Mct11 deficiency alters hepatic glucose metabolism and energy homeostasis

SUMMARYGenetic variation at the SLC16A11 locus contributes to the disproportionate impact of type 2 diabetes (T2D) on Latino populations. We recently demonstrated that T2D risk variants reduce SLC16A11 liver expression and function of MCT11, the monocarboxylate transporter encoded by the SLC16A11 gene. Here, we show that SLC16A11 expression within the liver is primarily localized to the low oxygen pericentral region, and that T2D risk variants disrupt oxygen-regulated SLC16A11 expression in human hepatocytes. Under physiologic oxygen conditions, MCT11 deficiency alters hepatocyte glucose metabolism, resulting in elevated intracellular lactate and a metabolic shift toward triacylglycerol accumulation. We also demonstrate an impact of Mct11 deficiency on glucose and lipid metabolism in Slc16a11 knockout mice, which display physiological changes that are observed in individuals with T2D. Our findings provide mechanistic insight into how SLC16A11 disruption impacts hepatic energy metabolism and T2D risk, and highlight MCT11-mediated regulation of lactate levels as a potential therapeutic target.

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Effects of DGAT1 deficiency on energy and glucose metabolism are independent of adiponectin

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00621.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. E388-E394 ◽

Cited By ~ 17

Author(s):

Ryan S. Streeper ◽

Suneil K. Koliwad ◽

Claudio J. Villanueva ◽

Robert V. Farese

Keyword(s):

Insulin Sensitivity ◽

Glucose Metabolism ◽

High Fat Diet ◽

Acid Oxidation ◽

Glucose And Lipid Metabolism ◽

Diet Induced Obesity ◽

Triacylglycerol Synthesis ◽

Triacylglycerol Accumulation ◽

Hepatic Triacylglycerol ◽

Deficient Mice

Mice lacking acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the terminal step in triacylglycerol synthesis, have enhanced insulin sensitivity and are protected from obesity, a result of increased energy expenditure. In these mice, factors derived from white adipose tissue (WAT) contribute to the systemic changes in metabolism. One such factor, adiponectin, increases fatty acid oxidation and enhances insulin sensitivity. To test the hypothesis that adiponectin is required for the altered energy and glucose metabolism in DGAT1-deficient mice, we generated adiponectin-deficient mice and introduced adiponectin deficiency into DGAT1-deficient mice by genetic crosses. Although adiponectin-deficient mice fed a high-fat diet were heavier, exhibited worse glucose tolerance, and had more hepatic triacylglycerol accumulation than wild-type controls, mice lacking both DGAT1 and adiponectin, like DGAT1-deficient mice, were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis. These findings indicate that adiponectin is required for normal energy, glucose, and lipid metabolism but that the metabolic changes induced by DGAT1-deficient WAT are independent of adiponectin and are likely due to other WAT-derived factors. Our findings also suggest that the pharmacological inhibition of DGAT1 may be useful for treating human obesity and insulin resistance associated with low circulating adiponectin levels.

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Insulin-like actions of tungstate in diabetic rats. Normalization of hepatic glucose metabolism.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)32125-7 ◽

1994 ◽

Vol 269 (31) ◽

pp. 20047-20053 ◽

Cited By ~ 4

Author(s):

A. Barberà ◽

J.E. Rodríguez-Gil ◽

J.J. Guinovart

Keyword(s):

Glucose Metabolism ◽

Diabetic Rats ◽

Hepatic Glucose Metabolism ◽

Hepatic Glucose

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Synergistic inhibition of glucagon-induced effects on hepatic glucose metabolism in the presence of insulin and a cAMP antagonist.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)66648-7 ◽

1986 ◽

Vol 261 (34) ◽

pp. 15895-15899

Author(s):

J S Marks ◽

L H Botelho

Keyword(s):

Glucose Metabolism ◽

Synergistic Inhibition ◽

Hepatic Glucose Metabolism ◽

Hepatic Glucose

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Lack of effect of parathyroid hormone on hepatic glucose metabolism in the dog

Metabolism ◽

10.1016/0026-0495(81)90182-7 ◽

1981 ◽

Vol 30 (5) ◽

pp. 469-475 ◽

Cited By ~ 13

Author(s):

S. Bevilacqua ◽

E. Barrett ◽

E. Ferrannini ◽

R. Gusberg ◽

A. Stewart ◽

...

