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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 circadian rhythm of glycogen metabolism in liver and skeletal muscle was studied in lean and gold thioglucose (GTG) induced-obese mice. The active forms of glycogen synthase (GSI) and phosphorylase (GPa) and the total activity of these enzymes were measured every three hours over a 24 h period in mice fed ad libitum. Hepatic and muscle glycogen content displayed a marked diurnal rhythm that was similar in lean and obese mice. In skeletal muscle the glycogen content, GSI and GPa were not significantly different in lean and obese animals over the 24 h period. The activities of muscle GSI and GPa were constant in both groups despite the diurnal variation in the muscle glycogen content. The absence of an increase in the glycogen content of skeletal muscle despite the pronounced hyperinsulinemia and hyperglycemia in the obese mice, may indicate the degree of insulin resistance in this tissue or the maximal capacity of muscle tissue to store glycogen. In liver, glycogen concentration and total glycogen storage were higher in obese mice. Unlike muscle, both hepatic GSI and GPa underwent significant changes in activity over the 24 h period. Hepatic GSI was lower and GPa was higher in obese mice. The circadian rhythm in enzyme activities was independent of both blood glucose and insulin levels. The total glycogen storage and the activities of total phosphorylase and GPa were significantly increased in the liver from GTG obese mice over a 24 h period and could be implicated in the development of insulin resistance and glucose intolerance in this model of obesity.
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PMID:Diurnal rhythms of glycogen metabolism in the liver and skeletal muscle in gold thioglucose induced-obese mice with developing insulin resistance. 133 47

The effect of long-term (12 weeks) oral treatment with sodium orthovanadate on hepatic glycogen metabolizing and lipogenic enzymes was studied in genetically diabetic db/db mice. These mice were characterized by significant (P less than .001) obesity, hyperglycemia, and hyperinsulinemia. Vanadate administration led to significant decreases in body weight (P less than .001) and plasma insulin levels (P less than .01) and the mice became normoglycemic. The total glycogen synthase (EC 2.4.1.11) activity in the livers of diabetic mice showed a 47% increase, which did not undergo any significant change after treatment with vanadate. Hepatic phosphorylase (EC 2.4.1.1) activities (a and total) showed twofold increases in db/db mice when compared with the nondiabetic ones. Vanadate caused significant decreases in phosphorylase a (P less than .02) and total phosphorylase (P less than .001) activities. Glucose-6-phosphate dehydrogenase (EC 1.1.1.49) and malic enzyme (EC 1.1.1.40) in diabetic liver had differential alterations, as indicated by a 50% decrease in glucose-6-phosphate dehydrogenase and 160% increase in malic enzyme activities. Vanadate administration led to normalization of both enzyme activities. In nondiabetic mice, vanadate treatment did not cause changes in any parameter, except for a 46% decrease in plasma insulin levels. This investigation indicates that vanadate can normalize many of the metabolic abnormalities seen in the liver of genetically diabetic db/db mice, a model for non-insulin-dependent diabetes mellitus (NIDDM). Vanadate also causes a decrease in plasma insulin level, along with normalization of plasma glucose, which suggests a partial reversal of insulin resistance.
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PMID:Long-term effects of vanadate treatment on glycogen metabolizing and lipogenic enzymes of liver in genetically diabetic (db/db) mice. 191 Jan 43

Hepatic glycogen metabolism was investigated in genetically diabetic C57BL/KsJ-db/db mice during their development. Initially, the development of obesity, hyperglycemia, hyperinsulinemia, and hyperglucagonemia in these mice was examined, which illustrated that the diabetes progressed normally. Little difference in hepatic glycogen concentrations was observed, averaging approximately 50 and 60 mg/g liver in diabetic (db/db) and control heterozygote (db/+) mice, respectively. Glycogen synthase activity (total and a-form) was significantly elevated by 5 wk in the diabetic mice relative to controls and reached maximum levels (two-fold higher than controls) around 8-9 wk. This activity then slowly declined during the rest of the 15-wk period examined. Both phosphorylase a and total phosphorylase activities were also elevated by 5 wk, reaching levels twofold higher than controls. These activities did not decline at the end of this 15-wk period, but instead continued to slowly increase. Glycogen synthase a activity showed a positive correlation (r = 0.54, N = 144) with circulating levels of insulin, and a similar correlation was seen for phosphorylase a activity and plasma glucagon levels (r = 0.64, N = 72). Protein kinase and phosphoprotein phosphatase activities were also measured, but no differences were detected between diabetic and control mice. This longitudinal study clarifies some of the changes in hepatic glycogen metabolism that occur during the progression of diabetes in the db/db mouse and indicates a role for circulating insulin and glucagon concentrations on the steady-state activities of glycogen synthase and phosphorylase, respectively.
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PMID:Age-related changes in hepatic glycogen metabolism in the genetically diabetic (db/db) mouse. 298 86

