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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The heart, like other organs, possesses an internal circadian clock. These clocks provide the selective advantage of anticipation, enabling the organ to prepare for a given stimulus, thereby optimizing the appropriate response. The heart in diabetes is associated with alterations in morphology, gene expression, metabolism and contractile performance. The present study investigated whether diabetes also alters the circadian clock in the heart. Insulin-dependent diabetes mellitus was induced in rats by treatment with streptozotocin (STZ; 65 mg/kg). STZ increased humoral (glucose and non-esterified fatty acids) and heart gene expression (myosin heavy chain beta, pyruvate dehydrogenase kinase 4 and uncoupling protein 3) markers of diabetes. The circadian patterns of gene expression of seven components of the mammalian clock (bmal1, clock, cry1, cry2, per1, per2 and per3), as well as three clock output genes (dbp, hlf and tef), were compared in hearts isolated from control and STZ-induced diabetic rats. All components of the clock investigated possessed circadian rhythms of gene expression. In the hearts isolated from STZ-induced diabetic rats, the phases of these circadian rhythms were altered (approximately 3 h early) compared to those observed for control hearts. The clock in the heart has therefore lost normal synchronization with its environment during diabetes. Whether this loss of synchronization plays a role in the development of contractile dysfunction of the heart in diabetes remains to be determined.
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PMID:Alterations of the circadian clock in the heart by streptozotocin-induced diabetes. 1185 61

In humans, skeletal muscle is a major site of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) expression, but its function in this tissue is unclear. We investigated the role of hPPAR-alpha in regulating muscle lipid utilization by studying the effects of a highly selective PPAR-alpha agonist, GW7647, on [(14)C]oleate metabolism and gene expression in primary human skeletal muscle cells. Robust induction of PPAR-alpha protein expression occurred during muscle cell differentiation and corresponded with differentiation-dependent increases in oleate oxidation. In mature myotubes, 48-h treatment with 10-1,000 nmol/l GW7647 increased oleate oxidation dose-dependently, up to threefold. Additionally, GW7647 decreased oleate esterification into myotube triacylglycerol (TAG), up to 45%. This effect was not abolished by etomoxir, a potent inhibitor of beta-oxidation, indicating that PPAR-alpha-mediated TAG depletion does not depend on reciprocal changes in fatty acid catabolism. Consistent with its metabolic actions, GW7647 induced mRNA expression of mitochondrial enzymes that promote fatty acid catabolism; carnitine palmityltransferase 1 and malonyl-CoA decarboxylase increased approximately 2-fold, whereas pyruvate dehydrogenase kinase 4 increased 45-fold. Expression of several genes that regulate glycerolipid synthesis was not changed by GW7647 treatment, implicating involvement of other targets to explain the TAG-depleting effect of the compound. These results demonstrate a role for hPPAR-alpha in regulating muscle lipid homeostasis.
Diabetes 2002 Apr
PMID:Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells. 1191 5

During short-term fasting, substrate utilization in skeletal muscle shifts from predominantly carbohydrate to fat as a means of conserving glucose. To examine the potential influence of short-term fasting and refeeding on transcriptional regulation in skeletal muscle, muscle biopsies were obtained from nine male subjects at rest, after 20 h of fasting, and 1 h after consuming either a high-carbohydrate (CHO trial) or a low-carbohydrate (FAT trial) meal. Fasting induced an increase in transcription of the pyruvate dehydrogenase kinase 4 (PDK4) (10-fold), lipoprotein lipase (LPL) ( approximately 2-fold), uncoupling protein 3 (UCP3) ( approximately 5-fold), and carnitine palmitoyltransferase I (CPT I) ( approximately 2.5-fold) genes. Surprisingly, transcription of PDK4 and LPL increased further in response to refeeding (both trials) to more than 50-fold and 6- to 10-fold, respectively, over prefasting levels. However, responses varied among subjects with two subjects in particular displaying far greater activation of PDK4 (>100-fold) and LPL (>20-fold) than the other subjects (mean approximately 8-fold and approximately 2-fold, respectively). Transcription of UCP3 decreased to basal levels after the CHO meal but remained elevated after the FAT meal, whereas CPT I remained elevated after both refeeding meals. The present findings demonstrate that short-term fasting/refeeding in humans alters the transcription of several genes in skeletal muscle related to lipid metabolism. Marked heterogeneity in the transcriptional response to the fasting/refeeding protocol suggests that individual differences in genetic profile may play an important role in adaptive molecular responses to metabolic challenges.
Diabetes 2003 Mar
PMID:Effect of short-term fasting and refeeding on transcriptional regulation of metabolic genes in human skeletal muscle. 1260 5

