Triphenyltin impairs insulin secretion by decreasing glucose-induced NADP(H) and ATP production in hamster pancreatic β-cells

Cystic fibrosis (CF)-related diabetes (CFRD) has become a critical complication that seriously affects the clinical outcomes of CF patients. Although CFRD has emerged as the most common nonpulmonary complication of CF, little is known about its etiopathogenesis. Additionally, whether oxidative stress (OxS), a common feature of CF and diabetes, influences CFRD pathophysiology requires clarification. The main objective of this study was to shed light on the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in combination with OxS in insulin secretion from pancreatic β-cells. CFTR silencing was accomplished in MIN6 cells by stable expression of small hairpin RNAs (shRNA), and glucose-induced insulin secretion was evaluated in the presence and absence of the valuable prooxidant system iron/ascorbate (Fe/Asc; 0.075/0.75 mM) along with or without the antioxidant Trolox (1 mM). Insulin output from CFTR-silenced MIN6 cells was significantly reduced (∼70%) at basal and at different glucose concentrations compared with control Mock cells. Furthermore, CFTR silencing rendered MIN6 cells more sensitive to OxS as evidenced by both increased lipid peroxides and weakened antioxidant defense, especially following incubation with Fe/Asc. The decreased insulin secretion in CFTR-silenced MIN6 cells was associated with high levels of NF-κB (the major participant in inflammatory responses), raised apoptosis, and diminished ATP production in response to the Fe/Asc challenge. However, these defects were alleviated by the addition of Trolox, thereby pointing out the role of OxS in aggravating the effects of CFTR deficiency. Our findings indicate that CFTR deficiency in combination with OxS may contribute to endocrine cell dysfunction and insulin secretion, which at least in part may explain the development of CFRD.

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Nε-(carboxymethyl) lysine-induced mitochondrial fission and mitophagy cause decreased insulin secretion from β-cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00151.2015 ◽

2015 ◽

Vol 309 (10) ◽

pp. E829-E839 ◽

Cited By ~ 19

Author(s):

Mei-Chen Lo ◽

Ming-Hong Chen ◽

Wen-Sen Lee ◽

Chin-I Lu ◽

Chuang-Rung Chang ◽

...

Keyword(s):

Insulin Secretion ◽

Mitochondrial Dysfunction ◽

Mitochondrial Fission ◽

Lipid Peroxide ◽

Mitochondrial Morphology ◽

Β Cells ◽

Pancreatic Β Cells ◽

Atp Production ◽

Mitochondrial Functions ◽

Carboxymethyl Lysine

Nε-(carboxymethyl) lysine-conjugated bovine serum albumin (CML-BSA) is a major component of advanced glycation end products (AGEs). We hypothesised that AGEs reduce insulin secretion from pancreatic β-cells by damaging mitochondrial functions and inducing mitophagy. Mitochondrial morphology and the occurrence of autophagy were examined in pancreatic islets of diabetic db/db mice and in the cultured CML-BSA-treated insulinoma cell line RIN-m5F. In addition, the effects of α-lipoic acid (ALA) on mitochondria in AGE-damaged tissues were evaluated. The diabetic db/db mouse exhibited an increase in the number of autophagosomes in damaged mitochondria and receptor for AGEs (RAGE). Treatment of db/db mice with ALA for 12 wk increased the number of mitochondria with well-organized cristae and fewer autophagosomes. Treatment of RIN-m5F cells with CML-BSA increased the level of RAGE protein and autophagosome formation, caused mitochondrial dysfunction, and decreased insulin secretion. CML-BSA also reduced mitochondrial membrane potential and ATP production, increased ROS and lipid peroxide production, and caused mitochondrial DNA deletions. Elevated fission protein dynamin-related protein 1 (Drp1) level and mitochondrial fragmentation demonstrated the unbalance of mitochondrial fusion and fission in CML-BSA-treated cells. Additionally, increased levels of Parkin and PTEN-induced putative kinase 1 protein suggest that fragmented mitochondria were associated with increased mitophagic activity, and ALA attenuated the CML-BSA-induced mitophage formation. Our study demonstrated that CML-BSA induced mitochondrial dysfunction and mitophagy in pancreatic β-cells. The findings from this study suggest that increased concentration of AGEs may damage β-cells and reduce insulin secretion.

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Role of mitochondrial phosphate carrier in metabolism–secretion coupling in rat insulinoma cell line INS-1

Biochemical Journal ◽

10.1042/bj20101708 ◽

2011 ◽

Vol 435 (2) ◽

pp. 421-430 ◽

Cited By ~ 18

Author(s):

Yuichi Nishi ◽

Shimpei Fujimoto ◽

Mayumi Sasaki ◽

Eri Mukai ◽

Hiroki Sato ◽

...

Keyword(s):

Insulin Secretion ◽

Critical Role ◽

Mitochondrial Fraction ◽

Β Cells ◽

Pancreatic Β Cells ◽

Atp Production ◽

Insulinoma Cell ◽

Consequent Reduction ◽

Phosphate Carrier

In pancreatic β-cells, glucose-induced mitochondrial ATP production plays an important role in insulin secretion. The mitochondrial phosphate carrier PiC is a member of the SLC25 (solute carrier family 25) family and transports Pi from the cytosol into the mitochondrial matrix. Since intramitochondrial Pi is an essential substrate for mitochondrial ATP production by complex V (ATP synthase) and affects the activity of the respiratory chain, Pi transport via PiC may be a rate-limiting step for ATP production. We evaluated the role of PiC in metabolism–secretion coupling in pancreatic β-cells using INS-1 cells manipulated to reduce PiC expression by siRNA (small interfering RNA). Consequent reduction of the PiC protein level decreased glucose (10 mM)-stimulated insulin secretion, the ATP:ADP ratio in the presence of 10 mM glucose and elevation of intracellular calcium concentration in response to 10 mM glucose without affecting the mitochondrial membrane potential (Δψm) in INS-1 cells. In experiments using the mitochondrial fraction of INS-1 cells in the presence of 1 mM succinate, PiC down-regulation decreased ATP production at various Pi concentrations ranging from 0.001 to 10 mM, but did not affect Δψm at 3 mM Pi. In conclusion, the Pi supply to mitochondria via PiC plays a critical role in ATP production and metabolism–secretion coupling in INS-1 cells.

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Dextromethorphan stimulates insulin secretion from pancreatic β cells—a new role for an old drug?

Nature Reviews Endocrinology ◽

10.1038/nrendo.2015.49 ◽

2015 ◽

Vol 11 (5) ◽

pp. 253-253

Author(s):

Jennifer Sargent

Keyword(s):

Insulin Secretion ◽

Β Cells ◽

Pancreatic Β Cells

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Congenital hyperinsulinism due to compound heterozygous mutations in ABCC8 responsive to diazoxide therapy

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0457 ◽

2020 ◽

Vol 33 (5) ◽

pp. 671-674

Author(s):

Tashunka Taylor-Miller ◽

Jayne Houghton ◽

Paul Munyard ◽

Yadlapalli Kumar ◽

Clinda Puvirajasinghe ◽

...

Keyword(s):

Insulin Secretion ◽

Compound Heterozygous ◽

Congenital Hyperinsulinism ◽

Β Cells ◽

Pancreatic Β Cells ◽

Newborn Period ◽

Case Presentation ◽

Male Baby ◽

Common Causes ◽

Compound Heterozygous Mutations

AbstractBackgroundCongenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic β cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI.Case presentationA term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide.ConclusionsBiallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.

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