Metabolic syndrome is a frequent precursor of type 2 diabetes mellitus (T2D), a disease that currently affects ∼8% of the adult population worldwide. Pancreatic beta-cell dysfunction and loss are ...central to the disease process, although understanding of the underlying molecular mechanisms is still fragmentary. Recent Advances: Oversupply of nutrients, including glucose and fatty acids, and the subsequent overstimulation of beta cells, are believed to be an important contributor to insulin secretory failure in T2D. Hypoxia has also recently been implicated in beta-cell damage. Accumulating evidence points to a role for oxidative stress in both processes. Although the production of reactive oxygen species (ROS) results from enhanced mitochondrial respiration during stimulation with glucose and other fuels, the expression of antioxidant defense genes is unusually low (or disallowed) in beta cells.
Not all subjects with metabolic syndrome and hyperglycemia go on to develop full-blown diabetes, implying an important role in disease risk for gene-environment interactions. Possession of common risk alleles at the SLC30A8 locus, encoding the beta-cell granule zinc transporter ZnT8, may affect cytosolic Zn
concentrations and thus susceptibility to hypoxia and oxidative stress.
Loss of normal beta-cell function, rather than total mass, is increasingly considered to be the major driver for impaired insulin secretion in diabetes. Better understanding of the role of oxidative changes, its modulation by genes involved in disease risk, and effects on beta-cell identity may facilitate the development of new therapeutic strategies to this disease. Antioxid. Redox Signal. 26, 501-518.
Zinc and diabetes Chabosseau, Pauline; Rutter, Guy A.
Archives of biochemistry and biophysics,
12/2016, Volume:
611
Journal Article
Peer reviewed
Open access
Zn2+ ions are essential for the normal processing and storage of insulin and altered pancreatic insulin content is associated with all forms of diabetes mellitus. Work of the past decade has ...identified variants in the human SLC30A8 gene, encoding the zinc transporter ZnT8 which is expressed highly selectively on the secretory granule of pancreatic islet β and α cells, as affecting the risk of Type 2 Diabetes. Here, we review the regulation and roles of Zn2+ ions in islet cells, the mechanisms through which SLC30A8 variants might affect glucose homeostasis and diabetes risk, and the novel technologies including recombinant targeted zinc probes and knockout mice which have been developed to explore these questions.
•Zinc is involved in the regulation of glucose homeostasis in mammals.•Type 2 diabetes patients present anomalies in zinc status.•Variants of the vesicular zinc transporter ZnT8 are associated with T2D risk.•Controversies concerning modulation of ZnT8 activity remain to be solved.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The arrangement of β cells within islets of Langerhans is critical for insulin release through the generation of rhythmic activity. A privileged role for individual β cells in orchestrating these ...responses has long been suspected, but not directly demonstrated. We show here that the β cell population in situ is operationally heterogeneous. Mapping of islet functional architecture revealed the presence of hub cells with pacemaker properties, which remain stable over recording periods of 2 to 3 hr. Using a dual optogenetic/photopharmacological strategy, silencing of hubs abolished coordinated islet responses to glucose, whereas specific stimulation restored communication patterns. Hubs were metabolically adapted and targeted by both pro-inflammatory and glucolipotoxic insults to induce widespread β cell dysfunction. Thus, the islet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus.
