Protein O-Glycosylation Induces Collagen Expression and Contributes to Diabetic Cardiomyopathy in Rat Cardiac Fibroblasts

Kohda, Yuka; Kanematsu, Miwa; Kono, Tatsuji; Terasaki, Fumio; Tanaka, Takao

doi:10.1254/jphs.09236sc

Cited by 21 publications

(21 citation statements)

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“…We demonstrated that expression of various proteins associated with progression and development of diabetic complications is accelerated (Kohda et al, 2008(Kohda et al, , 2009Tanaka et al, 2010). Furthermore, we evaluated the transcriptomic profiles of the livers of obese diabetic rats using microarrays, which suggested transcriptomic modification of genes involved in glucose metabolism, lipid metabolism, vascular physiology, and carcinogenesis in the liver .…”

Section: Introductionmentioning

confidence: 98%

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Streptozotocin-induced diabetic state triggers glucose-dependent insulinotropic polypeptide (GIP) expression in the rat liver

Kohda

Minamigawa

Matsuo

et al. 2016

Fundam. Toxicol. Sci.

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-Streptozotocin (STZ), a toxic glucose analogue for pancreatic β cells, has been demonstrated as a treatment option for insulinoma. Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, is secreted by K cells in the duodenum in response to food intake and acts on pancreatic β cells, leading to increased secretion of insulin. We previously reported that GIP gene expression in the liver is modified in a diabetic setting. However, the role of GIP in the liver has not been fully elucidated; we aimed to discover its effects on type 1 diabetes by focusing on GIP protein expression in a type 1 diabetes rat model following STZ administration. In this study, we assessed whether glucose and lipid metabolism affected GIP expression in the liver following STZ-induced diabetes. Diabetes was induced by intraperitoneal injection with 70 mg/kg STZ. We expected that blood glucose levels would be higher because of STZ treatment as a result of reduced insulin secretion in pancreatic β cells. Interestingly, GIP was expressed only in the liver of STZ-treated rats; however, blood glucose levels were not elevated. On the other hand, blood triglyceride and cholesterol levels were higher in STZ-treated rats with hepatic GIP protein expression than in control rats. These findings indicated that GIP protein expression in the liver possibly has hypoglycemic action, which may ameliorate the damage of pancreatic β cells induced by STZ treatment, rather than affect glycolipid metabolism.

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Section: Introductionmentioning

confidence: 98%

“…Diabetes treatment and the mechanism of diabetic complications are heavy topics of research, and some of these investigations have been conducted using a type 1 diabetes rat model via STZ administration (Lenzen, 2008;Kohda et al, 2008Kohda et al, , 2009.…”

Section: Introductionmentioning

confidence: 99%

Streptozotocin-induced diabetic state triggers glucose-dependent insulinotropic polypeptide (GIP) expression in the rat liver

Kohda

Minamigawa

Matsuo

et al. 2016

Fundam. Toxicol. Sci.

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“…We intend to elucidate the molecular mechanism underlying the effects of improved glucose metabolism on the pathologies of obesity and diabetic complications by focused research on protein glycosylation via the activation of the hexosamine synthetic pathway, which may be caused by disordered glucose metabolism (Kohda et al, 2008(Kohda et al, , 2009. Our ultimate research goal is to elucidate the pathologies of and establish means for preventing diabetic complications and obesity Kohda et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Metabolic fate of excessive glucose in fibroblast cells in a diabetic setting

Kohda

Iwatate

Tanaka

et al. 2015

Fundam. Toxicol. Sci.

