Degree Of Hypoglycemia Research Articles

Model of extreme hypoglycemia in dogs made ketotic with (R,S)-1,3-butanediol acetoacetate esters.

The rationale behind this study is that controlled starvation of poorly differentiated (anaplastic) fast-growing tumor cells, but not host cells, might be possible in vivo. The energy metabolism of anaplastic tumor cells, but not host cells, is largely dependent on carbohydrate metabolism at all times. Therefore depleting plasma of carbohydrate fuels could place these tumor cells at a significant metabolic disadvantage. Hence an animal model was developed in which all cells would be required to oxidize fatty acids, ketoacids, and/or 1,3-butanediol to satisfy their energy needs. To achieve this aim, one would need ketosis, severe hypoglycemia, and low lactatemia. Anesthetized normal dogs were infused with somatostatin and a mixture of (R,S)-1,3-butanediol monoacetoacetate and (R,S)-1,3-butanediol diacetoacetate; these latter compounds are nonionized precursors of ketoacids. They were infused at 90% of the dog's caloric requirement. After establishment of a moderate ketosis (2-3 mM) over < 100 min, a severe degree of hypoglycemia (close to 0.5 mM) without rebound and without hyperlactatemia was induced by infusing insulin and dichloroacetate. Tracer kinetic measurements showed 1) a 20% decrease in the rate of appearance of glucose, 2) 50 and 62% increases in glycerol and nonesterified fatty acid rates of appearance, reflecting stimulation of lipolysis, and 3) no change in the rate of glutamine appearance. We suggest that this model may prove useful for selectively starving those cancer cells that are unable to utilize fat-derived fuels while preserving nutrient supply to vital organs.

DISCREPANCIES BETWEEN PHYSIOLOGICAL AND PHARMACOLOGICAL TESTS OF GROWTH HORMONE (GH) SECRETION IN CHILDREN WITH BRAIN TUMOURS (BT)

We have performed a mixed longitudinal study of 59 spontaneous (24hr profiles) and stimulated (insulin-induced hypoglycaemia tests - ITT) measures of growth hormone (GH) secretion in 35 prepubertal children aged 1.5 to 11.2 years with BT distant from the hypothalamo-pituitary area before and at 6-12 monthly intervals up to 3 years after surgery ± radiotherapy ± chemotherapy. We have compared results with those obtained in 26 short normal controls (SN). The profiles were analysed by a distribution method. We observed discrepancies between peaks of spontaneous and stimulated GH in BT but not SN. The ratio was significantly greater in all BT groups compared to SN (p<0.05). Peak GH to ITT was not influenced either by the degree of hypoglycaemia (r=0.1, p = 0.65) nor by days off dexamethasone therapy in those children assessed before radiotherapy (r = 0.24, p = 0.37). In 14 BT children in whom GHRH tests at 2 doses (1 μg/kg and 0.1 μg/kg) were performed, correlation with spontaneous peaks was greater with the low dose (r=0.7, p=0.005) than the high dose (r=0.27, p=0.26). A spontaneous/stimulated ratio approaching 1.0 suggests intact hypothalamic GHRH and somatostatin (SS) tone. ITT results reflect SS tone which was abnormal in children with BT. 24hr profile results reflect GHRH secretion and low dose GHRH tests identified this.

Physiologic hyperinsulinemia enhances counterregulatory hormone responses to hypoglycemia in IDDM.

We evaluated the effect of physiologic hyperinsulinemia (plasma insulin 329 +/- 62 vs 687 +/- 62 pmol/L) on counterregulatory hormone responses in 8 IDDM subjects studied during a 2-hour hypoglycemic clamp study with an equivalent degree of hypoglycemia (plasma glucose 3.1 +/- 0.1 and 3.0 +/- 0.1 mmol/L, respectively). Plasma epinephrine levels were increased by 71% during the last 60 minutes of hypoglycemia in the high insulin study (840 +/- 180 vs 1440 +/- 310 pmol/L, respectively p = 0.006). In addition, plasma cortisol and norepinephrine were also increased in the high insulin study (by 19% and 24% respectively, p < 0.01, for both). Plasma growth hormone and glucagon concentrations were not altered by high dose insulin infusion. In spite of increased epinephrine secretion, the glucose infusion rate required to maintain glucose was 2-fold greater in the high insulin study, and there was greater suppression of lipolysis in that group. We conclude that hyperinsulinemia may enhance counterregulatory hormone secretion in IDDM.

