Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the mechanism by which a selective increase in arterial insulin can suppress hepatic glucose production in vivo. Isotopic (3-3H-glucose) and arteriovenous difference methods were used in overnight-fasted, conscious dogs. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon infusions) was used to control the endocrine pancreas. Equilibration (100 min) and basal (40 min) periods were followed by a 180-min test period. In control dogs (n = 5), basal insulin delivery was continued throughout the study. In the other two groups, peripheral insulin was selectively increased at the beginning of the test period by stopping the portal insulin infusion and infusing insulin peripherally at twice the basal portal rate. One group (INS + FAT; n = 6) received an infusion of 20% intralipid + heparin (0.5 U x kg(-1) x min(-1)) to clamp the nonesterified fatty acid (NEFA) levels during hyperinsulinemia; the other group (INS; n = 7) received only saline during the experimental period. In the INS group, a selective increase in peripheral insulin of 84 pmol/l was achieved (36 +/- 6 to 120 +/- 24 pmol/l, last 30 min) while portal insulin was unaltered (84 +/- 18 pmol/l). In the INS + FAT group, a similar increase in peripheral insulin was achieved (36 +/- 6 to 114 +/- 6 pmol/l, last 30 min); again, portal insulin was unaltered (96 +/- 12 pmol/l). In the control group, basal insulin did not change. Glucagon and glucose remained near basal values in all protocols. In the INS group, NEFA levels dropped from 700 +/- 90 (basal) to 230 +/- 65 micromol/l (last 30 min; P > 0.05), but in the INS + FAT group changed minimally (723 +/- 115 [basal] to 782 +/- 125 micromol/l [last 30 min]). In the INS group, net hepatic glucose output dropped by 6.7 micromol x kg(-1) x min(-1) (P < 0.05), whereas in the INS + FAT group it dropped by 3.9 micromol x kg(-1) x min(-1) (P < 0.05). When insulin levels were not increased (i.e., in the control group), net hepatic glucose output dropped 1.7 micromol x kg(-1) x min(-1) (P < 0.05). In all groups, the net hepatic glucose output data were confirmed by the tracer-determined glucose production data. In the INS group, net hepatic gluconeogenic substrate uptake (alanine, glutamine, glutamate, glycerol, glycine, lactate, threonine, and serine) fell slightly (10.4 +/- 1.3 [basal] to 7.2 +/- 1.3 micromol x kg(-1) x min(-1) [last 30 min]), whereas in the INS + FAT group it did not change (7.3 +/- 1.5 [basal] to 7.4 +/- 0.6 micromol x kg(-1) x min(-1) [last 30 min]), and in the control group it increased slightly (9.6 +/- 1.3 [basal] to 10.3 +/- 1.4 micromol x kg(-1) x min(-1) [last 30 min). These results indicate that peripheral insulin's ability to regulate hepatic glucose production is partially linked to its inhibition of lipolysis. When plasma NEFA levels were prevented from falling during a selective arterial hyperinsulinemia, approximately 55% of insulin's inhibition of net hepatic glucose output (NHGO) was eliminated. The fall in NEFA levels brings about a redirection of glycogenolytically derived carbon within the hepatocyte such that there is an increase in lactate efflux and a corresponding decrease in NHGO.
Diabetes 1997 Feb
PMID:The role of fatty acids in mediating the effects of peripheral insulin on hepatic glucose production in the conscious dog. 900 Jun 93

