Recently, the transcription factor 7-like 2 (TCF7L2) gene has been associated with type 2 diabetes in subjects of European origin in the DeCode study. We genotyped the two most associated variants (rs7903146 and rs12255372) in 2,367 French type 2 diabetic subjects and in 2,499 control subjects. Both the T-allele of rs7903146 and the T-allele of rs12255372 significantly increase type 2 diabetes risk with an allelic odds ratio (OR) of 1.69 (95% CI 1.55-1.83) (P ؍ 6.0 ؋ 10 ؊35 ) and 1.60 (1.47-1.74) (P ؍ 7.6 ؋ 10 ؊28 ), respectively. In nonobese type 2 diabetic subjects (BMI <30 kg/m 2 , n ؍ 1,346), the ORs increased to 1.89 (1.72-2.09) (P ؍ 2.1 ؋ 10 ؊38 ) and 1.79 (1.62-1.97) (P ؍ 5.7 ؋ 10 ؊31 ), respectively. The rs7903146 T at-risk allele associates with decreased BMI and earlier age at diagnosis in the type 2 diabetic subjects (P ؍ 8.0 ؋ 10 ؊3 and P ؍ 3.8 ؋ 10 ؊4 , respectively), which is supported by quantitative family-based association tests. TCF7L2 is expressed in most human tissues, including mature pancreatic -cells, with the exception of the skeletal muscle. In the subcutaneous and omental fat from obese type 2 diabetic subjects, TCF7L2 expression significantly decreased compared with obese normoglycemic individuals. During rat fetal -cell differentiation, TCF7L2 expression pattern mimics the key marker NGN3 (neurogenin 3), suggesting a role in islet development. These data provide evidence that TCF7L2 is a major determinant of type 2 diabetes risk in European populations and suggests that this transcription factor plays a key role in glucose homeostasis. Diabetes 55: [2903][2904][2905][2906][2907][2908] 2006 T o date, positional cloning for type 2 diabetes genes has not been very successful in detecting type 2 diabetes putative susceptibility genes. Although several positive reports have emerged (1,2), few have been consistently replicated (3). Several studies have shown linkage between type 2 diabetes and chromosome 10q in Mexican-American, French, English, and Icelandic populations (4 -7) with a strong association between type 2 diabetes and variation in the transcription factor 7-like 2 (TCF7L2) gene found in Icelandic, Danish, and American populations (8). Little is known about the physiological implication of this transcription factor in glucose homeostasis. It has been suggested that intestinal proglucagon gene expression may be regulated by the Wnt/TCF7L2 pathway in enteroendocrine cells (9). Thus, TCF7L2 variants may modify type 2 diabetes susceptibility through modulation of glucagon-like peptide-1 (GLP-1) secretion. Because French type 2 diabetic families exhibit evidence for linkage in a chromosome 10q region encompassing the TCF7L2 locus, we assessed the contribution of TCF7L2 genetic variation to type 2 diabetes genetic risk. Tissue profiling analyses were also performed in rodents and humans to help understand the regulation of TCF7L2 and its involvement in the physiology of type 2 diabetes.Among the previously reported TCF7L2 variants, the association between the T-alle...
The importance of mesenchymal-epithelial interactions for normal development of the pancreas was recognized in the early 1960s, and mesenchymal signals have been shown to control the proliferation of early pancreatic progenitor cells. The mechanisms by which the mesenchyme coordinates cell proliferation and differentiation to produce the normal number of differentiated pancreatic cells are not fully understood. Here, we demonstrate that the mesenchyme positively controls the final number of -cells that develop from early pancreatic progenitor cells. In vitro, the number of -cells that developed from rat embryonic pancreatic epithelia was larger in cultures with mesenchyme than without mesenchyme. The effect of mesenchyme was not due to an increase in -cell proliferation but was due to increased proliferation of early pancreatic duodenal homeobox-1 (PDX1)-positive progenitor cells, as confirmed by bromodeoxyuridine incorporation. Consequently, the window during which early PDX1؉ pancreatic progenitor cells differentiated into endocrine progenitor cells expressing Ngn3 was extended. Fibroblast growth factor 10 mimicked mesenchyme effects on proliferation of early PDX1؉ progenitor cells and induction of Ngn3 expression. Taken together, our results indicate that expansion of early PDX1؉ pancreatic progenitor cells represents a way to increase the final number of -cells developing from early embryonic pancreas. Diabetes 56:1248-1258, 2007 E pithelium-mesenchyme interactions play a crucial role during organogenesis. They are mediated at least in part by soluble factors produced by the mesenchyme and acting on the epithelium (1). Evidence points to a crucial role for epithelialmesenchymal interactions in cell proliferation and differentiation during pancreatic development (2). However, the mechanisms by which the mesenchyme coordinates cell proliferation and differentiation to produce a normal number of differentiated pancreatic cells are not fully understood.The mature pancreas contains endocrine islets composed of cells producing hormones, such as insulin (-cells) and glucagon (␣-cells), and exocrine tissue composed of acinar cells producing enzymes (e.g., carboxypeptidase-A) secreted into the intestine. The pancreas originates from the dorsal and ventral regions of the foregut endoderm. Recently, important findings have shed light on the processes controlling pancreatic endocrine cell development. Studies of genetically engineered mice identified a hierarchy of transcription factors regulating pancreas organogenesis and islet-cell differentiation (3-5). The endodermal region committed to a pancreatic fate first expresses transcription factor pancreatic duodenal homeobox-1 (Pdx1). Pdx1 is detected in mouse embryos on embryonic day 8.5 (E8.5) (E9 in rats) in early pancreatic progenitors. During adulthood, Pdx1 expression becomes largely confined to -cells, where it activates insulin gene transcription (6). Disruption of the Pdx1 gene in mice or human leads to pancreatic agenesis (7,8). These data indicate that P...
Understanding in detail how pancreatic endocrine cells develop is important for many reasons. From a scientific point of view, elucidation of such a complex process is a major challenge. From a more applied point of view, this may help us to better understand and treat specific forms of diabetes. Although a variety of therapeutic approaches are well validated, no cure for diabetes is available. Many arguments indicate that the development of new strategies to cure diabetic patients will require precise understanding of the way b-cells form during development. This is obvious for a future cell therapy using b-cells produced from embryonic stem cells. This also holds true for therapeutic approaches based on regenerative medicine. In this review, we summarize our current knowledge concerning pancreatic development and focus on the role of extracellular signals implicated in b-cell development from pancreatic progenitors.
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