Fetal liver-cell transplantation for surgically-induced acute hepatic failure in rats

Pediatric liver transplantation has become increasingly successful, but donor scarcity is a major limitation. We studied fetal liver-cell transplantation as an alternative to provide functional hepatic replacement and evaluated the efficacy of the intraperitoneal (i.p.) transplantation of fetal liver cells in the treatment of acute hepatic failure in rats. Outbred Wistar rat fetuses (18–20 days' gestation) were used as donors. In Wistar male rats (250–300 g), acute hepatic failure was achieved by simultaneous portacaval shunt and 70% hepatectomy. This model produced lethal hepatic failure in a highly reproducible manner. Fetal liver cells were isolated by the mechanical method. Group A consisted of 2×107 fetal liver cells suspended in 1 ml phosphate-buffered saline (PBS) while group B consisted of only 1 ml PBS. Both were injected i.p. just after surgery. Fetal liver-cell transplantation (group A) significantly improved survival. The degree of hypoglycemia was significantly less significant 1 day after surgery in group A and the levels of plasma insulin and glucagon 3 days after surgery were significantly lower in group A than in group B. The results indicate that i.p. transplantation of fetal liver cells can provide metabolic support in rats.

Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM. A vicious cycle.

Three hypoglycemia-associated clinical syndromes in people with insulin-dependent diabetes mellitus (IDDM)--defective glucose counterregulation, hypoglycemia unawareness, and elevated glycemic thresholds for symptoms and activation of counterregulatory systems during effective intensive therapy--have much in common. They segregate together, are associated with increased frequency of severe iatrogenic hypoglycemia, and share several pathophysiological features, including reduced autonomic nervous system responses to a given degree of hypoglycemia. In the setting of reduced glucagon responses, the reduced adrenomedullary epinephrine responses play a key role in the pathogenesis of iatrogenic hypoglycemia in affected patients. Thus, these syndromes are examples of hypoglycemia-associated autonomic failure in IDDM, a disorder distinct from classical diabetic autonomic neuropathy. The pathogenesis of hypoglycemia-associated autonomic failure is not known, need not be the same in all three syndromes, and could be multifactorial even in a given syndrome. The recent finding that short-term antecedent hypoglycemia results in reduced symptomatic and autonomic (including adrenomedullary) responses to subsequent hypoglycemia in nondiabetic humans leads logically to the following hypothesis concerning one potential pathogenetic mechanism: recent antecedent iatrogenic hypoglycemia is a major cause of hypoglycemia-associated autonomic failure in IDDM, and hypoglycemia-associated autonomic failure, by reducing both symptoms of and defenses against developing hypoglycemia, results in recurrent severe hypoglycemia, thus creating a vicious cycle. If this hypothesis is confirmed, it will suggest strategies to reduce the frequency of iatrogenic hypoglycemia in people with IDDM.

Hepatotoxicity Induced by Diethylnitrosamine Causes no Significant Disturbances of Systemic Glucose Homeostasis in Rats

In rats, a moderately hepatotoxic single dose of diethylnitrosamine (DEN) 100 mg/kg causing depletion of liver glycogen, elevation of aspartate aminotransferase and decreased liver uptake of 3-O-methylglucose, resulted in substantial changes in insulin and glucagon balance. Two days after DEN, insulin binding to liver membranes and insulin removal by the liver were sharply reduced whereas its binding to muscle and adipocyte membranes remained unaltered. Serum insulin (random and after an overnight fast) remained normal. Intravenous (I.V.) insulin (10 U/kg) caused the usual degree of hypoglycemia that, however, lasted longer than in the control animals. Removal of glucagon by liver was also depressed in spite of its normal binding to hepatocytes, and peripheral serum glucagon was increased three-fold. I.V. glucagon (40 micrograms/kg) resulted in a blunted response of plasma glucose. I.V. glucose tolerance test (1 g/kg) remained normal in spite of the insulin increase to a level twice as high as in the controls, and in spite of nonsuppressed glucagon. These changes were still present after 1-3 months, but disappeared by 6 months. The results demonstrate remarkable ability of homeostatic mechanisms to preserve normal plasma glucose and glucose tolerance in spite of dramatic changes in insulin and glucagon.

