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1.
Can J Diabetes ; 47(2): 207-221, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36481263

ABSTRACT

Navigating the coronavirus disease-2019 (COVID-19, now COVID) pandemic has required resilience and creativity worldwide. Despite early challenges to productivity, more than 2,000 peer-reviewed articles on islet biology were published in 2021. Herein, we highlight noteworthy advances in islet research between January 2021 and April 2022, focussing on 5 areas. First, we discuss new insights into the role of glucokinase, mitogen-activated protein kinase-kinase/extracellular signal-regulated kinase and mitochondrial function on insulin secretion from the pancreatic ß cell, provided by new genetically modified mouse models and live imaging. We then discuss a new connection between lipid handling and improved insulin secretion in the context of glucotoxicity, focussing on fatty acid-binding protein 4 and fetuin-A. Advances in high-throughput "omic" analysis evolved to where one can generate more finely tuned genetic and molecular profiles within broad classifications of type 1 diabetes and type 2 diabetes. Next, we highlight breakthroughs in diabetes treatment using stem cell-derived ß cells and innovative strategies to improve islet survival posttransplantation. Last, we update our understanding of the impact of severe acute respiratory syndrome-coronavirus-2 infection on pancreatic islet function and discuss current evidence regarding proposed links between COVID and new-onset diabetes. We address these breakthroughs in 2 settings: one for a scientific audience and the other for the public, particularly those living with or affected by diabetes. Bridging biomedical research in diabetes to the community living with or affected by diabetes, our partners living with type 1 diabetes or type 2 diabetes also provide their perspectives on these latest advances in islet biology.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Insulin-Secreting Cells , Islets of Langerhans , Animals , Mice , Biology , Diabetes Mellitus, Type 1/metabolism , Insulin/metabolism , Insulin-Secreting Cells/metabolism , Islets of Langerhans/metabolism , Humans
2.
Cells ; 11(3)2022 02 04.
Article in English | MEDLINE | ID: mdl-35159354

ABSTRACT

Oxidative stress caused by the exposure of pancreatic ß-cells to high levels of fatty acids impairs insulin secretion. This lipotoxicity is thought to play an important role in ß-cell failure in type 2 diabetes and can be prevented by antioxidants. Gamma-hydroxybutyrate (GHB), an endogenous antioxidant and energy source, has previously been shown to protect mice from streptozotocin and alloxan-induced diabetes; both compounds are generators of oxidative stress and yield models of type-1 diabetes. We sought to determine whether GHB could protect mouse islets from lipotoxicity caused by palmitate, a model relevant to type 2 diabetes. We found that GHB prevented the generation of palmitate-induced reactive oxygen species and the associated lipotoxic inhibition of glucose-stimulated insulin secretion while increasing the NADPH/NADP+ ratio. GHB may owe its antioxidant and insulin secretory effects to the formation of NADPH.


Subject(s)
Diabetes Mellitus, Type 2 , Islets of Langerhans , Sodium Oxybate , Animals , Antioxidants/pharmacology , Mice , NADP , Palmitates/pharmacology , Sodium Oxybate/pharmacology
3.
Endocrinology ; 163(1)2022 01 01.
Article in English | MEDLINE | ID: mdl-34718519

ABSTRACT

Pancreatic ß-cells can secrete insulin via 2 pathways characterized as KATP channel -dependent and -independent. The KATP channel-independent pathway is characterized by a rise in several potential metabolic signaling molecules, including the NADPH/NADP+ ratio and α-ketoglutarate (αKG). Prolyl hydroxylases (PHDs), which belong to the αKG-dependent dioxygenase superfamily, are known to regulate the stability of hypoxia-inducible factor α. In the current study, we assess the role of PHDs in vivo using the pharmacological inhibitor dimethyloxalylglycine (DMOG) and generated ß-cell-specific knockout (KO) mice for all 3 isoforms of PHD (ß-PHD1 KO, ß-PHD2 KO, and ß-PHD3 KO mice). DMOG inhibited in vivo insulin secretion in response to glucose challenge and inhibited the first phase of insulin secretion but enhanced the second phase of insulin secretion in isolated islets. None of the ß-PHD KO mice showed any significant in vivo defects associated with glucose tolerance and insulin resistance except for ß-PHD2 KO mice which had significantly increased plasma insulin during a glucose challenge. Islets from both ß-PHD1 KO and ß-PHD3 KO had elevated ß-cell apoptosis and reduced ß-cell mass. Isolated islets from ß-PHD1 KO and ß-PHD3 KO had impaired glucose-stimulated insulin secretion and glucose-stimulated increases in the ATP/ADP and NADPH/NADP+ ratio. All 3 PHD isoforms are expressed in ß-cells, with PHD3 showing the most distinct expression pattern. The lack of each PHD protein did not significantly impair in vivo glucose homeostasis. However, ß-PHD1 KO and ß-PHD3 KO mice had defective ß-cell mass and islet insulin secretion, suggesting that these mice may be predisposed to developing diabetes.


Subject(s)
Insulin Secretion , Insulin-Secreting Cells/metabolism , Insulin/metabolism , Prolyl Hydroxylases/metabolism , Protein Isoforms/chemistry , Adenosine Diphosphate/metabolism , Adenosine Triphosphate/metabolism , Animals , Apoptosis , Gene Expression Regulation , Glucose/metabolism , Glucose Tolerance Test , Homeostasis , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Ketoglutaric Acids/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NADP/metabolism , Oxidative Phosphorylation , Oxygen Consumption , Phenotype , Protein Domains
4.
Int J Mol Sci ; 22(24)2021 Dec 08.
Article in English | MEDLINE | ID: mdl-34948019

ABSTRACT

The NAD-dependent deacetylase SIRT1 improves ß cell function. Accordingly, nicotinamide mononucleotide (NMN), the product of the rate-limiting step in NAD synthesis, prevents ß cell dysfunction and glucose intolerance in mice fed a high-fat diet. The current study was performed to assess the effects of NMN on ß cell dysfunction and glucose intolerance that are caused specifically by increased circulating free fatty acids (FFAs). NMN was intravenously infused, with or without oleate, in C57BL/6J mice over a 48-h-period to elevate intracellular NAD levels and consequently increase SIRT1 activity. Administration of NMN in the context of elevated plasma FFA levels considerably improved glucose tolerance. This was due not only to partial protection from FFA-induced ß cell dysfunction but also, unexpectedly, to a significant decrease in insulin clearance. However, in conditions of normal FFA levels, NMN impaired glucose tolerance due to decreased ß cell function. The presence of this dual action of NMN suggests caution in its proposed therapeutic use in humans.


Subject(s)
Fatty Acids, Nonesterified/blood , Glucose Intolerance/drug therapy , Glucose/adverse effects , Insulin/metabolism , Nicotinamide Mononucleotide/administration & dosage , Oleic Acid/adverse effects , Animals , Glucose Intolerance/blood , Glucose Intolerance/chemically induced , Hep G2 Cells , Humans , Infusions, Intravenous , Male , Mice , Mice, Inbred C57BL , NAD/metabolism , Nicotinamide Mononucleotide/pharmacology , Sirtuin 1/metabolism , Up-Regulation
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