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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

Glucose disposal into muscle glycogen has previously been directly studied after intravenous, but not after physiological, oral administration. In this study 100 g glucose, containing 50 microCi [U-14C]glucose, were taken orally by premenopausal women in the overnight fasting state or after a carbohydrate-rich meal. After 4 h, biopsies were taken from the vastus lateralis muscle and abdominal and femoral subcutaneous adipose tissue for determinations of label in isolated glycogen and triglycerides, respectively. Uptake of administered glucose carbon in muscle glycogen was estimated to be approximately 20 g in the fasting and approximately 9 g in the carbohydrate-fed groups, respectively. Total uptake in adipose tissue triglycerides was approximately 2 g. Glucose carbon uptake in muscle glycogen correlated positively with glucose infusion rates during euglycemic hyperinsulinemic glucose clamps, glycogen synthase activity in vitro, and type I muscle fiber distribution and fiber area. Negative correlations were found between glucose uptake in adipose tissue triglycerides, type II fiber distribution and fiber area, as well as the waist-to-hip circumference ratio and degree of obesity. It was concluded that muscle glycogen is probably not a major pathway for disposal of oral glucose carbon in the sedentary condition.
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PMID:Uptake of glucose carbon in muscle glycogen and adipose tissue triglycerides in vivo in humans. 141 27

The metabolic syndrome (syndrome X) is characterised by an association of elevated insulin levels, a tendency to obesity of the android type, a disturbance of lipid metabolism with elevated triglyceride levels and commonly associated hypertension. The underlying common cause of this syndrome appears to be insulin resistance of the skeletal muscles, which is related in particular to the non-oxidative glucose utilization on the part of the muscle. The molecular cause of this syndrome has not been clarified, but a defect in the signal transduction chain between the insulin receptor and glycogen synthase is suspected. Epidemiological studies have shown that the metabolic syndrome may be considered a preliminary stage of manifest type II diabetes. In addition, it appears to play a major role in the development of cardiovascular complications in certain high-risk groups.
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PMID:[Pathophysiologic principles of metabolic syndrome. Consequences for early diagnosis and prevention]. 148 14

In order to evaluate the importance of a defect in insulin mediated non-oxidative glucose metabolism and glycogen synthase activity in skeletal muscles in obese subjects with and without Type 2 (non-insulin-dependent) diabetes mellitus we studied: 10 lean and 10 obese control subjects and 12 obese diabetic patients using the euglycaemic hyperinsulinaemic clamp technique (basal, 20 mU.(m2)-1.min-1, 80 mU.(m2)-1.min-1) in combination with indirect calorimetry. Muscle biopsies were taken from m. vastus lateralis at each insulin level. We found that non-oxidative glucose metabolism could be stimulated by insulin in all three groups (p less than 0.01). The values obtained at the highest insulin levels (around 140 microU/ml) were lower in both obese groups compared to the lean control subjects (118 +/- 21, 185 +/- 31, 249 +/- 14 mg.(m2)-1.min-1 (p less than 0.01]. Insulin stimulation of the glycogen synthase activity at a glucose-6-phosphate concentration of 0.1 mmol/l was absent in both obese groups, while activities increased significantly in the lean control subjects (19.6 +/- 4.2% to 45.6 +/- 6.8%, p less than 0.01). Glycogen synthase activities at the highest insulin concentrations only differed significantly between lean control subjects and obese diabetic patients (45 +/- 7% and 31 +/- 5%, p less than 0.05). We conclude that insulin resistance in peripheral tissues in obese subjects with and without Type 2 diabetes may be partly explained by a reduced insulin mediated non-oxidative glucose metabolism and that this abnormality might be due to an absent insulin stimulation of glycogen synthase in skeletal muscles. This enzyme defect is correlated to obesity itself.
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PMID:Reduced glycogen synthase activity in skeletal muscle from obese patients with and without type 2 (non-insulin-dependent) diabetes mellitus. 190 24

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

Macrovascular disease, especially coronary heart diseases, have been found to be linked to glucose intolerance. Insulin resistance in respect to glucose uptake in peripheral tissues seems to play an important role in the development of glucose intolerance, since subjects with coronary heart disease mainly are hyperinsulinemic. Insulin resistance may induce not only glucose intolerance but also hypertension, obesity, and dyslipoproteinemia (high very low-density lipoprotein and low high-density lipoprotein values), all variables that add to the risk of coronary heart disease. On the basis of these findings, a new syndrome has been postulated-syndrome X. This syndrome may be caused by inherited insulin resistance in skeletal muscles, and secondary to that arterial hypertension, obesity, and dyslipoproteinemia may develop. Insulin resistance in noninsulin-dependent diabetic persons and in hypertensive subjects is located in skeletal muscles, where insulin's ability to promote nonoxidative glucose metabolism is reduced. The key enzyme in this pathway, glycogen synthase, is proposed as the causal defect responsible for the insulin resistance state, at least in noninsulin-dependent diabetic patients. The pill (sex steroids) may induce a clinical situation that is similar to syndrome X. However, it is important to emphasize that many more studies are needed to substantiate these hypothetical mechanisms behind coronary heart disease.
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PMID:Impairment of glucose tolerance: mechanism of action and impact on the cardiovascular system. 211 96

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

Diabetes and obesity are epidemic in the Pima Indians of the Southwestern United States, and the prevalence of diabetes is increasing. The most likely link between obesity and diabetes is tissue insulin resistance. If obesity is defined as an excess of body fat, then it can only be accurately assessed by measurements of body composition and not by approximations such as body mass index or percent of ideal weight. To compare the metabolic data of individuals of varying size, an accurate measure of metabolic size is needed. Total body weight is not an appropriate means of comparing individuals since obese subjects have a greater proportion of nonmetabolizing mass (triglyceride). Body surface area shows a sex difference, and this may distort data if both sexes are present. From studies of metabolic rate we have determined that metabolic rate is directly proportional to the fat-free mass plus 18 kg, and we suggest that this weight can be equated with metabolic size. Glucose storage in skeletal muscle appears to be important in the disposal of an intravenous glucose load. Consistent with its role in glycogen storage, glycogen synthase enzyme is activated in proportion to the ability to dispose of glucose during a hyperinsulinemic, euglycemic clamp. The role of glycogen synthase is most notable at supraphysiological plasma insulin concentrations; and since glucose uptake at these insulin concentrations is highly familial independent of the degree of obesity, we suggest that there may be a specific genetic defect expressed in skeletal muscle that reduces insulin responsiveness in some subjects. The lack of correlation between 24 hour respiratory quotient measured in a metabolic chamber (a measure of the proportion of fat derived calories) and degree of obesity indicates that in obese Pima Indians insulin resistance is not due to an inhibition of glucose metabolism by free fatty acids (glucose-fatty acid-ketone cycle). Obesity is associated with an increase in fat-free mass almost kilogram- for kilogram with fat mass when compared to the lean state. A role for this increase in fat-free tissue in producing insulin resistance has been given insufficient attention in the past. With an increase in fat-free mass, muscle cells are hypertrophied and capillaries in muscle are more widely spaced. We propose that these biophysical changes in muscle mediate, at least in part, the effects of obesity to produce a reduction in insulin sensitivity and the abnormal kinetics of insulin action found in the obese.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Obesity and insulin resistance: lessons learned from the Pima Indians. 306 59


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