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

To determine the dose-response characteristics of impaired glucose oxidation in non-insulin-dependent diabetes mellitus (NIDDM), indirect calorimetry was performed on eight matched control and NIDDM subjects during the basal state and during three glucose clamps at insulin infusion rates of 150, 300, and 1,500 pmol.m-2.min-1. Hyperglycemia was used to achieve matched rates of glucose uptake at each insulin infusion. Glucose uptake in the basal state was greater in NIDDM [3.75 +/- 0.23 vs. 2.50 +/- 0.10 mg.kg fat-free mass (FFM)-1.min-1, P less than 0.005] but was similar at approximately 8, 12, and 26 mg.kg FFM-1.min-1 at each insulin infusion. Basal protein oxidation, fat oxidation, and plasma free fatty acids were similar and equally sensitive to suppression by insulin in both groups. Glucose oxidation was reduced 20-26%, and circulating lactate increased 50-90% at physiological but not at pharmacological insulin concentrations in NIDDM. The dose-response relationship between serum insulin and glucose oxidation was right shifted in NIDDM with half-maximal activation at 368 +/- 91 vs. 179 +/- 27 pM in controls (P less than 0.05). In conclusion, glucose oxidation is reduced at physiological insulin concentrations in NIDDM and cannot be explained by concomitant obesity, increased fat oxidation, or reduced glucose uptake but results from impaired sensitivity to stimulation by insulin, possibly at pyruvate dehydrogenase.
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PMID:Dose-response characteristics of impaired glucose oxidation in non-insulin-dependent diabetes mellitus. 185 69

This study investigated possible mechanisms underlying insulin resistance in the New Zealand Obese (NZO) mouse, an animal model for obese, non-insulin-dependent diabetes. Insulin binding, mediator generation, and action both at the level of glucose utilization and enzyme modulation were compared in adipocytes from lean control New Zealand Chocolate (NZC) mice and NZO mice during the development of the syndrome. Abnormalities of insulin stimulation of glucose transport and utilization in NZO mouse adipocytes were found which involved both decreased sensitivity and responsiveness to insulin. The defects were evident at an early age (4 weeks) and could not be attributed to differences in nonstimulated glucose metabolism, which was similar in the control NZC and obese NZO strains of mouse. Insulin binding to its receptor was only moderately decreased in adipocytes of NZO mice. Pyruvate dehydrogenase (PDH) activity of NZO mouse adipocytes was totally unresponsive to insulin in contrast to the impaired but still significant insulin stimulation of glucose transport and utilization, suggesting a postreceptor defect at the level of insulin stimulation of this enzyme. Insulin stimulated the production of a low molecular weight factor which activated pyruvate dehydrogenase in NZC mouse adipocytes (insulin mediator) but, paradoxically, caused a decrease in mediator production or activity in adipocytes from NZO mice. Thus, insulin either inhibited mediator production or stimulated generation of an inhibitory mediator in adipocytes from this strain. No evidence for the latter mechanism was found. This study demonstrates in adipocytes of NZO mice: (1) a receptor defect and (2) a postreceptor defect of insulin action at the level of pyruvate dehydrogenase activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired insulin action in adipocytes of New Zealand obese mice: a role for postbinding defects in pyruvate dehydrogenase and insulin mediator activity. 305 Mar 67

To determine whether 1) insulin stimulates pyruvate dehydrogenase (PDH) and glycogen synthase (GS) in isolated human adipocytes and 2) adipocytes from subjects with obesity or noninsulin-dependent diabetes mellitus (NIDDM) are resistant to the effects of insulin, PDH and GS were assayed in adipocytes from 11 control, 8 obese, and 9 NIDDM subjects. Basal PDH activities were 123 +/- 20, 129 +/- 21, and 128 +/- 25 pmol pyruvate oxidized/min per 2 X 10(5) adipocytes in these groups. Insulin stimulated PDH activity to a maximum of 223 +/- 38 pmol/min per 2 X 10(5) in adipocytes from control subjects, but did not significantly increase values from obese subjects. Insulin significantly decreased PDH activity in cells from NIDDM subjects (99 +/- 20 pmol/min per 2 X 10(5) cells, P less than 0.05). PDH activity assayed with high magnesium and calcium concentrations was significantly stimulated by insulin in adipocytes from control, but not obese or NIDDM subjects. GS assayed with 1 mM glucose 6-phosphate did not differ significantly among control, obese, or NIDDM subjects (446 +/- 110, 451 +/- 156, and 291 +/- 35 pmol incorporated into glycogen, respectively). Insulin significantly stimulated glycogen synthase in all three groups (827 +/- 179, 764 +/- 177, and 569 +/- 51 pmol incorporated) to a similar extent. Glycogen synthase assayed with 10 mM glucose 6-phosphate was decreased in NIDDM (1,335 +/- 131 pmol incorporated) compared with obese or control subjects (2,512 +/- 451 and 2,239 +/- 230 pmol incorporated, respectively, P less than 0.01).
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PMID:Adipocyte glycogen synthase and pyruvate dehydrogenase in obese and type II diabetic subjects. 309 77

