Menachem Nitzan

Carbohydrate Metabolism in Pregnancy: XI. Response of Plasma Glucagon to Overnight Fast and Oral Glucose during Normal Pregnancy and in Gestational Diabetes

Plasma glucagon was examined after overnight fast and in response to 100 gm. oral glucose in sixteen subjects with normal carbohydrate metabolism and in ten gestational diabetics during week 30 to 40 of pregnancy and again five to eight weeks postpartum. In comparison to nulliparous, nongravid subjects, plasma glucagon after overnight fast was not significantly changed antepartum. However, on a pair-matched basis, small but significant and as yet unexplained reductions in plasma glucagon were evident during the postpartum period. Thus, hyperglucagonemia cannot be implicated in the accelerated starvation that is already manifest after overnight fast in late pregnancy, and altered basal glucagon does not constitute one of the diabetogenic factors of gestation. Following glucose administration, plasma glucagon in normal subjects subjects fell to a greater degree antepartum than postpartum. The paired observations suggest that this heightened suppressibility of circulating glucagon may be linked to the more prolonged hyperglycemia and hyperinsulinemia that occur during normal oral glucose tolerance in late pregnancy. In the gestational diabetics, oral glucose also elicited suppression of plasma glucagon antepartum, whereas suppressibility was not seen postpartum. Therefore, overt diabetogenesis in vulnerable subjects during pregnancy cannot be ascribed to lack of alpha cell suppressibility by glucose. Conversely, the exaggerated hyperinsulinemia and hyperglycemia in response to oral glucose during late pregnancy in gestational diabetics may obscure an intrinsically diminished sensitivity of their alpha cells to glucose.

Placental Transfer of Analogs of Glucose and Amino Acids in Experimental Intrauterine Growth Retardation

Summary: We have employed the model in which one uterine artery is ligated to study maternofetal transport and tissue uptake of glucose and amino acids in the intrauterine growth-retarded rat. On the 18th day of gestation, the artery supplying one uterine horn was ligated. Two days later the rats received [3H]2-deoxyglucose and |14C;[alpha;-aminoisobutyric acid iv. One hour later the growth-retarded and control fetuses were delivered by Cesarean section and appropriate blood samples were obtained. The growth-retarded fetuses had an average weight reduction of 27%, significantly increased placental to fetal weight ratio and brain to body ratio, and a significantly reduced liver to body ratio. Total radioactivity derived from tritiated deoxyglucose in whole fetal tissues, placenta, liver, and brain were significantly decreased in the intrauterine growth-retarded (IUGR) fetuses; this was also true per gram of tissue except for liver. Liver to plasma, brain to plasma, and whole fetal tissue to plasma 3H ratios were significantly increased in the IUGR group. The radioactivity derived from [14C;[alpha;-aminoisobutyric acid was significantly reduced in whole fetal tissues, placenta, liver, and brain in the IUGR fetuses whether expressed per whole organ or per gram of tissue. Significant differences in liver to plasma, brain to plasma, and whole tissue to plasma 14C ratios were not observed.Speculation: The large reduction in maternofetal transfer of deoxyglucose and α-aminoisobutryric acid when uterine blood flow is reduced raises the possibility that one of the major causes of retarded growth in utero is a diminished supply of glucose and amino acids to the fetus. The fetal liver appears to be especially effective in increasing its extraction of 2-deoxyglucose from fetal plasma during this period of nutrient restriction. Since a major cause of fetal growth retardation in man is an impairment in maternal circulatory supply to the placenta, a similar mechanism of growth retardation may contribute to human IUGR. The possibility that nutritional supplementation may be of value in improving the growth conditions for the fetus when uterine blood flow is restricted would seem worthy of further investigation. More information is also required about the mechanisms responsible for the apparent improved extraction of glucose from plasma in IUGR.

Glucose Intolerance in Hypernatremic Rats

A study has been made of the effect of hypernatremia on carbohydrate metabolism in the rat. It was shown that rats rendered hypernatremic by subcutaneous injections of hypertonie sodium solutions manifest increased fasting blood glucose levels, as well as a decreased ability to dispose of an exogenous glucose load. The mechanism by which hypernatremia alters carbohydrate metabolism has not been determined. However, an impairment of normal cellular functions known to accompany hypertonicity of body fluids as well as disturbed secretion of the hormones which regulate carbohydrate metabolism, could explain the metabolic abnormality.