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in later life. We have developed a model of uteroplacental insufficiency, a common cause of intrauterine growth retardation, in the rat. Early in life, the animals are insulin resistant and by 6 mo of age they develop diabetes. Glycogen content and insulin-stimulated 2-deoxyglucose uptake were significantly decreased in muscle from IUGR rats. IUGR muscle mitochondria exhibited significantly decreased rates of state 3 oxygen consumption with pyruvate, glutamate, alpha-ketoglutarate, and succinate. Decreased pyruvate oxidation in IUGR mitochondria was associated with decreased ATP production, decreased pyruvate dehydrogenase activity, and increased expression of pyruvate dehydrogenase kinase 4. Such a defect in IUGR mitochondria leads to a chronic reduction in the supply of ATP available from oxidative phosphorylation. Impaired ATP synthesis in muscle compromises energy-dependent GLUT4 recruitment to the cell surface, glucose transport, and glycogen synthesis, which contribute to insulin resistance and hyperglycemia of type 2 diabetes.
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PMID:Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats. 1263 57

Type 2 diabetes has been related to a decrease of mitochondrial DNA (mtDNA) content. In this study, we show increased expression of the peroxisome proliferator-activated receptor-alpha (PPARalpha) and its target genes involved in fatty acid metabolism in skeletal muscle of Zucker Diabetic Fatty (ZDF) (fa/fa) rats. In contrast, the mRNA levels of genes involved in glucose transport and utilization (GLUT4 and phosphofructokinase) were decreased, whereas the expression of pyruvate dehydrogenase kinase 4 (PDK-4), which suppresses glucose oxidation, was increased. The shift from glucose to fatty acids as the source of energy in skeletal muscle of ZDF rats was accompanied by a reduction of subunit 1 of complex I (NADH dehydrogenase subunit 1, ND1) and subunit II of complex IV (cytochrome c oxidase II, COII), two genes of the electronic transport chain encoded by mtDNA. The transcript levels of PPARgamma Coactivator 1 (PGC-1) showed a significant reduction. Treatment with troglitazone (30 mg/kg/day) for 15 days reduced insulin values and reversed the increase in PDK-4 mRNA levels, suggesting improved insulin sensitivity. In addition, troglitazone treatment restored ND1 and PGC-1 expression in skeletal muscle. These results suggest that troglitazone may avoid mitochondrial metabolic derangement during the development of diabetes mellitus 2 in skeletal muscle.
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PMID:Impaired expression of NADH dehydrogenase subunit 1 and PPARgamma coactivator-1 in skeletal muscle of ZDF rats: restoration by troglitazone. 1456 25

Cardiac and skeletal muscle both respond to elevated fatty acid availability by increasing fatty acid oxidation, an effect mediated in large part by peroxisome proliferator-activated receptor-alpha (PPAR alpha). We hypothesized that cardiac and skeletal muscle alter their responsiveness to fatty acids over the course of the day, allowing optimal adaptation when availability of this substrate increases. In the current study, pyruvate dehydrogenase kinase 4 (pdk4) was utilized as a representative PPAR alpha-regulated gene. Opposing diurnal variations in pdk4 expression were observed in cardiac and skeletal muscle isolated from the ad libitum-fed rat; pdk4 expression peaked in the middle of the dark and light phases, respectively. Elevation of circulating fatty acid levels by high-fat feeding, fasting, and streptozotocin-induced diabetes increased pdk4 expression in both heart and soleus muscle. Highest levels of induction were observed during the dark phase, regardless of muscle type or intervention. Specific activation of PPAR alpha with WY-14643 rapidly induced pdk4 expression in heart and soleus muscle. Highest levels of induction were again observed during the dark phase. The same pattern of induction was observed for the PPAR alpha-regulated genes malonyl-CoA decarboxylase and uncoupling protein 3. Investigation into the potential mechanism(s) for these observations exposed a coordinated upregulation of transcriptional activators of the PPAR alpha system during the night, with a concomitant downregulation of transcriptional repressors in both muscle types. In conclusion, responsiveness of cardiac and skeletal muscle to fatty acids exhibits a marked diurnal variation. These observations have important physiological and pathophysiological implications, ranging from experimental design to pharmacological treatment of patients.
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PMID:Diurnal variations in the responsiveness of cardiac and skeletal muscle to fatty acids. 1529 29