The amount of pyruvate dehydrogenase in the active form (PDHa) was increased 1.7-fold compared with controls in heart muscle of mice 1 week after induction of obesity with a single injection of gold-thioglucose. At 4 weeks post injection, the amount of PDHa was decreased to 32% of control, a value which was observed in later stages of the obesity syndrome. In contrast, liver PDHa was increased and remained at an increased activity during the development of obesity. Despite normal post-prandial serum insulin contents, liver membrane insulin-receptor numbers were decreased 1 week after gold-thioglucose injection, and there was no change in receptor affinity. The decrease in heart PDHa in the obese animals was reversed by a single dose of 2-tetradecylglycidic acid, but this inhibitor of mitochondrial fatty acid oxidation did not affect liver PDHa in these animals. These early and diverse changes in PDHa argue for a multifactorial aetiology in the development of the whole-body insulin resistance seen in older gold-thioglucose-treated obese animals.
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PMID:The activity of the pyruvate dehydrogenase complex in heart and liver from mice during the development of obesity and insulin resistance. 311 55

Pyruvate dehydrogenase complex activity is the major determinant of glucose oxidation in animal cells. Tissue glucose oxidation is reduced in obesity and states of insulin resistance and alternate fuels are utilized for energy and pyruvate dehydrogenase activity is reduced in cardiac muscle in obesity. The effect of four different diets (standard laboratory chow, high-carbohydrate, high-protein and high-fat) on weight gain, cardiac pyruvate dehydrogenase activity (PDHa) and serum insulin, glucose and free fatty acids was studied in the gold thioglucose obese mouse. All four diets produced significant weight gain in the gold thioglucose injected animal. Cardiac PDHa was influenced by both obesity and diet composition. The obese chow-fed animals had significantly reduced PDHa. On high-carbohydrate and high-protein feeding lean controls had a significant decrease in cardiac PDHa compared to chow-fed controls, but only in high-carbohydrate-fed animals was this further reduced by obesity. High-fat feeding produced a rapid and almost complete suppression of PDHa in both lean and obese animals. Serum insulin, glucose and free fatty acids were also affected by diet as well as obesity. The highest serum insulins were found in chow-fed obese animals whereas the highest serum glucoses were in high-carbohydrate-fed obese animals. Hyperinsulinaemia did not develop in the high-fat-fed obese animal, but the highest serum free fatty acids were found in high-fat feeding. It is concluded that both diet composition and obesity affect cardiac PDHa and therefore glucose utilization in this tissue. Insulin resistance in the acute stages of obesity development is also affected by diet composition.
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PMID:The effect of diet composition on weight gain and pyruvate dehydrogenase activity in heart muscle in the gold thioglucose obese mouse. 312 9

The proportion of pyruvate dehydrogenase (PDH) complex in the active dephosphorylated form was decreased (compared with fed lean control mice) in heart muscle mitochondria after the induction of obesity with gold-thioglucose (by 54%) or starvation of lean mice for 48 h (by 81%). The effects of obesity to inactivate PDH complex were demonstrable 4 weeks after administration of gold-thioglucose, and occurred despite significant hyperinsulinaemia in obese animals. Phosphorylation and inactivation of PDH complex in mouse heart muscle in starvation was attributed to a stable increase (2.7-fold) in the activity of PDH kinase as measured in extracts of mitochondria mediated by increased specific activity of a protein activator of PDH kinase (KAP) [Denyer, Kerbey & Randle (1986) Biochem. J. 239, 347-354]. In obese mice no such increase in kinase activity was observed, and we conclude that phosphorylation and inactivation of PDH complex in heart muscle in obesity is not mediated by KAP, but rather is a consequence of increased lipid oxidation.
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PMID:Inactivation of pyruvate dehydrogenase complex in heart muscle mitochondria of gold-thioglucose-induced obese mice is not due to a stable increase in activity of pyruvate dehydrogenase kinase. 313 85

The influence of obesity on myocardial function and metabolism was studied in obese (fa/fa) and thin (Fa/Fa) Zucker rats using the isolated perfused heart as model. Cardiac performance of obese Zucker rats was not impaired. Instead, left ventricular pressure and contractility were increased as compared to controls. In agreement with these findings, creatine phosphate and the ratios of ATP/ADP and creatine phosphate creatine were elevated. The uptake and the conversion of glucose by hearts of obese Zucker rats were impaired. Insulin stimulated the uptake and oxidation of glucose. However, the responsiveness of these processes to insulin was diminished. Lipolysis of endogenous lipids was accelerated severalfold in obesity. Inhibition of fatty acid oxidation by a specific carnitine palmitoyl-transferase inhibitor, phenylalkyloxirane carboxylic acid (POCA), led to a slow rate of lipolysis, and to an acceleration of glucose oxidation and of the basal, noninsulin-dependent uptake of glucose. In the presence of POCA, insulin had, however, no additional stimulatory effect on the glucose uptake by hearts of obese rats. In contrast to hearts of ketotic, acutely diabetic rats where POCA fully restored myocardial responsiveness of glucose uptake and conversion to insulin, in hearts of obese rats only a shift in the glucose pathway from glycolytic formation of lactate and pyruvate to oxidation to CO2 was observed. Thus, POCA can be used as a tool to distinguish different forms of insulin resistance in obesity: 1) a lipid metabolism-dependent defect--presumably an inhibition of phosphofructokinase and pyruvate dehydrogenase by metabolites of fatty acid oxidation, influenced by inhibition of carnitine palmitoyltransferasei, and 2) a lipid metabolism-independent defect in the activation of uptake of glucose and glycogen synthesis by insulin not affected by POCA.
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PMID:Different types of postinsulin receptor defects contribute to insulin resistance in hearts of obese Zucker rats. 373 68