Effect of Postnatal Malnutrition on Plasma Proteins and Growth Hormone in the Rat1

Dietary restriction of rats during the suckling period is known to result in irreversible growth stunting, which cannot be corrected even by ample supply of food after weaning. In order to determine w

Homocysteic acid: An examination of its possible growth hormone-like activity☆

Hypophysectomized rats were injected intraperitoneally for 4 days with various doses of homocysteic acid or growth hormone. The effects of these compounds on epiphyseal cartilage thickness and circulating somatomedin activity levels were evaluated in an attempt to repeat the results of Clopath, Smith, and McCully, who reported that this compound had growth hormone-like activity. DNA polymerase activity in livers of animals treated with growth hormone or with 10 mg/day of homocysteic acid was also measured. Using larger number of animals and including higher doses of homocysteic acid than those previously employed, we did not observe an increase of epiphyseal cartilage thickness in homocysteic acid treated hypophysectomized rats. Growth hormone significantly increased cartilage thickness. DNA polymerase levels in homocysteic acid treated hypophysectomized rats were not substantially increased although a larger, dose-dependent increase was observed with pGH and hGH. Neither homocysteic acid nor GH increased circulating somatomedin activity under the conditions used in this investigation. These observations demonstrate that homocysteic acid was not a substance with growth hormone-like activity in our hands and cast doubt on its possible future usefullness as a substitute for GH in clinical situations.

The effects of acute uremia on plasma glucose, insulin and growth hormone in the rat☆

Abstract The effects of acute uremic syndrome upon plasma glucose, insulin and growth hormone were evaluated in the fasted rat 24 hours following bilateral nephrectomy. Appropriate control studies were instituted to correct for the non-specific effects of surgical intervention. The mean levels of plasma glucose, IRI and GH, as well as insulin to glucose ratio were significantly higher in the uremic animals than in the sham-operated controls. The fasting hyperglycemia in the presence of high levels of circulating IRI observed in the nephrectomized rats suggest impaired responsiveness of the peripheral tissues to the action of insulin. Since similar findings have been reported in chronic renal failure in the human, it is suggested that the acutely uremic rat might be employed as an experimental model for further elucidating the underlying mechanisms of glucose intolerance in uremia.

289 COMPARISON OF HOMOCYSTEIC ACID (HCA) AND GROWTH HORMONE (GH) IN THE HYPOPHYSECTOMIZED RAT

HCA reportedly acts like GH in increasing the thickness of tibial epiphyseal cartilage and increasing serum somatomedin activity in hypophysectomized rats (Science 192, 372, 1976). We hypophysectomized Sprague-Dawley rats at 26 days of age and beginning 12 days later they received HCA, GH or 0.9% NaCl I.P. daily for 4 days. Average rat weight was 62.6 gms. HCA did not increase cartilage thickness, while GH was effective (p<.001)Liver DNA polymerase activity was also measured (Endocrinol. 92, 194, 1973) on 8-14 animals in each of several groups. Human GH increased polymerase activity 30%, (p<.01), but 10,000 ug HCA was ineffective. On this regimen, neither HCA nor GH significantly increased serum somatomedin levels in selected animals (Endocrinol. 99, 304, 1976); this result is not surprising since the method is less sensitive than the tibial thickness bioassay. HCA was not an active GH substitute in our laboratory. Our results contrast sharply with those reported previously by others on a smaller series of animals, and suggest that HCA will not, prove valuable in treating human GH deficiency states.

MATERNO-FETAL TRANSFER AND UPTAKE OF 2-DEOXY-GLUCOSE (DG) AND α-AMINOISOBUTYRIC ACID (AIB) IN INTRAUTERINE GROWTH RETARDATION (IUGR) ASSOCIATED WITH RESTRICTED UTERINE BLOOD SUPPLY

The mechanism by which restriction of uterine blood flow causes IUGR is not clearly established. We induced IUGR in rat fetuses by ligation at 18 days gestation of the artery supplying one uterine horn. Two days later, the pregnant rats received intravenously 25 μC H3-DG (10 C/mM) and 1 μC C14-AIB (9 mC/mM) per 100 gm. After 60 minutes IUGR and control (unligated horn) fetuses and placentas were delivered by C-section, and radioactivity determined (dual channel) in homogenates of placenta, fetus, liver, and brain, and in fetal and maternal plasma. Plasma concentrations and fetal/maternal ratios of both AIB and DG averaged 35% less in IUGR. Uptake of AIB per gram tissue by placenta, whole fetus, brain, and liver was 34, 44, 37 and 22% smaller respectively in IUGR. Uptake of DG per gram tissue by placenta, whole fetus, and brain was reduced 14, 15, and 16% respectively in IUGR. (All differences, p<.05). In contrast, liver uptake of DG averaged 17% greater in IUGR (p=0.2). The ratio of DG in fetal liver/fetal plasma, and in fetal brain/fetal plasma, was greater in IUGR than control (both p<.05). We conclude that in this IUGR model: there is reduction in transfer of DG and AIB into most fetal tissues; reduced growth in utero can reasonably be explained by diminished supply of amino acids and glucose; the IUGR fetal liver adapts glucose uptake more effectively than does fetal brain to reduced glucose supply.