GLP-1-related proteins attenuate the effects of mitochondrial membrane damage in pancreatic β cells

Ogata, Makiko; Iwasaki, Naoko; Ide, Risa; Takizawa, Miho; Uchigata, Yasuko

doi:10.1016/j.bbrc.2014.03.143

Cited by 16 publications

(12 citation statements)

References 27 publications

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“…Our results support the finding that Liraglutide attenuates the effects of mitochondrial membrane damage in pancreatic β cells (Ogata et al . ). Dihydrolipoamide acetyltransferase and lipoamide dehydrogenase along with Pyruvate dehydrogenase forms the pyruvate dehydrogenase (PDH) complex.…”

Section: Discussionmentioning

confidence: 97%

Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone inSH‐SY5Y cells

Jalewa

Sharma

Hölscher

2016

Journal of Neurochemistry

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Currently, there is no viable treatment available for Parkinson's disease (PD) that stops or reverses disease progression. Interestingly, studies testing the glucagon-like-peptide-1 (GLP-1) mimetic Exendin-4 have shown neuroprotective/neurorestorative properties in pre-clinical tests and in a pilot clinical study of PD. Incretin analogues were originally developed to treat type 2 diabetes and several are currently on the market. In this study, we tested novel incretin analogues on the dopaminergic SH-SY5Y neuroblastoma cells against a toxic mitochondrial complex I inhibitor, Rotenone. Here, we investigate for the first time the effects of six different incretin receptor agonists - Liraglutide, D-Ser2-Oxyntomodulin, a GLP-1/GIP Dual receptor agonist, dAla(2)-GIP-GluPal, Val(8)GLP-1-GluPal and exendin-4. Post-treatment with doses of 1, 10 or 100 nM of incretin analogues for 12 h increased the survival of SH-SY5Y cells treated with 1 μM Rotenone for 12 h. Furthermore, we studied the post-treatment effect of 100 nM incretin analogues against 1 μM Rotenone stress on apoptosis, mitochondrial stress and autophagy markers. We found significant protective effects of the analogues against Rotenone stress on cell survival and on mitochondrial and autophagy-associated markers. The novel GLP-1/GIP Dual receptor agonist was superior and effective at a tenfold lower concentration compared to the other analogues. Using the Phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, we further show that the neuroprotective effects are partially PI3K-independent. Our data suggest that the neuroprotective properties exhibited by incretin analogues against Rotenone stress involve enhanced autophagy, increased Akt-mediated cell survival and amelioration of mitochondrial dysfunction. These mechanisms can explain the neuroprotective effects of incretin analogues reported in clinical trials. GLP-1, GIP and dual incretin receptor agonists showed protective effects in SH-SY5Y cells treated with the stressor Rotenone. The novel GLP-1/GIP dual receptor agonist was superior and effective at a tenfold lower concentration compared to the other analogues. The drugs protected the cells from rotenone-induced impairment in cell growth and Akt activation, mitochondrial damage, impairments of autophagy and apoptotic cell signalling. See paper for details.

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Section: Discussionmentioning

confidence: 97%

Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone inSH‐SY5Y cells

Jalewa

Sharma

Hölscher

2016

Journal of Neurochemistry

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“…Some HbA1c, hemoglobin A1c; L/P, lactate to pyruvate ratio; CSF, cerebrospinal fluid; FGF21, fibroblast growth factor 21; GDF15, growth differentiation factor 15; JMDRS, the total scores of section 1 and 2 of the Japanese mitochondrial disease rating scale; NMDAS, the total scores of section I and II of the Newcastle Mitochondrial Disease Adult Scale. previous studies using model cells of mitochondrial diabetes mellitus have reported that GLP-1 and GLP-1 receptor agonists may possibly attenuate mitochondrial damage in pancreatic beta cells (Fan et al 2010;Mukai et al 2011;Ogata et al 2014;Ciregia et al 2015). Therefore, sustained glycemic control in our case may demonstrate the potential favorable effect of liraglutide on beta cells, although improved glycemic control because of intensive insulin therapy itself largely contributed to the recovery of beta cell functions and glycemic control.…”

Section: Discussionmentioning

confidence: 53%

Successful Glycemic Control Decreases the Elevated Serum FGF21 Level without Affecting Normal Serum GDF15 Levels in a Patient with Mitochondrial Diabetes

Murakami

Ueba

Shinoto

et al. 2016

Tohoku J. Exp. Med.

