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

Questions concerning whether malonyl-CoA is regulated in human muscle and whether malonyl-CoA modulates fatty acid oxidation are still unanswered. To address these questions, whole-body fatty acid oxidation and the concentration of malonyl-CoA, citrate, and malate were determined in the vastus lateralis muscle of 16 healthy nonobese Swedish men during a sequential euglycemic-hyperinsulinemic clamp. Insulin was infused at rates of 0.25 and 1.0 mU x kg(-1) x min(-1), and glucose was infused at rates of 2.0 +/- 0.2 and 8.1 +/- 0.7 mg x kg(-1) x min(-1), respectively. During the low-dose insulin infusion, whole-body fatty acid oxidation, as determined by indirect calorimetry, decreased by 22% from a basal rate of 0.94 +/- 0.06 to 0.74 +/- 0.07 mg x kg(-1) x min(-1) (P = 0.005), but no increase in malonyl-CoA was observed. In contrast, during the high-dose insulin infusion, malonyl-CoA increased from 0.20 +/- 0.01 to 0.24 +/- 0.01 nmol/g (P < 0.001), and whole-body fatty acid oxidation decreased by an additional 41% to 0.44 +/- 0.06 mg x kg(-1) x min(-1) (P < 0.001). The increase in malonyl-CoA was associated with 30-50% increases in the concentrations of citrate (102 +/- 6 vs. 137 +/- 7 nmol/g, P < 0.001), an allosteric activator of the rate-limiting enzyme in the malonyl-CoA formation, acetyl-CoA carboxylase, and malate (80 +/- 6 vs. 126 +/- 9 nmol/g, P = 0.002), an antiporter for citrate efflux from the mitochondria. Significant correlations were observed between the concentration of malonyl-CoA and both glucose utilization (r = 0.53, P = 0.002) and the sum of the concentrations of citrate and malate (r = 0.52, P < 0.001), a proposed index of the cytosolic concentration of citrate. In addition, an inverse correlation between malonyl-CoA concentration and fatty acid oxidation was observed (r = -0.32, P = 0.03). The results indicate that an infusion of insulin and glucose at a high rate leads to increases in the concentration of malonyl-CoA in skeletal muscle and to decreases in whole-body and, presumably, muscle fatty acid oxidation. Furthermore, they suggest that the increase in malonyl-CoA in this situation is due, at least in part, to an increase in the cytosolic concentration of citrate. Because cytosolic citrate is also an inhibitor of phosphofructokinase, an attractive hypothesis is that changes in its concentration are part of an autoregulatory mechanism by which glucose modulates its own use and the use of fatty acids as fuels for skeletal muscle.
Diabetes 2000 Jul
PMID:Fatty acid oxidation and the regulation of malonyl-CoA in human muscle. 1090 61

5'AMP-activated protein kinase (AMPK) has been suggested to be a key regulatory protein in exercise signaling of muscle glucose transport. To test this hypothesis, we investigated whether muscle glycogen levels affect AMPK activation and glucose transport stimulation similarly during contractions. Rats were preconditioned by a combination of swimming exercise and diet to obtain a glycogen-supercompensated group (high muscle glycogen content [HG]) with approximately 3-fold higher muscle glycogen levels than a glycogen-depleted group (low muscle glycogen content [LG]). In perfused fast-twitch muscles, contractions induced significant increases in AMPK activity and glucose transport and decreases in acetyl-CoA carboxylase (ACC) activity in both HG and LG groups. Contraction-induced glucose transport was nearly 2-fold (P < 0.05) and AMPK activation was 3-fold (P < 0.05) higher in the LG group compared with the HG group, whereas ACC deactivation was not different between groups. Thus, there was a significant positive correlation between AMPK activity and glucose transport in contracting fast-twitch muscles (r = 0.80, P < 0.01). However, in slow-twitch muscles with HG, glucose transport was increased 6-fold (P < 0.05) during contractions, whereas AMPK activity did not increase. In contracting slow-twitch muscles with LG, the increase in AMPK activity (315%) and the decrease in ACC activity (54 vs. 34% at 0.2 mmol/l citrate, LG vs. HG) was higher (P < 0.05) compared with HG muscles, whereas the increase in glucose transport was identical in HG and LG. In conclusion, in slow-twitch muscles, high glycogen levels inhibit contraction-induced AMPK activation without affecting glucose transport. This observation suggests that AMPK activation is not an essential signaling step in glucose transport stimulation in skeletal muscle.
Diabetes 2000 Aug
PMID:Dissociation of AMP-activated protein kinase activation and glucose transport in contracting slow-twitch muscle. 1092 26