Lean and genetically obese (fa/fa) rats were fed ad libitum, or fasted for 17 h and then meal-fed for varying time intervals. During refeeding, glucose-6-phosphatase activity of lean rats declined to the low value that was present in livers of fasted obese rats and which remained unchanged in the obese group during the meal. Refeeding also resulted in increases in hepatic concentrations of glucose-6-phosphate and fructose-6-phosphate, fructose 1,6-bisphosphate, fructose-2,6-bisphosphate, alpha-glycerophosphate, pyruvate and lactate in lean and obese rats, absolute values being higher in the fasted obese than in the fasted lean group. Obese animals had higher postprandial portal blood insulin, glucose and lactate concentrations than lean animals. In spite of this, the rate of hepatic glycogen deposition was the same in both groups and was accompanied by similar glycogen synthase a levels. Following refeeding, phosphorylase was transiently inactivated in livers of lean but not of obese animals, while glycogen synthase was inactivated in both groups. The data suggest that in lean animals refeeding was associated with a stimulation of liver glycolysis, presumably by insulin; in fasted obese rats hepatic glycolysis was already in a stimulated state and was only slightly enhanced further after the meal, in keeping with their unaltered hyperinsulinaemia; there was an increased turnover of liver glycogen or a resistance to insulin stimulation of glycogen synthesis in fa/fa rats during refeeding.
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PMID:The onset of liver glycogen synthesis in fasted-refed lean and genetically obese (fa/fa) rats. 303 11

The activity ratio of phosphofructokinase in perfused rat heart and its activation by epinephrine was examined in non-obese, fat-fed obese, and genetically obese rats. For non-obese colony rats there was an age-dependent increase in the activity ratio of phosphofructokinase from 0.2 at 40 days to 0.4 at mature age (greater than 200 days). Epinephrine (10 microM) treatment of the heart for 5 min increased the ratio at all ages but the proportional increase diminished with age. For mature-age lean Zucker rats carrying the genetic determinant for obesity the results were similar to those obtained for comparable non-obese colony rats. For fat-fed obese rats the activity ratio of phosphofructokinase at 200 days of age was 0.2 and was increased to 0.6 by epinephrine treatment. For mature-age obese Zucker rats the activity ratio was 0.2 and no significant response to epinephrine occurred. The activity ratio of glycogen phosphorylase and its response to epinephrine (beta-adrenergic receptor mediated) in heart was unaffected by age, diet or the gene for obesity. The present findings indicate a specific defect in the adrenergic regulatory mechanism for phosphofructokinase in genetically obese rats.
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PMID:Obesity and the regulation of phosphofructokinase in heart: an apparent insensitivity to adrenergic activation in mature-age genetically obese rats. 629 Aug 38

Impaired glycogen synthesis is present in subjects at risk for developing non-insulin-dependent diabetes mellitus (NIDDM), suggesting that it is a primary defect in NIDDM. To examine whether defects in glycogen metabolism are present at birth in an animal model of NIDDM, glycogen synthase (GS), glycogen phosphorylase (GP), and total glycogen content were measured in liver and quadriceps muscle of 1-day- and 20-week-old insulin-resistant New Zealand Obese (NZO) mice and control (NZC) mice. In livers of both neonatal and adult NZO mice, active GS was reduced by 54% and 36%, respectively, as compared with that in NZC mice (P < .03). Total liver GS activity was the same in neonates, but was 65% higher in adult NZO as compared with NZC mice (P < .02). Liver glycogen was 28% lower at birth in NZO mice (P < .03), but was 49% higher at 20 weeks of age. Active and total GP were the same in NZO and NZC animals, despite hyperinsulinemia in 20-week-old NZO mice. In muscle, active GS was reduced by 41% in both 1-day- and 20-week-old NZO mice (P < .02). Total GS was also lower in NZC mice at 1 day of age (P < .01), but not at 20 weeks. No differences were detected in GP activity or in total glycogen content in muscle. Therefore, reduced GS activity is an early defect present at birth in the insulin-resistant NZO mouse in both liver and muscle. However, it is not the sole determinant of the amount of glycogen deposited in tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Defects in liver and muscle glycogen metabolism in neonatal and adult New Zealand obese mice. 747 88

A study of glycogen metabolism in the liver has been carried out in gold thioglucose (GTG) injected mice during the development of obesity. In GTG obese mice, overt obesity, hyperglycaemia and hyperinsulinaemia had developed by 6 weeks after the injection of GTG. Beyond 6 weeks after GTG injection, the gain of body weight and increment in serum glucose and insulin levels with age in obese mice were not obvious when compared with those of age-matched control animals. The glycogen concentration, total glycogen storage, activity of glycogen synthase R and activity of phosphorylase a in the liver from GTG obese mice were significantly greater than those in lean mice from 2-4 weeks after GTG injection and remained higher thereafter. These results demonstrate that the increased liver glycogen storage and increased activity of glycogen synthase and phosphorylase occur early in the development of obesity and at a similar time to previously reported increases in pyruvate dehydrogenase activity (Caterson et al. (1987) Biochem. J. 243, 549-553) and lipid synthesis in liver (Cooney et al. (1989) Biochem. J. 259, 651-657). The emergence of these abnormalities in glycogen metabolism early in the development of obesity may contribute to the establishment of glucose intolerance and insulin resistance in this model of obesity which became apparent at approximately the same time after GTG injection.
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PMID:Changes in glycogen metabolism in liver of gold thioglucose injected mice during the development of obesity. 781 17

