Dynamics of carbohydrate metabolism in the heart muscle in early ontogenesis]

The dynamics of glycolysis and glycogenolysis in the postnatal period, determined from the accumulation of lactate in the homogenate of the heart muscle, indicates that the glycolytic activity begins to subside right after the birth and becomes constant after a lapse of 15-20 days. The activity of the phosphorylase, phosphohexoisomerase, enolase and pyruvate-kinase in the heart muscle extract was found to remain virtually unchanged. Some decline is noted in the activity of the aldolase and hexokinase, while that of the phosphofructokinase and lactate-dehydrogenase rises by 50-60 per cent. These data suggest that in the early ontogenesis the increasing capacity of the mitochondrial system in the heart muscle is paralled by an adjustable conditioned inhibition of the glycolytic phosphorylation, with concurrently rising activity of the phosphofructokinas and, consequently, also of the potential capacity of glycolysis and glycogenolysis.     

Effect of extracellular pH on insulin secretion and glucose metabolism in neonatal and adult rat pancreatic islets

Changes in extracellular pH are known to affect glucose-stimulated insulin secretion. In the present study, glucose metabolism in pancreatic islets cultured at different pHs was investigated. Also, for islet transplantation purposes, insulin secretion and glucose metabolism were compared in neonatal and adult islets at different pHs to determine which islet preparation is more tolerant to acidity and alkalinity. The results revealed a dependency of insulin secretion on the external pH in both neonatal and adult islets. Reduction of insulin secretion was observed at both the acidic and alkaline sides of pH 7.3. Glucose stimulated increases of insulin secretion in all cases. Similar results were obtained for ATP and pyruvate contents. Intracellular insulin increased with the increase of pH value. In contrast, calcium content decreased with the increase of pH. The results demonstrate that neonatal islets are more acid tolerant than adult islets. Both basal and glucose-stimulated insulin secretions, as well as other parameters of neonatal islets were significantly higher than those of adult islets in response to low pH. The differences under alkaline conditions were not significant but give an indication that neonatal islets are more tolerant to alkalinity than are adult islets. Received: 10 February 2001 / Accepted in revised form: 29 June 2001     

Study on the effect of insulin on carbohydrate and lipid metabolism in obese subjects with normal glucose tolerance]

In altogether 32 test persons with normal weight and obese test persons glucose-insulin-tolerance-tests were carried out. In obese persons with normal carbohydrate tolerance -- characterized by 50 g oral glucose tolerance test -- by the decreased glucose assimilation coefficients and the significantly increased level of glycaemia after intravenous application of glucose a disturbance of the glucose-insulin-homoeostasis is already implied. Basal and glucose-stimulated concentrations of IRI in the peripheral venous blood were significantly increased in obese persons. The parameters of lipolysis glycerol and free fatty acids show after a glucose-stimulated insulin excretion and after exogenic insulin application a somewhat retarded decrease in obese persons compared with the control group. In connection with the significantly increased insulin levels in obese persons these findings might refer to a decreased antilipolytic effect of insulin. The two fundamental physiological effects of insulin in the carbohydrate and fat metabolism -- glucose utilization and inhibition of lipolysis -- seem to be distrubed in the same way in obesity.     

Changes in the receptor binding of dexamethasone and insulin by blood cells in rats after hydrocortisone administration in early postnatal ontogenesis

A study was made of the effect of hydrocortisone, administered in early postnatal ontogenesis, on insulin and glucocorticoid reception in erythrocytes and mononuclear leukocytes. Hydrocortisone was administered to rat weanlings intraperitoneally at different ages of their life (5 days, 13, 15, 17 days, 1, 2 and 3 months). It has been assumed that extensive corticosteroid therapy resulting in prolonged imbalance of the level of the adrenocortical hormones and blood insulin, changes the receptor binding of these hormones on target cells as a result of a decrease in the hormone regulated receptor pool.     

The effect of prednisolone administration in early postnatal ontogeny on the circadian activity of the hypothalamo-hypophyseal-adrenal cortical system in adult rats

The disturbance of glucocorticoid balance in early postnatal ontogenesis (17-19 days) as a result of prednisolone administration was shown to lead to change in diurnal periodicity of the hypothalamo-hypophysial-adrenocortical system (HHAS) in adult rats. Diurnal rhythms of zona fasciculata-reticulata relative areas, the quantity of Gomori-positive neurosecretory material in the external zone of median eminence and in the posterior pituitary of these animals was undetectable. The amplitudes of plasma corticosterone rhythm and variations of cell nuclei volume in the zona fasciculata externa was decreased more than two-fold. Diurnal periodicity of nucleoli volume of Gomori-positive neurons in a hypothalamic paraventricular nucleus (PVN) as ventromedial as dorsolateral parts was attenuated and their maximum shifted to morning hours as compared to the night peak in control animals.     

