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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Based on the consideration that insulin does not act directly on metabolic processes but affects membrane carriers and key-enzymes that regulate metabolic pathways, determination of insulin responsiveness of the various key-enzymes is suggested as a very appropriate method for studying insulin resistance. Insulin resistance, as it occurs in obese or obese-diabetic humans and animals, is most often associated with hyperinsulinemia, and is characterized not only by increased activity of key-enzymes of pathways known to be stimulated by insulin (glycolysis, lipogenesis), with the possible exception of glycogen synthesis, but also by a trend towards increased activity of key-enzymes of 'catabolic pathways', normally depressed by insulin. In the adipose tissue there is a normal-to-enhanced basal lipolysis, which in man would result from the prevalence of the active over the inactive form of triacylglycerol lipase. In muscle, the increased amino-acid release that can be inferred from the elevated blood level of both alanine and branched-chain amino acids suggests an enhanced proteolysis. In liver, there is an elevation in the activity of the key gluconeogenic enzymes, which forms the basis of the augmented gluconeogenesis. In both muscle and liver, phosphorylase is also elevated with no change in glycogen synthase. Therefore, insulin resistance seems to consist of the failure of insulin to depress the key-enzymes of catabolic pathways. Possible resistance of glycogen synthetase, which might account for decreased glucose utilization in muscle, may be due to the opposing effects of the phosphorylation process on glycogen synthetase and phosphorylase, implying that activation of phosphorylase (which occurs in obesity) entails inhibition of the synthetase. The fact that insulin insensitivity concerns only the 'catabolic' but not most 'anabolic' pathways makes it unlikely that the unresponsiveness is due to a reduction in insulin receptors or increase in insulin degradation. Since resistance to insulin is shown by enzymes regulated by such different mechanisms as induction-repression (gluconeogenic enzymes), covalent modifications (lipase, phosphorylase), and changes in lysosome stability (lysosomal proteases responsible for proteolysis, a single basic mechanism for explaining insulin insensitivity cannot be envisaged at present.
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PMID:Insulin resistance in obesity: a critical analysis at enzyme level. A review. 39 47

The synergistic effects of dietary obesity produced by the feeding of a high fat diet and stress induced by electric shocks on glucose tolerance and glucose-induced insulin release from the perfused pancreas were investigated. Male Wistar rats weighing 90 approximately 100 g were fed ad libitum for 12 weeks either a control (50% Starch; C) or a high fat diet (40% Butter; F). Some of the rats on both diets received 100 electric shocks of 1 sec. duration in the stress session for 1 hour per day for the last 3 weeks of the experimental period. Low stress (LS) groups were shocked at a fixed time (Inter Shock Interval: 36 sec.). High stress (HS) groups were shocked at random (ISI: mean = 36 sec, 9 approximately 108 sec. variable). Non-stress (NS) groups were not given any shocks. Rats were killed at 24 hours after the final stress session. Under NS conditions, rats in the F-NS group gained a significant amount of weight and had normal levels of fasting plasma glucose and insulin but an impaired glucose tolerance (k = 3.49). Insulin release from the perfused pancreas in the F-NS group showed a delay in the initiation of release by the stimulation of glucose (16.7 mM), but the total amounts of insulin released did not differ from that in the C-NS group. On the other hand, the levels of plasma 11-OHCS in the fed state were much more highly elevated in the HS group than in the LS group, which was not influenced by the high fat diet. The fasting levels of plasma glucose in the F-HS group (121 +/- 7 mg/100 microliter) were significantly higher than those in the C-HS group (101 +/- 7 mg/100 microliter) in spite of a normal insulin concentration in plasma. In contrast to the normal glucose tolerance in the C-HS group (k = 5.14), glucose tolerance in the F-HS group (k = 3.04) was impaired. Insulin release from the perfused pancreas in response to glucose in both diet group was not significantly altered under LS conditions. In the C-HS group, however, the total amount of insulin released in the second phase was enhanced to 165% of that in the C-NC group. Conversely, in the F-HS group the total amount of insulin released in the first phase was significantly decreased to 40% of that in the F-NS group. These findings indicate that the elevation of plasma 11-OHCS levels provoked by shocks at random rather than in a fixed time schedule is caused by the difficulty in predicting shocks, and a chronic stress induced by electric shocks at random further impairs glucose tolerance and suppresses glucose-induced insulin release in rats fed a high fat diet.
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PMID:[The effects of electric stress on pancreatic B cell function in rats fed a high fat diet (I). Glucose tolerance and glucose-induced insulin release from the perfused pancreas (author's transl)]. 39 67

