Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes

Macfarlane, Wendy M.; Frayling, Timothy M.; Ellard, Sian; Evans, Julie; Allen, Lisa; Bulman, Michael P.; Ayres, S. C.; Shepherd, Maggie; Clark, Penny; Millward, Ann; Demaine, Andrew; Wilkin, Terence J.; Docherty, Kevin; Hattersley, Andrew T.

doi:10.1172/jci7449

Cited by 234 publications

(193 citation statements)

References 30 publications

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“…Pdx1 haploinsufficiency does not appear to physically or functionally impinge upon pancreas development in Pdx1+/− mice [12,13], however, such mice exhibit strikingly impaired glucose tolerance and glucose-stimulated insulin secretion with age [56,57]. Similarly impaired β cell function in the setting of Pdx1 deficiency has been observed in several other animal models (rat, fish, and sand rat [58][59][60][61][62]), as well as in humans with single allelic mutations in Ipf1 (where the development of impaired glucose responsiveness and frank diabetes occurs) [17][18][19][20][21]. The sand rat (Psammomys obesus) is a particularly an interesting case, as Pdx1 is not normally found in islets from these animals; however, gene transfer experiments show that repletion of Pdx1 in these islets greatly enhances insulin content and glucose-stimulated insulin transcription [62].…”

Section: Role Of Pdx1 In the Adult Pancreasmentioning

confidence: 99%

“…Pdx1 also appears to be crucial for the function of the mature β cell. Heterozygous missense and frameshift mutations of the Ipf1 gene in humans (while not impairing pancreas formation) result in defective insulin secretion and the development of a form of diabetes known as maturity onset diabetes of the young 4 (MODY4) [17][18][19][20][21]. Similarly, studies of animal models of insulin resistance suggest that the down regulation of pdx1 expression in the β cell may underlie the pathogenesis of β cell failure and type 2 diabetes [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

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A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Babu

Deering

Mirmira

2007

Molecular Genetics and Metabolism

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Emerging evidence over the past decade indicates a central role for transcription factors in the embryonic development of pancreatic islets and the consequent maintenance of normal glucose homeostasis. Pancreatic and duodenal homeobox 1 (Pdx1) is the best studied and perhaps most important of these factors. Whereas deletion or inactivating mutations of the Pdx1 gene causes whole pancreas agenesis in both mice and humans, even haploinsufficiency of the gene or alterations in its expression in mature islet cells causes substantial impairments in glucose tolerance and the development of a late-onset form of diabetes known as maturity onset diabetes of the young. The study of Pdx1 has revealed crucial phenotypic interrelationships of the varied cell types within the pancreas, particularly as these impinge upon cellular differentiation in the embryo and neogenesis and regeneration in the adult. In this review, we describe the actions of Pdx1 in the developing and mature pancreas and attempt to unify these actions with its known roles in modulating transcriptional complex formation and chromatin structure at the molecular genetic level.

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Section: Role Of Pdx1 In the Adult Pancreasmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Babu

Deering

Mirmira

2007

Molecular Genetics and Metabolism

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“…This PDX-1 antibody was raised against a fusion protein of GST with N-terminal 75 amino acids of mouse PDX-1. 8 It specifically recognizes PDX-1 on Western blots 9,10 and was also used in several immunohistochemical studies in the developing and regenerating pancreas. 11 Binding of the primary antibodies was detected using biotinylated swine anti-rabbit antisera (1:50; Dako, Hamburg, Germany), and a streptavidin-biotinylated alkaline phosphatase complex (Dako).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Gastric PDX-1 expression in pancreatic metaplasia and endocrine cell hyperplasia in atrophic corpus gastritis