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•Optogenetic targeting reveals a pacemaker-like β cell subpopulation•These cells, termed hubs, are required for normal insulin release•Hubs are highly metabolic and transcriptionally immature•Hubs are targeted by a diabetic milieu to induce islet failure
Combining optogenetics and photopharmacology, Johnston et al. show that a few (1%–10%) β cells exert disproportionate control over islet responses to glucose. These specialized cells, called hubs, are transcriptionally immature and highly metabolic. Their failure during type 2 diabetes mellitus may lead to reduced insulin secretion and impaired glucose homeostasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The α-cell in diabetes mellitus Gromada, Jesper; Chabosseau, Pauline; Rutter, Guy A
Nature reviews. Endocrinology,
12/2018, Volume:
14, Issue:
12
Journal Article
Peer reviewed
Findings from the past 10 years have placed the glucagon-secreting pancreatic α-cell centre stage in the development of diabetes mellitus, a disease affecting almost one in every ten adults ...worldwide. Glucagon secretion is reduced in patients with type 1 diabetes mellitus, increasing the risk of insulin-induced hypoglycaemia, but is enhanced in type 2 diabetes mellitus, exacerbating the effects of diminished insulin release and action on blood levels of glucose. A better understanding of the mechanisms underlying these changes is therefore an important goal. RNA sequencing reveals that, despite their opposing roles in the control of blood levels of glucose, α-cells and β-cells have remarkably similar patterns of gene expression. This similarity might explain the fairly facile interconversion between these cells and the ability of the α-cell compartment to serve as a source of new β-cells in models of extreme β-cell loss that mimic type 1 diabetes mellitus. Emerging data suggest that GABA might facilitate this interconversion, whereas the amino acid glutamine serves as a liver-derived factor to promote α-cell replication and maintenance of α-cell mass. Here, we survey these developments and their therapeutic implications for patients with diabetes mellitus.
Insulin release from pancreatic β-cells is required to maintain normal glucose homoeostasis in man and many other animals. Defective insulin secretion underlies all forms of diabetes mellitus, a ...disease currently reaching epidemic proportions worldwide. Although the destruction of β-cells is responsible for Type 1 diabetes (T1D), both lowered β-cell mass and loss of secretory function are implicated in Type 2 diabetes (T2D). Emerging results suggest that a functional deficiency, involving de-differentiation of the mature β-cell towards a more progenitor-like state, may be an important driver for impaired secretion in T2D. Conversely, at least in rodents, reprogramming of islet non-β to β-cells appears to occur spontaneously in models of T1D, and may occur in man. In the present paper, we summarize the biochemical properties which define the 'identity' of the mature β-cell as a glucose sensor par excellence. In particular, we discuss the importance of suppressing a group of 11 'disallowed' housekeeping genes, including Ldha and the monocarboxylate transporter Mct1 (Slc16a1), for normal nutrient sensing. We then survey the changes in the expression and/or activity of β-cell-enriched transcription factors, including FOXO1, PDX1, NKX6.1, MAFA and RFX6, as well as non-coding RNAs, which may contribute to β-cell de-differentiation and functional impairment in T2D. The relevance of these observations for the development of new approaches to treat T1D and T2D is considered.
SLC30A8
encodes the secretory granule-resident and largely endocrine pancreas-restricted zinc transporter ZnT8. Interest in this gene product was sparked amongst diabetologists in 2007 when the first ...genome-wide association study for type 2 diabetes identified polymorphisms in
SLC30A8
as affecting disease risk. Thus, the common polymorphism rs13266634 was associated with lowered beta cell function and a 14% increase in diabetes abundance per risk (C) allele. This non-synonymous variant encodes a tryptophan-to-arginine switch at position 325 in the protein’s intracellular carboxy-terminal domain, resulting in reduced zinc transport activity and, consequently, decreased intragranular zinc levels. Whereas insulin secretion from isolated islets is most often increased in mice inactivated for
Slc30a8
, null animals usually show impaired glucose tolerance and lowered circulating insulin. Since
Slc30a8
null animals display little, if any, zinc secretion from islets, the lower plasma insulin levels could be explained by increased hepatic clearance as a result of lowered local zinc levels, or less efficient insulin action on target tissues. Despite the emerging consensus on the role of ZnT8 in glucose homeostasis, a recent genetic study in humans has unexpectedly identified loss-of-function
SLC30A8
mutants that are associated with
protection
from diabetes. Here, we attempt to reconcile these apparently contradictory findings, implicating (1) differing degrees of inhibition of ZnT8 activity in carriers of common variants vs rare loss-of-function forms, (2) effects dependent on age or hypoxic beta cell stress. We propose that these variables conspire to affect both the size and the direction of the effect of
SLC30A8
risk alleles in man.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Stimulation of mitochondrial oxidative metabolism by Ca2+ is now generally recognised as important for the control of cellular ATP homeostasis. Here, we review the mechanisms through which ...Ca2+ regulates mitochondrial ATP synthesis. We focus on cardiac myocytes and pancreatic β-cells, where tight control of this process is likely to play an important role in the response to rapid changes in workload and to nutrient stimulation, respectively. We also describe a novel approach for imaging the Ca2+ -dependent regulation of ATP levels dynamically in single cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Glucocorticoids are steroid hormones produced by the adrenal cortex and are essential for the maintenance of various metabolic and homeostatic functions. Their function is regulated at the tissue ...level by 11β-hydroxysteroid dehydrogenases and they signal through the glucocorticoid receptor, a ligand-dependent transcription factor. Clinical observations have linked excess glucocorticoid levels with profound metabolic disturbances of intermediate metabolism resulting in abdominal obesity, insulin resistance and dyslipidaemia. In this review, we discuss the physiological mechanisms of glucocorticoid secretion, regulation and function, and survey the metabolic consequences of excess glucocorticoid action resulting from elevated release and activation or up-regulated signaling. Finally, we summarize the reported impact of weight loss by diet, exercise, or bariatric surgery on circulating and tissue-specific glucocorticoid levels and examine the therapeutic possibility of reversing glucocorticoid-associated metabolic disorders.