In an attempt to determine whether the decreased number of insulin's receptors in obesity is a result of downregulation of the receptors, diazoxide (5 mg/kg/d) was given to 10 obese subjects. Insulin's suppression by diazoxide in these 10 subjects resulted in a mild glucose intolerance and an increase in insulin's receptors in seven of the 10 subjects. The subjects could be divided into three groups by analyzing the Scatchard plots of their insulin receptor studies before and after diazoxide. Four subjects exhibited an increase in both high affinity and low affinity receptors, three showed an increase only in high affinity receptors, and three failed to demonstrate any change in receptors in response to diazoxide. These studies support the concept that the decreased number of insulin's receptors observed in obesity is a result of the downregulation of the receptors and is not the primary, underlying cause of insulin resistance in obesity, although a contributory role cannot be ruled out.
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PMID:Downregulation of insulin receptors in obese man. 43 66

The insulin response to oral glucose and to i.v tolbutamide was stuied in a group of hyperuricemic subjects and in a group of weight-matched controls. Glucose tolerance was impaired only in obese hyperuricemic subjects. Insulin response to oral glucose was enhanced in hyperuricemic subjects. Tolbutamide gave rise to a sharp increase in IRI levels already 2 min after the injection and this rise was significantly higher in hyperuricemic subjects than in controls. The same result was observed also after i.v. fructose. The interpretation of these data is not easy. Uric acid plasma level and obesity do not seem to be directly involved because an abnormal IRI response has been observed also after a rapid fall in uric acid plasma level after allopurinol treatment and is evident also in lean subjects. In our opinion the problem is more complex and must be considered from the point of view of a change involving carbohydrate as well as purine metabolism.
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PMID:Insulin release in hyperuricemic patients. 59 3

Diabetes mellitus is a complex disease with two dominant pathogenic lesions, one resulting from a failure of the beta cells of the islets of Langerhans and the other from resistance to the actions of insulin in peripheral tissue. Patients may demonstrate varying degrees of either or both lesions. Diet has an important place in the treatment of all diabetics. The most important objective is control of total caloric intake to attain and maintain ideal body weight. Obesity is diabetogenic. The diet of children with diabetes should allow them to grow and develop normally. Insulin-dependent diabetics must eat meals on a regular schedule. Carbohydrate intake should not be disproportionately restricted. Fat intake in diabetics and in nondiabetics should comprise only about 30% of total calories. Dietary instruction should not be a one-time affair. Physicians should seek the assistance of diet counselors when they are available. Many basic questions about diet and diabetes remain unanswered.
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PMID:Diet and diabetes mellitus: concepts and objectives. 65 76

Plasma lipids and lipoproteins, glucose tolerance, plasma insulin response to glucose load, and liver function were examined in 81 relatives of 12 index cases with primary endogenous hypertriglyceridemia, hyperinsulinemia, and hepatic steatosis, as well as in 90 nonrelatives, including the spouses, as controls. Insulin hypersecretion (with or without glucose intolerance), endogenous hypertriglyceridemia, and abnormal liver function suggesting hepatic steatosis were shown to exist in the relatives mostly in combined fashion. Correlation analysis and stepwise multiple regression analysis revealed that the combined disorder developed on the basis of obesity. The incidence of diabetes mellitus was significantly high in the relatives (14.8 per cent) as compared with the normal Japanese population (3.5 per cent). Although the vertical transmission of the combined disorder was noted in almost all pedigrees, the frequency distribution analysis of insulin response, glucose tolerance, and plasma triglyceride showed the histograms of these variables similarly skewed to the right as compared with those of the controls, with no apparent bimodality. In view of the hitherto suggested role of insulin in triglyceride metabolism, it is concluded that hyperinsulinemia coupled with obesity seems to be the basic trait of this form of familial hypertriglyceridemia and hepatic steatosis, though the mode of transmission remains to be elucidated.
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PMID:Interactions of obesity and glucose-stimulated insulin secretion in familial hypertriglyceridemia. 65 14

