Paired box 6 programs essential exocytotic genes in the regulation of glucose-stimulated insulin secretion and glucose homeostasis
| Autor: | Adrian Kee Keong Teo, Guy A. Rutter, Wai Nam Liu, Weiping Han, Wing Yan So |
|---|---|
| Přispěvatelé: | MRC Programme Grant, Wellcome Trust |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
PAX6 MUTATION
CYCLIC-AMP Type 2 diabetes Research & Experimental Medicine 0302 clinical medicine Insulin-Secreting Cells Insulin Secretion Glucose homeostasis Homeostasis Insulin 11 Medical and Health Sciences 0303 health sciences CREB TRANSCRIPTIONAL REGULATION INDUCTION General Medicine medicine.anatomical_structure Medicine Research & Experimental Beta cell Life Sciences & Biomedicine EXPRESSION medicine.medical_specialty endocrine system EARLY-ONSET Biology 03 medical and health sciences Islets of Langerhans Insulin resistance BETA-CELLS Internal medicine Diabetes mellitus medicine Humans 030304 developmental biology Science & Technology Pancreatic islets DIABETES-MELLITUS Cell Biology PANCREATIC-ISLETS 06 Biological Sciences medicine.disease eye diseases Endocrinology Glucose Diabetes Mellitus Type 2 biology.protein PAX6 sense organs 030217 neurology & neurosurgery |
| Popis: | The paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in humans. However, the molecular mechanism of PAX6 in controlling insulin secretion in human beta cells and its pathophysiological role in type 2 diabetes (T2D) remain ambiguous. We investigated the molecular pathway of PAX6 in the regulation of insulin secretion and the potential therapeutic value of PAX6 in T2D by using human pancreatic beta cell line EndoC-βH1, the db/db mouse model, and primary human pancreatic islets. Through loss- and gain-of-function approaches, we uncovered a mechanism by which PAX6 modulates glucose-stimulated insulin secretion (GSIS) through a cAMP response element-binding protein (CREB)/Munc18-1/2 pathway. Moreover, under diabetic conditions, beta cells and pancreatic islets displayed dampened PAX6/CREB/Munc18-1/2 pathway activity and impaired GSIS, which were reversed by PAX6 replenishment. Adeno-associated virus-mediated PAX6 overexpression in db/db mouse pancreatic beta cells led to a sustained amelioration of glycemic perturbation in vivo but did not affect insulin resistance. Our study highlights the pathophysiological role of PAX6 in T2D-associated beta cell dysfunction in humans and suggests the potential of PAX6 gene transfer in preserving and restoring beta cell function. |
| Databáze: | OpenAIRE |
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