Evidence that therapeutic alterations of a circadian rhythm for gastric emptying response may be possible.
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Animals↗
Biomedical subjects
S J Bhathena
Publications and source records attributed to S J Bhathena.
Simultaneous extraction of beta-endorphin and leu- and met-enkephalins from human and rat plasma.
A simple, rapid and reliable procedure is described to simultaneously concentrate and purify beta-endorphin, leu- and met-enkephalins from small volumes of human and rat plasma before radioimmunoassay is performed. It uses C18 Sep-Pak reverse phase cartridges. The effectiveness of different protease inhibitors in preventing degradation of opiates by plasma and different solvent systems for eluting opiates is also evaluated.
Animals↗
Dietary fat and hormonal effects on erythrocyte membrane fluidity and lipid composition in adult women.
Erythrocyte ghost membrane fluidity and phospholipid linoleate were significantly increased when higher levels of polyunsaturated fats were fed to healthy, free living, premenopausal women. Fluidity was assessed by diphenylhexatriene (DPH) fluorescence polarization measurements with hypotonically lysed red blood cells from 31 female subjects fed one of two sets of diets, which were formulated from typical US foods to contain polyunsaturate to saturate ratios (P/S) of 1.0 or 0.3. Both groups of women were fed diets with 40% of energy as fat for four menstrual cycles followed by low-fat diets having 20% of energy as fat for the next four menstrual cycles. Blood was sampled during the fourth cycle of each dietary period at times estimated to correspond to maximum secretions of estrogen and progesterone to assess interactive hormonal and dietary effects on membrane composition and fluidity. Red blood cell membranes were most fluid following higher levels of linoleate intake, either by higher (40%) total fat or higher P/S levels. Membrane fluidity was directly related to the phospholipid oleate and linoleate contents and inversely related to the molar cholesterol/phospholipid ratio. Hormonal status effects on the membranes were not extensive. Membrane fluidity in cells from women fed P/S = 0.3 diets was higher at 40% than at 20% fat during the luteal phase of the fourth cycle. In contrast, women fed the P/S = 1.0 diets had more fluid red cells at 40% fat during the follicular phase of the cycle. Regression analysis showed a direct linear correlation between membrane fluidity and red cell membrane insulin binding demonstrating a relation between receptor binding and cell membrane fluidity in the human female.
Adult↗
Hormones regulating lipid and carbohydrate metabolism in premenopausal women: modulation by dietary lipids.
The effect of high- and low-fat diets with different levels of fatty acid unsaturation on plasma hormones involved in lipid metabolism was studied during different phases of the menstrual cycle in 31 premenopausal women. Subjects were divided into two groups and were fed controlled diets containing 39% fat with a ratio of polyunsaturated to saturated fatty acids (P:S) of either 0.3 or 1.0 for four menstrual cycles and then switched to a 19% fat diet with the same P:S for another four cycles. Blood samples were analyzed during both the follicular and luteal phases. A significant direct effect of level of dietary fat was observed on plasma cortisol and dehydroepiandrosterone-sulphate whereas an inverse relationship was seen for plasma insulin. Both plasma insulin and growth hormone levels were higher during the luteal compared with the follicular phase of the menstrual cycle. None of the hormones was affected by the level of unsaturation of dietary fats.
Adult↗
Dietary fat and menstrual-cycle effects on the erythrocyte ghost insulin receptor in premenopausal women.
The effect of high- and low-fat diets with different levels of fatty acid unsaturation on insulin receptors of erythrocyte ghosts was studied during different phases of the menstrual cycle in 31 healthy premenopausal women. Subjects were divided into two groups and consumed controlled diets containing 39% fat with a ratio of polyunsaturated to saturated fatty acids (P:S) of either 0.30 or 1.00 for four menstrual cycles. They were switched to 19% fat at the same P:S for another four cycles. Fasting blood samples were collected during the follicular and luteal phases. Insulin receptors were measured from right-side-out ghosts. Insulin binding was significantly lower due to fewer receptors when subjects were fed the low-fat, high-carbohydrate diet compared with the high-fat, low-carbohydrate diet. There was no significant effect of level of unsaturation or time of menstrual cycle on insulin binding. Thus, insulin receptors on erythrocytes respond to dietary lipids.
