KATP channels and insulin secretion: a key role in health and disease

2006 ◽  
Vol 34 (2) ◽  
pp. 243-246 ◽  
Author(s):  
F.M. Ashcroft
Keyword(s):  
Glucose Intolerance ◽  
Katp Channel ◽  
Cell Function ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Β Cell ◽  
Channel Inhibition ◽  
Β Cell Function ◽  
Health And Disease ◽  
And Function

This review summarizes advances in our understanding of the structure and function of the ATP-sensitive potassium (KATP) channel of the pancreatic β-cell that have been made over the last 5 years. It discusses recent structural studies of the octameric KATP channel complex and studies of the regulation of KATP channel activity by nucleotides. It then considers the molecular mechanism by which gain-of-function mutations in the Kir6.2 subunit of the KATP channel reduce channel inhibition by ATP and thereby lead to neonatal diabetes, and how identification of these mutations has led to changes in therapy. Finally, it illustrates how mouse models of glucose intolerance or diabetes can provide fresh insight into β-cell function, using the C57BL/6J mouse, whose glucose intolerance arises from mutations in nicotinamide nucleotide transhydrogenase, as an example.

scholarly journals Sulfonylureas suppress the stimulatory action of Mg-nucleotides on Kir6.2/SUR1 but not Kir6.2/SUR2A KATP channels: A mechanistic study

2014 ◽  
Vol 144 (5) ◽  
pp. 469-486 ◽  
Author(s):  
Peter Proks ◽  
Heidi de Wet ◽  
Frances M. Ashcroft
Keyword(s):  
Katp Channel ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Nucleotide Binding ◽  
Mechanistic Study ◽  
Xenopus Laevis Oocytes ◽  
Sulfonylurea Receptor ◽  
Β Cell ◽  
Stimulatory Action ◽  
Channel Inhibition

Sulfonylureas, which stimulate insulin secretion from pancreatic β-cells, are widely used to treat both type 2 diabetes and neonatal diabetes. These drugs mediate their effects by binding to the sulfonylurea receptor subunit (SUR) of the ATP-sensitive K+ (KATP) channel and inducing channel closure. The mechanism of channel inhibition is unusually complex. First, sulfonylureas act as partial antagonists of channel activity, and second, their effect is modulated by MgADP. We analyzed the molecular basis of the interactions between the sulfonylurea gliclazide and Mg-nucleotides on β-cell and cardiac types of KATP channel (Kir6.2/SUR1 and Kir6.2/SUR2A, respectively) heterologously expressed in Xenopus laevis oocytes. The SUR2A-Y1206S mutation was used to confer gliclazide sensitivity on SUR2A. We found that both MgATP and MgADP increased gliclazide inhibition of Kir6.2/SUR1 channels and reduced inhibition of Kir6.2/SUR2A-Y1206S. The latter effect can be attributed to stabilization of the cardiac channel open state by Mg-nucleotides. Using a Kir6.2 mutation that renders the KATP channel insensitive to nucleotide inhibition (Kir6.2-G334D), we showed that gliclazide abolishes the stimulatory effects of MgADP and MgATP on β-cell KATP channels. Detailed analysis suggests that the drug both reduces nucleotide binding to SUR1 and impairs the efficacy with which nucleotide binding is translated into pore opening. Mutation of one (or both) of the Walker A lysines in the catalytic site of the nucleotide-binding domains of SUR1 may have a similar effect to gliclazide on MgADP binding and transduction, but it does not appear to impair MgATP binding. Our results have implications for the therapeutic use of sulfonylureas.

scholarly journals Acyl-Ghrelin Influences Pancreatic β-Cell Function by Interference with KATP Channels