Malnutrition is a serious complication in patients on long-term CAPD treatment. Accordingly, quantitative evaluation of nutritional status is a critical issue. This study aimed to assess nutritional status by dual photon energy x-ray absorptiometry (DEXA) in CAPD patients. Total lean body mass (D-TBM), right arm lean mass (D-RAM) and body fat percent (D-% FAT) measured by DEXA were compared with mid-arm muscle circumference (MAMC) and body fat percent (AP-% FAT) measured by anthropometrics (AP) in 51 CAPD patients. The subjects were stratified into groups by gender, age, duration on CAPD, and diabetes mellitus or non-diabetes. There was significant correlation between D-TBM, D-RAM and MAMC (r = 0.519, p = 0.001, r = 0.545, p = 0.001) or D-% FAT and AP-% FAT (r = 0.763, p = 0.0001). However, in the groups of females with over 50 years and over 48 months of dialysis duration, there was no correlation between D-TBM, D-RAM and MAMC. The DEXA method is useful in the quantitative evaluation of nutritional status of dialysis patients serially.
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PMID:[Evaluation of nutritional status of patients on continuous ambulatory peritoneal dialysis (CAPD) by dual photon energy X-ray absorptiometry (DEXA)]. 901 82

Much biochemical evidence has implicated rat adipocyte CD36 (FAT) in membrane binding and transport of long-chain fatty acids (FA). Expression of the mRNA favored tissues with active FA metabolism and was upregulated in vivo with diabetes and with high fat feeding. In culture, CD36 mRNA was a strong marker of preadipocyte differentiation and was modulated by the same factors effective on mRNAs coding for other proteins involved in FA metabolism. In preadipocytes, long-chain FA or 2-bromopalmitate but not short-chain FA strongly induced CD36 mRNA within 8 h to an optimum within 24 h. Removal of the FA resulted in a decay of CD36 mRNA with a half life of about 12 h. In differentiated adipocytes, levels of CD36 mRNA were downregulated by the 3': 5'-cyclic adenosine monophosphate, cAMP, analog, 8-(4-chlorophenylthio) adenosine, 8-CPT, at concentrations of 1-100 microM. The effect, observed within 6 h, was optimal after 18 h and independent of the action of 8-CPT to mobilize FA. Regulation of CD36 expression by factors effective on expression of other proteins implicated in FA metabolism is consistent with its role in membrane FA transport.
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PMID:Regulation of FAT/CD36 gene expression: further evidence in support of a role of the protein in fatty acid binding/transport. 925 Jun 3

Long-chain fatty acids (LCFAs) are an important energy source for many tissues. The dogma that LCFAs are freely diffusible has been challenged. It is now known that LCFAs are transported into many tissues. Our studies have shown that LCFAs are also transported into skeletal muscle and into the heart. In recent years a number of putative fatty acid transport proteins have been identified. These are known as plasma membrane fatty acid binding protein (FABPpm, 43 kDa), fatty acid translocase (FAT, 88 kDa) and fatty acid transporter protein (FATP, 63 kDa). All three proteins are present in skeletal muscle and in the heart. The existence of an LCFA transport system in muscle may be essential 1) to facilitate the rapid and regulatable transport of LCFA to meet the metabolic requirements of working muscles and 2) to cope with an increase in circulating LCFAs in some pathological conditions (e.g. diabetes). There is now some evidence that metabolic changes and chronically increased muscle activity can increase the transport of LCFAs and increase the expression of putative LCFA transporters.
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PMID:Skeletal muscle fatty acid transport and transporters. 978 26