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Mitochondrial diabetes mellitus is a subtype of diabetes linked to mutations in mitochondrial DNA. In patients with mitochondrial diabetes mellitus, the effect of glycemic control on the serum concentrations of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) has not been evaluated. FGF21 and GDF15 have been reported to be useful biomarkers for the diagnosis and severity assessment of mitochondrial diseases like mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Recent studies have shown FGF21 acts in an endocrine fashion to regulate glucose and lipid metabolism in type 2 diabetes mellitus, while the exact biological functions of GDF15 remain unknown. Although mitochondrial diabetes mellitus is commonly found in cases with mitochondrial diseases, the comparison of FGF21 and GDF15 levels between those with and without diabetes has not been performed. Here, we report a 24-year-old woman with mitochondrial diabetes mellitus, who showed a high level of serum FGF21, but not serum GDF15, at diagnosis. In our case, liraglutide, a glucagon-like peptide-1 receptor agonist, added to insulin glargine was effective for her glycemic control and showed no adverse effects, including gastrointestinal symptoms and hypoglycemia, during a 14-week observation. The successful glycemic control caused a decrease in the FGF21 level, without affecting the GDF15 level. Thus, we should consider patients' glycemic control levels in using FGF21 values for the diagnosis of mitochondrial diseases. In addition, sustained GDF15 levels during glycemic treatment in our case suggest the usefulness of GDF15 as a marker for clinical severity of muscle-manifested mitochondrial diseases.

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“…Recent researches into the extra-pancreatic functions of incretins have shown possible beneficial effects on diabetic microangiopathy [9]. Moreover, GLP-1RAs have been reported to ameliorate pancreatic beta-cell loss by reducing apoptosis in animal models, in addition to their effect to increase insulin secretion [5]. The two patients with mitochondrial diabetes reported here showed improved insulin secretion after the administration of GLP-1RAs, implying a beneficial effect of GLP-1RAs on their pancreatic beta-cell function.…”

Section: Discussionmentioning

confidence: 61%

“…Insulin therapy is usually prescribed for patients with mitochondrial diabetes [4]. However, glucagon-like peptide-1 receptor agonists (GLP-1Ras) have been reported to improve pancreatic beta-cell function [5] and neuropathy [6]. Therefore, we investigated the feasibility of using GLP-1RAs for the treatment of mitochondrial diabetes with neuropathy.…”

Section: Introductionmentioning

confidence: 99%

Two Cases of Mitochondrial Diabetes in Which Pancreatic Beta-Cell Function and Neuropathy Were Improved by Glucagon-Like Peptide-1 Receptor Agonist Therapy

Minezaki¹,

Abe²,

Koga³

et al. 2019

J Endocrinol Metab

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Mitochondrial diabetes is a refractory type of diabetes mellitus where pancreas beta-cell function attenuates. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) has been reported for pleiotropic effects in addition to effect to glucose tolerance. In animal models, GLP-1RAs were reported to recover mitochondrial function of pancreas beta-cells and increase the growth rate of nerve cells. Our two cases appear to be the first reported cases in the literature of mitochondrial diabetes where GLP-1RAs improved insulin secretion and neuropathy.

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GLP-1-related proteins attenuate the effects of mitochondrial membrane damage in pancreatic β cells

Cited by 16 publications

References 27 publications

Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone inSH‐SY5Y cells

Novel incretin analogues improve autophagy and protect from mitochondrial stress induced by rotenone inSH‐SY5Y cells

Successful Glycemic Control Decreases the Elevated Serum FGF21 Level without Affecting Normal Serum GDF15 Levels in a Patient with Mitochondrial Diabetes

Two Cases of Mitochondrial Diabetes in Which Pancreatic Beta-Cell Function and Neuropathy Were Improved by Glucagon-Like Peptide-1 Receptor Agonist Therapy

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