et al. 2003

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The homeodomain transcription factor PDX-1 plays a key role in endocrine and exocrine differentiation processes of the pancreas. PDX-1 is also essential for differentiation of endocrine cells in the gastric antrum. The role of PDX-1 in the pathogenesis of endocrine cell hyperplasia and pancreatic metaplasia in corpus and fundus gastritis has not been evaluated. By immunohistochemistry and double-immunofluorescence, we investigated the expression of PDX-1 in 10 tissue specimens with normal human gastric mucosa, nonatrophic and atrophic gastritis and in pancreatic metaplasia, respectively. In normal corpus mucosa and in nonatrophic corpus gastritis, PDX-1 was mainly absent. In pancreatic metaplasia, PDX-1 was found in metaplastic cells and in adjacent gastric glands. In contrast to normal gastric corpus mucosa, PDX-1 could be strongly detected in the cytoplasm of the parietal cells surrounding metaplastic areas. Furthermore, PDX-1 expression was found in hyperplastic endocrine cells and in the surrounding gastric glands in chronic atrophic gastritis. Hyperplastic endocrine cells coexpressed the b-subunit of the gastric H,K-ATPase. We conclude that PDX-1 represents a candidate switch factor for glandular exocrine and endocrine transdifferentiation in chronic gastritis and that an impaired parietal cell differentiation might play a key role in disturbed gastric morphogenic processes. Keywords: PDX-1; gastritis; gastric atrophy; pancreatic metaplasia; endocrine cell hyperplasia In recent years, several factors have been characterized that play a key role in pancreatic organogenesis. 1 The homeobox transcription factor PDX-1 (pancreatic duodenal homeobox-1) also termed IPF-1 could be regarded as master switch for glandular exocrine and endocrine differentiation in the pancreas. Mutations within the PDX-1 gene are associated with type II diabetes mellitus or even with pancreatic agenesis. 2 In the stomach, PDX-1 has been shown to be essential for the differentiation of endocrine cells in the antropyloric region of mice and targeted deletion of PDX-1 leads to severely impaired development of gastrin cells in the antrum. 3 However, no study concerning the potential role of PDX-1 in glandular differentiation processes of the oxyntic mucosa in the corpus and fundus region has been undertaken. In these areas, pancreatic (acinar) metaplasia is frequently found and is associated with chronic gastritis. 4,5 Histologically, this type of metaplasia is characterized by acinus-like nests of epithelial cells producing pancreatic enzymes such as amylase, lipase and trypsinogen. 4 Furthermore, the so-called hyperplastic endocrine nodules can be regularly found in severe atrophic corpus gastritis. These nodules represent precursor lesions for neuroendocrine tumors within the gastric mucosa. 6 The molecular pathogenesis of both, pancreatic metaplasia and endocrine cell hyperplasia, is only poorly understood. To investigate the potential role of PDX-1 in these pathological conditions within the glandular compartment of the gastric mucos...

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“…[76]. Mutations in IPF-1 have very recently been suggested to confer susceptibility to late-onset Type II diabetes [77,78]. The rare MODY5 subform has been linked to HNF-1b [79].…”

Section: Maturity-onset Diabetes Of the Youngmentioning

confidence: 99%

“…Although MODY is a monogenic disease, it can teach us many lessons for the better understanding of the more common forms of Type II diabetes. In particular, the role of transcription factors in the aetiology of the disease must be further investigated [77,78]. induced.…”

Section: Beta-cell Model Of Mody3mentioning

confidence: 99%

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Wollheim¹

2000

Diabetologia

176

149

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In previous lectures, Claude Bernard's many scientific contributions have been highlighted. Among others he suggested in 1850 that the liver stores glucose and 7 years later, in 1857, he finally isolated glycogen [2]. Before that, in 1849, Claude Bernard reported his ªPiqßre sucrØeº to the SociØtØ de Biologie, Paris [3]. In analogy to his experiments in which stimulation of the fifth cranial nerve caused saliva secretion, he assumed that stimulation of the vagus nerve would elicit glucose secretion from the liver. In unanaesthetised rabbits and dogs, the pricking of the bottom of the fourth ventricle resulted in pronounced hyperglycaemia and glucosuria within 20 min. The ªdiabetesº was transient and disappeared after a few hours. He later showed that this effect was mediated, not by the vagus, but by sympathetic nerves. His discovery of glycogen made Claude Bernard the true father of Diabetologia (2000) AbstractInsulin is stored in secretory granules in the beta-cell and is secreted by exocytosis. This process is precisely controlled to achieve blood glucose homeostasis. Many forms of diabetes mellitus display impaired glucose-induced insulin secretion. This has been shown to be the primary cause of the disease in the various forms of maturity-onset diabetes of the young (MODY) and has also been implicated in adult-onset Type II (non-insulin-dependent) diabetes mellitus. Glucose generates ATP and other metabolic coupling factors in the beta-cell mitochondria. By plasma membrane depolarisation ATP promotes Ca 2+ influx, which raises cytosolic Ca 2+ and triggers insulin exocytosis. Through hyperpolarisation of the mitochondrial membrane glucose also increases the Ca 2+ concentration in the mitochondrial matrix activating Ca 2+ -sensitive dehydrogenases in the tricarboxylic acid cycle. The resulting generation of glutamate participates in Ca 2+ -stimulated exocytosis. Mitochondrial DNA (mtDNA) encodes some of the polypeptides of the respiratory chain enzyme complexes. Mutations in mtDNA lead to maternally inherited diabetes mellitus characterised by impaired insulin secretion. The impact of altered mtDNA on insulin secretion has been shown in mtDNA-deficient beta-cell lines which have lost glucose-stimulated insulin secretion but retain a Ca 2+ -induced insulin secretion. A cellular model of MODY3 expressing dominant-negative hepatocyte nuclear factor-1a (HNF-1a) also displayed deletion of glucose-induced but not Ca 2+ -induced insulin secretion. Reduced mitochondrial metabolism explains this secretory pattern. Thus, genetically manipulated beta-cell lines are essential tools in the investigation of the molecular basis of beta-cell dysfunction in diabetes and should explain the role of other transcription factors in the disease. [Diabetologia (2000) 43: 265±277]

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Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes

Cited by 234 publications

References 30 publications

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Gastric PDX-1 expression in pancreatic metaplasia and endocrine cell hyperplasia in atrophic corpus gastritis

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

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