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Science, Technology and Medicine open access publisher.Publish, read and share novel research. Beta-Cell Function and Failure in Type 2 DiabetesSimona Popa1 and Maria Mota1[1] Department of Diabetes, Nutrition and Metabolic Diseases; University of Medicine and Pharmacy, Craiova, Romania1.
Type-2 diabetes (T2D) is a complex metabolic disease associated with obesity and insulin resistance due to pancreatic beta-cell dysfunction. In a recent study researchers have discovered a gene that can cause defects in insulin secretion in people with Type-2 diabetes as well as in those with Down syndrome. The researchers, in experiments with mice, found that the overexpression of the gene RCAN1 can cause these problems common in both the disorders.
For the study, the team led by Damien Keating, professor at Flinders University in Australia, used four mouse models, two with high blood sugar and two without to identify genes duplicated in Down syndrome that contributed to problems with insulin secretion. Problems with insulin secretion experienced by people with Type 2 diabetes, parallel similar problems with insulin-secreting beta cells in many individuals with Down syndrome.
Many individuals with Down syndrome experience lower insulin secretion, mitochondrial dysfunction and increased oxidative stress in the insulin-producing beta cells of the pancreas; conditions that also appear in people with Type 2 diabetes. The results of the study not only explain why individuals with Down syndrome are more likely to have Type 1 diabetes, but have revealed the function of a gene that may be playing a lead role in development of Type 2 diabetes in the general population. Monsanto’s Round Up herbicide, containing the likely-carcinogenic glyphosate, is causing widespread mitochondrial dysfunction in cells. The mitochondria of our cells complete some of the most important functions of cellular respiration. We’ve been exposed to this chemical since the 1970’s and the bioaccumulation is killing our cells’ ability to heal themselves. Perspective: emerging evidence for signaling roles of mitochondrial anaplerotic products in insulin secretion.
Glucokinase as glucose sensor and metabolic signal generator in pancreatic betacells and hepatocytes.
Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells. Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year followup of the Belfast Diet Study. An overview of pancreatic beta-cell defects in human type 2 diabetes: Implications for treatment. Kir6.2 variant E23K increases ATP-sensitive K+ channel activity and is associated with impaired insulin release and enhanced insulin sensitivity in adults with normal glucose tolerance. A candidate type 2 diabetes polymorphism near the HHEX locus affects acute glucose-stimulated insulin release in European populations: results from the EUGENE2 study.
The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients – the EUGENE2 study.
Single-nucleotide polymorphism rs7754840 of CDKAL1 is associated with impaired insulin secretion in nondiabetic offspring of type 2 diabetic subjects and in a large sample of men with normal glucose tolerance. Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps. Quantitative trait analysis of type 2 diabetes susceptibility loci identified from whole genome association studies in the Insulin Resistance Atherosclerosis Family Study. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release, proinsulin conversion, and insulin sensitivity in 5,327 nondiabetic Finnishmen.
Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIPand GLP-1 receptors and impaired beta- cell function. Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation. Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion. A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion.
Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function in a British Europid population.
TCF7L2 controls insulin gene expression and insulin secretion in mature pancreatic beta-cells.
TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas. In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion. Increased glucose sensitivity of both triggering and amplifying pathways of insulin secretion in rat islets cultured for 1 wk in high glucose. Role of ATP production and uncoupling protein-2 in the insulin secretory defect induced by chronic exposure to high glucose or free fatty acids and effects of peroxisome proliferator-activated receptor-gamma inhibition.
Role of beta-cell dysfunction, ectopic fat accumulation and insulin resistance in the pathogenesis of type 2 diabetes mellitus. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Palmitate activates AMPactivated protein kinase and regulates insulin secretion from beta cells.
Chronic activation of liver X receptor induces beta-cell apoptosis through hyperactivation of lipogenesis: liver X receptor-mediated lipotoxicity in pancreatic beta-cells. Inhibition of PKCepsilon improves glucose-stimulated insulin secretion and reduces insulin clearance.
Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of Langerhans.
Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. Evidence against the involvement of oxidative stress in fatty acid inhibition of insulin secretion.
Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Free fatty acid-induced beta-cell defects are dependent on uncoupling protein 2 expression.
Many individuals with Down syndrome experience lower insulin secretion, mitochondrial dysfunction and increased oxidative stress in the insulin-producing beta cells of the pancreas.
The findings suggest that this gene may be playing a lead role in development of Type-2 diabetes in the general population. They narrowed down the list by comparing it to genes overexpressed in beta cells from humans with Type-2 diabetes.
A new study, published on May 19 in PLOS Genetics by Professor Damien Keating of Flinders University and colleagues, has used this knowledge to identify a single gene that may cause these problems.


Down syndrome is the most common genetic disorder and occurs when a person has an extra copy of some or all of chromosome 21. This approach could be applied to other health disorders with symptoms that also appear in individuals with Down syndrome. This is associated with a long list of degenerative disease and chronic health conditions including autism, Alzheimer’s, chronic fatigue, fibromyalgia, type 2 Diabetes, Parkinson’s, and obesity. Folks over at the Institute for Responsible Technology have posted a wonderful video that explains this seeming complexity in simple terms.
