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.

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 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.

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 Effects of the novel mitochondrial protein mimitin in insulin-secreting cells

2012 ◽  
Vol 445 (3) ◽  
pp. 349-359 ◽  
Author(s):  
Katarzyna Hanzelka ◽  
Lukasz Skalniak ◽  
Jolanta Jura ◽  
Sigurd Lenzen ◽  
Ewa Gurgul-Convey
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Mitochondrial Protein ◽  
Atp Synthesis ◽  
Nuclear Factor Κb ◽  
Β Cells ◽  
Β Cell ◽  
Atp Production ◽  
Β Cell Function ◽  
The Impact

Mimitin, a novel mitochondrial protein, has been shown to act as a molecular chaperone for the mitochondrial complex I and to regulate ATP synthesis. During Type 1 diabetes development, pro-inflammatory cytokines induce mitochondrial damage in pancreatic β-cells, inhibit ATP synthesis and reduce glucose-induced insulin secretion. Mimitin was expressed in rat pancreatic islets including β-cells and decreased by cytokines. In the ob/ob mouse, a model of insulin resistance and obesity, mimitin expression was down-regulated in liver and brain, up-regulated in heart and kidney, but not affected in islets. To further analyse the impact of mimitin on β-cell function, two β-cell lines, one with a low (INS1E) and another with a higher (MIN6) mimitin expression were studied. Mimitin overexpression protected INS1E cells against cytokine-induced caspase 3 activation, mitochondrial membrane potential reduction and ATP production inhibition, independently from the NF-κB (nuclear factor κB)–iNOS (inducible NO synthase) pathway. Mimitin overexpression increased basal and glucose-induced insulin secretion and prevented cytokine-mediated suppression of insulin secretion. Mimitin knockdown in MIN6 cells had opposite effects to those observed after overexpression. Thus mimitin has the capacity to modulate pancreatic islet function and to reduce cytokine toxicity.

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.

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.

Time-resolved metabolomics analysis of β-cells implicates the pentose phosphate pathway in the control of insulin release

2013 ◽  
Vol 450 (3) ◽  
pp. 595-605 ◽  
Author(s):  
Peter Spégel ◽  
Vladimir V. Sharoyko ◽  
Isabel Goehring ◽  
Anders P. H. Danielsson ◽  
Siri Malmgren ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pentose Phosphate Pathway ◽  
Metabolic Response ◽  
Cell Metabolism ◽  
Pentose Phosphate ◽  
Β Cells ◽  
Β Cell ◽  
Time Resolved ◽  
Atp Production ◽  
Rat Islets

Insulin secretion is coupled with changes in β-cell metabolism. To define this process, 195 putative metabolites, mitochondrial respiration, NADP+, NADPH and insulin secretion were measured within 15 min of stimulation of clonal INS-1 832/13 β-cells with glucose. Rapid responses in the major metabolic pathways of glucose occurred, involving several previously suggested metabolic coupling factors. The complexity of metabolite changes observed disagreed with the concept of one single metabolite controlling insulin secretion. The complex alterations in metabolite levels suggest that a coupling signal should reflect large parts of the β-cell metabolic response. This was fulfilled by the NADPH/NADP+ ratio, which was elevated (8-fold; P<0.01) at 6 min after glucose stimulation. The NADPH/NADP+ ratio paralleled an increase in ribose 5-phosphate (>2.5-fold; P<0.001). Inhibition of the pentose phosphate pathway by trans-dehydroepiandrosterone (DHEA) suppressed ribose 5-phosphate levels and production of reduced glutathione, as well as insulin secretion in INS-1 832/13 β-cells and rat islets without affecting ATP production. Metabolite profiling of rat islets confirmed the glucose-induced rise in ribose 5-phosphate, which was prevented by DHEA. These findings implicate the pentose phosphate pathway, and support a role for NADPH and glutathione, in β-cell stimulus-secretion coupling.

scholarly journals Loss-of-Function Mutation of the Galanin Gene Is Associated with Perturbed Islet Function in Mice

Endocrinology ◽  
2004 ◽  
Vol 145 (7) ◽  
pp. 3190-3196 ◽  
Author(s):  
Bo Ahrén ◽  
Giovanni Pacini ◽  
David Wynick ◽  
Nils Wierup ◽  
Frank Sundler
Keyword(s):  
Insulin Secretion ◽  
Islet Cells ◽  
Insulin Response ◽  
Tolerance Test ◽  
Glucose Disposal ◽  
Islet Function ◽  
Loss Of Function ◽  
Euglycemic Hyperinsulinemic Clamp

Abstract The neuropeptide galanin is expressed in sympathetic nerve terminals that surround islet cells and inhibits insulin secretion. To explore its role for islet function, we studied mice with a loss-of-function mutation in the galanin gene [galanin knockout (KO) mice]. Intravenous 2-deoxy-glucose, which activates both the sympathetic and parasympathetic branches of the autonomic nervous system, caused an initial (1–5 min) inhibition of insulin secretion that was impaired in galanin KO mice (P = 0.027), followed by a subsequent stimulation of insulin secretion that was augmented in galanin KO mice (P &lt; 0.01). Similar effects were seen after chemical sympathectomy by 6-hydroxydopamine. In contrast, galanin KO mice had a reduced insulin response to glucose, both in vivo (P &lt; 0.001) and in isolated islets (P &lt; 0.001), and to arginine, both in vivo (P = 0.012) and in vitro (P = 0.018). During an iv glucose tolerance test, galanin KO mice had impaired glucose disposal (P = 0.005) due to a reduced insulin response (P &lt; 0.001) and a reduced insulin-independent glucose elimination (glucose effectiveness; P = 0.040). Insulin sensitivity, as judged by a euglycemic, hyperinsulinemic clamp technique, was slightly increased in galanin KO mice (P = 0.032). We conclude that 1) galanin may contribute to sympathetic influences inhibiting insulin secretion in mice, and 2) galanin KO mice have a reduced glucose-induced insulin secretion.

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