Studies in rats suggest that increases in fatty acid oxidation in skeletal muscle during exercise are related to the phosphorylation and inhibition of acetyl-CoA carboxylase (ACC), and secondary to this, a decrease in the concentration of malonyl-CoA. Studies in human muscle have not revealed a consistent decrease in the concentration of malonyl-CoA during exercise; however, measurements of ACC activity have not been reported. Thus, whether the same mechanism operates in human muscle in response to physical activity remains uncertain. To investigate this question, ACC was immunoprecipitated from muscle of human volunteers and its activity assayed in the same individual at rest and after one-legged knee-extensor exercise at 60, 85, and 100% of knee extensor VO2max. ACC activity was diminished by 50-75% during exercise with the magnitude of the decrease generally paralleling exercise intensity. Treatment of the immunoprecipitated enzyme with protein phosphatase 2A restored activity to resting values, suggesting the decrease in activity was due to phosphorylation. The measurement of malonyl-CoA in the muscles revealed that its concentration is 1/10 of that in rats, and that it is diminished (12-17%) during the higher-intensity exercises. The respiratory exchange ratio increased with increasing exercise intensity from 0.84 +/- 0.02 at 60% to 0.99 0.04 at 100% VO2max. Calculated rates of whole-body fatty acid oxidation were 121 mg/min at rest and 258 +/- 35, 264 +/- 63, and 174 +/- 76 mg/min at 60, 85, and 100% VO2max, respectively. The results show that ACC activity, and to a lesser extent malonyl-CoA concentration, in human skeletal muscle decrease during exercise. Although these changes may contribute to the increases in fat oxidation from rest to exercise, they do not appear to explain the shift from mixed fuel to predominantly carbohydrate utilization when exercise intensity is increased.
Diabetes 2000 Aug
PMID:Exercise diminishes the activity of acetyl-CoA carboxylase in human muscle. 1092 28

S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P <.05). Treatment with S15261 or S15511 decreased plasma insulin levels in fed rats and prevented the postprandial peak in insulin levels in a meal tolerance test. Y415 had no effect on insulin levels. Troglitazone halved the insulin response to the test meal, but metformin gave no improvement. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carboxylase and acyl-CoA synthase. S15261 also reduced the expression of carnitine palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesenteric resistance vessels to norepinephrine, and increased the maximal nitric oxide-mediated relaxation. S15261, through S15511, increased insulin sensitivity, decreased insulin levels, and reduced the vasculopathy of the JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.
 ...
PMID:Beneficial insulin-sensitizing and vascular effects of S15261 in the insulin-resistant JCR:LA-cp rat. 1104 15

Acetyl-CoA carboxylase (ACC) catalyzes the formation of malonyl-CoA, a precursor in the biosynthesis of long-chain fatty acids, which have been implicated in physiological insulin secretion. The catalytic function of ACC is regulated by phosphorylation (inactive)-dephosphorylation (active). In this study we investigated whether similar regulatory mechanisms exist for ACC in the pancreatic islet beta-cell. ACC was quantitated in normal rat islets, human islets, and clonal beta-cells (HIT-15 or INS-1) using a [(14)C]bicarbonate fixation assay. In the beta-cell lysates, ACC was stimulated by magnesium in a concentration-dependent manner. Of all the dicarboxylic acids tested, only glutamate, albeit ineffective by itself, significantly potentiated magnesium-activated ACC in a concentration-dependent manner. ACC stimulation by glutamate and magnesium was maximally demonstrable in the cytosolic fraction; it was markedly reduced by okadaic acid (OKA) in concentrations (<50 nmol/l) that inhibited protein phosphatase 2A (PP2A). Furthermore, pretreatment of the cytosolic fraction with anti-PP2A serum attenuated the glutamate- and magnesium-mediated activation of ACC, thereby suggesting that ACC may be regulated by an OKA-sensitive PP2A-like enzyme. Streptavidin-agarose chromatography studies have indicated that glutamate- and magnesium-mediated effects on ACC are attributable to activation of ACC's dephosphorylation; this suggests that the stimulatory effects of glutamate and magnesium on ACC might involve activation of an OKA-sensitive PP2A-like enzyme that dephosphorylates and activates ACC. In our study, 5-amino-imidazolecarboxamide (AICA) riboside, a stimulator of AMP kinase, significantly inhibited glucose-mediated activation of ACC and insulin secretion from isolated beta-cells. Together, our data provide evidence for a unique regulatory mechanism for the activation of ACC in the pancreatic beta-cell, leading to the generation of physiological signals that may be relevant for physiological insulin secretion.
Diabetes 2001 Jul
PMID:Activation of acetyl-CoA carboxylase by a glutamate- and magnesium-sensitive protein phosphatase in the islet beta-cell. 1142 79