Dietary Fats↗
Liver insulin receptor tyrosine kinase activity in a rat model of type II diabetes mellitus and obesity.
Spontaneous hypertensive-corpulent rats (SHR/N-corpulent), homozygous for the corpulent gene (cp/cp), are obese, hyperinsulinemic and exhibit abnormal glucose tolerance and thus represent a model for type II diabetes and obesity. In view of their overall insulin resistance, we examined liver insulin receptor binding and tyrosine kinase activity from corpulent rats and lean littermates fed purified diets containing 54% sucrose or starch for about 12 wk. Specific 125I-insulin binding to crude liver membranes from female corpulent rats fed either starch or sucrose was reduced to approximately 50% of that seen in lean rats (14 vs. 7%). Affinity of insulin receptors was similar in all groups, suggesting that hyperinsulinemic corpulent rats possess fewer hepatic insulin receptors than do lean rats. Using similar numbers of wheat germ agglutinin-agarose (WGA)-purified insulin receptors with similar affinities for insulin, it was found that basal and insulin-stimulated phosphorylation of the synthetic tyrosine-specific kinase substrate poly(Glu, Tyr)4:1 was similar in lean and obese rats fed sucrose or starch. It is suggested that the contribution of the liver to the insulin resistance in obese SHR/N-cp rats probably lies distal to the insulin receptor tyrosine kinase.
Animals↗
Comparison of insulin secretory patterns in obese nondiabetic LA/N-cp and obese diabetic SHR/N-cp rats. Role of hyperglycemia.
Obese diabetic SHR/N-(cp/cp) rats are a genetic model for non-insulin-dependent diabetes mellitus. When SHR/N-cp rats are overtly diabetic, they are hyperinsulinemic and hyperglycemic in the fed state when consuming commercial chow or semipurified high-carbohydrate diets. Obese SHR/N-cp rats were hyperinsulinemic by 4 wk of age, although hyperglycemia did not appear until 3-4 wk later and was exacerbated by a high-sucrose diet (mean +/- SE 1488 +/- 238 microU/ml insulin and 425 +/- 51 mg/dl glucose). The control SHR/N-cp rats (+/?) on the sucrose diet remained lean and normoglycemic. The obese diabetic SHR/N-cp rats showed three alterations in pancreas perfusion data (not present in control rats): 1) paradoxically high insulin secretion at low glucose levels (2.5 mM), 2) secretion of insulin in response to arginine (10 mM) in the absence of glucose, and 3) impaired response of insulin secretion to high glucose (16.7 mM). To determine whether hyperglycemia was responsible for the abnormalities of insulin secretion, perfusion studies were conducted in obese nondiabetic LA/N-cp rats and compared with the SHR/N-cp rats. The obese LA/N-cp rats resembled the corpulent SHR/N-cp rats in every way, except that they were normoglycemic on the sucrose diet. The obese LA/N-cp rats had two of the three alterations in insulin secretion shown by obese SHR/N-cp rats, lacking only the impaired response to high glucose, suggesting that hyperglycemia was required for that defect to occur.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of dietary carbohydrates on insulin and glucagon receptors in a new model of noninsulin-dependent diabetes-SHR/N-corpulent rat.
A new congenic strain of rat, the SHR/N-corpulent, provides a good model for noninsulin-dependent diabetes and was used in the present study. Corpulent rats as compared to their lean littermates are obese, hyperlipidemic, and severely hyperinsulinemic, and show an age-dependent loss of glucose tolerance. Mild fasting hyperglycemia is seen only in corpulent rats fed sucrose. Since dietary sucrose is more lipogenic than starch and since insulin and glucagon are involved in lipid and carbohydrate metabolism, we studied the effect of the type of dietary carbohydrate on insulin and glucagon levels and their receptors in lean and corpulent SHR/N rats. A significant phenotypic effect was observed (corpulent greater than lean) on plasma levels of triglyceride, cholesterol, and insulin. Dietary sucrose increased these parameters in corpulent rats but not in lean rats. Insulin and glucagon binding to liver plasma membranes was lower in corpulent rats than in lean; decreases were due to fewer receptors without a significant change in affinity. Thus, in corpulent rats, in addition to hyperinsulinemia, fewer glucagon receptors and their failure to be regulated by plasma glucagon levels appear to contribute to the hyperlipidemia. Furthermore, the hyperglycemia observed in sucrose-fed corpulent rats may be due to extreme resistance to insulin despite lower plasma glucagon and fewer glucagon receptors.