Diabetes ◽  
2020 ◽  
pp. db200231
Author(s):  
Julia Kaiser ◽  
Peter Krippeit-Drews ◽  
Gisela Drews
Keyword(s):  
Cell Function ◽  
Katp Channels ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function ◽  
Acyl Ghrelin

scholarly journals Gut Metabolite Trimethylamine N-Oxide Protects INS-1 β-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1892
Author(s):  
Emily S. Krueger ◽  
Joseph L. Beales ◽  
Kacie B. Russon ◽  
Weston S. Elison ◽  
Jordan R. Davis ◽  
...  
Keyword(s):  
Cell Function ◽  
Cell Mass ◽  
Caloric Intake ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Granule Formation ◽  
Β Cell Function ◽  
Molecular Effects ◽  
And Function

Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic β-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional β-cell mass. We hypothesized that TMAO may damage functional β-cell mass by inhibiting β-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 β-cells and primary rat islets with physiological TMAO concentrations and compared functional β-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded β-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in β-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects β-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.

scholarly journals Role of the Rho-ROCK (Rho-Associated Kinase) Signaling Pathway in the Regulation of Pancreatic β-Cell Function

Endocrinology ◽  
2008 ◽  
Vol 150 (5) ◽  
pp. 2072-2079 ◽  
Author(s):  
Eva Hammar ◽  
Alejandra Tomas ◽  
Domenico Bosco ◽  
Philippe A. Halban
Keyword(s):  
Extracellular Matrix ◽  
Insulin Secretion ◽  
Actin Cytoskeleton ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
And Function

Extracellular matrix has a beneficial impact on β-cell spreading and function, but the underlying signaling pathways have yet to be fully elucidated. In other cell types, Rho, a well-characterized member of the family of Rho GTPases, and its effector Rho-associated kinase (ROCK), play an important role as downstream mediators of outside in signaling from extracellular matrix. Therefore, a possible role of the Rho-ROCK pathway in β-cell spreading, actin cytoskeleton dynamics, and function was investigated. Rho was inhibited using a new cell-permeable version of C3 transferase, whereas the activity of ROCK was repressed using the specific ROCK inhibitors H-1152 and Y-27632. Inhibition of Rho and of ROCK increased spreading and improved both short-term and prolonged glucose-stimulated insulin secretion but had no impact on basal secretion. Inhibition of this pathway led to a depolymerization of the actin cytoskeleton. Furthermore, the impact of the inhibition of ROCK on stimulated insulin secretion was acute and reversible, suggesting that rapid signaling such as phosphorylation is involved. Finally, quantification of the activity of RhoA indicated that the extracellular matrix represses RhoA activity. Overall these results show for the first time that the Rho-ROCK signaling pathway contributes to the stabilization of the actin cytoskeleton and inhibits glucose-stimulated insulin secretion in primary pancreatic β-cells. Furthermore, they indicate that inhibition of this pathway might be one of the mechanisms by which the extracellular matrix exerts its beneficial effects on pancreatic β-cell function.

scholarly journals Metabolic regulation of insulin secretion in health and disease

2021 ◽  
Vol 43 (2) ◽  
pp. 4-8
Author(s):  
Elizabeth Haythorne ◽  
Frances M Ashcroft
Keyword(s):  
Insulin Secretion ◽  
Metabolic Regulation ◽  
Cell Function ◽  
Cell Metabolism ◽  
Neonatal Diabetes ◽  
Β Cell ◽  
Membrane Pore ◽  
Glucose Levels ◽  
Global Pandemic ◽  
Β Cell Function

Despite the current media focus, Covid-19 is not the only current pandemic. There is also a global pandemic of diabetes. It is caused by an insufficiency of the hormone insulin, which lowers blood glucose levels. Here we highlight recent work that addresses the question of how insulin is normally secreted from the β-cells of the pancreas and what goes wrong with this process in diabetes. We focus on the metabolic regulation of the ATP-sensitive potassium channel, an ATP-gated membrane pore that regulates insulin secretion. We show that when this pore is shut, insulin is released, and when it is open, insulin release is prevented. As may be expected, genetic mutations that impair the ability of ATP to close the channel cause neonatal diabetes. We also consider if a failure of β-cell metabolism to generate enough ATP to close the channel may lead to the progressive decline in β-cell function in type 2 diabetes.

scholarly journals STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and its Deficiency Induces Glucose Intolerance in Obesity