Glucose-6-phosphatase (G6Pase) is a key enzyme in hepatic glucose metabolism. Altered G6Pase activity in glycogen storage disease and diabetic states is associated with disturbances in lipid metabolism. We studied the effects of acute inhibition of G6Pase activity on hepatic lipid metabolism in nonanesthetized rats. Rats were infused with an inhibitor of the glucose-6-phosphate (G6P) translocator (S4048, 30 mg. kg(-1). h(-1)) for 8 h. Simultaneously, [1-(13)C]acetate was administered for determination of de novo lipogenesis and fractional cholesterol synthesis rates by mass isotopomer distribution analysis. In a separate group of rats, Triton WR 1339 was injected for determination of hepatic VLDL-triglyceride production. S4048 infusion significantly decreased plasma glucose (-11%) and insulin (-48%) levels and increased hepatic G6P (201%) and glycogen (182%) contents. Hepatic triglyceride contents increased from 5.8 +/- 1.4 micromol/g liver in controls to 20.6 +/- 5.5 micromol/g liver in S4048-treated animals. De novo lipogenesis was increased >10-fold in S4048-treated rats, without changes in cholesterol synthesis rates. Hepatic mRNA levels of acetyl-CoA carboxylase and fatty acid synthase were markedly induced. Plasma triglyceride levels increased fourfold, but no differences in plasma cholesterol levels were seen. Surprisingly, hepatic VLDL-triglyceride secretion was not increased in S4048-treated rats. These studies demonstrate that inhibition of the G6Pase system leads to acute stimulation of fat synthesis and development of hepatic steatosis, without affecting hepatic cholesterol synthesis and VLDL secretion. The results emphasize the strong interactions that exist between hepatic carbohydrate and fat metabolism.
Diabetes 2001 Nov
PMID:Acute inhibition of glucose-6-phosphate translocator activity leads to increased de novo lipogenesis and development of hepatic steatosis without affecting VLDL production in rats. 1167 39

Intracellular triacylglycerol (TG) content of liver and skeletal muscle contributes to insulin resistance, and a significant correlation exists between TG content and the development of insulin resistance. Because acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme for liver fatty acid biosynthesis and a key regulator of muscle fatty acid oxidation, we examined whether ACC plays a role in the accumulation of intracellular TG. We also determined the potential role of 5'-AMP-activated protein kinase (AMPK) in this process, since it can phosphorylate and inhibit ACC activity in both liver and muscle. TG content, ACC, and AMPK were examined in the liver and skeletal muscle of insulin-resistant JCR:LA-cp rats during the time frame when insulin resistance develops. At 12 weeks of age, there was a threefold elevation in liver TG content and a sevenfold elevation in skeletal muscle TG content. Hepatic ACC activity was significantly elevated in 12-week-old JCR:LA-cp rats compared with lean age-matched controls (8.75 +/- 0.53 vs. 3.30 +/- 0.18 nmol. min(-1). mg(-1), respectively), even though AMPK activity was also increased. The observed increase in hepatic ACC activity was accompanied by a 300% increase in ACC protein expression. There were no significant differences in ACC activity, ACC protein expression, or AMPK activity in the skeletal muscle of the 12-week JCR:LA-cp rats. Treatment of 12-week JCR:LA-cp rats with MEDICA 16 (an ATP-citrate lyase inhibitor) resulted in a decrease in hepatic ACC and AMPK activities, but had no effect on skeletal muscle ACC and AMPK. Our data suggest that alterations in ACC or AMPK activity in muscle do not contribute to the development of insulin resistance. However, increased liver ACC activity in the JCR:LA-cp rat appears to contribute to the development of lipid abnormalities, although this increase does not appear to occur secondary to a decrease in AMPK activity.
Diabetes 2002 May
PMID:MEDICA 16 inhibits hepatic acetyl-CoA carboxylase and reduces plasma triacylglycerol levels in insulin-resistant JCR: LA-cp rats. 1197 55

Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2.
Diabetes 2002 Jul
PMID:Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. 1208 35

Endurance training has been shown to increase fat oxidation both at rest and during exercise. However, most exercise training studies have been performed at high exercise intensity in well-trained athletes, and not much is known about the effect of a low-intensity training program on fat oxidation capacity in lean sedentary humans. Here, we examine the effect of 3-month low-intensity training program on total and intramuscular triglyceride (IMTG)- and/or VLDL-derived fat oxidation capacity and skeletal muscle mRNA expression. Six healthy untrained subjects (aged 43 +/- 2 years, BMI 22.7 +/- 1.1 kg/ m(2), V(O)(2max) 3.2 +/- 0.2 l/min) participated in a supervised 12-week training program at 40% V(O)(2max) three times weekly. Total and plasma-derived fatty acid oxidation at rest and during 1 h exercise was measured using [(13)C]palmitate, and in a separate test, [(13)C]acetate recovery was determined. Muscle biopsies were taken after an overnight fast. Total fat oxidation during exercise increased from 1,241 +/- 93 to 1,591 +/- 130 micromol/min (P = 0.06), and IMTG- and/or VLDL-derived fatty acid oxidation increased from 236 +/- 84 to 639 +/- 172 micromol/min (P = 0.09). Acetyl-CoA carboxylase-2 mRNA expression was significantly decreased after training (P = 0.005), whereas lipoprotein lipase mRNA expression tended to increase (P = 0.07). In conclusion, a minimal amount of physical activity tends to increase fat oxidation and leads to marked changes in the expression of genes encoding for key enzymes in fat metabolism.
Diabetes 2002 Jul
PMID:The effect of a 3-month low-intensity endurance training program on fat oxidation and acetyl-CoA carboxylase-2 expression. 1208 53

Acetyl-CoA carboxylase I (ACCI) is a key lipogenic enzyme whose induction in islet beta-cells may contribute to glucolipotoxicity. Here, we provide evidence that enhanced insulin release plays an important role in the activation of this gene by glucose. Glucose (30 vs. 3 mmol/l) increased ACCI mRNA levels approximately 4-fold and stimulated ACCI (pII) promoter activity >30-fold in MIN6 cells. The latter effect was completely suppressed by blockade of insulin release or of insulin receptor signaling. However, added insulin substantially, but not completely, mimicked the effects of glucose, suggesting that intracellular metabolites of glucose may also contribute to transcriptional stimulation. Mutational analysis of the ACCI promoter, and antibody microinjection, revealed that the effect of glucose required sterol response element binding protein (SREBP)-1c. Moreover, adenoviral transduction with dominant-negative-acting SREBP1c blocked ACCI gene induction, whereas constitutively active SREBP1c increased ACCI mRNA levels. Finally, glucose also stimulated SREBP1c transcription, although this effect was independent of insulin release. These data suggest that glucose regulates ACCI gene expression in the beta-cell by complex mechanisms that may involve the covalent modification of SREBP1c. However, overexpression of SREBP1c also decreased glucose-stimulated insulin release, implicating SREBP1c induction in beta-cell lipotoxicity in some forms of type 2 diabetes.
Diabetes 2002 Aug
PMID:Stimulation of acetyl-CoA carboxylase gene expression by glucose requires insulin release and sterol regulatory element binding protein 1c in pancreatic MIN6 beta-cells. 1214 68


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>