Animals↗
Immunoreactive beta-endorphin and met- and leu-enkephalin contents in pancreas and pituitary of corpulent (cp/cp) rats.
Previous reports have provided suggestive evidence for a role of endogenous opiates in modulating feeding behavior as well as insulin secretion from the pancreas. This evidence includes pharmacologic studies as well as studies of endogenous opioid peptides in tissues of genetically obese rodent models. In the present study, content of three opioid peptide immunoreactivities (beta-endorphin, met-enkephalin and leu-enkephalin) were measured in pituitary and pancreas of two recently described, genetically obese rats, the LA/N-cp and the SHR/N-cp. Although both of these inbred strains carry the same cp allele, the SHR-cp rat is obese and diabetic by 8 weeks of age, while the LA/N-cp is obese but remains euglycemic. There were no significant differences in content of immunoreactive beta-endorphin, met-enkephalin or leu-enkephalin in whole pituitary, posterior or anterior lobes of the pituitary, or pancreas which could be ascribed to the effect of the obese phenotype. These data are in contrast to previously reported studies in which significant alterations in opioid peptide immunoreactivities were found in genetically obese Zucker fa/fa rats, C57BL/6 ob/ob mice and C57BL/Ks db/db mice. The present work provides no support for pathological involvement of opioid peptides in the genetically obese cp/cp rat.
Animals↗
Comparative hormonal profile of two newly developed obese congenic rat strains.
1. The effect of feeding diets containing either 54% sucrose or cooked corn starch for 12 weeks on levels of fasting plasma insulin, corticosterone, growth hormone and glucagon were compared in two newly developed genetically obese rat strains--the normoglycemic LA/N-cp and the diabetic SHR/N-cp. 2. In corpulent rats of either strain, levels of plasma insulin and corticosterone were greater when compared to the lean littermates. Corpulent LA/N-cp rats had lower levels of plasma glucagon and higher levels of plasma growth hormone than did lean LA/N-cp rats. 3. SHR/N-cp rats fed sucrose had greater levels of corticosterone and glucagon than did SHR/N-cp rats fed starch.
Animals↗
Reversible impairment of glucose-induced insulin secretion in SHR/N-cp rats. Genetic model of type II diabetes.
The SHR/N-cp rat is a new genetically obese model for non-insulin-dependent diabetes mellitus. Expression of the diabetes is enhanced by a high-sucrose (54%) diet. After 4 wk on the diet, the cp/cp rats weigh significantly more than their +/? controls, have postprandial hyperglycemia (greater than 400 mg/dl), and are hyperinsulinemic, with immunoreactive insulin (IRI) levels 10- to 20-fold greater than controls. Total pancreatic IRI tends to be increased 1.6-fold in the cp/cp rats (although not significantly). There is no increase in pancreatic proinsulin content as a percent of total IRI. Studies of in vitro pancreatic function were carried out with the isolated nonrecirculating perfused pancreas method. The cp/cp rats (n = 10) showed impaired or absent IRI responses to 16.5 mM glucose, whereas +/? rats (n = 9) responded with classic biphasic curves. Comparison of insulin secreted in 20 min revealed a greater than 53% decrease in IRI secretion in cp/cp rats (P less than .05). A paradoxical hypersecretion of IRI at glucose concentrations of 0-2.7 mM was noted in cp/cp but not lean rats, i.e., 1.8 +/- 0.2 mU/min IRI in cp/cp rats vs. 0.04 +/- 0.007 mU/min in +/? rats. Perfusion of pancreases for 45 min with buffers containing no glucose resulted in restoration of a normal biphasic IRI response to 16.5 mM glucose in the cp/cp rats, whereas response in the lean rats was markedly reduced. Brisk IRI responses to 10 mM arginine in buffers with no glucose also occurred in cp/cp but not +/? rats. Glucagon secretion was relatively suppressed in the cp/cp rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Increased insulin receptors in carbohydrate-sensitive subjects: a mechanism for hyperlipaemia in these subjects?
