ReviewThe central role of calcium in the effects of cytokines on beta-cell function: Implications for type 1 and type 2 diabetes
Section snippets
Overview
In the pancreatic beta-cell, cytokine-induced disruptions in calcium handling can impair insulin release in response to glucose stimulation, and more severe calcium disruptions can lead to cell death. The focus of this review is on calcium's role in cytokine-mediated dysfunction and death of pancreatic islets and the potential role of key calcium handling organelles: the endoplasmic reticulum, mitochondria, nucleus and cytosolic spaces [1], [2], [3], [4]. Detailed descriptions of the molecular
Normal islet function in response to glucose stimulation
Islets of Langerhans are micro-organs within the pancreas that regulate blood glucose and body energy metabolism [11], [12] and possess their own extensive microvasculature [13], [14]. The islet is composed of insulin-producing beta-cells (∼60–80% of the total islet mass in rodents), glucagon-secreting alpha-cells (10–30%), somatostatin-secreting delta-cells (5–10%), and others [15], [16]. At the level of the individual beta-cell, the ‘Consensus Model’ provides a detailed description of the
Cytokines, calcium, and islet dysfunction
Pro-inflammatory cytokines are broadly considered immunomodulators that consist of several families of signaling molecules, including interleukins and interferons. Cytokines play a prominent role in the pathophysiology of type 1 diabetes (T1D) [28], [29], [30], [31], [32], [33], but increasing evidence suggests a significant role for cytokines in the loss of beta-cell mass in T2D as well [34], [35]. There are notable similarities and differences in the action of cytokines on the beta-cell
Cytokines and cell membrane sources of [Ca2+]i
The influx of calcium through various ion channels and exchangers in the cell membrane provides a key source of [Ca2+]i for the signaling cascades of proinflammatory cytokines [46], [79], [81], [82]. Although the L-type calcium channel is dominant and considered critical to normal islet function, several other subtypes may also be physiologically relevant including the N-type and T-type calcium-channels [83], [84]. The subunits that form these various channels can also vary, thus affecting
Cytokines, ER calcium homeostasis, and ER stress
The ER plays an important role in calcium storage and signaling. The resting intra-ER calcium concentration is three to four orders of magnitude higher than cytosolic calcium [46]. When cytoplasmic calcium is high, the ER will sequester calcium, while when it is low, the ER will release calcium [116], [117], [118]. ER dysfunction is manifested by deficiencies in normal ER calcium handling due primarily to the changes in the sarco(endo)plasmic reticulum calcium ATP-ase (SERCA2b) pump in
Mitochondrial calcium and cytokine action
Mitochondrial metabolism and cytosolic calcium have a dynamic and often reciprocal relationship. Nutrient-stimulated changes in metabolism initially hyperpolarize the mitochondrial membrane potential (Δψm), but increases in [Ca2+]i tend to increase mitochondrial calcium, which depolarizes the Δψm and can reduce ATP production [147], [148], [149], [150]. Mitochondria can thus act as calcium buffers that compensate for temporary increases in [Ca2+]i levels; however, an overload in mitochondrial
Nuclear calcium and the effects of cytokines on the nucleus
Calcium's most important role is in the nucleus due to its involvement in the transcription of genes regulating proliferation, apoptosis, and other key components of basic cellular life [1], [2], [177]. In the beta-cell, nutrients such as glucose are known to modulate the expression of many immediate early genes involved in these key processes in a [Ca2+]i dependent manner [178]. In addition, nutrient-driven increases in calcium are thought to be the greatest in the nucleus. As demonstrated by
Final thoughts
As we have reviewed, glucose stimulates dynamic changes in cytosolic calcium that occur through extracellular influx and uptake/release from the ER, mitochondria, and nucleus (see Fig. 3). The potential for calcium-mediated interplay among these organelles suggests that tremendously intricate communication may be necessary to carryout the dynamic events involved with the triphasic response to glucose stimulation and subsequent oscillations in [Ca2+]i and insulin release [188], [189]. The
Acknowledgments
This work was supported NIH K01 DK081621 and R01 DK089182 to C.S.N. Mouse islets were acquired through the UVA Cell and Islet Isolation Core facility. A special thanks to Kathryn Corbin for technical support for this project. Thanks also to colleagues for their support and critiques, especially Drs. K. Maedler and D. Luciani.
References (198)
Calcium signaling
Cell
(2007)- et al.