The frequent development of Type 2 diabetes in the obese suggests a relationship between obesity and diabetes. This study presents evidence for a continuum form obesity to diabetes via glucose intolerance and hyperinsulinemic diabetes. The defect which seems to be at the origin of this development resides in the increase in lipid oxidation already present in the early stages of obesity. It reflects the increased utilisation of fatty acids for energy purpose in the obese, at the expenses of glucose. In non-diabetic obese subjects, insulin resistance can be demonstrated by the inhibition of glucose storage during a euglycemic, hyperinsulinemic, clamp. This defect in glucose storage is not observed during a oral glucose tolerance test (OGTT), as it is compensated by hyperinsulinemia and hyperglycemia during glucose tolerance. Glucose tolerance appears with the inhibition of glucose oxidation by the augmented lipid oxidation. This decreased glucose utilization causes a slowdown of the utilization of glycogen stores which leads, as a consequence, to the inhibition of glycogen synthase by its product, glycogen. Diabetes appears when the increase in glycemia and insulinemia does not compensate any more for the inhibition of glucose storage. The rise in basal glycemia simultaneously with the fall in glucose storage corresponds to the transition to diabetes. The decreased glucose mobilization together with the inhibition of glycogen phosphorylase are such in the diabetic patient that glycogen stores tend to remain full and glycogen synthase is inhibited by negative feedback. The retrograde inhibition of glycogen stores on glycogen synthase activity brings up incapacity to store glucose and leads to a rise in glycemia. Finally, the evolution of obesity to diabetes leads to a decrease in insulin secretion with increase in hepatic glucose production through gluconeogenesis and decreased capacity to store glucose. Therapeutic implications are discussed in this review.
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PMID:[From obesity to diabetes]. 859 98

The syndrome of insulin resistance comprises the following H-phenomena: 1. Hyperinsulinism compensating the inborn postreceptor insulin resistance, 2. Hyperglycaemia-non-insulin-dependent diabetes mellitus, 3. Hyperlipoproteinaemia with android obesity, 4. Hypertension, 5. Hirsutism with the syndrome of polycystic ovaries as a manifestation of a hyperandrogenic situation in the female organism. Molecular syndromes of this syndrome of insulin resistance are obscure. They are the subject of intensive studies because H-phenomena are an aggregation of the main risk factors of atherogenesis. Recently attention is focused also on amylin--a 37 amino acid peptide with a 50% homologous amino acid sequence with a calcitonin-gene--related peptide (CGRP), which is the product of a gene made up of three introns on the 12th chromosome. Amylin acts in the beta-cells of the pancreas as a co-secretion of insulin. If in excess, it is deposited in the form of an amyloid in the beta-cells. In the early stage of NIDDM it alters the physiological response of the beta-cell to glycaemic stimuli and food, in later stages of the disease, after accumulation, it causes apoptosis of the beta-cell and reduces thus the secretory capacity of the Langerhans islets. It is excreted in the urine and thus, if the glomerular filtration is reduced, it cumulates in the blood stream and thus enhances insulin resistance already in the early stages of chronic renal insufficiency, or in diabetic nephropathy. In type II diabetes similarly as insulin levels also amylin levels are elevated, while in type I diabetes with early autoimmune destruction of the beta-cells the insulin and amylin levels are reduced or even zero. Amylin reduces in the muscle, probably by inhibition of glycogen synthase, the insulin stimulated non-oxidative utilization of glucose into muscle glycogen and conversely by stimulation of phosphorylase it stimulates glycogenolysis and thus also lactate production and gluconeogenesis in the liver which all are anti-insulin effects which intensify the insulin resistance of the main target tissues. Amylin, similarly as CGRP or calcitonin, reduces Ca blood levels and has a vasodilatating effect; it reduces the BP but in different minimal and maximal doses and by a different mechanism and via special receptors because the link of amylin to calcitonin receptors is 100 times lower and does not produce a rise of cAMP in the target cell. The effect on the enhancement of insulin resistance in muscle was proved also by direct measurements using an hyperinsulinaemic euglycaemic clamp. After prolongation of the clamp to more than two hours the effect on insulin resistance disappeared, although the hypocalcinaemic effect persisted. Amylin is able by its biological action to modify the secretion as well as the effectiveness of insulin to pathological values. These two characteristics are typical for impaired glucose tolerance in type II diabetes. Studies are under way to find out whether the effect of amylin is involved directly also in the pathogenesis of the other H-phenomena or only via accentuation of hyperinsulinism. In any case amylin is a new link the role of which in the pathogenesis of NIDDM and the syndrome of insulin resistance awaits evaluation. Due to its effect on gastric evacuation it participates also in the postprandial glycaemic control in particular in type I diabetes where it it begins to be used in therapy. Perhaps it will be possible to administer it in these patients along with insulin to improve diabetes compensation.
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PMID:[Amylin as an additional possible pathogenic factor in NIDDM and the insulin resistance syndrome]. 896 27


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