Evidence that GLUT-2 mRNA and protein concentrations are decreased by hyperinsulinaemia and increased by hyperglycaemia in liver of diabetic rats

Burcelin, Rémy; Eddouks, Mohamed; Kandé, J.; Assan, R; Girard, Jean

doi:10.1042/bj2880675

Cited by 75 publications

(62 citation statements)

References 33 publications

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“…Also, liver GLUT2 expression in rats is reduced during starvation and increases to normal levels after refeeding [41]. In diabetic rats, liver GLUT2 expression is increased, but is corrected to regular levels when exogenous insulin returns the hyperglycemic conditions to normal [42]. These data suggest that GLUT2 expression in the liver is stimulated by glucose and downregulated by insulin.…”

Section: Effects On Carbohydrate Metabolismmentioning

confidence: 47%

Hepatic Steatosis in Type 1 Diabetes

Regnell

Lernmark

2011

Rev Diabet Stud

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■ AbstractIslet autoimmunity in type 1 diabetes results in the loss of the pancreatic β-cells. The consequences of insulin deficiency in the portal vein for liver fat are poorly understood. Under normal conditions, the portal vein provides 75% of the liver blood supply. Recent studies suggest that non-alcoholic fatty liver disease (NAFLD) may be more common in type 1 diabetes than previously thought, and may serve as an independent risk marker for some chronic diabetic complications. The pathogenesis of NAFLD remains obscure, but it has been hypothesized that hepatic fat accumulation in type 1 diabetes may be due to lipoprotein abnormalities, hyperglycemia-induced activation of the transcription factors carbohydrate response element-binding protein (ChREBP) and sterol regulatory element-binding protein 1c (SREBP-1c), upregulation of glucose transporter 2 (GLUT2) with subsequent intrahepatic fat synthesis, or a combination of these mechanisms. Novel approaches to non-invasive determinations of liver fat may clarify the consequences for liver metabolism when the pancreas has ceased producing insulin. This article aims to review the factors potentially contributing to hepatic steatosis in type 1 diabetes, and to assess the feasibility of using liver fat as a prognostic and/or diagnostic marker for the disease. It provides a background and a case for possible future studies in the field.

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Section: Effects On Carbohydrate Metabolismmentioning

confidence: 47%

Hepatic Steatosis in Type 1 Diabetes

Regnell

Lernmark

2011

Rev Diabet Stud

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“…In the only previous study that examined GLUT2 in liver of type 2 diabetic subjects, GLUT2 transporter protein was found to be increased approximately twofold compared with lean nondiabetic control subjects (32). Because hyperglycemia has been found to upregulate GLUT2 in animal models of diabetes (33), one could argue that the magnitude of the increase in GLUT2 protein described by Burguera et al (32) was inappropriate. Nonetheless, when viewed in absolute terms, in the only study in which it was measured, hepatic GLUT2 protein was found to be increased in type 2 diabetic patients compared with lean nondiabetic control subjects.…”

Section: Discussionmentioning

confidence: 72%

“…Consistent with this scenario, we found a positive correlation between decreased SGU and the HbA 1c , suggesting that poor glycemic control may sensitize the liver to the inhibitory effect of elevated plasma FFA levels. With regard to this, animal studies have shown that hyperglycemia impairs hepatic glucokinase activity (33,38). Furthermore, it is possible that if the present study was performed at each subject's elevated fasting plasma glucose concentration (i.e., without an overnight insulin infusion), an even greater FFA-induced inhibition of SGU may have been observed.…”

Section: Discussionmentioning

confidence: 95%

Free Fatty Acids Reduce Splanchnic and Peripheral Glucose Uptake in Patients With Type 2 Diabetes

et al. 2002

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Splanchnic glucose uptake (SGU) plays a major role in the disposal of an oral glucose load (OGL). To investigate the effect of an elevated plasma free fatty acid (FFA) concentration on SGU in patients with type 2 diabetes, we measured SGU in eight diabetic patients (mean age 51 ؎ 4 years, BMI 29.3 ؎ 1.4 kg/m 2 , fasting plasma glucose 9.3 ؎ 0.7 mmol/l) during an intravenous Intralipid/heparin infusion and 7-10 days later during a saline infusion. SGU was estimated by the OGL insulin clamp method: subjects received a 7-h euglycemichyperinsulinemic clamp (insulin infusion rate ‫؍‬ 100 mU ⅐ m ؊2 ⅐ min ؊1 ), and a 75-g OGL was ingested 3 h after starting the insulin clamp. After glucose ingestion, the steady-state glucose infusion rate during the insulin clamp was decreased appropriately to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in glucose infusion rate during the 4-h period after glucose ingestion from the ingested glucose load (75 g). 3-[ 3 H]glucose was infused during the 3-h insulin clamp before glucose ingestion to determine the rates of endogenous glucose production and glucose disappearance (R d ). Intralipid/heparin or saline infusion was initiated 2 h before the start of the OGL clamp. Plasma FFA concentrations were significantly higher during the OGL clamp with the intralipid/heparin infusion than with the saline infusion (2.5 ؎ 0.3 vs. 0.11 ؎ 0.02 mmol/l, P < 0.001). During the 3-h insulin clamp period before glucose ingestion, Intralipid/heparin infusion reduced R d (4.4 ؎ 0.3 vs. 5.3 ؎ 0.3 mg ⅐ kg ؊1 ⅐ min ؊1 , P < 0.01). During the 4-h period after glucose ingestion, SGU was significantly decreased during the intralipid/heparin versus saline infusion (30 ؎ 2 vs. 37 ؎ 2%, P < 0.01). In conclusion, an elevation in plasma FFA concentration impairs both peripheral and SGU in patients with type 2 diabetes. Diabetes 51:3043-3048, 2002 S planchnic glucose uptake (SGU) plays a major role in the disposal of an oral glucose load (OGL) (1-6). Hyperglycemia per se enhances SGU in proportion to the increase in plasma glucose concentration, such that the splanchnic glucose clearance remains unchanged (2). This mass action effect of hyperglycemia to augment SGU depends on maintained portal insulin levels (2). Insulin per se, in the absence of hyperglycemia, does not increase SGU (2,7). Studies by DeFronzo et al. (3) and Adkins et al. (5) haveshown that the gastrointestinal route of glucose administration has a specific enhancing effect on SGU (3) and that after glucose ingestion, the fractional, as well as absolute uptake of glucose by the splanchnic tissues is significantly greater than the combined effects of hyperinsulinemia plus hyperglycemia created by intravenous glucose/insulin administration (2,5).Disturbances in free fatty acid (FFA) metabolism are characteristic in type 2 diabetic individuals (8 -11), who manifest day-long increased plasma FFA levels (11) and increased rates of lipolysis (8 -11). Elevated plasma FFA concentrations have been shown to impair glucose met...