Regulation of counterregulatory hormone secretion in man during exercise and hypoglycemia.

We examined the role of the plasma glucose concentration per se in the secretion of counterregulatory hormones during exercise. Ten men (average age, 24 yr; maximal aerobic capacity, 31.8 mL/kg.min) were studied during two 50-min bicycle exercise periods at either normal glucose [87 +/- 1 (+/- SE) mg/dL (4.8 +/- 0.1 mmol/L)] or low glucose [59 +/- 1 mg/dL (3.3 +/- 0.1 mmol/L)]. The plasma glucose targets were achieved by exogenous insulin and variable glucose infusions. These results were compared to studies in which saline was infused. Exercise at normal glucose was associated with significant increments in plasma epinephrine (maximum 3- to 5-fold above baseline) and norepinephrine (2-fold), comparable to those that occurred during saline administration. Plasma GH increased only at the most intense exercise level, while plasma cortisol and glucagon did not increase significantly. In low glucose-exercise studies, the increase in plasma epinephrine during exercise was significantly greater than that at normal glucose (P less than 0.01), although proportional to basal preexercise levels (r = 0.73; P less than 0.001). Plasma glucagon increased almost 100%, and plasma cortisol and GH increased by 150% and 400%, respectively. Compared to the effect of the same degree of hypoglycemia in the absence of exercise, only plasma epinephrine (P = 0.002) and norepinephrine (P less than 0.001) displayed effects independent of hypoglycemia during exercise. When low glucose was reversed to normal at the midpoint of exercise, plasma epinephrine and glucagon returned to the levels obtained for the same duration of exercise at normal glucose, while norepinephrine, GH, and cortisol were only partially responsive to the rise in plasma glucose. These data suggest that 1) moderate exercise is a stimulus for a sympathoadrenal and GH response, but not a peripheral glucagon response; 2) during exercise and hypoglycemia, plasma epinephrine and norepinephrine are enhanced, while the glucagon response is entirely glucose dependent; and 3) the epinephrine response to hypoglycemia can be dissociated from that to exercise, suggesting differing control mechanisms. We conclude that the activation of counterregulatory hormones during exercise is regulated by glucose-independent mechanisms, although these responses may be augmented by concurrent hypoglycemia.

Changes in the activity of glutamate related enzymes in cerebral cortex, during insulin-induced seizures.

The activity of glutamate related enzymes and the concentration of glutamine, glutamate and gamma-amino n-butyric acid (GABA) were investigated in the cerebral cortex of rats, in different stages of insulin-induced hypoglycemia. Hypoglycemia was produced by intraperitoneal injection of insulin 0.05-100 units per kg body weight. The minimum required dose to produce irreversible severe hypoglycemia was 0.5 units/kg. In 85% of the cases an insulin induced hypoglycemic convulsion, was achieved 130-150 minutes after injection. Blood glucose levels during insulin induced seizures ranged between 8-15 mg%. In the range of 0.5-100 u insulin/kg the degree of hypoglycemia and the onset of convulsions were identical. The concentration of glutamine was significantly reduced during convulsive and postconvulsive stages. Glutamate and GABA concentrations were reduced significantly in all stages of insulin-induced hypoglycemia. The decrease in glutamine concentration was concurrent with an increase in the activity of its degradative enzyme, glutaminase. This was apparent at the preconvulsive, convulsive and postconvulsive stages. The activity of other enzymes related to energy production such as glutamate dehydrogenase (GDH), glutamate transaminase (GPT) and aspartate aminotransferase (AAT) were also increased. The activity of glutamine synthase (GS) was unaffected by hypoglycemia. Insulin induced changes in glutamine, glutamate and their related enzymes could not be attributed to convulsion since a similar pattern of changes was observed in the preconvulsive and postconvulsive stages, and no changes were detected following picrotoxin-induced seizures.

