Supplement of TCA cycle intermediates protects against high glucose/palmitate-induced INS-1 beta cell death

Choi, Sung Eun; Lee, Youn Jung; Hwang, Gwi Seo; Chung, Joo Hee; Lee, Soo Jin; Lee, Ji Hyun; Han, Seung Jin; Kim, Hae Jin; Lee, Kwan Woo; Kim, Youngsoo; Jun, Hee-Sook; Kang, Yup

doi:10.1016/j.abb.2010.10.011

Cited by 18 publications

(18 citation statements)

References 59 publications

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“…Moreover, the effect of BCH on wild-type mice was not reported. As shown by the authors in INS-1 cells (Choi et al 2011), BCH is a strong insulinotropic agent (Sener et al 1981). While BCH may preserve b-cell function, it may also act as a permanently stimulating agent, resulting in elevated blood insulin levels and potentially hypoglycemia.…”

Section: Therapeutic Implications Of Gdh Activationmentioning

confidence: 99%

“…The results by Han and colleagues suggest that some of this overload may be balanced by the metabolism of other fuels in the TCA cycle. Although the previous studies by the group indicated that mitochondrial metabolism to some extent was normalized by culture in BCH (Choi et al 2011), a more detailed analysis is warranted. The following questions remain to be answered: is GDH activity and/or expression affected under pathological conditions?…”

Section: Future Perspectivesmentioning

confidence: 99%

“…Their hypothesis was that promotion of anaplerosis in b-cells may stabilize b-cell function and perhaps make them more resistant in a stressful metabolic environment. Their assumption was based on a previous study where they showed that BCH increased the levels of TCA cycle intermediates, restored ATP levels, enhanced the oxidation rate, and protected against high glucose/palmitic acid (HG/PA)-induced apoptosis in INS-1 cells (Choi et al 2011). Presently, they first confirmed that BCH is an efficient potentiator of GSIS.…”

Section: Could Activation Of Gdh Protect B-cells In Type 2 Diabetes?mentioning

confidence: 99%

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Glutamate dehydrogenase, insulin secretion, and type 2 diabetes: a new means to protect the pancreatic β-cell?

Göhring¹,

Mulder

2012

Journal of Endocrinology

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In this issue of Journal of Endocrinology, Dr Han and colleagues report a protective effect of the glutamate dehydrogenase activator 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) under diabetes-like conditions that impair b-cell function in both a pancreatic b-cell line and db/db mice. Based on these observations, the authors suggest that BCH could serve as a novel treatment modality in type 2 diabetes. The present commentary discusses the importance of the findings. Some additional questions are raised, which may be addressed in future investigations, as there is some concern regarding the BCH treatment of b-cell failure.

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Section: Therapeutic Implications Of Gdh Activationmentioning

confidence: 99%

Section: Future Perspectivesmentioning

confidence: 99%

Section: Could Activation Of Gdh Protect B-cells In Type 2 Diabetes?mentioning

confidence: 99%

See 1 more Smart Citation

Glutamate dehydrogenase, insulin secretion, and type 2 diabetes: a new means to protect the pancreatic β-cell?

Göhring¹,

Mulder

2012

Journal of Endocrinology

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“…Recently, we demonstrated that metabolic impairment in mitochondria is associated with b-cell glucolipotoxicity (Choi et al 2011). According to these results, long-term treatment of INS-1 cells with HG/palmitate (PA) impaired energy-producing metabolism and caused depletion of TCA cycle intermediates.…”

Section: Introductionmentioning

confidence: 99%

“…PA/BSA conjugates were prepared as described previously (Choi et al 2011). Briefly, a 20 mM solution of PA in 0 .…”

Section: Preparation Of Pamentioning

confidence: 99%

β-Cell-protective effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid as a glutamate dehydrogenase activator in db/db mice

Han¹,

Choi²,

Yi³

et al. 2011

Journal of Endocrinology

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2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) is an activator of glutamate dehydrogenase (GDH), which is a mitochondrial enzyme with an important role in insulin secretion. We investigated the effect of BCH on the highglucose (HG)-induced reduction in glucose-stimulated insulin secretion (GSIS), the HG/palmitate (PA)-induced reduction in insulin gene expression, and HG/PA-induced b-cell death. We also studied whether long-term treatment with BCH lowers blood glucose and improves b-cell integrity in db/db mice. We evaluated GSIS, insulin gene expression, and DNA fragmentation in INS-1 cells exposed to HG or HG/PA in the presence or absence of BCH. An in vivo study was performed in which 7-week-old diabetic db/db mice were treated with BCH (0 . 7 g/kg, nZ10) and placebo (nZ10) every other day for 6 weeks. After treatment, an intraperitoneal glucose tolerance test and immunohistological examinations were performed. Treatment with BCH blocked HG-induced GSIS inhibition and the HG/PA-induced reduction in insulin gene expression in INS-1 cells. In addition, BCH significantly reduced HG/PA-induced INS-1 cell death and phospho-JNK level. BCH treatment improved glucose tolerance and insulin secretion in db/db mice. BCH treatment also increased the ratio of insulin-positive b-cells to total islet area (P!0 . 05) and reduced the percentage of b-cells expressing cleaved caspase 3 (P!0 . 05). In conclusion, the GDH activator BCH improved glycemic control in db/db mice. This anti-diabetic effect may be associated with improved insulin secretion, preserved islet architecture, and reduced b-cell apoptosis.

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Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes

et al. 2017

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SummaryWe explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic β cells (Fh1βKO mice) appear normal for 6–8 weeks but then develop progressive glucose intolerance and diabetes. Glucose tolerance is rescued by expression of mitochondrial or cytosolic FH but not by deletion of Hif1α or Nrf2. Progressive hyperglycemia in Fh1βKO mice led to dysregulated metabolism in β cells, a decrease in glucose-induced ATP production, electrical activity, cytoplasmic [Ca2+]i elevation, and GSIS. Fh1 loss resulted in elevated intracellular fumarate, promoting succination of critical cysteines in GAPDH, GMPR, and PARK 7/DJ-1 and cytoplasmic acidification. Intracellular fumarate levels were increased in islets exposed to high glucose and in islets from human donors with type 2 diabetes (T2D). The impaired GSIS in islets from diabetic Fh1βKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D.

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Supplement of TCA cycle intermediates protects against high glucose/palmitate-induced INS-1 beta cell death

Cited by 18 publications

References 59 publications

Glutamate dehydrogenase, insulin secretion, and type 2 diabetes: a new means to protect the pancreatic β-cell?

Glutamate dehydrogenase, insulin secretion, and type 2 diabetes: a new means to protect the pancreatic β-cell?

β-Cell-protective effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid as a glutamate dehydrogenase activator in db/db mice

Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes

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