An insulin-sensitive subcellular system was developed from rat adipocytes consisting of plasma membranes and mitochondria. Direct addition of insulin, concanavalin A or anti-insulin receptor antibody to this system resulted in the production of a mediator substance from the plasma membrane that caused dephosphorylation of the alpha subunit of pyruvate dehydrogenase in the mitochondria with concomitant activation of the enzyme. The mediator activated pyruvate dehydrogenase by activating the pyruvate dehydrogenase phosphatase and not by inhibiting the pyruvate dehydrogenase kinase. This was similar to the mechanism by which insulin causes activation of the enzyme in the intact cell. The insulin-sensitive mediator material from the adipocyte plasma membrane was acid-stable with a molecular weight of 1,000 to 1,500. Our laboratory has shown that the mediator that activates pyruvate dehydrogenase was present in intact adipocytes, hepatoma cells, and IM-9 lymphocytes. Insulin altered the amount or activity of the mediator consistent with the effect of the hormone on the cell. Other laboratories have shown similar effects on skeletal muscle and liver. We have shown the mediator to mimic insulin action on the low Km cyclic adenosine monophosphate (AMP) phosphodiesterase and the (calcium++-magnesium++)-adenosine triphosphatase (Ca++-Mg++)-ATPase of adipocyte plasma membranes in addition to pyruvate dehydrogenase. Other laboratories have shown the mediator to activate glycogen synthase. A body of direct and indirect evidence exists that demonstrates that more than one mediator exists. The chemical nature of the mediator is unknown but probably represents a new family of intracellular mediators of hormone action. These mediators may have clinical relevance in postreceptor defects of obesity and type II diabetes (noninsulin-dependent diabetes mellitus).
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PMID:The chemical mediators of insulin action: possible targets for postreceptor defects. 633 85

The proportion of active, dephosphorylated, pyruvate dehydrogenase complex was decreased in the mouse heart by obesity (by 56%), and this decrease in enzyme activity persisted during preparation and extraction of heart mitochondria. Phosphorylation and inactivation of pyruvate dehydrogenase may be a major factor in mediating the inhibitory effects of obesity on glucose oxidation in muscle, and this may represent an important mechanism in the development and/or expression of cellular insulin-resistance.
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PMID:Proportion of active dephosphorylated pyruvate dehydrogenase complex in heart and isolated heart mitochondria is decreased in obese hyperinsulinaemic mice. 642 Dec 78

Changes of the pyruvate dehydrogenase complex in liver and epididymal fat pad were examined longitudinally in obese mice (C57BL/6J-ob/ob) and their lean controls as a function of age. Total pyruvate dehydrogenase in liver was expressed on several reference bases because of differences in hepatic cellularity and protein content between obese mice and their age-matched lean controls. When total hepatic pyruvate dehydrogenase was expressed on a protein basis, the enzyme activity was elevated in obese mice older than 28 weeks in age when compared to lean controls of a similar age. However, when expressed on a DNA basis, total pyruvate dehydrogenase activity in livers of obese mice up to 10 weeks in age was increased when compared to the age-matched lean control. The proportion of hepatic pyruvate dehydrogenase in the active form was also augmented significantly in obese mice from 5 to 28 weeks of age. In 18-week-old obese mice, the proportion of total pyruvate dehydrogenase in the active form of adipose tissue was significantly higher than that of the lean controls. When expressed on a DNA basis, total pyruvate dehydrogenase in the fat pad was also increased in obese mice up to 10 weeks in age when compared to age-matched controls. Total pyruvate dehydrogenase activity in the epididymal fat pad was higher in obese mice than the lean controls in animals as old as 32 weeks in age when the enzyme activity was expressed per 100 g body weight. The increase in the active form and total activity of pyruvate dehydrogenase in both liver and epididymal fat pad during the dynamic early phase of obesity would augment the capacity for acetyl-coenzyme A formation necessary in the support of an accelerated lipogenesis and fat deposition.
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PMID:Age-related changes in liver and adipose tissue pyruvate dehydrogenase of genetically obese mice. 671 96


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