Type 2 diabetes is a chronic disease marked by hyperglycemia; impaired insulin secretion by pancreatic β-cells is a hallmark of this disease. Recent studies have shown that hypoxia occurs in the β-cells of patients with type 2 diabetes and hypoxia, in turn, contributes to the insulin secretion defect and β-cell loss through various mechanisms, including the activation of hypoxia-inducible factors, induction of transcriptional repressors, and activation of AMP-activated protein kinase. This review focuses on advances in our understanding of the contribution of β-cell hypoxia to the development of β-cell dysfunction in type 2 diabetes.
View Article and Find Full Text PDFHypoxia can occur in pancreatic β-cells in type 2 diabetes. Although hypoxia exerts deleterious effects on β-cell function, the associated mechanisms are largely unknown. Here, we show that the transcriptional repressor basic helix-loop-helix family member e40 (BHLHE40) is highly induced in hypoxic mouse and human β-cells and suppresses insulin secretion.
View Article and Find Full Text PDFBrown adipose tissue plays a central role in the regulation of the energy balance by expending energy to produce heat. NAD-dependent deacylase sirtuins have widely been recognized as positive regulators of brown adipose tissue thermogenesis. However, here we reveal that SIRT7, one of seven mammalian sirtuins, suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions.
View Article and Find Full Text PDFSirtuins (SIRT1-7 in mammals) are evolutionarily conserved nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases that regulate fundamental biological processes including aging. In this study, we reveal that male knockout (KO) mice exhibited an extension of mean and maximum lifespan and a delay in the age-associated mortality rate. In addition, aged male KO mice displayed better glucose tolerance with improved insulin sensitivity compared with wild-type (WT) mice.
View Article and Find Full Text PDFJ Diabetes Investig
October 2021
Aims/introduction: Peroxisome proliferator-activated receptor (PPAR)-γ2 is a transcription factor crucial for regulating adipogenesis and glucose/lipid metabolism, and synthetic PPARγ ligands, such as thiazolidinediones, are effective oral medication for type 2 diabetes. Sirtuin 7 (SIRT7), a nicotinamide adenine dinucleotide-dependent deacetylase, also controls metabolism. However, it is not known whether SIRT7 regulates the function of PPARγ2 by its deacetylation.
View Article and Find Full Text PDFBiochim Biophys Acta Mol Basis Dis
November 2020
Hepatocyte nuclear factor 1α (HNF1α) is a transcription factor required for normal insulin secretion and maintenance of β-cell number in the pancreas. HNF1α is also expressed in pancreatic α-cells, but its role in these cells is unknown. The aim of this study was to clarify the role of HNF1α in α-cells.
View Article and Find Full Text PDFRecent evidence has revealed a novel signaling mechanism through which brown adipose tissue (BAT)-derived exosomal microRNAs (miRNAs) influence hepatic gene expression. Here, we uncover neuronal control of these miRNAs and identify exosomal miR-132-3p as a regulator of hepatic lipogenesis under cold stress conditions. Norepinephrine, a sympathetic nervous system neurotransmitter mediating cold-induced BAT activation, altered the composition of brown adipocyte (BAC)-derived exosomal miRNAs; among them, miR-132-3p was significantly induced.
View Article and Find Full Text PDFHypoxia plays a role in the deterioration of β-cell function. Hepatocyte nuclear factor 4α (HNF4α) has an important role in pancreatic β-cells, and mutations of the human gene cause a type of maturity-onset diabetes of the young (MODY1). However, it remains unclear whether hypoxia affects the expression of HNF4α in β-cells.
View Article and Find Full Text PDFHuman embryonic stem cells (ESCs) show a characteristic feature in that they are highly dependent on methionine metabolism. Undifferentiated human ESCs cannot survive under condition that methionine is deprived from culture medium. We describe here a procedure for definitive endoderm differentiation from human ESCs, in which human ESCs are subject to 10 days' (d) differentiation combined with methionine deprivation between differentiation days (d) 8 to (d) 10.
View Article and Find Full Text PDFHuman embryonic stem cells (ESCs) show a characteristic feature in that they are highly dependent on methionine metabolism. Undifferentiated human ESCs cannot survive under the condition that methionine is deprived from culture medium. We describe here a procedure for definitive endoderm differentiation from human ESCs, in which human ESCs are subject to 10 days (d) differentiation combined with methionine deprivation between differentiation day (d) 8 to d10.
View Article and Find Full Text PDFMouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are in a high-flux metabolic state, with a high dependence on threonine catabolism. However, little is known regarding amino acid metabolism in human ESCs/iPSCs. We show that human ESCs/iPSCs require high amounts of methionine (Met) and express high levels of enzymes involved in Met metabolism.
View Article and Find Full Text PDFIslet transplantation is a promising potential therapy for patients with type 1 diabetes. The outcome of islet transplantation depends on the transplantation of a sufficient amount of β-cell mass. However, the initial loss of islets after transplantation is problematic.
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