Evidence for a Role of Frataxin in Pancreatic Islets Isolated from Multi-Organ Donors with and Without Type 2 Diabetes Mellitus

Abstract

Frataxin (FXN) is a mitochondrial protein involved in iron metabolism and in the modulation of reactive oxygen and/or nitrogen species production. No information is currently available as for the role of frataxin in isolated human pancreatic islets. We studied islets from pancreases of multi-organ donors with (T2DM) and without (Ctrl) Type 2 diabetes mellitus. In these islets, we determined FXN gene and protein expression by qualitative and quantitative Real-Time RT-PCR, nitrotyrosine concentration, and insulin release in response to glucose stimulation (SI). FXN gene and protein were expressed in human islets, though the level of expression was much lower in T2DM islets. The latter also had lower insulin release and higher concentration of nitrotyrosine. A positive correlation was apparent between SI and FXN gene expression, while a negative correlation was found between nitrotyrosine islet concentration and FXN expression. Transfection of Ctrl islets with siRNA FXN caused reduction of FXN expression, increase of nitrotyrosine concentration, and reduction of insulin release. In conclusion, in human pancreatic islets FXN contributes to regulation of oxidative stress and insulin release in response to glucose. In islets from T2DM patients FXN expression is reduced while oxidative stress is increased and insulin release in response to glucose impaired.

The impact of nimodipine administration combined with nerve‐muscle pedicle implantation on long‐term denervated rat thyroarytenoid muscle

“…Frataxin‐deficient INS‐1E cells tended to have increased insulin content (Fig 4), suggesting that frataxin deficiency does not impair insulin synthesis in β cells. The knockdown did not modify basal insulin secretion, but it reduced glucose‐ or glucose + forskolin‐stimulated insulin secretion, in keeping with recent findings in human islets 46. Glucose‐stimulated ATP production, which regulates insulin secretion, was impaired in frataxin‐deficient β cells.…”

The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity

“…The presence of oxidative stress 3, 37 and increased expression of UPR pathway factors such as CHOP 14 has been observed in islets from type 2 diabetic individuals. We investigated if proapoptotic molecules are also upregulated in human type 2 diabetes.…”

Central role and mechanisms of β‐cell dysfunction and death in friedreich ataxia–associated diabetes

“…The knockdown did not modify basal insulin secretion, but it reduced glucose-or glucose + forskolin-stimulated insulin secretion, in keeping with recent findings in human islets. 46 Glucose-stimulated ATP production, which regulates insulin secretion, was impaired in frataxin-deficient β cells. In addition, frataxin depletion reduced mitochondrial membrane potential in β cells (Supplementary Fig 2).…”

“…54–56 Of note, it was recently shown that islets from T2D donors have lower frataxin mRNA and protein expression. 46 The cause(s) of β -cell dysfunction/death in T2D is not well understood; genetic and environmental factors including sedentary lifestyle and energy-dense diets contribute. Abdominal obesity has been linked to loss of β -cell function in T2D, 54,57 and FFAs may mediate this deleterious effect.…”