Frataxin deficiency in pancreatic islets causes diabetes due to loss of β cell mass

Ristow, Michael; Mulder, Hindrik; Pomplun, Doreen; Schulz, Tim J.; Müller-Schmehl, Katrin; Krause, Anja; Fex, Malin; Puccio, Hélène; Müller, Jörg; Isken, Frank; Spranger, Joachim; Müller‐Wieland, Dirk; Magnuson, Mark A.; Möhlig, Matthias; Kœnig, M.; Pfeiffer, Andreas F. H.

doi:10.1172/jci18107

Cited by 124 publications

(109 citation statements)

References 42 publications

(19 reference statements)

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“…Hyperglycemia exerts dual and opposing effects on β-cells. Chronically elevated glucose levels result in pathological protein glycosylation, enhanced Fas-receptor expression, and superoxide-mediated activation of uncoupling protein 2 (Liu et al, 2000;Maedler et al, 2001;Ristow et al, 2003). On the other hand, glucose stimulates β-cell growth and has been found to be anti-apoptotic (Bonner-Weir, 2000; Bonner-Weir et al, 1989; Hoorens et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

The Metabolisable Hexoses D-Glucose and D-Mannose Enhance the Expression of IRS-2 but not of IRS-1 in Pancreatic β-Cells

Amacker-Françoys

Mohanty

Nießen

et al. 2005

Exp Clin Endocrinol Diabetes

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D-glucose regulates maintenance and function of pancreatic beta-cells. Several studies have shown that IRS-2, but not IRS-1, is necessary to maintain and sufficient to expand functional beta-cell mass. We therefore analyzed the expression of IRS-2 and IRS-1 in beta-cells after culture in the presence of various concentrations of D-glucose and other metabolisable or non-metabolisable hexoses. D-glucose increased Irs-2 transcription and IRS-2 accumulation in a dose-dependent manner (1.6 to 25 mmol/l), with a 3-fold increased plateau after 10 h. In contrast, the expression of IRS-1 remained unaffected. D-glucose also induced phosphorylation of IRS-2 while non-metabolisable hexoses did neither affect expression nor phosphorylation. D-glucose-mediated elevation and phosphorylation of IRS-2 were independent of autocrine insulin action although insulin itself could transiently and slightly enhance IRS-2 expression.

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Section: Discussionmentioning

confidence: 99%

The Metabolisable Hexoses D-Glucose and D-Mannose Enhance the Expression of IRS-2 but not of IRS-1 in Pancreatic β-Cells

Amacker-Françoys

Mohanty

Nießen

et al. 2005

Exp Clin Endocrinol Diabetes

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“…Frataxin is thought to play a role in the assembly of ironsulphur complexes (Puccio & Koenig 2000), which are found in respiratory chain proteins, as well as in the TCA cycle enzymes, such as aconitase. These patients develop a fatal neurological disorder: one-third of patients also develop diabetes (Ristow et al 2003, Ristow 2004, Cnop et al 2013. Moreover, several studies have shown linkage of T2D with the FRDA locus (9q13) (Lindgren et al 2002).…”

Section: Nuclear-encoded Genes and Control Of Mitochondrial Functionmentioning

confidence: 99%

“…Moreover, several studies have shown linkage of T2D with the FRDA locus (9q13) (Lindgren et al 2002). β-cell-specific knockout mice for frataxin develop insulin-dependent diabetes with loss of β-cell mass, due to cellular growth arrest and increased apoptosis, which is paralleled by an increase of ROS in islets (Ristow et al 2003). Friedreich's ataxia patients exhibit insulin resistance, which is not sufficiently compensated for by increased insulin secretion, evident from a reduced disposition index (Cnop et al 2012).…”

Section: Nuclear-encoded Genes and Control Of Mitochondrial Functionmentioning

confidence: 99%

The pathogenetic role of β-cell mitochondria in type 2 diabetes

Fex

Nicholas

Vishnu

et al. 2018

Journal of Endocrinology

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Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.

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“…Pfeiffer and colleagues generated a conditional mouse model with frataxin deficiency exclusively in pancreatic β-cells (Cre under the rat insulin promoter 2), to explore the link between frataxin deficiency and diabetes mellitus [14]. These mice show a slowly progressive reduction in the mass and number of islet cells, causing an impaired insulin secretory response to glucose and carbohydrates and culminating in overt diabetes.…”

Section: ■ Constitutive and Conditional Knockoutmentioning

confidence: 99%

Multicellular models of Friedreich ataxia

Puccio¹

2009

J Neurol

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Patients with Friedreich ataxia (FRDA) have severely reduced levels of the mitochondrial protein frataxin, which results from a large GAA triplet-repeat expansion within the frataxin gene (FXN). High evolutionary conservation of frataxin across species has enabled the development of disease models of FRDA in various unicellular and multicellular organisms. Mouse models include classical knockout models, in which the Fxn gene is constitutively inactivated, and knock-in models, in which a GAA repeat mutation or the conditional allele is inserted into the genome. Recently, "humanised" GAA repeat expansion mouse models were obtained by combining the constitutive knockout with the transgenic expression of a yeast artificial chromosome carrying the human FRDA locus. In lower organisms such as Caenorhabditis elegans and Drosophila, straight-forward and conditional RNA interference technology has provided an easy way to knock down frataxin expression. Conditional mouse models have been used for pre-clinical trials of potential therapeutic agents, including idebenone, MnTBAP (a superoxide dismutase mimetic), and iron chelators. Various models of FRDA have shown that different, even opposite, phenotypes can be observed, depending on the level of frataxin expression. Additional studies with animal models will be essential for an enhanced understanding of the disease pathophysiology and for the development of better therapies.

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Frataxin deficiency in pancreatic islets causes diabetes due to loss of β cell mass

Cited by 124 publications

References 42 publications

The Metabolisable Hexoses D-Glucose and D-Mannose Enhance the Expression of IRS-2 but not of IRS-1 in Pancreatic β-Cells

The Metabolisable Hexoses D-Glucose and D-Mannose Enhance the Expression of IRS-2 but not of IRS-1 in Pancreatic β-Cells

The pathogenetic role of β-cell mitochondria in type 2 diabetes

Multicellular models of Friedreich ataxia

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