Keyword(s):

Parathyroid Hormone ◽

Glucose Metabolism ◽

Hepatic Glucose Metabolism ◽

Hepatic Glucose

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Lack of skeletal muscle IL-6 influences hepatic glucose metabolism in mice during prolonged exercise

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00373.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. R626-R636 ◽

Cited By ~ 5

Author(s):

Lærke Bertholdt ◽

Anders Gudiksen ◽

Camilla L. Schwartz ◽

Jakob G. Knudsen ◽

Henriette Pilegaard

Keyword(s):

Skeletal Muscle ◽

Glucose Metabolism ◽

Phosphoenolpyruvate Carboxykinase ◽

Prolonged Exercise ◽

Hepatic Glycogen ◽

Glucose Content ◽

Hepatic Glucose Metabolism ◽

Hepatic Glucose ◽

Single Bout ◽

Substrate Choice

The liver is essential in maintaining and regulating glucose homeostasis during prolonged exercise. IL-6 has been shown to be secreted from skeletal muscle during exercise and has been suggested to signal to the liver. Therefore, the aim of this study was to investigate the role of skeletal muscle IL-6 on hepatic glucose regulation and substrate choice during prolonged exercise. Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice (age, 12–14 wk) and littermate lox/lox (Control) mice were either rested (Rest) or completed a single bout of exercise for 10, 60, or 120 min, and the liver was quickly obtained. Hepatic IL-6 mRNA was higher at 60 min of exercise, and hepatic signal transducer and activator of transcription 3 was higher at 120 min of exercise than at rest in both genotypes. Hepatic glycogen was higher in IL-6 MKO mice than control mice at rest, but decreased similarly during exercise in the two genotypes, and hepatic glucose content was lower in IL-6 MKO than control mice at 120 min of exercise. Hepatic phosphoenolpyruvate carboxykinase mRNA and protein increased in both genotypes at 120 min of exercise, whereas hepatic glucose 6 phosphatase protein remained unchanged. Furthermore, IL-6 MKO mice had higher hepatic pyruvate dehydrogenase (PDH)Ser232 and PDHSer300 phosphorylation than control mice at rest. In conclusion, hepatic gluconeogenic capacity in mice is increased during prolonged exercise independent of muscle IL-6. Furthermore, Skeletal muscle IL-6 influences hepatic substrate regulation at rest and hepatic glucose metabolism during prolonged exercise, seemingly independent of IL-6 signaling in the liver.

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When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen

International Journal of Cell Biology ◽

10.1155/2011/470597 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 16

Author(s):

Katrin Schlie ◽

Jaeline E. Spowart ◽

Luke R. K. Hughson ◽

Katelin N. Townsend ◽

Julian J. Lum

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Patient Treatment ◽

Low Oxygen ◽

Tumor Environment ◽

And Function ◽

The Impact

Hypoxia is a signature feature of growing tumors. This cellular state creates an inhospitable condition that impedes the growth and function of all cells within the immediate and surrounding tumor microenvironment. To adapt to hypoxia, cells activate autophagy and undergo a metabolic shift increasing the cellular dependency on anaerobic metabolism. Autophagy upregulation in cancer cells liberates nutrients, decreases the buildup of reactive oxygen species, and aids in the clearance of misfolded proteins. Together, these features impart a survival advantage for cancer cells in the tumor microenvironment. This observation has led to intense research efforts focused on developing autophagy-modulating drugs for cancer patient treatment. However, other cells that infiltrate the tumor environment such as immune cells also encounter hypoxia likely resulting in hypoxia-induced autophagy. In light of the fact that autophagy is crucial for immune cell proliferation as well as their effector functions such as antigen presentation and T cell-mediated killing of tumor cells, anticancer treatment strategies based on autophagy modulation will need to consider the impact of autophagy on the immune system.

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Improvement of glucose and lipid metabolism in diabetic rats treated with molybdate

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.270.2.e344 ◽

1996 ◽

Vol 270 (2) ◽

pp. E344-E352 ◽

Cited By ~ 9

Author(s):

A. T. Ozcelikay ◽

D. J. Becker ◽

L. N. Ongemba ◽

A. M. Pottier ◽

J. C. Henquin ◽

...

Keyword(s):

Lipid Metabolism ◽

Phosphoenolpyruvate Carboxykinase ◽

Fatty Acid Synthase ◽

Diabetic Rats ◽

Nonesterified Fatty Acids ◽

Insulin Resistant ◽

Hepatic Glucose Metabolism ◽

Glucose And Lipid Metabolism ◽

Glycogen Stores

Molybdenum mimics certain insulin actions in vitro. We have investigated the effects of oral administration of Na2MoO4 (Mo) for 8 wk on carbohydrate and lipid metabolism in streptozotocin-diabetic rats. Mo decreased hyperglycemia and glucosuria by 75% and corrected the elevation of plasma nonesterified fatty acids. Tolerance to glucose loads was improved, and glycogen stores were replenished. These effects were not due to a rise of insulinemia. In liver, Mo restored the blunted mRNA and activity of glucokinase and pyruvate kinase and decreased to normal phosphoenolpyruvate carboxykinase values. Finally, Mo totally reversed the low expression and activity of acetyl-CoA carboxylase and fatty acid synthase in liver, but not in white adipose tissue. In conclusion, Mo exerts a marked blood glucose-lowering effect in diabetic rats by an insulin-like action. This effect results in part from a restoration of hepatic glucose metabolism and is associated with a tissue-specific correction of lipogenic enzyme gene expression, both processes being essentially mediated by reversal of impaired pretranslational regulatory mechanisms. These observations raise new therapeutic perspectives in diabetes, particularly in the insulin-resistant condition.

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