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“…The expression of the genes for several other proteins is regulated by glucose; these include genes for L-type pyruvate kinase (13,14), fatty-acid synthase (15,16), PEPCK (17,18), and the type 2 glucose transporter (GLUT-2) (19,20). The mechanism by which glucose regulates the expression of these genes remains largely unknown.…”

Section: From the Department Of Nutrition Case Western Reserve Univementioning

confidence: 99%

“…Hepatic Glc-6-Pase activity is effectively regulated by hormonal and nutritional status. For example, fasting and hormones that increase cAMP concentration stimulate its gene expression while refeeding and insulin decrease it (1, 2, 6 -12).The expression of the genes for several other proteins is regulated by glucose; these include genes for L-type pyruvate kinase (13, 14), fatty-acid synthase (15, 16), PEPCK (17, 18), and the type 2 glucose transporter (GLUT-2) (19,20). The mechanism by which glucose regulates the expression of these genes remains largely unknown.…”

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confidence: 99%

Regulation of the Glucose-6-phosphatase Gene by Glucose Occurs by Transcriptional and Post-transcriptional Mechanisms

Massillon¹

2001

Journal of Biological Chemistry

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To understand how glucose regulates the expression of the glucose-6-phosphatase gene, the effect of glucose was studied in primary cultures of rat hepatocytes. Glucose-6-phosphatase mRNA levels increased about 10-fold when hepatocytes were incubated with 20 mM glucose. The rate of transcription of the glucose-6-phosphatase gene increased about 3-fold in hepatocytes incubated with glucose. The half-life of glucose-6-phosphatase mRNA was estimated to be 90 min in the absence of glucose and 3 h in its presence. Inhibition of the oxidative and the nonoxidative branches of the pentose phosphate pathway blocked the stimulation of glucose-6-phosphatase expression by glucose but not by xylitol or carbohydrates that enter the glycolytic/gluconeogenic pathways at the level of the triose phosphates. These results indicate that (i) the glucose induction of the mRNA for the catalytic unit of glucose-6-phosphatase occurs by transcriptional and post-transcriptional mechanisms and that (ii) xylitol and glucose increase the expression of this gene through different signaling pathways.Glc-6-Pase 1 (EC 3.1.3.9) is a multicomponent protein complex comprising catalytic and transporting entities (1-5). The complex is tightly associated with the endoplasmic reticulum, and the enzymatic component catalyzes the hydrolysis of glucose 6-phosphate to glucose, a final common step to both the pathways of glycogenolysis and gluconeogenesis. Hepatic Glc-6-Pase activity is effectively regulated by hormonal and nutritional status. For example, fasting and hormones that increase cAMP concentration stimulate its gene expression while refeeding and insulin decrease it (1, 2, 6 -12).The expression of the genes for several other proteins is regulated by glucose; these include genes for L-type pyruvate kinase (13, 14), fatty-acid synthase (15, 16), PEPCK (17, 18), and the type 2 glucose transporter (GLUT-2) (19,20). The mechanism by which glucose regulates the expression of these genes remains largely unknown. Recently, Kahn and colleagues (21, 22) have proposed a signaling pathway model to explain the molecular mechanism by which glucose regulates the expression of the L-type pyruvate kinase. This model consists of the following details: (i) the presence of glucose is sensed in the cell; (ii) this information is transduced by intracellular messengers; (iii) a second messenger, presumably xylulose 5-phosphate, rises and then modulates the activity of protein kinase and protein phosphatase involved in a cascade of phosphorylation/dephosphorylation. This cascade then leads to a modification of the phosphorylation state of the glucoseresponsive complex, followed by an increase in the transcriptional rate of the target gene. In this model, the presence of an active glucokinase that phosphorylates glucose to glucose 6-phosphate (Glc-6-P) is paramount.The molecular mechanism by which glucose regulates the expression of the Glc-6-Pase gene is currently unknown. Here we show that glucose regulation of the expression of this gene involves metabolism of glucose...

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Evidence that GLUT-2 mRNA and protein concentrations are decreased by hyperinsulinaemia and increased by hyperglycaemia in liver of diabetic rats

Cited by 75 publications

References 33 publications

Hepatic Steatosis in Type 1 Diabetes

Hepatic Steatosis in Type 1 Diabetes

Free Fatty Acids Reduce Splanchnic and Peripheral Glucose Uptake in Patients With Type 2 Diabetes

Regulation of the Glucose-6-phosphatase Gene by Glucose Occurs by Transcriptional and Post-transcriptional Mechanisms

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