We sought to ascertain whether pretreatment with troglitazone (20 days) could prevent acute free fatty acid (FFA)-induced insulin resistance in male Wistar rats. Animals were divided into three groups: 1) control, 2) FFA infusion alone (FFA1), and 3) thiazolidinedione (TZD)-treated + FFA infusion (FFA1). Days before a hyperinsulinemic-euglycemic clamp, all animals were cannulated in the jugular vein (infusion) and carotid artery (sampling). Animals were allowed 5 days to recover from surgery and fasted 12 h before the experiment. Glucose (variable), insulin (40 mU. kg(-1). min(-1)), and Liposyn (heparinized 10% lipid emulsion) infusions were initiated simultaneously and continued from 0-120 min. Steady-state glucose, 8.3 +/- 0.14 mmol/l, and insulin concentrations, 7.3 +/- 2.45 nmol/l, were the same between groups. Interestingly, steady-state FFA levels were significantly lower in animals pretreated with TZD compared with FFA alone (1.83 +/- 0.26 vs. 2.96 +/- 0.25 mmol/l; P = 0.009), despite matched intralipid infusion rates. A second group of TZD-treated animals (TZD + FFA2) were infused with intralipid at a higher infusion rate (44%) to match the arterial concentrations of FFA1. The glucose infusion and insulin-stimulated glucose disposal rates (GDRs) were significantly decreased (40%) for untreated Liposyn infused (FFA1) compared with control rats. In addition, insulin receptor substrate-1 (IRS-1) phosphorylation and IRS-1-associated phosphatidylinositol (PI) 3-kinase activity was significantly reduced, 30-50%, in FFA1 rats. TZD pretreatment prevented the FFA-induced decrement in insulin signaling. Fatty acid translocase (FAT/CD36) also was significantly reduced (56%) in untreated FFA1 rats after the clamp but remained identical to control values for TZD-treated rats. In conclusion, acutely elevated FFA levels 1) induced a significant reduction in tracer-determined GDR paralleled by impaired tyrosine phosphorylation of IRS-1 and reduced IRS-1-associated PI 3-kinase activity and 2) induced a significant reduction in FAT/CD36 total protein. TZD pretreatment prevented FFA-induced decrements in insulin action and prevented the reduction in FAT/CD36 protein.
Diabetes 2001 Oct
PMID:Thiazolidinedione treatment prevents free fatty acid-induced insulin resistance in male wistar rats. 1157 14

It is well described that excessive lipid metabolism can cause insulin resistance in both animals and humans, and this has been implicated as a causative factor in the development of insulin resistance and type 2 diabetes in humans. Recently, we have shown that intravenous lipid emulsion (liposyn) infusion during a 120-min euglycemic-hyperinsulinemic clamp led to significant reductions in insulin action and fatty acid translocase (FAT/CD36) skeletal muscle protein expression. After reviewing the literature, it became evident that essentially all past studies, including our own, were conducted in male animals. Therefore, to determine whether there were sex determinants of fat-induced insulin resistance, we assessed the impact of free fatty acid (FFA) elevation on insulin action in female rats. Here, we report that a fourfold elevation in plasma FFA concentration induced a 40% reduction in the insulin-stimulated glucose disposal rate, a 30% decline in insulin-stimulated skeletal muscle insulin substrate receptor-1 (IRS-1) phosphorylation, a 48% decrease in IRS-1-associated phosphatidylinositol (PI) 3-kinase activity, and a 50% reduction in muscle FAT/CD36 protein expression in male rats. In striking contrast, we found no effect of FFA elevation to cause insulin resistance, changes in IRS-1/PI 3-kinase, or FAT/CD36 protein levels in female animals. Our findings indicate that female animals are protected from lipid-induced reductions in insulin action.
Diabetes 2002 Jun
PMID:Female rats do not exhibit free fatty acid-induced insulin resistance. 1203 80

We have examined the effects of streptozotocin (STZ)-induced diabetes (moderate and severe) on fatty acid transport and fatty acid transporter (FAT/CD36) and plasma membrane-bound fatty acid binding protein (FABPpm) expression, at the mRNA and protein level, as well as their plasmalemmal localization. These studies have shown that, with STZ-induced diabetes, 1) fatty acid transport across the plasma membrane is increased in heart, skeletal muscle, and adipose tissue and is reduced in liver; 2) changes in fatty acid transport are generally not associated with changes in fatty acid transporter mRNAs, except in the heart; 3) increases in fatty acid transport in heart and skeletal muscle occurred with concomitant increases in plasma membrane FAT/CD36, whereas in contrast, the increase and decrease in fatty acid transport in adipose tissue and liver, respectively, were accompanied by concomitant increments and reductions in plasma membrane FABPpm; and finally, 4) the increases in plasma membrane transporters (FAT/CD36 in heart and skeletal muscle; FABPpm in adipose tissue) were attributable to their increased expression, whereas in liver, the reduced plasma membrane FABPpm appeared to be due to its relocation within the cell in the face of slightly increased expression. Taken together, STZ-induced changes in fatty acid uptake demonstrate a complex and tissue-specific pattern, involving different fatty acid transporters in different tissues, in combination with different underlying mechanisms to alter their surface abundance.
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PMID:Changes in fatty acid transport and transporters are related to the severity of insulin deficiency. 1216 56