Twenty male subjects, 11 normal and 9 carbohydrate-sensitive, participated in a study in which the effect of feeding diets low in copper (1.03 mg/d) on the number and affinity of insulin receptors was determined. Since carbohydrate-sensitive subjects are hyperinsulinaemic, it was anticipated that they would demonstrate a down-regulation of insulin receptors. The subjects were fed a low copper diet for 11 weeks and then replenished with copper (3 mg/d) for 3 weeks. Regardless of diets fed, carbohydrate-sensitive subjects showed increased insulin binding. The increase was due to the number of receptors without any change in their affinity. This unusual and unexpected observation in carbohydrate-sensitive subjects suggests an altered response of the insulin receptor, namely the failure of plasma insulin to down-regulate the number of receptors. It is possible that such an alteration could lead to a shift of the biological response curve of insulin to the left in some target tissues thereby causing hyperlipaemia by diverting glucose into triglyceride. The exact mechanism of hyperlipaemia in carbohydrate-sensitive subjects remains to be clarified.
Adult↗
Effects of supplemental chromium on patients with symptoms of reactive hypoglycemia.
To determine if chromium (Cr) is involved in hypoglycemia, eight female patients with symptoms of hypoglycemia were supplemented with 200 micrograms of Cr as chromic chloride for three months in a double-blind crossover experimental design study. Chromium supplementation alleviated the hypoglycemic symptoms and significantly raised the minimum serum glucose values observed two to four hours following a glucose load. Insulin binding to red blood cells and insulin receptor number also improved significantly during Cr supplementation. These data suggest that impaired Cr nutrition and/or metabolism may be a factor in the etiology of hypoglycemia.
Adult↗
A study on Asian Indian and American vegetarians: indications of a racial predisposition to glucose intolerance.
Sixty-two Asian Indian and American vegetarians participated in a 3-h glucose tolerance test after an overnight fast to study clinical indices of glucose homeostasis. The Asian Indians had a higher (p less than 0.0035) insulinogenic score than the Americans. The Asian Indians had significantly higher insulin levels than the Americans at every sampling time during the glucose tolerance test except for the 3-h sample. The Indian men had significantly higher (p less than 0.05) plasma glucose than the other three groups at 2 h after the glucose load. American subjects had higher (p less than 0.0008) insulin binding to erythrocytes than the Asian Indian subjects. Scatchard analysis and competition-inhibition plots of the insulin-receptor data indicated that decreased binding in the Indian group results from a lowered number and decreased affinity of erythrocyte receptors. These results suggest that Asian Indians exhibit several clinical indications associated with an increased risk for the development of insulin-independent diabetes.
Adult↗
Effect of dietary carbohydrates on glucagon and insulin receptors in genetically obese female Zucker rats.
Obese Zucker rats are hyperlipemic and mildly hyperglycemic. Because insulin and glucagon are involved in lipid and carbohydrate metabolism and they act via their receptors, we investigated the role of insulin and glucagon receptors in obese and lean female Zucker rats. Because dietary sucrose is more lipogenic than starch, we also studied the effect of dietary carbohydrates on the receptors. Significant phenotypic effect (obese greater than lean) was observed on plasma levels of glucose, triglyceride and insulin. Binding of insulin and glucagon to liver plasma membranes was significantly lower in obese rats than in lean rats. Lower insulin binding was due to a lower number of receptors as well as a lower affinity, whereas the lower glucagon binding was due only to a lower receptor number. Insulin binding in lean rats but not in obese rats was lower in sucrose-fed than in starch-fed rats. Diet had no effect on glucagon binding. We propose that in obese Zucker rats, in addition to hyperinsulinemia, impaired glucagon activity as manifested by decreased glucagon binding to target tissues may be an important contributor to the hyperlipemia and obesity.