2021 ◽  
Author(s):  
Anaïs Schaschkow ◽  
Lokman Pang ◽  
Valerie Vandenbempt ◽  
Bernat Elvira ◽  
Sara A. Litwak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Cell Function ◽  
Mitochondrial Gene ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Deficient Mice

Most obese and insulin-resistant individuals do not develop diabetes. This is the result of the capacity of β-cells to adapt and produce enough insulin to cover the needs of the organism. The underlying mechanism of β-cell adaptation in obesity, however, remains unclear. Previous studies have suggested a role for STAT3 in mediating β-cell development and human glucose homeostasis, but little is known about STAT3 in β-cells in obesity. We observed enhanced cytoplasmic expression of STAT3 in severely obese and diabetic subjects. To address the functional role of STAT3 in adult β-cells, we generated mice with tamoxifen-inducible partial or full deletion of STAT3 in β-cells and fed them a high-fat diet before analysis. Interestingly, β-cell heterozygous and homozygous STAT3-deficient mice showed glucose intolerance when fed a high-fat diet. Gene expression analysis by RNA-Seq showed reduced expression of mitochondrial genes in STAT3 knocked down human EndoC-βH1 cells and was confirmed in FACS-purified β-cells from obese STAT3-deficient mice. Moreover, silencing of STAT3 impaired mitochondria activity in EndoC-βH1 cells and human islets, suggesting a mechanism for STAT3-modulated β-cell function. We propose STAT3 as a regulator of β-cell function, improving glucose-induced insulin secretion in obesity.

Longitudinal Glycaemic Profiles during Remission in 6q24-Related Transient Neonatal Diabetes Mellitus

2021 ◽  
Vol 94 (5-6) ◽  
pp. 229-234
Author(s):  
Yasuhiro Sato ◽  
Tsuyoshi Isojima ◽  
Kiyomi Takamiya ◽  
Kahoko Motoyama ◽  
Shigehiro Enkai ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cell Function ◽  
Neonatal Diabetes ◽  
Model Assessment ◽  
Homeostasis Model Assessment ◽  
Β Cell ◽  
Transient Neonatal Diabetes Mellitus ◽  
Glucose Intake ◽  
Β Cell Function ◽  
Transient Neonatal Diabetes

<b><i>Introduction:</i></b> Transient neonatal diabetes mellitus (TNDM) is a rare condition that is characterized by the presence of diabetes mellitus during the first 6 months of life and remission by 18 months of age. It usually relapses at a median age of 14 years. Hyperinsulinaemic hypoglycaemia is a relatively common complication during remission. Although β-cell function is reported to be impaired at relapse, the clinical course of glycaemic profiles during remission in patients with TNDM remains largely unknown. <b><i>Case Presentation:</i></b> Longitudinal glycaemic profiles were investigated annually from remission (185 days) to relapse (14.5 years) in a patient with TNDM due to paternal 6q24 duplication using the oral glucose tolerance test (glucose intake: 1.75 g/kg to a maximum of 75 g). The patient’s β-cell function and insulin sensitivity were assessed by calculating the insulinogenic index, homeostasis model assessment of β-cell function (HOMA-β), homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index, and Matsuda index. Early insulin response to glucose intake was impaired throughout remission, whereas fasting insulin and β-cell function by HOMA-β gradually increased in the first few years since remission, followed by a gradual decline in function. In contrast, HOMA-IR fluctuated and peaked at 6.5 years of age. <b><i>Conclusion:</i></b> This is the first report of annual longitudinal glycaemic profiles in a patient with 6q24-related TNDM during remission. We identified fluctuations in β-cell function and insulin resistance during remission.

scholarly journals Insulin Regulates Islet α-Cell Function by Reducing KATP Channel Sensitivity to Adenosine 5′-Triphosphate Inhibition