Ca2+ microdomains and the control of insulin secretion
Cell Calcium
(2006) - et al.
Calcium domains associated with individual channels can account for anomalous voltage relations of CA-dependent responses
Biophys. J.
(1984) - et al.
Cytokine production by islets in health and diabetes: cellular origin, regulation and function
Trends Endocrinol. Metab.
(2010) Why are the islets of Langerhans?
Lancet
(1969)- et al.
Metabolic control of beta-cell function
Semin. Cell Dev. Biol.
(2000) - et al.
Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus
Biochem. Pharmacol.
(1998) - et al.
Species differences in human and rat islet sensitivity to human cytokines. Monoclonal anti-interleukin-1 (IL-1) influences on direct and indirect IL-1-mediated islet effects
Cytokine
(1991) - et al.
TNF-alpha and IFN-gamma potentiate the deleterious effects of IL-1 beta on mouse pancreatic islets mainly via generation of nitric oxide
Cytokine
(1994) - et al.
Evidence that low-grade systemic inflammation can induce islet dysfunction as measured by impaired calcium handling
Cell Calcium
(2010)
Death effectors of beta-cell apoptosis in type 1 diabetes
Mol. Genet. Metab.
Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels
Trends Pharmacol. Sci.
Auxiliary subunits: essential components of the voltage-gated calcium channel complex
Curr. Opin. Neurobiol.
Interleukin-1 inhibits glucose-induced Ca2+ uptake by islets of Langerhans
FEBS Lett.
Modulation of calcium signalling by intracellular organelles seen with targeted aequorins
Acta Physiol. (Oxf.)
Interferon signalling in pancreatic beta cells
Front. Biosci.
Recent progress in research on beta-cell apoptosis by cytokines
Front. Biosci.
Cytokines and beta-cell biology: from concept to clinical translation
Endocr. Rev.
Cytokine signalling in the beta-cell: a dual role for IFNgamma
Biochem. Soc. Trans.
Role of IL-1beta in type 2 diabetes
Curr. Opin. Endocrinol. Diabetes Obes.
Pancreatic islet glucose metabolism and regulation of insulin secretion
Diabetes. Metab. Rev.
New perspectives on the microvasculature of the islets of Langerhans
Diabetes
From endothelial to beta cells: insights into pancreatic islet microendothelium
Curr. Diabetes Rev.
The unique cytoarchitecture of human pancreatic islets has implications for islet cell function
Proc. Natl. Acad. Sci. U.S.A.
Islet architecture: a comparative study
Islets
ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion
Biochem. Soc. Trans.
Role of mitochondria in metabolism-secretion coupling of insulin release in the pancreatic beta-cell
Biofactors
Regulation of insulin secretion: a matter of phase control and amplitude modulation
Diabetologia
Facilitative glucose transporters
Eur. J. Biochem.
Human and rat beta cells differ in glucose transporter but not in glucokinase gene expression
J. Clin. Invest.
Metabolic cycling in control of glucose-stimulated insulin secretion
Am. J. Physiol. Endocrinol. Metab.
Importance of nonionic signals for glucose-induced biphasic insulin secretion
Diabetes
Glucose activates both K(ATP) channel-dependent and K(ATP) channel-independent signaling pathways in human islets
Diabetes
The K+-ATP channel-independent pathway of regulation of insulin secretion by glucose: in search of the underlying mechanism
Diabetes
Triggering and amplifying pathways of regulation of insulin secretion by glucose
Diabetes
Cytokines cause functional and structural damage to isolated islets of Langerhans
Allergy
Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans
Science
Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans
Diabetologia
HLA class II induction in human islet cells by interferon-gamma plus tumour necrosis factor or lymphotoxin
Nature
Destruction of rat islet cell monolayers by cytokines. Synergistic interactions of interferon-gamma, tumor necrosis factor, lymphotoxin, and interleukin 1
Diabetes
Inflammation and metabolic disorders
Nature
Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes
Eur. J. Clin. Invest.
Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes
J. Mol. Med.
Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities
Diabetes
Increased number of islet-associated macrophages in type 2 diabetes
Diabetes
Islet inflammation impairs the pancreatic beta-cell in type 2 diabetes
Physiology (Bethesda)
Minireview: secondary beta-cell failure in type 2 diabetes—a convergence of glucotoxicity and lipotoxicity
Endocrinology
Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes
Diabetes
Beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms
Diabetes
Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis
Endocr. Rev.
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