Plasma Met-enkephalin and catecholamine responses to insulin-induced hypoglycaemia in greyhounds.

The involvement of endogenous opioid peptides in the stress response was investigated by measuring plasma concentrations of Met-enkephalin-like immunoreactivity (MLI), adrenaline and noradrenaline during insulin-induced hypoglycaemia in conscious greyhounds. Moreover, the molecular forms of circulating MLI were characterized using gel filtration chromatography. In the first group of animals, i.v. administration of insulin (0.3 units/kg) provoked marked hypoglycaemia (blood glucose concentrations fell from 4.4 +/- 0.1 to 1.5 +/- 0.2 mmol/l; mean +/- S.E.M.) which was associated with significant (P less than 0.001) rises in plasma MLI concentrations from a basal concentration of 45 +/- 8 to a peak of 189 +/- 39 ng/l. A within-subject study comparing five different insulin doses ranging from 0.004 to 0.3 units/kg showed dose-related effects on blood glucose with nadir concentrations of 4.1 +/- 0.6 mmol/l (after the smallest dose of insulin) and 0.8 +/- 0.1 mmol/l (after the largest dose of insulin). This was associated with dose-related rises in plasma MLI with peak concentrations of 56 +/- 17 and 558 +/- 35 ng/l, plasma adrenaline with peak concentrations of 0.45 +/- 0.06 and 15.76 +/- 1.33 nmol/l and plasma noradrenaline with peak concentrations of 0.49 +/- 0.07 and 2.27 +/- 0.45 nmol/l following the smallest and largest doses of insulin respectively. These results are the first demonstration of raised plasma MLI concentrations following hypoglycaemia. Moreover, they show that the hormonal responses vary with the degree of hypoglycaemia achieved. Together with reports by other investigators these findings might suggest opioid modulation of the responses of the sympathoadrenal system to hypoglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous opioid modulation of pancreatic hormone secretion: Studies in dogs

The role of endogenous opioid peptides in the modulation of secretion of hormones from the endocrine pancreas was studied in dogs. In response to insulin-induced hypoglycemia, plasma glucagon secretion significantly increased, followed by an increase in plasma somatostatin immunoreactivity. Pretreatment with the opiate antagonist, naloxone, prevented the somatostatin response but had no effect on the augmented glucagon secretion. Neither the degree of hypoglycemia nor recovery from the induced glucose nadir were affected by naloxone. Arginine Hcl administration resulted in prompt increases in immunoreactive glucagon and insulin secretion, as well as a rise in serum glucose. Pretreatment with naloxone failed to affect any of these responses. Our results suggest that endogenous opioid peptides mediate the somatostatin response following hypoglycemia-induced glucagon secretion.

Normalization by sodium salicylate of the impaired counterregulatory glucagon response to hypoglycemia in insulin-dependent diabetes. A possible role for endogenous prostaglandins.

The present study was undertaken to evaluate the influence of sodium salicylate on the counterregulatory glucagon response to insulin-induced hypoglycemia in both insulin-dependent diabetic subjects (IDDM) and normal controls. The IDDM group consisted of 5 patients with recent onset of disease (less than 45 days), a normal glucagon response to hypoglycemia, and no detectable insulin antibodies (group 1); and 7 patients with duration of disease between 1 and 5 yr, a reduced glucagon response to hypoglycemia, and no insulin antibodies (group 2). Ten healthy subjects served as a control group. The infusion of sodium salicylate (40 mg/min) during insulin-induced hypoglycemia (1 mU/kg-min for 60 min) in normal subjects caused a significant increase of the counterregulatory glucagon response both in terms of glucagon peak and integrated areas. Sodium salicylate itself significantly increased basal insulin and decreased glucose, but did not change basal glucagon. In the diabetic subjects of group 1, sodium salicylate amplified the glucagon response to the same degree of hypoglycemia without affecting the rates of glucose fall and recovery. Compared with normals and diabetic subjects of group 1, diabetic subjects of group 2 presented, in basal conditions, a reduced glucagon response to hypoglycemia and a slower rate of glucose recovery. Sodium salicylate normalized both defects. These results indicate that sodium salicylate may augment glucagon responses by improving the recognition of hypoglycemia in both normals and IDDM. Moreover, the restoration by sodium salicylate of a normal glucagon response to hypoglycemia in diabetic subjects of group 2 suggests a role for endogenous prostaglandins in this selective deficiency of the counterregulatory response.

