Targeted Overactivity of β Cell KATP Channels Induces Profound Neonatal Diabetes

@article{Koster2000TargetedOO,
  title={Targeted Overactivity of $\beta$ Cell KATP Channels Induces Profound Neonatal Diabetes},
  author={Jc. Koster and Barbara Marshall and Nancy J. Ensor and John A. Corbett and Cg. Nichols},
  journal={Cell},
  year={2000},
  volume={100},
  pages={645-654}
}
A paradigm for control of insulin secretion is that glucose metabolism elevates cytoplasmic [ATP]/[ADP] in beta cells, closing K(ATP) channels and causing depolarization, Ca2+ entry, and insulin release. Decreased responsiveness of K(ATP) channels to elevated [ATP]/[ADP] should therefore lead to decreased insulin secretion and diabetes. To test this critical prediction, we generated transgenic mice expressing beta cell K(ATP) channels with reduced ATP sensitivity. Animals develop severe… 

Figures and Tables from this paper

Expression of ATP-Insensitive KATP Channels in Pancreatic β-Cells Underlies a Spectrum of Diabetic Phenotypes
TLDR
It is demonstrated that a range of phenotypes can be expected for a reduction in ATP sensitivity of β-cell KATP channels and provide models for the corollary neonatal diabetes in humans.
Hyperinsulinism induced by targeted suppression of beta cell KATP channels
  • J. Koster, M. Remedi, +4 authors C. Nichols
  • Medicine, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2002
TLDR
The results suggest that incomplete suppression of KATP channel activity can give rise to a maintained hyperinsulinism.
The ABCs of Sulfonylurea Receptors, Islet K ATP Channels and the Control of Insulin Secretion
The proper and timely release of insulin from pancreatic islet beta cells is essential to controlling glucose homeostasis. Any dysfunction in the appropriate insulin secretory response can lead to
Mouse Models of β-cell KATP Channel Dysfunction.
TLDR
Mice with KATP channel gain-of-function mutations are hyperglycaemic and have impaired glucose-stimulated insulin secretion, a phenotype that accurately mimics human diabetes.
The role of membrane excitability in pancreatic β-cell glucotoxicity
TLDR
It is clearly demonstrated here that in vitro, hyperexcitability is detrimental to islets whereas underexcitability is protective in in vivo animal models, directly opposite to the effects observed in vitro.
Pancreatic β-cell KATP channels: Hypoglycaemia and hyperglycaemia
TLDR
This review highlights the important role of the β-cell KATP channel in glucose physiology and provides an introduction to some of the other review articles in this special edition of the Reviews in Endocrine and Metabolic Disorders.
ATP-sensitive potassium channels in health and disease
The ATP-sensitive potassium (KATP) channel plays a crucial role in insulin secretion and thus glucose homeostasis. KATP channel activity in the pancreatic β-cell is finely balanced; increased
ATP-sensitive potassium channels and insulin secretion diseases
TLDR
The chapter discusses the molecular regulation of K ATP channel activity and elaborates K ATP genetic defects underlying PHHI and suggests that insulin release may be induced by glucose through a mechanism distinct from the closure of K ATM channels or alterations in Ca 2+ , which may imply metabolic coupling factors other than intracellular nucleotides.
Defects in beta cell Ca2+ signalling, glucose metabolism and insulin secretion in a murine model of KATP channel-induced neonatal diabetes mellitus
TLDR
The primary defect in KATP-induced neonatal diabetes mellitus is failure of glucose metabolism to elevate [Ca2+]i, which suppresses insulin secretion and mildly alters islet glucose metabolism, which is secondary to the long-term hyperglycaemia and/or hypoinsulinaemia that result from the absence of glucose-dependent insulin secretion.
ATP-sensitive K+ channel signaling in glucokinase-deficient diabetes.
TLDR
The significant abrogation ofnGK(-/-) and nGK(+/-) phenotypes in the absence of K(ATP) demonstrate that a major factor in glucokinase deficiency is indeed altered K( ATP) signaling, and have implications for understanding and therapy of glucokin enzyme-related diabetes.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 138 REFERENCES
Abnormalities of pancreatic islets by targeted expression of a dominant-negative KATP channel.
  • T. Miki, F. Tashiro, +8 authors S. Seino
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1997
TLDR
A high frequency of apoptotic beta cells before the appearance of hyperglycemia in the transgenic mice is found, suggesting that the KATP channel might play a significant role in beta cell survival in addition to its role in the regulation of insulin secretion.
Defective Pancreatic β-Cell Glycolytic Signaling in Hepatocyte Nuclear Factor-1α-deficient Mice*
TLDR
It is concluded that hepatocyte nuclear factor-1α diabetes results from defective β-cell glycolytic signaling, which is potentially correctable using substrates that bypass the defect.
Electrophysiology of Stimulus-Secretion Coupling in Human β-Cells
TLDR
It is suggested that combinations of Cm measurements and electrical activity/membrane current measurements may help define the roles of diverse electrical activity patterns, displayed by human β-cells, in stimulus-induced insulin secretion.
Adenosine Diphosphate as an Intracellular Regulator of Insulin Secretion
TLDR
By binding to SUR NBF2 and antagonizing ATP inhibition of KATP channels, intracellular MgADP may regulate insulin secretion.
Glucose action `beyond ionic events' in the pancreatic β cell
TLDR
This review discusses how the KATP channel-Ca2+ hypothesis was formulated, what was overlooked in the hypothesis, and provides a comprehensive view of stimulus-secretion coupling in the beta cell, with an emphasis on non-ionic glucose actions.
ATP-Sensitive K+ Channels in Pancreatic β-Cells: Spare-Channel Hypothesis
TLDR
A simple mathematical model is used to demonstrate that there is no major discrepancy and that, in fact, given the electrophysiological mechanisms existing in the β-cell, the extreme sensitivity of the channels to ATP is appropriate and even mandatory for their physiological function.
Delayed rectifier K+ channel overexpression in transgenic islets and beta-cells associated with impaired glucose responsiveness.
TLDR
The results, employing the first ion channel transgenic mouse, demonstrate the importance of membrane potential regulation in excitation-secretion coupling in the pancreatic beta-cell.
Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor
TLDR
It is shown that the primary site at which ATP acts to mediate K-ATP channel inhibition is located on Kir6.2, and that SUR1 is required for sensitivity to sulphonylureas and diazoxide and for activation by Mg-ADP.
Glucose modulation of ATP-sensitive K-currents in wild-type, homozygous and heterozygous glucokinase knock-out mice
TLDR
The idea that defective glycolytic metabolism, produced by a loss (-/- mice) or reduction ( + /- mice) of glucokinase activity, leads to defective KATP channel regulation and thereby to the selective loss, or reduction, of glucose-induced insulin secretion is supported.
Leptin Suppression of Insulin Secretion by the Activation of ATP-Sensitive K+ Channels in Pancreatic β-Cells
TLDR
An important physiological role for leptin as an inhibitor of insulin secretion is indicated and the failure of leptin to inhibit insulin secretion from the β-Cells of ob/ob and db/db mice may explain, in part, the development of hyperinsulinemia, insulin resistance, and the progression to NIDDM.
...
1
2
3
4
5
...