Animal models with genetic or experimentally produced (lesions of hypothalamus) obesities are numerous and unlikely to ever be reduced to a single pathophysiologic entity. However, obese animals have many similar traits in common. They are all hyperinsulinemic, an abnormality that occurs early in the development of these syndromes and appears to be of prime importance in producing most of the metabolic changes observed both in the early and late phases of the obesity syndromes. In all instances, obesity is an evolutional syndrome in which the early phase is different from the later one. The early phase is principally characterized by increased hepatic very low density lipoprotein (VLDL) output, increased adipose tissue lipogenesis and VLDL uptake, hence, increased fat accretion and fat cell size. These abnormalities are secondary to hyperinsulinemia and can be reversed toward normal by normalizing circulating insulin levels. The late phase is characterized by the continuation of the disorders of the early one plus a superimposed abnormality, the insulin resistance state, that is detectable particularly at the level of adipose and muscle tissues, and eventually brings about hyperglycemia. Insulin resistance is a multifactorial pathological condition that includes at least: (a) a decrease (more or less marked) in insulin binding to target tissues that is responsible for the decrease in tissue sensitivity to the hormone; (b) intracellular defects that are probably responsible for the decreased insulin responsiveness of target tissues. The origin of hyperinsulinemia in animal obesities is still ill-defined. Lesions of the ventromedial hypothalamus (VMH) produce rapid and lasting hyperinsulinemia. Such lesions produce, in addition, increased secretion of insulin and glucagon and changes in pancreatic insulin, glucagon, and somatostatin content in subsequently perfused pancreases. The locus responsible for these effects is not defined and may actually involve a series of interrelated loci. Whatever the latter may be, one of the routes of CNS influence upon endocrine pancreas is the vagus nerve, although a humoral factor has also been claimed. The etiology of hyperinsulinemia in genetically obese animals is unknown. Genetic inheritance could bear primarily upon some hypothalamic or other CNS sites, with secondary alterations in the endocrine pancreas function, or primarily on the islets of Langerhans with possible alteration in the respective function of the A, B, and D cells with resulting excessive insulin secretion.
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PMID:Hyperinsulinemia in obesity syndromes: its metabolic consequences and possible etiology. 72 39

Effects of insulin (1 mU/ml) on diaphragms removed from older-obese (70--110 days, 350--520 g) male Sprague-Dawley rats were compared to responses on muscle removed from younger-lean (27--36 days, 80--150 g) animals. Insulin antagonism on glucose transport (2DG uptake), glucose uptake, glycogen synthesis, glycolysis (lactate production), and glucose oxidation was demonstrated in tissue from the older-obese rats. Extracellular water spaces (measured with inulin-H3) were significantly decreased in these tissue. To determine if insulin antagonism of glucose transport could be secondary to inhibition of a rate-limiting reaction in the Embden-Meyerhof pathway with a subsequent negative feedback on transport, both tissue levels of glycolytic intermediates and oxidation of intracellular lipids were measured. No free intracellular glucose was found in diaphragms from either group of rats. Levels of G-6-P, F-6-P, F-1, 6-diP, PEP, and pyruvate were all lower in muscle from the older-obese animals. Incorporation of C14-FFA into tissue TG was slightly, but significantly, lower in this same tissue. Oxidation of intracellular TG and PL was similar in the two groups. In conclusion, diaphragms from older-obese rats manifest insulin antagonism of glucose transport that is probably responsible for the diminished hormonal effect on glucose uptake and the intracellular pathways of glycogen synthesis, glycolysis, and glucose oxidation. This inhibition of insulin action cannot be accounted for by changes in glycolytic intermediates causing a negative feedback on transport or enhanced lipid oxidation and therefore should be considered primary. The relative effects of age and obesity will need to be evaluated in future studies.
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PMID:Primary insulin antagonism of glucose transport in muscle from the older-obese rat. 72 47

The smooth muscle cell plays an important role in the process of atherogenesis, proliferating in the arterial intima and becoming filled with lipid during the course of the disease. In these experiments the effect of insulin and glucose on sterol synthesis in cultured rat arterial smooth muscle cells was studied. Arterial smooth muscle cells were cultured from pieces of intima and inner media of young rat aortas. The cells were grown in Petri dishes in culture medium with foetal calf serum and when confluent were exposed to insulin or glucose for 24 hours. Insulin in concentrations of 10 micromicron-100 millimicron per ml stimulated the incorporation of sodium [2-(14)C]acetate into non-saponifiable lipids and digitonin precipitable sterols. However, insulin had no effect on the incorporation of labelled mevalonate into cell sterols. Increasing concentrations of glucose in the medium up to 140 mM had had no effect on the incorporation of isotope into sterols, but higher concentrations of glucose caused cell damage and sterol synthesis was markedly depressed. These results may have relevance to the development of atherosclerosis in diabetes and obesity.
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PMID:The effect of insulin and glucose on sterol synthesis in cultured rat arterial smooth muscle cells. 90 24

Administration of monosodium glutamate (MSG) to KK mice during the neonatal period resulted in a syndrome of obesity, stunting and hypogonadism. In some animals the genetic predisposition to diabetes was unmasked with the development of marked hyperglycaemia and or hyperinsulinaemia. Food intake was not increased compared to controls. The elevated plasma glucose and insulin in fed MSG treated mice fell rapidly with food deprivation. Glucose disposal was comparable in MSG treated and control mice after IP glucose, but after oral glucose MSG treated mice showed impaired glucose tolerance. Insulin secretion was defective in MSG treated mice after IP but not after oral glucose.
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PMID:Effects of monosodium glutamate administration in the neonatal period on the diabetic syndrome in KK mice. 100 51


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