scholarly journals Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel

2016 ◽  
Vol 149 (1) ◽  
pp. 75-84 ◽  
Author(s):  
Maria S. Remedi ◽  
Jonathan B. Friedman ◽  
Colin G. Nichols
Keyword(s):  
Insulin Secretion ◽  
Katp Channel ◽  
Vascular System ◽  
Wild Type Mouse ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Gain Of Function ◽  
Insulin Promoter

Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of KATP channels have been identified as the most common cause of human neonatal diabetes mellitus. The critical effect of these mutations is confirmed in mice expressing Kir6.2-GOF mutations in pancreatic β cells. A second KATP channel pore-forming subunit, Kir6.1, was originally cloned from the pancreas. Although the prominence of this subunit in the vascular system is well documented, a potential role in pancreatic β cells has not been considered. Here, we show that mice expressing Kir6.1-GOF mutations (Kir6.1[G343D] or Kir6.1[G343D,Q53R]) in pancreatic β cells (under rat-insulin-promoter [Rip] control) develop glucose intolerance and diabetes caused by reduced insulin secretion. We also generated transgenic mice in which a bacterial artificial chromosome (BAC) containing Kir6.1[G343D] is incorporated such that the transgene is only expressed in tissues where Kir6.1 is normally present. Strikingly, BAC-Kir6.1[G343D] mice also show impaired glucose tolerance, as well as reduced glucose- and sulfonylurea-dependent insulin secretion. However, the response to K+ depolarization is intact in Kir6.1-GOF mice compared with control islets. The presence of native Kir6.1 transcripts was demonstrated in both human and wild-type mouse islets using quantitative real-time PCR. Together, these results implicate the incorporation of native Kir6.1 subunits into pancreatic KATP channels and a contributory role for these subunits in the control of insulin secretion.

scholarly journals A novel high-affinity inhibitor against the human ATP-sensitive Kir6.2 channel

2018 ◽  
Vol 150 (7) ◽  
pp. 969-976 ◽  
Author(s):  
Yajamana Ramu ◽  
Yanping Xu ◽  
Zhe Lu
Keyword(s):  
Insulin Secretion ◽  
Specific Inhibitor ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Sulfonylurea Receptor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
High Affinity ◽  
New Strategy ◽  
Extracellular Side

The adenosine triphosphate (ATP)-sensitive (KATP) channels in pancreatic β cells couple the blood glucose level to insulin secretion. KATP channels in pancreatic β cells comprise the pore-forming Kir6.2 and the modulatory sulfonylurea receptor 1 (SUR1) subunits. Currently, there is no high-affinity and relatively specific inhibitor for the Kir6.2 pore. The importance of developing such inhibitors is twofold. First, in many cases, the lack of such an inhibitor precludes an unambiguous determination of the Kir6.2's role in certain physiological and pathological processes. This problem is exacerbated because Kir6.2 knockout mice do not yield the expected phenotypes of hyperinsulinemia and hypoglycemia, which in part, may reflect developmental adaptation. Second, mutations in Kir6.2 or SUR1 that increase the KATP current cause permanent neonatal diabetes mellitus (PNDM). Many patients who have PNDM have been successfully treated with sulphonylureas, a common class of antidiabetic drugs that bind to SUR1 and indirectly inhibit Kir6.2, thereby promoting insulin secretion. However, some PNDM-causing mutations render KATP channels insensitive to sulphonylureas. Conceptually, because these mutations are located intracellularly, an inhibitor blocking the Kir6.2 pore from the extracellular side might provide another approach to this problem. Here, by screening the venoms from >200 animals against human Kir6.2 coexpressed with SUR1, we discovered a small protein of 54 residues (SpTx-1) that inhibits the KATP channel from the extracellular side. It inhibits the channel with a dissociation constant value of 15 nM in a relatively specific manner and with an apparent one-to-one stoichiometry. SpTx-1 evidently inhibits the channel by primarily targeting Kir6.2 rather than SUR1; it inhibits not only wild-type Kir6.2 coexpressed with SUR1 but also a Kir6.2 mutant expressed without SUR1. Importantly, SpTx-1 suppresses both sulfonylurea-sensitive and -insensitive, PNDM-causing Kir6.2 mutants. Thus, it will be a valuable tool to investigate the channel's physiological and biophysical properties and to test a new strategy for treating sulfonylurea-resistant PNDM.