Modeling the effects of subcutaneous insulin administration and carbohydrate consumption on blood glucose

Background

Estimation of the magnitude and duration of effects of carbohydrate (CHO) and subcutaneously administered insulin on blood glucose (BG) is required for improved BG regulation in people with type 1 diabetes mellitus (T1DM). The goal of this study was to quantify these effects in people with T1DM using a novel protocol.

Methods

The protocol duration was 8 hours: a 1–3 U subcutaneous (SC) insulin bolus was administered and a 25-g CHO meal was consumed, with these inputs separated by 3–5 hours. The DexCom SEVEN® PLUS continuous glucose monitor was used to obtain SC glucose measurements every 5 minutes and YSI 2300 Stat Plus was used to obtain intravenous glucose measurements every 15 minutes.

Results

The protocol was tested on 11 subjects at Sansum Diabetes Research Institute. The intersubject parameter coefficient of variation for the best identification method was 170%. The mean percentages of output variation explained by the bolus insulin and meal models were 68 and 69%, respectively, with root mean square error of 14 and 10 mg/dl, respectively. Relationships between the model parameters and clinical parameters were observed.

Conclusion

Separation of insulin boluses and meals in time allowed unique identification of model parameters. The wide intersubject variation in parameters supports the notion that glucose-insulin models and thus insulin delivery algorithms for people with T1DM should be personalized. This experimental protocol could be used to refine estimates of the correction factor and the insulin-to-carbohydrate ratio used by people with T1DM.     

Effect of glibenclamide therapy on carbohydrate and lipid metabolism and insulin secretion in patients with glucose tolerance disorders : a 5-year study

In normal weight persons with impaired glucose tolerance (IGT; normal fasting glycaemia and pathological glucose tolerance) and still normal or already decreased insulin secretion the influence of glibenclamide (maninil) on the carbohydrate and lipid metabolism as well as the insulin secretion was studied after one year (n = 18), after 2 years (n =13), after 3 years (n = 10) and after 5 years (n = 6). Glucose tolerance and insulin secretion were characterized by means of a 2 hours' glucose infusion test (0.33 g/kg as bolus and 12 mg/kg/min over 120 min). In no case the diabetes became manifest during the 5-year duration of the observation. An improvement of the glucose tolerance could be observed up to 3 years, whereas after a 5-year glibenclamide therapy no certain influence on the glucose tolerance and insulin secretion could be proved. In general the improvement of the glucose tolerance was not associated with an increased secretion of insulin, so that an extrapancreatic effect of glibenclamide (improvement of the peripheral insulin sensitivity?) seems to be possible. A complete normalization of the glucose tolerance could be observed only in some individual cases. The body-weight remained constant in all groups, whereas the concentration of triglyceride and cholesterol decreased in their tendency. From clinical and practical point of view the findings would support the opinion that normal weight persons with IGT, particularly in already decreased insulin secretion, have an indication for a glibenclamide therapy.     

Acute effects of ghrelin administration on glucose and lipid metabolism

CONTEXT: Ghrelin infusion increases plasma glucose and nonesterified fatty acids, but it is uncertain whether this is secondary to the concomitant release of GH. OBJECTIVE: Our objective was to study direct effects of ghrelin on substrate metabolism. DESIGN: This was a randomized, single-blind, placebo-controlled two-period crossover study. SETTING: The study was performed in a university clinical research laboratory. PARTICIPANTS: Eight healthy men aged 27.2 +/- 0.9 yr with a body mass index of 23.4 +/- 0.5 kg/m(2) were included in the study. INTERVENTION: Subjects received infusion of ghrelin (5 pmol x kg(-1) x min(-1)) or placebo for 5 h together with a pancreatic clamp (somatostatin 330 microg x h(-1), insulin 0.1 mU x kg(-1) x min(-1), GH 2 ng x kg(-1) x min(-1), and glucagon 0.5 ng.kg(-1) x min(-1)). A hyperinsulinemic (0.6 mU x kg(-1) x min(-1)) euglycemic clamp was performed during the final 2 h of each infusion. RESULTS: Basal and insulin-stimulated glucose disposal decreased with ghrelin [basal: 1.9 +/- 0.1 (ghrelin) vs. 2.3 +/- 0.1 mg x kg(-1) x min(-1), P = 0.03; clamp: 3.9 +/- 0.6 (ghrelin) vs. 6.1 +/- 0.5 mg x kg(-1) x min(-1), P = 0.02], whereas endogenous glucose production was similar. Glucose infusion rate during the clamp was reduced by ghrelin [4.0 +/- 0.7 (ghrelin) vs. 6.9 +/- 0.9 mg.kg(-1) x min(-1); P = 0.007], whereas nonesterified fatty acid flux increased [131 +/- 26 (ghrelin) vs. 69 +/- 5 micromol/min; P = 0.048] in the basal period. Regional lipolysis (skeletal muscle, sc fat) increased insignificantly with ghrelin infusion. Energy expenditure during the clamp decreased after ghrelin infusion [1539 +/- 28 (ghrelin) vs. 1608 +/- 32 kcal/24 h; P = 0.048], but the respiratory quotient did not differ. Minor but significant elevations in serum levels of GH and cortisol were observed after ghrelin infusion. CONCLUSIONS: Administration of exogenous ghrelin causes insulin resistance in muscle and stimulates lipolysis; these effects are likely to be direct, although a small contribution of GH and cortisol cannot be excluded.     

