growth hormone (GH) on splanchnic exchange of glucose and glucogenic precursors was investigated in 11 healthy subjects using the hepatic venous catheter technique. GH was infused intravenously at the rate of 40 \g=m\g/kgbody weight over 30 min. A peak plasma GH level of 219 \m=+-\25 ng/ml was obtained. During GH infusion the blood glucose concentration fell slightly but significantly. In addition, the splanchnic glucose output decreased by approximately 35\p=n-\40 % during and immediately after GH infusion. The splanchnic uptake of the glucogenic precursors lactate, pyruvate, alanine and glycerol was not significantly influenced by GH infusion. The arterial concentration of insulin fell slightly, while the glucagon level remained unchanged during the infusion but decreased 20\p=n-\30 min after the end of GH infusion. Indirect estimates of the peripheral glucose utilization indicated that GH infusion was accompanied by a 25 % reduction in peripheral glucose uptake. The influence of GH on the inhibition of splanchnic glucose output induced by endogenous insulin in connection with intravenous glucose infusion (2 mg/kg/min) was studied in 6 subjects. GH infusion, given 60 min before the onset of glucose administration, did not significantly modify the splanchnic glucose output response to glucose infusion. It is concluded that a) GH may exert a direct inhibitory influence on splanchnic glucose output which is independent of changes in insulin and glucagon, b) hepatic glycogenolysis, but probably not gluconeogenesis is influenced by GH, and c) GH infusion is accompanied by decreased peripheral utilization of glucose.
(GH) exerts complex effects on carbohydrate metabolism. Its diabetogenic action has been documented in detail by several investigators, and constitutes the classical action of GH on glucose homoeostasis (for reviews, see Kipnis 1965; Adamson 1975). However, it has been known since many decades that GH may also induced hypoglycaemia and thus mimic the action of insulin (Marx et al. 1944; Kurtz et al. 1951; Westermeyer 8c Raben 1954; Zahnd et al. 1960; Pearsson et al. 1960; Frohman et al. 1967; Cheng 8c Kulant 1970; Fineberg 8c Merimee 1974). We have recently shown that even moderate to small doses of GH, infused over 30 min, may acutely lower the blood glucose level in normal man (Adamson 8c Cerasi 1975a). Neither the metabolic significance, nor the underlying mechanism of this insulin-like action of GH are well understood (for review see Merimee 8c Rabin 1973). Since the liver is the major site of regulation of the glucose homoeostasis, the present series of experiments have been performed in order to evaluate the influence of GH on glucose output and precursor uptake of the splanchnic area in man. Growth hormone
MATERIAL AND METHODS Eleven healthy men, mostly blood donors, with a mean age of 34 years (range 26-45) were studied. All had normal iv glucose tolerance, with a K value of 2.66 ± 0.31 % min-1 (range 1.19-4.08) (Ikkos 8c Luft 1957), and normal insulin response to glucose infusion (high insulin responders) (Cerasi Se Luft 1967). The mean body weight of the subjects was 90.2 ± 2.0 °/o (range 80-101 °/o) of the ideal weight, taking into account sex, age and height (Documenta Geigy 1960). Hepatic vein catheterizations were performed in the morning after an overnight fast. Teflon catheters were inserted into a brachial artery and an antecubital vein. A Ccurnand catheter was inserted percutaneously into an antecubital vein, and advanced under fluoroscopic control to a right-sided hepatic vein. The tip of the catheter was positioned 3-4 cm from the wedge position, and its location checked repeatedly by fluoroscopy during the study. When the catheters were in place, simultaneous arterial and hepatic venous blood samples were collected at 7.5-15 min intervals before, during and up to 30 min (60 min in 6 subjects) after the infusion of GH (Crescormon®, Kabi Stockholm), which was given as a 30 min constant rate infusion (40 jig/kg). In 6 of the subjects, the GH infusion was followed after 60 min by a glucose infusion (2 mg/kg/min for 45 min). These subjects were studied a second time without GH infusion, thus serving as their own controls. The hepatic blood flow was measured by the continuous infusion technique (Bradley 1948) using indocyanine green dye (Rowell et al. 1966). The splanchnic output of glucose was calculated as the product of the difference between the arterial and hepatic venous concentrations and the estimated hepatic blood flow. Blood glucose was measured in whole blood by the glucose oxidase procedure (Huggett Se Nixon 1957). Lactate (Wahren 1966), pyruvate (Segal et al. 1956), glycerol (Wieland 1962), and alanine (Karl et al. 1972) by enzymatic techniques. A commercially available kit (the Radiochemical Centre, Amersham, England) was used for insulin assay. Plasma GH was measured by a double antibody radioimmunoassay technique
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