Pharmacological modulation of KATP channels

2002 ◽  
Vol 30 (2) ◽  
pp. 333-339 ◽  
Author(s):  
F. M. Gribble ◽  
F. Reimann
Keyword(s):  
Type 2 Diabetes ◽  
Cardiac Muscle ◽  
Katp Channel ◽  
Katp Channels ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Tissue Specific ◽  
Pharmacological Modulation ◽  
Clinical Conditions

Pharmacological modulation of ATP-sensitive K+ (KATP) channels is used in the treatment of a number of clinical conditions, including type 2 diabetes and angina. The sulphonylureas and related drugs, which are used to treat type 2 diabetes, stimulate insulin secretion by closing KATP channels in pancreatic β-cells. Agents used to treat angina, by contrast, act by opening KATP channels in vascular smooth and cardiac muscle. Both the therapeutic KATP channel inhibitors and the KATP channel openers target the sulphonylurea receptor (SUR) subunit of the KATP channel, which exists in several isoforms expressed in different tissues (SUR1 in pancreatic β-cells, SUR2A in cardiac muscle and SUR2B in vascular smooth muscle). The tissue-specific action of drugs that target the KATP channel is attributed to the properties of these different SUR subtypes. In this review, we discuss the molecular basis of tissue-specific drug action, and its implications for clinical practice.

The Imidazoline RX871024 Stimulates Insulin Secretion in Pancreatic β-Cells from Mice Deficient in KATP Channel Function

2001 ◽  
Vol 284 (4) ◽  
pp. 918-922 ◽  
Author(s):  
Alexander M. Efanov ◽  
Marianne Høy ◽  
Robert Bränström ◽  
Sergei V. Zaitsev ◽  
Mark A. Magnuson ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Katp Channel ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Channel Function

scholarly journals The Krüppel-Like Protein Gli-Similar 3 (Glis3) Functions as a Key Regulator of Insulin Transcription

2013 ◽  
Vol 27 (10) ◽  
pp. 1692-1705 ◽  
Author(s):  
Gary T. ZeRuth ◽  
Yukimasa Takeda ◽  
Anton M. Jetten
Keyword(s):  
Transcriptional Regulation ◽  
Regulatory Region ◽  
Neonatal Diabetes ◽  
Creb Binding Protein ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Synergistic Activation ◽  
Transcriptional Regulatory ◽  
Insulin Promoter ◽  
Regulatory Complex

Transcriptional regulation of insulin in pancreatic β-cells is mediated primarily through enhancer elements located within the 5′ upstream regulatory region of the preproinsulin gene. Recently, the Krüppel-like transcription factor, Gli-similar 3 (Glis3), was shown to bind the insulin (INS) promoter and positively influence insulin transcription. In this report, we examined in detail the synergistic activation of insulin transcription by Glis3 with coregulators, CREB-binding protein (CBP)/p300, pancreatic and duodenal homeobox 1 (Pdx1), neuronal differentiation 1 (NeuroD1), and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA). Our data show that Glis3 expression, the binding of Glis3 to GlisBS, and its recruitment of CBP are required for optimal activation of the insulin promoter in pancreatic β-cells not only by Glis3, but also by Pdx1, MafA, and NeuroD1. Mutations in the GlisBS or small interfering RNA−directed knockdown of GLIS3 diminished insulin promoter activation by Pdx1, NeuroD1, and MafA, and neither Pdx1 nor MafA was able to stably associate with the insulin promoter when the GlisBS were mutated. In addition, a GlisBS mutation in the INS promoter implicated in the development of neonatal diabetes similarly abated activation by Pdx1, NeuroD1, and MafA that could be reversed by increased expression of exogenous Glis3. We therefore propose that recruitment of CBP/p300 by Glis3 provides a scaffold for the formation of a larger transcriptional regulatory complex that stabilizes the binding of Pdx1, NeuroD1, and MafA complexes to their respective binding sites within the insulin promoter. Taken together, these results indicate that Glis3 plays a pivotal role in the transcriptional regulation of insulin and may serve as an important therapeutic target for the treatment of diabetes.