Energy restriction (ER) causes metabolic improvement in the prediabetic and diabetic state. Little information exists on the mechanism of action of ER, for example, on the changes at the transcriptional gene level in insulin-sensitive tissues. To gain further insight, we have investigated changes in gene expressions in skeletal muscle, liver, fat, and pancreatic islets after ER in male Zucker diabetic fatty rats. Eighteen Zucker diabetic fatty rats were divided at the age of 7 weeks into a control group (ad libitum diet) and an ER group (30% ER compared with the control group). Blood glucose, weight, and food intake were measured weekly. After 5 weeks, blood samples, and skeletal muscle, liver, visceral fat (epididymal fat pads), and islets tissue were collected. Gene expression was quantified with high-density oligonucleotide, microarray GeneChip technology. ER ameliorated the development of hyperglycemia, increased the levels of plasma insulin, and reduced plasma total cholesterol and the glucagon-insulin ratio (P < .05). In skeletal muscle, the expression of 55 genes increased and 245 decreased involving genes related to glucose metabolism (eg, phosphorylase kinase, pyruvate dehydrogenase kinase 4), lipid metabolism (eg, carnitine palmitoyltransferase 1, fatty acid transporter), and signaling pathways (eg, mitogen-activated protein kinases, protein kinase C). In the liver, the expression of 123 genes increased and 103 decreased involving genes related primarily to lipid metabolism. In pancreatic islets, the expression of 110 genes increased and that of 127 decreased, whereas in visceral fat, the expression of 279 genes increased and that of 528 decreased. ER counteracts the development of diabetes and causes changes in the expression of multiple genes involved in glucose and lipid metabolism in skeletal muscle, liver, and pancreatic islets, which may play an important role for the prevention of diabetes.
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PMID:Energy restriction prevents the development of type 2 diabetes in Zucker diabetic fatty rats: coordinated patterns of gene expression for energy metabolism in insulin-sensitive tissues and pancreatic islets determined by oligonucleotide microarray analysis. 1632 18

Pancreatic preservation is an important part of diabetes management that may occur with improved peripheral insulin sensitivity and attenuated low-grade adipose tissue inflammation. The objective of the current study was to determine the response of obese, insulin-resistant fa/fa Zucker rats vs lean controls to dietary conjugated linoleic acid (CLA) supplementation with respect to pancreatic islet size, insulin resistance, and markers of inflammation and adipose glucose uptake. Six-week-old fa/fa and lean Zucker rats (n = 20 per genotype) were fed either a 1.5% CLA mixture or control diet for 8 weeks. Oral glucose tolerance testing was conducted at 7.5 weeks. Fasting serum haptoglobin, insulin, and C-peptide were assayed, and select messenger RNA (mRNA) and protein markers of inflammation and glucose metabolism were measured in adipose and liver tissues. CLA-fed fa/fa Zucker rats had smaller islet cell size, improved oral glucose tolerance and insulinemia, and attenuated serum haptoglobin levels compared with control-fed fa/fa Zucker rats, despite no differences in body weight and a slightly higher visceral adipose mass. CLA did not alter insulin sensitivity or islet size in lean Zucker rats. The CLA-fed fa/fa rats also had greater adipose glucose transporter-4 mRNA and less adipose tumor necrosis factor alpha mRNA and protein compared with control-fed fa/fa rats. In contrast, other markers of inflammation and glucose metabolism including adipose macrophage inflammatory factor, macrophage inflammatory protein-2, and liver pyruvate carboxylase and pyruvate dehydrogenase kinase 4 were not significantly changed. These results suggest that CLA supplementation preserved pancreatic function in conjunction with improved peripheral glucose use and reduced inflammation in fa/fa Zucker rats.
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PMID:Dietary conjugated linoleic acid preserves pancreatic function and reduces inflammatory markers in obese, insulin-resistant rats. 1716 Dec 37