Animals↗
Tissue somatostatin levels in three models of genetic obesity in rats.
A potential role for somatostatin (SRIF) in the pathogenesis of the hyperinsulinemia of obese rats was considered. SRIF like immunoreactivity (ng/mg protein) was therefore measured in hot 2 N acetic acid extracts of pancreas, stomach, pituitary, and hypothalamus in tissues obtained from three models of genetic obesity in rats. These models included the obese and lean controls of LA/N-cp, SHR/N-cp, and Zucker rats. To assess the effects of diet on SRIF levels, mixed diets were provided ad lib which contained a carbohydrate as either sucrose or starch. Some groups were fed chow diets. No significant dietary effects on tissue levels of SRIF were obtained. However, two of the three models (Zucker and SHR/N-cp) showed phenotypic effects on SRIF levels in pancreas; namely, obese rats showed a significantly greater concentration of SRIF (P less than 0.0005 and less than 0.0002, respectively) than did the lean littermates. These findings were confirmed by measurement of total pancreas SRIF content. Gastric levels were significantly altered only in the obese Zucker rats (P less than 0.005) where obese tissues had lower concentrations than those of lean animals. However similar directional changes in pancreas and stomach were observed in all models. It is concluded that the hyperinsulinemia of the obese animals studied is not due to absolute deficiency in pancreatic SRIF content. It is postulated however that decreased pancreatic SRIF secretion (paracrine or otherwise) relative to pancreatic insulin content could still play a role.
Animals↗
Decreased plasma enkephalins in copper deficiency in man.
Twenty-four male subjects participated in a study in which the effect of feeding diets low in copper (1.03 mg/day) on plasma opiates was determined. The subjects were fed a low-copper diet for 11 wk with either starch or fructose as a major source of carbohydrate. Feeding low-copper diet decreased serum copper level significantly. In addition, plasma leu- and met-enkephalins decreased significantly while beta-endorphin levels rose. On repletion with copper (3 mg/day) for 3 wk, plasma enkephalins increased while beta-endorphin levels decreased to pretest values. These results suggest that feeding low copper decreases plasma enkephalins, which may reflect a copper-dependent process affecting enkephalin biosynthesis and/or release.
Catecholamines↗
Genetic obesity and dietary sucrose decrease hepatic glucagon and insulin receptors in LA/N-corpulent rats.
A catabolic and hypolipemic effect of glucagon has been described in normal animals. We therefore studied the role of glucagon in genetically obese, hyperlipemic rats. Twelve genetically obese hyperlipemic LA/N-cp/cp (corpulent) rats and 12 lean littermates were fed either 54% starch or 54% sucrose for 12 weeks. Plasma glucagon and insulin levels and glucagon and insulin binding to liver membranes were measured. Comparing all corpulent and lean animals regardless of diet, a significant (P less than 0.0001) phenotypical effect (cp/cp greater than lean) was observed in plasma insulin levels (464 +/- 54 vs 70.3 +/- 7.6 muu/ml, mean +/- SEM). Insulin binding (2.68 vs 16.1%/50 micrograms protein) and glucagon binding (25.6 vs 47.3%/50 micrograms protein) were both significantly lower (P less than 0.0001) in corpulent rats as compared to their lean littermates. Sucrose feeding had marginal effect on plasma insulin or insulin binding. It, however, decreased glucagon binding in corpulent rats but not in their controls. A significant negative correlation was observed between plasma insulin and insulin binding, while a positive correlation was seen for plasma glucagon and glucagon binding. A significant negative correlation was observed between plasma glucagon and lipogenic enzymes (glucose-6-phosphate dehydrogenase and malic enzyme) in liver and between glucagon binding and these enzymes. We propose that in these genetically obese rats, in addition to hyperinsulinemia, impaired glucagon activity as manifested by decreased glucagon binding to target cells may be an important contributor to the hyperlipemia and obesity. A further decrease in glucagon binding in rats fed sucrose indicates that sucrose, per se, may be an additional contributory factor.
Animals↗