The existence of an intracellular pool of fatty acid translocase (FAT/CD36), an 88-kDa membrane transporter for long-chain fatty acids (FAs), and the ability of insulin to induce translocation events prompted us to investigate the direct effects of insulin on cellular uptake of FA by the heart. Insulin (0.1 nmol/l and higher) increased FA uptake by isolated rat cardiac myocytes by 1.5-fold. This insulin-induced increase in FA uptake was completely blocked by phloretin, sulfo-N-succinimidylpalmitate (SSP), and wortmannin, indicating the involvement of FAT/CD36 and the dependence on phosphatidylinositol-3 (PI-3) kinase activation. Subcellular fractionation of insulin-stimulated cardiac myocytes demonstrated a 1.5-fold increase in sarcolemmal FAT/CD36 and a 62% decrease in intracellular FAT/CD36 with parallel changes in subcellular distribution of GLUT4. Induction of cellular contractions upon electrostimulation at 4 Hz enhanced cellular FA uptake 1.6-fold, independent of PI-3 kinase. The addition of insulin to 4 Hz-stimulated cells further stimulated FA uptake to 2.3-fold, indicating that there are at least two functionally independent intracellular FAT/CD36 pools, one recruited by insulin and the other mobilized by contractions. In conclusion, we have demonstrated a novel role of insulin in cardiac FA utilization. Malfunctioning of insulin-induced FAT/CD36 translocation may be involved in the development of type 2 diabetic cardiomyopathies.
Diabetes 2002 Oct
PMID:Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36. 1235 56

Long chain fatty acid uptake across the plasma membrane occurs, in part, via a protein-mediated process involving a number of fatty acid binding proteins known as fatty acid transporters. A critical step in furthering the understandings of fatty acid transport was the discovery that giant vesicles, prepared from tissues such as muscle and heart, provided a suitable system for measuring fatty acid uptake. These vesicles are large (10-15 microm diameter), are oriented fully right side out, and contain cytosolic FABP in the lumen, which acts as a fatty acid sink, while none of the fatty acid taken up is metabolized or associated with the plasma membrane. The key fatty acid transporters FAT/CD36 and FABPpm are expressed in muscle and heart and their plasma membrane content is positively correlated with rates of fatty acid transport. These transporters are regulated acutely (within minutes) and chronically (days). For instance, both muscle contraction and insulin can translocate FAT/CD36 from an intracellular pool to the plasma membrane, thereby increasing fatty acid transport. With obesity, fatty acid transport is increased along with a concomitant increase in plasmalemmal FAT/CD36 (heart, muscle) and FABPpm (heart only), but without change in the expression of these transporters. This latter observation suggests that some of the fatty acid transporters are permanently relocated to the plasma membrane. In other studies it also appears that fatty acid transport rates are altered in a reciprocal manner to glucose transport. Since disorders in lipid metabolism appear to be an important factor contributing to the etiology of a number of common human diseases such as diabetes and obesity, our evidence that protein-mediated fatty acid transport is a key step in lipid metabolism allows the speculation that malfunctioning of the fatty acid transport process could be a common critical factor in the pathogenesis of these diseases.
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PMID:Regulation of fatty acid transport and membrane transporters in health and disease. 1247 84

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


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