Obesity and diabetes are associated with increased fatty acid availability in excess of muscle fatty acid oxidation capacity. This mismatch is implicated in the pathogenesis of cardiac contractile dysfunction and also in the development of skeletal-muscle insulin resistance. We tested the hypothesis that 'Western' and high fat diets differentially cause maladaptation of cardiac- and skeletal-muscle fatty acid oxidation, resulting in cardiac contractile dysfunction. Wistar rats were fed on low fat, 'Western' or high fat (10, 45 or 60% calories from fat respectively) diet for acute (1 day to 1 week), short (4-8 weeks), intermediate (16-24 weeks) or long (32-48 weeks) term. Oleate oxidation in heart muscle ex vivo increased with high fat diet at all time points investigated. In contrast, cardiac oleate oxidation increased with Western diet in the acute, short and intermediate term, but not in the long term. Consistent with fatty acid oxidation maladaptation, cardiac power decreased with long-term Western diet only. In contrast, soleus muscle oleate oxidation (ex vivo) increased only in the acute and short term with either Western or high fat feeding. Fatty acid-responsive genes, including PDHK4 (pyruvate dehydrogenase kinase 4) and CTE1 (cytosolic thioesterase 1), increased in heart and soleus muscle to a greater extent with feeding a high fat diet compared with a Western diet. In conclusion, we implicate inadequate induction of a cassette of fatty acid-responsive genes, and impaired activation of fatty acid oxidation, in the development of cardiac dysfunction with Western diet.
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PMID:Western diet, but not high fat diet, causes derangements of fatty acid metabolism and contractile dysfunction in the heart of Wistar rats. 1755 Mar 47

Type 2 diabetes is characterized by a progressive resistance of peripheral tissues to insulin. Recent data have established the lipid phosphatase SH2 domain-containing inositol phosphatase 2 (SHIP2) as a critical negative regulator of insulin signal transduction. Mutations in the SHIP2 gene are associated with type 2 diabetes. Here, we used hyperglycemic and hyperinsulinemic KKA(y) mice to gain insight into the signaling events and metabolic changes triggered by SHIP2 inhibition in vivo. Liver-specific expression of a dominant-negative SHIP2 mutant in KKA(y) mice increased basal and insulin-stimulated Akt phosphorylation. Protein levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase were significantly reduced, and consequently the liver produced less glucose through gluconeogenesis. Furthermore, SHIP2 inhibition improved hepatic glycogen metabolism by modulating the phosphorylation states of glycogen phosphorylase and glycogen synthase, which ultimately increased hepatic glycogen content. Enhanced glucokinase and reduced pyruvate dehydrogenase kinase 4 expression, together with increased plasma triglycerides, indicate improved glycolysis. As a consequence of the insulin-mimetic effects on glycogen metabolism, gluconeogenesis, and glycolysis, the liver-specific inhibition of SHIP2 improved glucose tolerance and markedly reduced prandial blood glucose levels in KKA(y) mice. These results support the attractiveness of a specific inhibition of SHIP2 for the prevention and/or treatment of type 2 diabetes.
Diabetes 2007 Sep
PMID:Normalization of prandial blood glucose and improvement of glucose tolerance by liver-specific inhibition of SH2 domain containing inositol phosphatase 2 (SHIP2) in diabetic KKAy mice: SHIP2 inhibition causes insulin-mimetic effects on glycogen metabolism, gluconeogenesis, and glycolysis. 1759 4


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