scholarly journals Somatostatin Inhibits Oxidative Respiration in Pancreatic β-Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1527-1535 ◽  
Author(s):  
Mathew Daunt ◽  
Oliver Dale ◽  
Paul A. Smith
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Somatostatin Receptor ◽  
Katp Channels ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
K Channels ◽  
Min6 Cells ◽  
Voltage Gated ◽  
Mouse Islets

Somatostatin potently inhibits insulin secretion from pancreatic β-cells. It does so via activation of ATP-sensitive K+-channels (KATP) and G protein-regulated inwardly rectifying K+-channels, which act to decrease voltage-gated Ca2+-influx, a process central to exocytosis. Because KATP channels, and indeed insulin secretion, is controlled by glucose oxidation, we investigated whether somatostatin inhibits insulin secretion by direct effects on glucose metabolism. Oxidative metabolism in β-cells was monitored by measuring changes in the O2 consumption (ΔO2) of isolated mouse islets and MIN6 cells, a murine-derived β-cell line. In both models, glucose-stimulated ΔO2, an effect closely associated with inhibition of KATP channel activity and induction of electrical activity (r > 0.98). At 100 nm, somatostatin abolished glucose-stimulated ΔO2 in mouse islets (n = 5, P < 0.05) and inhibited it by 80 ± 28% (n = 17, P < 0.01) in MIN6 cells. Removal of extracellular Ca2+, 5 mm Co2+, or 20 μm nifedipine, conditions that inhibit voltage-gated Ca2+ influx, did not mimic but either blocked or reduced the effect of the peptide on ΔO2. The nutrient secretagogues, methylpyruvate (10 mm) and α-ketoisocaproate (20 mm), also stimulated ΔO2, but this was unaffected by somatostatin. Somatostatin also reversed glucose-induced hyperpolarization of the mitochondrial membrane potential monitored using rhodamine-123. Application of somatostatin receptor selective agonists demonstrated that the peptide worked through activation of the type 5 somatostatin receptor. In conclusion, somatostatin inhibits glucose metabolism in murine β-cells by an unidentified Ca2+-dependent mechanism. This represents a new signaling pathway by which somatostatin can inhibit cellular functions regulated by glucose metabolism.

scholarly journals Leptin-induced Trafficking of KATP Channels: A Mechanism to Regulate Pancreatic β-cell Excitability and Insulin Secretion

2019 ◽  
Vol 20 (11) ◽  
pp. 2660 ◽  
Author(s):  
Veronica Cochrane ◽  
Show-Ling Shyng
Keyword(s):  
Insulin Secretion ◽  
Katp Channel ◽  
Energy Homeostasis ◽  
Katp Channels ◽  
Channel Conductance ◽  
Β Cells ◽  
Β Cell ◽  
Peripheral Tissues ◽  
Membrane Hyperpolarization ◽  
Channel Trafficking

The adipocyte hormone leptin was first recognized for its actions in the central nervous system to regulate energy homeostasis but has since been shown to have direct actions on peripheral tissues. In pancreatic β-cells leptin suppresses insulin secretion by increasing KATP channel conductance, which causes membrane hyperpolarization and renders β-cells electrically silent. However, the mechanism by which leptin increases KATP channel conductance had remained unresolved for many years following the initial observation. Recent studies have revealed that leptin increases surface abundance of KATP channels by promoting channel trafficking to the β-cell membrane. Thus, KATP channel trafficking regulation has emerged as a mechanism by which leptin increases KATP channel conductance to regulate β-cell electrical activity and insulin secretion. This review will discuss the leptin signaling pathway that underlies KATP channel trafficking regulation in β-cells.