Effects of bipiperidyl mustard (BPM) lesions on insulin hypoglycemic convulsions

Systemic gold thioglucose (GTG) is well known to produce hyperphagia, resulting in obesity, and histological damage focused relatively selectively in the ventromedial hypothalamus (VMH). Although structurally very different, bipiperidyl mustard (BPM) produces apparently similar effects. However, a proposed mechanism for concentration and hence localization of GTG toxicity depends on its structural similarity to glucose, binding it to glucoreceptors and focusing the cytotoxicity of the gold thio-portion. We recently showed that GTG treatment also produces an early decrease and a later increase in sensitivity to insulin hypoglycemic convulsions. We report here that BPM also produces a similar biphasic change in sensitivity to insulin hypoglucemic convulsions. For both, the differences are in the brain's convulsive response to hypoglycemia, rather than in the degree of hypoglycemia in response to insulin. Thus, GTG and BPM cytotoxic lesions appear similar in this regard as well. BPM is another way of producing a relatively discrete brain lesion which alters the brain's functional adjustment to hypoglycemia. The significance of this control center and its relationship to the control(s) of feeding and systemic metabolism are discussed.

Evidence for cholinergic and vagal noncholinergic mechanisms modulating plasma motilin-like immunoreactivity.

Basal concentrations of plasma motilin-like immunoreactivity (MLI) and responses to insulin-induced hypoglycemia were measured in healthy subjects (n = 13) in diabetics with clinical evidence of autonomic neuropathy (AN; n = 7), in diabetics without AN (n = 9), and in five recently (6--12 months) vagotomized subjects. Mean basal MLI concentrations were similar in the healthy subjects (141 +/- 21.5 pg/ml) and diabetics without AN (124 +/- 22.4 pg/ml), but were significantly higher in diabetics with AN (349 +/- 71.5 pg/ml) and in vagotomized subjects (381 +/- 47.6 pg/ml). In both healthy subjects and diabetics without AN, the acute administration of insulin (0.1--0.2 U/kg) caused a fall in the mean MLI concentration, reaching a nadir within 20 min, returning to the basal concentration by 60 min, and rising above basal levels by 90 min. In diabetics with AN and vagotomized subjects, the fall in MLI persisted for 90 min. Intravenous atropine administered 15 min after the insulin injection in healthy subjects did not impair the return to basal. The responses were not related to the degree of hypoglycemia, the absolute or relative fall in blood glucose concentrations, or differences in blood glucose among healthy subjects, diabetics, or vagotomized subjects. It appears, therefore, that insulin lowers plasma MLI levels, which are restored to basal by a vagal noncholinergic mechanism. Furthermore, the vagus exerts a suppressive effect on basal MLI levels, and vagotomy and diabetic autovagotomy are associated with abnormal elevation of MLI levels. Since motilin is thought to be important in interdigestive intestinal motility, abnormalities in MLI secretion in diabetics with autonomic neuropathy may contribute to gastrointestinal stasis and erratic diabetic control.