All forms of diabetes mellitus involve the loss or dysfunction of pancreatic beta cells, with the former predominating in type 1 diabetes and the latter in type 2 diabetes. Deeper understanding of ...the coupling mechanisms that link glucose metabolism in these cells to the control of insulin secretion is therefore likely to be essential to develop new therapies. Beta cells display a remarkable metabolic specialisation, expressing high levels of metabolic sensing enzymes, including the glucose transporter GLUT2 (encoded by
SLC2A2
) and glucokinase (encoded by
GCK
). Genetic evidence flowing from both monogenic forms of diabetes and genome-wide association studies for the more common type 2 diabetes, supports the importance for normal glucose-stimulated insulin secretion of metabolic signalling via altered ATP generation, while also highlighting unsuspected roles for Zn
2+
storage, intracellular lipid transfer and other processes. Intriguingly, genes involved in non-oxidative metabolic fates of the sugar, such as those for lactate dehydrogenase (
LDHA
) and monocarboxylate transporter-1 (MCT-1
SLC16A1
), as well as the acyl-CoA thioesterase (
ACOT7
) and others, are selectively repressed (‘disallowed’) in beta cells. Furthermore, mutations in genes critical for mitochondrial oxidative metabolism, such as
TRL-CAG1–7
encoding tRNALeu, are linked to maternally inherited forms of diabetes. Correspondingly, impaired Ca
2+
uptake into mitochondria, or collapse of a normally interconnected mitochondrial network, are associated with defective insulin secretion. Here, we suggest that altered mitochondrial metabolism may also impair beta cell–beta cell communication. Thus, we argue that defective oxidative glucose metabolism is central to beta cell failure in diabetes, acting both at the level of single beta cells and potentially across the whole islet to impair insulin secretion.
Graphical abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A reduction in mitochondrial Ca2+ uptake through altered Mcu expression or impairment of the mitochondrial fusion and fission machinery may be potential pathways towards β-cell failure in type 2 ...diabetes.
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•Mitochondrial Ca2+ uptake is essential for normal β-cell function and insulin secretion.•Changes in mitochondrial ultrastructure are observed in type 2 diabetes and may be driven by altered Ca2+ homeostasis.•mtDNA mutations lead to impaired GSIS and diabetes in rodents and humans.
Mitochondria play a central role in glucose metabolism and the stimulation of insulin secretion from pancreatic β-cells. In this review, we discuss firstly the regulation and roles of mitochondrial Ca2+ transport in glucose-regulated insulin secretion, and the molecular machinery involved. Next, we discuss the evidence that mitochondrial dysfunction in β-cells is associated with type 2 diabetes, from a genetic, functional and structural point of view, and then the possibility that these changes may in part be mediated by dysregulation of cytosolic Ca2+. Finally, we review the importance of preserved mitochondrial structure and dynamics for mitochondrial gene expression and their possible relevance to the pathogenesis of type 2 diabetes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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