Nicotinamide nucleotide transhydrogenase: a link between insulin secretion, glucose metabolism and oxidative stress

2006 ◽  
Vol 34 (5) ◽  
pp. 806-810 ◽  
Author(s):  
H. Freeman ◽  
K. Shimomura ◽  
R.D. Cox ◽  
F.M. Ashcroft
Keyword(s):  
Insulin Secretion ◽  
Katp Channel ◽  
Mitochondrial Protein ◽  
Katp Channels ◽  
Tolerance Test ◽  
Ros Production ◽  
Loss Of Function ◽  
Β Cells ◽  
Atp Production ◽  
Nicotinamide Nucleotide Transhydrogenase

This paper reviews recent studies on the role of Nnt (nicotinamide nucleotide transhydrogenase) in insulin secretion and detoxification of ROS (reactive oxygen species). Glucose-stimulated insulin release from pancreatic β-cells is mediated by increased metabolism. This elevates intracellular [ATP], thereby closing KATP channels (ATP-sensitive potassium channels) and producing membrane depolarization, activation of voltage-gated Ca2+ channels, Ca2+ influx and, consequently, insulin secretion. The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion, which results from a naturally occurring deletion in the Nnt gene. Transgenic expression of the wild-type Nnt gene in C57BL/6J mice rescues the phenotype. Knockdown of Nnt in the insulin-secreting cell line MIN6 with small interfering RNA dramatically reduced Ca2+ influx and insulin secretion. Similarly, mice carrying ENU (N-ethyl-N-nitrosourea)-induced loss-of-function mutations in Nnt were glucose intolerant and secreted less insulin during a glucose tolerance test. Islets isolated from these mice showed impaired insulin secretion in response to glucose, but not to the KATP channel blocker tolbutamide. This is explained by the fact that glucose failed to elevate ATP in Nnt mutant islets. Nnt is a nuclear-encoded mitochondrial protein involved in detoxification of ROS. β-Cells isolated from Nnt mutant mice showed increased ROS production on glucose stimulation. We hypothesize that Nnt mutations enhance glucose-dependent ROS production and thereby impair β-cell mitochondrial metabolism, possibly via activation of uncoupling proteins. This reduces ATP production and lowers KATP channel activity. Consequently, glucose-dependent electrical activity and insulin secretion are impaired.

Decreased KATP channel activity contributes to the low glucose threshold for insulin secretion of rat neonatal islets

Endocrinology ◽  
2021 ◽  
Author(s):  
Juxiang Yang ◽  
Batoul Hammoud ◽  
Changhong Li ◽  
Abigail Ridler ◽  
Daphne Yau ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Katp Channel ◽  
Cultured Cells ◽  
Katp Channels ◽  
Lower Threshold ◽  
Β Cells ◽  
Membrane Area ◽  
Rat Islets ◽  
Glucose Threshold

Abstract Transitional hypoglycemia in normal newborns occurs in the first 3 days of life and has clinical features consistent with hyperinsulinism. We found a lower threshold for glucose-stimulated insulin secretion from freshly isolated embryonic day (E)22 rat islets, which persisted into the first postnatal days. The threshold reached the adult level by postnatal day (P)14. Culturing P14 islets also decreased the glucose threshold. Freshly isolated P1 rat islets had a lower threshold for insulin secretion in response to BCH (2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid), a non-metabolizable leucine analog, and diminished insulin release in response to tolbutamide, an inhibitor of β-cell KATP channels. These findings suggested that decreased KATP channel function could be responsible for the lower glucose threshold for insulin secretion. Single-cell transcriptomic analysis did not reveal a lower expression of KATP subunit genes in E22 compared to P14 β-cells. The investigation of electrophysiological characteristics of dispersed β-cells showed that early neonatal and cultured cells had fewer functional KATP channels per unit membrane area. Our findings suggest that decreased surface density of KATP channels may contribute to the observed differences in glucose threshold for insulin release.

scholarly journals Glucose Controls Cytosolic Ca2+ and Insulin Secretion in Mouse Islets Lacking Adenosine Triphosphate-Sensitive K+ Channels Owing to a Knockout of the Pore-Forming Subunit Kir6.2

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 33-45 ◽  
Author(s):  
Magalie A. Ravier ◽  
Myriam Nenquin ◽  
Takashi Miki ◽  
Susumu Seino ◽  
Jean-Claude Henquin
Keyword(s):  
Insulin Secretion ◽  
High Glucose ◽  
Katp Channel ◽  
Katp Channels ◽  
Metabolic Effects ◽  
Β Cells ◽  
Subsequent Increase ◽  
K Channels ◽  
Channel Dependent ◽  
Amplifying Pathway