Comparison of insulin hypoglycemia-induced and fluoroacetate-induced convulsions in gold thioglucose lesioned mice

In addition to its well known effects in producing hyperphagia, resulting in obesity, and histological damage focused relatively selectively in the ventromedial hypothalamic area, systemically administered gold thioglucose (GTG) also increased the sensitivity to insulin hypoglycemic convulsions. The change was in the convulsive response to equal hypoglycemia, rather than in the degree of hypoglycemia in response to insulin. The effect suggests that a relatively discrete control center is involved in adjusting brain function to metabolic alterations, in this case hypoglycemia. These results compare the effects of GTG lesions on insulin hypoglycemic- and fluoroacetate-induced convulsions. Gold thioglucose lesions did not alter the sensitivity to another metabolic convulsant, fluoroacetate, which blocks the Krebs cycle by blocking the conversion of citrate to isocitrate. Thus, although related in both cases to a shortage of available cellular fuel, the metabolic convulsions induced by insulin hypoglycemia and by fluoroacetate must be qualitatively different. Moreover, operation of the glucose sensing and regulatory mechanism lesioned by gold thioglucose, i.e. the ”gold thioglucose lesioned glucostat“, did not appear to require the Krebs cycle as blocked by fluoroacetate.

Plasma cyclic nucleotide responses to insulin-induced hypoglycaemia and methacholine in patients with hyperthyroidism.

The effect of insulin-induced hypoglycaemia and methacholine on plasma cAMP and cGMP levels was studied in normal volunteers, hyperthyroid and hypothyroid patients. A significant positive correlation existed between the maximal increase in plasma cAMP and the maximal decrease in plasma glucose in normals during insulin-induced hypoglycaemia. Therefore, the plasma cAMP response is considered to be dependent on the degree of hypoglycaemia, rather than the dose of insulin. The cAMP response to hypoglycaemia was significantly higher in hyperthyroid patient, and was lower in patients with hypothyroidism than in normals. The cAMP response of the hyperthyroid patients was normalized when their hyperthyroidism was controlled after 3 months of treatment. The plasma level of cGMP was slightly elevated during hypoglycaemia, but there was no significant difference between controls and hyperthyroid patients. The cGMP response to methacholine, which is probably mediated by cholinergic receptors, was significantly potentiated in hyperthyroid patients. The cAMP response, which is presumably dependent on endogenous catecholamines secreted during methacholine-induced hypotension, was also enhanced in hyperthyroid patients. It is likely that beta-adrenergic receptor responses and cholinergic receptor responses are both enhanced in hyperthyroidism.

Dopamine affects basal and augmented pituitary hormone secretion.

Although the role of the neurotransmitter, dopamine (DA), in the regulation of PRL has been well documented, controversy exists regarding its participation in the regulation of the other pituitary hormones. Consequently, we infused DA into six healthy male subjects (ages 19-32) and studied its effects on both basal pituitary hormone levels and augmented hormonal release induced by insulin hypoglycemia (ITT), TRH, and gonadotropin-releasing hormone (GnRH). DA alone produced a modest though significant increase in GH concentration from 2.2 +/- 0.5 to 11.9 +/- 3.7 ng/ml (P less than 0.05) by 60 min, but the peak incremental GH response to ITT was significantly inhibited by DA (43.5 +/- 5.0 vs. 16.3 +/- 3.3 ng/ml; P less than 0.01). PRL concentrations fell during the DA infusion (20.4 +/- 3.0 to 10.6 +/- 1.5 ng/ml; P less than 0.02) at 235 min, and the PRL responses to both ITT and TRH were completely abolished. Although the basal LH and FSH concentrations were unaffected by DA, the incremental LH response to GnRH was inhibited (45.5 +/- 10.6 to 24.4 +/- 5.4 mIU/ml; P less than 0.05), while the FSH response was unchanged. DA significantly reduced the basal TSH concentration from 3.9 +/- 0.2 to 2.5 +/- 0.2 micro U/ml (P less than 0.01) at 230 min and blunted the peak incremental TSH response to TRH (6.0 +/- 1.5 vs. 2.9 +/- 0.9 microU/ml; P less than 0.01). DA had no effect on basal cortisol levels, the cortisol response to ITT, basal plasma glucose, or the degree of hypoglycemia after ITT. Our data provide new evidence that DA has an inhibitory as well as a stimulatory role in the regulation of GH secretion in normal humans. It inhibits centrally as well as peripherally mediated PRL secretion and blunts the LH response to GnRH. In addition, DA lowers both basal and TRH-mediated TSH release, confirming the reports of other investigators.