Diuretics and carbohydrate metabolism: The effects of furosemide and amiloride on blood glucose,plasma insulin and cations in the rat

Summary The effects of two unrelated diuretics, furosemide and amiloride on blood glucose, plasma insulin and glucose tolerance in the conscious rat are reported. Furosemide (1 mg/kg or 2 mg/kg) given intravenously caused an immediate but highly transient 23% and 53% fall in plasma insulin followed by a rise in blood glucose. The hyperglycaemic effect alone occurred in mild streptozotocin diabetic animals. Furosemide given with or 30 min before intravenous glucose (0.5 G/kg) caused glucose intolerance with diminished insulin response. None of these effects were observed in adrenalectomised animals. Amiloride (1, 5 or 10 mg/kg) given I.V. alone immediately increased plasma insulin (up to 213 U/ml) without affecting blood glucose. This effect was attenuated by mild streptozotocin diabetes. Amiloride given with or 30 min before glucose increased the insulin area without affecting glucose disappearance. Chronic administration enhanced glucose disappearance with increased plasma insulin response, and caused hyperkalaemia. Chronic furosemide administration had no effects. Possible mechanisms for these effects are discussed.Presented in part at the 7th Annual meeting of the European Association for the study of diabetes, Southampton, 1971.Wellcome Junior Research Fellow.     

The role of “diabetogenic” hormones on carbohydrate and lipid metabolism following oral glucose loading in insulin dependent diabetics: Effects of acute hormone administration

Summary To evaluate the relative role of diabetogenic hormones as insulin antagonists in severe derangements of diabetic control, glucagon, cortisol, growth hormone and adrenaline were administered by continuous intravenous infusion, separately and in combination, to ketosis-prone insulin-dependent diabetics (n=11). The amount of insulin required for the assimilation of a 50 g glucose load during the various hormone infusions was determined by means of an automated glucose-controlled insulin infusion system and used as an index of insulin effectiveness. Raising plasma hormone concentrations acutely into the range seen in severe diabetic states (glucagon 517±70 pg/ml; cortisol 32±3 g/dl; growth hormone 14±3 ng/ml) did not alter significantly blood glucose profile and insulin requirement (control 11.3±1.1 U; glucagon 11.6±2.0 U; cortisol 11.1±0.4 U; growth hormone 12.9±1.4U), except for adrenaline (plasma level 550±192 pg/ml), which caused a marked rise in blood glucose levels and a threefold increase in insulin demand (31.1±3.7 U). Combined infusion of all hormones did not potentiate significantly the latter effect (38.3±4.7 U). The effectiveness of metabolic control by insulin was assessed by a marked decrease in plasma non-esterified free fatty acids and ketone bodies upon its administration after glucose ingestion in all groups studied. It is concluded that from the hormones investigated within this study adrenaline exerts the strongest diabetogenic action during its short term administration followed by that of growth hormone. Whereas it may well be that over-insulinization of the patients by the glucose controlled insulin infusion system has overcome and disguised the smaller diabetogenic effects of cortisol and glucagon.     