Endocrinology ◽  
2006 ◽  
Vol 147 (5) ◽  
pp. 2155-2162 ◽  
Author(s):  
Yuk M. Leung ◽  
Ishtiaq Ahmed ◽  
Laura Sheu ◽  
Xiaodong Gao ◽  
Manami Hara ◽  
...  
Keyword(s):  
Katp Channel ◽  
Cell Function ◽  
Fluorescent Protein ◽  
Glucagon Secretion ◽  
Katp Channels ◽  
Β Cell ◽  
Major Mechanism ◽  
Insulin Promoter ◽  
Atp Inhibition ◽  
Green Fluorescent

Glucose regulates pancreatic islet α-cell glucagon secretion directly by its metabolism to generate ATP in α-cells, and indirectly via stimulation of paracrine release of β-cell secretory products, particularly insulin. How the cellular substrates of these pathways converge in the α-cell is not well known. We recently reported the use of the MIP-GFP (mouse insulin promoter-green fluorescent protein) mouse to reliably identify islet α- (non-green cells) and β-cells (green cells), and characterized their ATP-sensitive K+ (KATP) channel properties, showing that α-cell KATP channels exhibited a 5-fold higher sensitivity to ATP inhibition than β-cell KATP channels. Here, we show that insulin exerted paracrine regulation of α-cells by markedly reducing the sensitivity of α-cell KATP channels to ATP (IC50 = 0.18 and 0.50 mm in absence and presence of insulin, respectively). Insulin also desensitized β-cell KATP channels to ATP inhibition (IC50 = 0.84 and 1.23 mm in absence and presence of insulin, respectively). Insulin effects on both islet cell KATP channels were blocked by wortmannin, indicating that insulin acted on the insulin receptor-phosphatidylinositol 3-kinase signaling pathway. Insulin did not affect α-cell A-type K+ currents. Glutamate, known to also inhibit α-cell glucagon secretion, did not activate α-cell KATP channel opening. We conclude that a major mechanism by which insulin exerts paracrine control on α-cells is by modulating its KATP channel sensitivity to ATP block. This may be an underlying basis for the proposed sequential glucose-insulin regulation of α-cell glucagon secretion, which becomes distorted in diabetes, leading to dysregulated glucagon secretion.

Downregulation of Fas activity rescues early onset of diabetes in c-KitWv/+ mice

2013 ◽  
Vol 304 (6) ◽  
pp. E557-E565 ◽  
Author(s):  
Zhi-Chao Feng ◽  
Matthew Riopel ◽  
Jinming Li ◽  
Lisa Donnelly ◽  
Rennian Wang
Keyword(s):  
Cell Survival ◽  
Cell Apoptosis ◽  
Fas Ligand ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Apoptotic Pathway ◽  
Β Cell Function ◽  
And Function

c-Kit and its ligand stem cell factor (SCF) are important for β-cell survival and maturation; meanwhile, interactions between the Fas receptor (Fas) and Fas ligand are capable of triggering β-cell apoptosis. Disruption of c-Kit signaling leads to severe loss of β-cell mass and function with upregulation of Fas expression in c-Kit Wv/+ mouse islets, suggesting that there is a critical balance between c-Kit and Fas activation in β-cells. In the present study, we investigated the interrelationship between c-Kit and Fas activation that mediates β-cell survival and function. We generated double mutant, c-Kit Wv/+ ;Fas lpr/lpr ( Wv −/−), mice to study the physiological and functional role of Fas with respect to β-cell function in c-Kit Wv/+ mice. Isolated islets from these mice and the INS-1 cell line were used. We observed that islets in c-Kit Wv/+ mice showed a significant increase in β-cell apoptosis along with upregulated p53 and Fas expression. These results were verified in vitro in INS-1 cells treated with SCF or c-Kit siRNA combined with a p53 inhibitor and Fas siRNA. In vivo, Wv −/− mice displayed improved β-cell function, with significantly enhanced insulin secretion and increased β-cell mass and proliferation compared with Wv +/+ mice. This improvement was associated with downregulation of the Fas-mediated caspase-dependent apoptotic pathway and upregulation of the cFlip/NF-κB pathway. These findings demonstrate that a balance between the c-Kit and Fas signaling pathways is critical in the regulation of β-cell survival and function.

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