Serum somatomedin and insulin levels in tumor hypoglycemia

Serum concentrations of somatomedin and immunoreactive insulin were measured during the hypoglycemic phase of 3 patients with tumor hypoglycemia. Normal amounts of somatomedin were detected in their fasting sera, but they may have been inappropriate (or associated with enhanced insulin-like activity) considering the degree of hypoglycemia. Fasting serum insulin levels were consistently depressed, and in two of the cases remained low even after an oral glucose load. Nevertheless, the blood glucose concentrations of these two patients fell to hypoglycemic levels again by 3 hours; the mechanism of this reactive hypoglycemia remains unclear.

AN INVESTIGATION INTO GONADAL DYSFUNCTION IN PATIENTS WITH IDIOPATHIC HAEMOCHROMATOSIS

Endocrine studies were performed on twelve patients with proven idiopathic haemochromatosis. Basal gonadotrophin levels and/or their responses to LH releasing hormone (LHRH) were low in nine patients, all of whom showed low plasma testosterone levels and clinical evidence of hypogonadism. Those patients with normal gonadotrophin responses had higher testosterone values, suggesting that the poor testosterone secretion was primarily due to inadequate trophic stimulation. No patient showed hypothyroidism of hypothalamic-pituitary origin, while the cortisol response to hypoglycaemia was normal in all six patients studied. GH responses were more variable and difficult to interpret, since the number of the patients studied was small and the degree of hypoglycaemia after insulin was unpredictable.

Association of hypoglycemia and pancreatic islet tissue with micromelia in Malathion-treated chick embryos

Chick embryos were given a teratogenic dose of Malathion at the 5-day incubation stage and the effects of this treatment on leg length, blood glucose, and amounts of pancreatic islet tissue were studied during the 11- to 19-day incubation period. The Malathion caused a reduction in leg length (micromelia) and hypoglycemia, which persisted throughout the period studied. The severity of the micromelic condition correlated with the degree of hypoglycemia: the least micromelic embryos were the least hypoglycemic, the moderately micromelic embryos were moderately hypoglycemic, and the severely micromelic embryos were the most severely hypoglycemic. Finally, the Malathion increased differentiation of pancreatic islet tissue, particularly beta tissue. Again, the greatest increases in islet tissue were shown by those embryos exhibiting the most severe micromelic and hypoglycemic conditions.

Perinatal development of gluconeogenesis in guinea-pig liver

1. 1. At mid-gestation the activities of guinea-pig liver pyruvate carboxylase, glucose-6-phosphatase and cytosolic phosphoenolpyruvate carboxykinase were less than 0.4 unit/g, whereas the activity of fructose-1,6-diphosphatase was 1.6 unit/g. Throughout gestation the activity of cytosolic phosphoenolpyruvate carboxykinase remained unchanged while all other enzymes exhibited a 2- to 3-fold increase over the levels at mid-gestation, beginning at 45–50 days. The activities of pyruvate carboxylase and phosphoenolpyruvate carboxykinase in the foetus were largely mitochondrial. 2. 2. No increases in enzyme activities were evident in the first 2–3 hr following birth. Subsequently, increases were noted for all enzymes examined, with an overshoot occurring between 7 and 14 days post partum for pyruvate carboxylase, glucose-6-phosphatase, and fructose-1,6-diphosphatase. 3. 3. The increases in enzyme activities following birth could be prevented by treating the newborns with actinomycin D. 4. 4. In the immediate postnatal period, the degree of hypoglycaemia was not pronounced, the initial 40% drop in blood glucose level 1 hr after birth being reduced to less than 20% at 2hr. 5. 5. Livers taken from near-term foetuses and perfused immediately after Caesarean delivery synthesized appreciable amounts of glucose from lactate and glycerol. 6. 6. The data show that the capacity for hepatic gluconeogenesis in guinea-pigs is acquired before birth.