Glucose-induced insulin secretion is classically attributed to the cooperation of an ATP-sensitive potassium (KATP) channel-dependent Ca2+ influx with a subsequent increase of the cytosolic free Ca2+ concentration ([Ca2+]c) (triggering pathway) and a KATP channel-independent augmentation of secretion without further increase of [Ca2+]c (amplifying pathway). Here, we characterized the effects of glucose in β-cells lacking KATP channels because of a knockout (KO) of the pore-forming subunit Kir6.2. Islets from 1-yr and 2-wk-old Kir6.2KO mice were used freshly after isolation and after 18 h culture to measure glucose effects on [Ca2+]c and insulin secretion. Kir6.2KO islets were insensitive to diazoxide and tolbutamide. In fresh adult Kir6.2KO islets, basal [Ca2+]c and insulin secretion were marginally elevated, and high glucose increased [Ca2+]c only transiently, so that the secretory response was minimal (10% of controls) despite a functioning amplifying pathway (evidenced in 30 mm KCl). Culture in 10 mm glucose increased basal secretion and considerably improved glucose-induced insulin secretion (200% of controls), unexpectedly because of an increase in [Ca2+]c with modulation of [Ca2+]c oscillations. Similar results were obtained in 2-wk-old Kir6.2KO islets. Under selected conditions, high glucose evoked biphasic increases in [Ca2+]c and insulin secretion, by inducing KATP channel-independent depolarization and Ca2+ influx via voltage-dependent Ca2+ channels. In conclusion, Kir6.2KO β-cells down-regulate insulin secretion by maintaining low [Ca2+]c, but culture reveals a glucose-responsive phenotype mainly by increasing [Ca2+]c. The results support models implicating a KATP channel-independent amplifying pathway in glucose-induced insulin secretion, and show that KATP channels are not the only possible transducers of metabolic effects on the triggering Ca2+ signal. Glucose can stimulate insulin secretion from beta cells by increasing Ca2+ influx, cytosolic Ca2+ concentration, and Ca2+ action independently of ATP-sensitive K channels.

scholarly journals Decreased KATP channel activity contributes to the low glucose threshold for insulin secretion in the early postnatal period

2021 ◽  
Author(s):  
Juxiang Yang ◽  
Batoul Hammoud ◽  
Changhong Li ◽  
Abigail Ridler ◽  
Daphne Yau ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Single Cell ◽  
Insulin Release ◽  
Katp Channel ◽  
Katp Channels ◽  
Postnatal Period ◽  
Β Cells ◽  
Lower Glucose ◽  
Low Glucose ◽  
Glucose Threshold

Objective: Transitional hypoglycemia in normal newborns occurs in the first 3 days of life and has clinical features consistent with hyperinsulinism. We hypothesized that this transitional hyperinsulinism is due to the persistence of a fetal lower glucose threshold for insulin release from β-cells into the first postnatal days. Methods: We tested dynamic insulin secretion from freshly isolated rat islets between late gestation and adult age and from rat islets kept in culture for 1 or 2 days. We used single-cell transcriptomic and electrophysiology approaches to investigate the mechanism for insulin secretion at low glucose concentrations. Results: We found that a lower threshold for glucose-stimulated insulin secretion (GSIS) is present in embryonic day (E)22 islets and persists into the first postnatal days. The glucose threshold increases in the postnatal period and reaches the adult level by postnatal day (P)14. We also demonstrated that culturing P14 islets for 24-48 hrs can also decrease the glucose threshold. Insulin release in response to BCH, a non-metabolizable leucine analog activating glutamate dehydrogenase, had a similar lower threshold in P1 compared to P14 islets. This showed that the low threshold for GSIS is determined at a step downstream of the glycolytic pathway. P1 islets had lower insulin release in response to tolbutamide, an inhibitor of β-cell KATP channels, compared to P14 islets, suggesting that decreased KATP channel expression and/or function could be responsible for the lower glucose threshold for insulin secretion. Single-cell transcriptomic analysis did not reveal differences in transcripts between E22 and P14 β-cells supporting the lower glucose threshold. The investigation of electrophysiological characteristics of dispersed β cells showed that early neonatal cells and cultured islet cells had fewer functional KATP channels per unit membrane area. Conclusion: These findings suggest that decreased surface density of KATP channels may contribute to the observed differences in glucose threshold for insulin release.

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