Effect of masoprocol on carbohydrate and lipid metabolism in a rat model of Type II diabetes

Summary Extracts of the creosote bush (Larrea tridentata, family Zygophyllaceae) have long been used as a folk remedy for Type II (non-insulin-dependent) diabetes by native Americans in southwestern North America. In this study we have evaluated the metabolic effects of masoprocol, a pure compound isolated from the creosote bush, in a rat model of Type II diabetes. Animals were fed a 20 % fat (by weight) diet for 2 weeks prior to intravenous injection with streptozotocin (STZ, 0.19 mmol/kg). Diabetic animals (glucose 16–33 mmol/l) were treated with vehicle, metformin (0.83 mmol/kg body weight) or masoprocol (0.83 mmol/kg body weight) twice a day for 4 days. Masoprocol treatment lowered glucose concentrations an average of 35 % compared with vehicle (14.2 ± 1.1 vs 21.7 ± 1.0 mmol/l, p < 0.001), a reduction similar to metformin treatment (12.8 ± 0.9 mmol/l), without any change in insulin concentration. Masoprocol treatment also lowered triglyceride concentrations 80 % compared with vehicle (1.0 ± 0.1 vs 4.8 ± 0.3 mmol/l, p < 0.001), a reduction far greater than following metformin treatment (3.6 ± 0.3 mmol/l). Non-esterified fatty acid and glycerol concentration were decreased by approximately 65 % by masoprocol compared with vehicle, a reduction approximately twice as great as seen with metformin (p < 0.001). The effect of masoprocol on in vivo insulin-mediated glucose disposal was evaluated by infusing fat-fed/STZ rats with glucose (0.22 mmol · kg · min^–1) and insulin (30 pmol · kg · min^–1) for 5 h. In response to the infusion, steady-state plasma glucose concentrations were reduced 30 % in masoprocol-treated animals compared with vehicle controls (p < 0.05) with no change noted in rats treated with metformin. The effect of masoprocol treatment was also tested in primary adipocytes isolated from normal animals. Adipocytes treated with masoprocol (30 μmol/l) had higher basal and insulin-stimulated glucose clearance than did adipocytes treated with vehicle (p < 0.05). These data show that masoprocol decreases both plasma glucose and triglyceride concentrations in fat-fed/STZ rats, presumably as a result of its ability to both increase glucose disposal and decrease lipolysis. [Diabetologia (1999) 42: 102–106] Received: 3 April 1998 and in final revised form: 21 August 1998     

Effect of chromium on carbohydrate and lipid metabolism in a rat model of type 2 diabetes mellitus: the fat-fed, streptozotocin-treated rat

Chromium supplements are widely used as an alternative remedy for type 2 diabetes mellitus (T2DM). In vitro study findings show that chromium picolinate (CrPic) may improve insulin sensitivity by enhancing intracellular insulin receptor. In this study, we evaluated the metabolic effects of CrPic in a rat model of T2DM. Male Sprague-Dawley rats (n = 45, 8 weeks old) were divided into 3 groups. The controls (group I) received a standard diet (12% of calories as fat); group II received a high-fat diet (HFD; 40% of calories as fat) for 2 weeks and then were intraperitoneally injected with streptozotocin (STZ, 40 mg/kg; HFD/STZ) on day 14; group III rats were given group II diets with the addition of 80 microg CrPic per kilogram body weight per day. The addition of CrPic in the group III treatment lowered glucose by an average of 63% (P < .001), total cholesterol by 9.7% (P < .001), and triglycerides by 6.6% (P < .001) compared with group II treatment. Compared with group II, CrPic treatment also lowered free fatty acid levels by 24% (P < .001), blood urea by 33% (P < .05), and creatinine level by 25% (P < .01), and reduced the severity of glomerular sclerosis (P < .0001). Histopathologic findings suggest that the CrPic-treated group had normal renal tubular appearance compared with the HFD/STZ-treated group. Normal appearance of hepatocytes was observed in the CrPic-treated group. These results showed that CrPic has marked beneficial effects against microvascular complications. In conclusion, HFD/STZ rats provide a novel animal model for T2DM. Further treatment with CrPic for 10 weeks significantly ameliorated changes in metabolic risk factors including favorable changes in histopathology of the liver, kidney, and pancreas, suggesting its potential role in the management of diabetes.     

Level of glucocorticoid hormones in the early postnatal ontogenesis and circadian rhythms of endocrine-metabolic functions in adult rats

The disturbance of glucocorticoid balance in early postnatal ontogenesis (17-19 days) as a result of prednisolone administration was shown to lead to partial suppression of circadian adrenocortical activity in adult rats. Circadian rhythm of FFA in these groups of animals was undetectable and circadian acrophase of blood glucose concentration changes while diurnal urine periodicity remained unchanged. Diurnal rhythm of locomotor activity in prednisolone-pretreated tars was characterized by later onset of increasing its activity and shorter duration.