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-Glucose is important for energy; however, excessive daily intake of sugar may act as a toxin inducing the body to become overweight or obese. High blood glucose level reduces secretion of insulin, and glucose toxicity worsens insulin resistance. We investigated the metabolic fate of excess glucose by changing glucose levels in MRC-5 fibroblasts. Uptake of glucose into fibroblasts, the first stage of glucose metabolism, was measured. Treatment of fibroblasts under diabetic conditions led to rapid glucose incorporation. Glucose was absorbed into the cell almost constantly and reached excessive levels, and its metabolism was assessed by 14 CO 2 output from [U-14 C] D-glucose, the glucose metabolism end product. When fibroblasts were cultured in the presence of high glucose levels, CO 2 production decreased significantly in comparison with normal glucose conditions. Glucose metabolism in the diabetic setting was not accompanied by an increase in glucose uptake. Diabetic patients exercise tight glycemic control to avert disorders from such glucose toxicity. Pyruvate dehydrogenase (PDH) activity is reduced in diabetes; therefore, we investigated the influence of thiamine on PDH activity and intracellular glucose concentration in fibroblast cells exposed to diabetic conditions. Thiamine reversed high glucose-induced PDH inhibition and prevented glucose accumulation. These results, taken together with those of our previous report, suggest that thiamine partially plays a role in modifying the metabolic fate of glucose and reducing glucose toxicity.

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“…It is, therefore, speculated to be involved in diabetes mellitus and the development of diabetic complications (25). We reported that the hexosamine biosynthesis pathway is activated and the level of O -glycosylated protein in the diabetic rat hearts and RCFs are increased (17,26). OGT is present in mitochondria (27); therefore, PDH can be a substrate of OGT.…”

Section: Discussionmentioning

confidence: 99%

Thiamine Ameliorates Diabetes-Induced Inhibition of Pyruvate Dehydrogenase (PDH) in Rat Heart Mitochondria: Investigating the Discrepancy Between PDH Activity and PDH E1α Phosphorylation in Cardiac Fibroblasts Exposed to High Glucose

et al. 2010

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Abstract. The activity of pyruvate dehydrogenase (PDH) is reduced in diabetic patients. Phosphorylation of the PDH E1 α subunit by PDH kinase contributes to the suppression of PDH activity. PDH requires thiamine as a coenzyme. We investigated the exact mechanism of diabetes-induced PDH inhibition, and the effect of thiamine in both in vivo and in vitro experiments. Treatment of rats with thiamine significantly, although partially, recovered streptozotocin (STZ)-induced reductions in mitochondrial PDH activity. Nevertheless, we found that PDH E1 α phosphorylation in the thiamine-treated STZ group was perfectly diminished to the same level as that in the control group. STZ treatment significantly caused enhancements of the expression of O -glycosylated protein in the rat hearts, which was decreased by thiamine repletion. Next, the rat cardiac fibroblasts (RCFs) were cultured in the presence of high glucose levels. Thiamine dramatically recovered high glucose-induced PDH inhibition. High glucose loads did not alter the phosphorylated PDH E1 α . PDH inhibition in RCFs was not accompanied by an increase in the PDH E1 α phosphorylation. The Oglycosylated protein was markedly increased in RCFs exposed to high glucose, which was inhibited by thiamine. These results suggest that thiamine ameliorates diabetes-induced PDH inhibition by suppressing the increased expression of the O -glycosylated protein. The O -glycosylation of PDH E1 α may be involved in the regulation of the PDH activity.

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Protein O-Glycosylation Induces Collagen Expression and Contributes to Diabetic Cardiomyopathy in Rat Cardiac Fibroblasts

Cited by 21 publications

References 21 publications

Streptozotocin-induced diabetic state triggers glucose-dependent insulinotropic polypeptide (GIP) expression in the rat liver

Streptozotocin-induced diabetic state triggers glucose-dependent insulinotropic polypeptide (GIP) expression in the rat liver

Metabolic fate of excessive glucose in fibroblast cells in a diabetic setting

Thiamine Ameliorates Diabetes-Induced Inhibition of Pyruvate Dehydrogenase (PDH) in Rat Heart Mitochondria: Investigating the Discrepancy Between PDH Activity and PDH E1α Phosphorylation in Cardiac Fibroblasts Exposed to High Glucose

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