Two experts discuss just how toxic Round Up is and how it affects mitochondria in your body. Normal beta-cell functionThe main role of beta-cell is to synthesize and secrete insulin in order to maintain circulating glucose levels within physiological range.
Sites of pretranslational regulation by glucose of glucose-induced insulin release in pancreatic islets.
To identify genes duplicated in Down syndrome that contribute to problems with insulin secretion, scientists screened the genes of four mouse models of the disorder–two had high blood sugar and two did not.
You could read dozens of books on this topic, but you can also obtain a quick understanding from an under-utilized video that represents vast quantities of data on the subject in a nutshell, presented by Stephanie Seneff and Alex Vasquez.
Although there exist several triggers of insulin secretion like nutrients (amino acids such as leucine, glutamine in combination with leucine, nonesterified fatty acid), hormones, neurotransmitters and drugs (sulfonylurea, glinides), glucose represents the main physiological insulin secretagogue [1].According to the most widely accepted hypothesis, insulin secretion is a multistep process initiated with glucose transport into beta-cell through specific transporters (GLUT1 and GLUT2 in particular) and phosphorylation by glucokinase, which directs metabolic flux through glycolysis, producing pyruvate as the terminal product of the pathway [2].
They narrowed down the list by comparing it to genes overexpressed in beta cells from humans with Type 2 diabetes. Pyruvate then enters the mitochondria and is decarboxylated to acetyl-CoA, which enters the tricarboxylic acid cycle. The comparison identified a single gene, RCAN1, which, when overexpressed in mice, causes them to have abnormal mitochondria in their beta cells, produce less ATP and secrete less insulin in the presence of glucose. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.AbstractMuscle mitochondrial metabolism is a tightly controlled process that involves the coordination of signaling pathways and factors from both the nuclear and mitochondrial genomes. The tricarboxylic acid cycle proper begins with a condensation of acetyl-CoA and oxaloacetate, to form citrate, a reaction catalysed by citrate synthase.
Perhaps the most important pathway regulating metabolism in muscle is mitochondrial biogenesis.
In response to physiological stimuli such as exercise, retrograde signaling pathways are activated that allow crosstalk between the nucleus and mitochondria, upregulating hundreds of genes and leading to higher mitochondrial content and increased oxidation of substrates. NAD-linked isocitrate dehydrogenase then oxidatively decarboxylates isocitrate to form ?-ketoglutarate.
With type 2 diabetes, these processes can become dysregulated and the ability of the cell to respond to nutrient and energy fluctuations is diminished. The ?-ketoglutarate is oxidised to succinyl-CoA in a reaction catalysed by ?-ketoglutarate dehydrogenase. This, coupled with reduced mitochondrial content and altered mitochondrial morphology, has been directly linked to the pathogenesis of this disease.
Succinyl-CoA synthase then catalyses the conversion of succinyl-CoA to succinate, with the concomitant phosphorylation of GDP to GTP.
In this paper, we will discuss our current understanding of mitochondrial dysregulation in skeletal muscle as it relates to type 2 diabetes, placing particular emphasis on the pathways of mitochondrial biogenesis and mitochondrial dynamics, and the therapeutic value of exercise and other interventions.1. Fumarase catalyses the conversion of fumarate to malate and after that malate dehydrogenase catalyses the ?nal step of the tricarboxylic acid cycle, oxidising malate to oxaloacetate and producing NADH.Three pathways enable the recycling of the tricarboxylic acid cycle intermediates into and out of mitochondrion, allowing a continuous production of intracellular messengers [3-5].
Type 2 diabetes is characterized by insulin resistance and is commonly associated with several clinical complications such as hypertension, atherosclerosis, and cardiovascular disease, and these are often collectively referred to as the metabolic syndrome [1].
Although the specific molecular mechanisms underlying type 2 diabetes are not well understood, insulin resistance is believed to result from reductions in glucose transport and phosphorylation and impaired fatty acid metabolism in a number of tissues, notably skeletal muscle [1, 2]. Malate exits the mitochondria to the cytoplasm where it is subsequently oxidised to pyruvate concomitant with the production of NADPH by cytosolic malic enzyme. Specifically, defects in this series of reactions are directly associated with increased levels of plasma and intracellular free fatty acids and alterations in insulin signaling pathways [3, 4]. Mitochondria have several functions but are most known for their role as key regulators of metabolic activity within the cell by converting energy from the oxidation of macronutrients to ATP. Citrate then exits the mitochondrion to the cytoplasm where it is converted back to oxaloacetate and acetyl-CoA by ATP-citrate lyase. Mitochondrial activity and function in skeletal muscle is a highly controlled process, under the influence of a variety of nuclear and mitochondrial factors that act as metabolic sensors and can adapt to perturbations in cellular nutrient and energy status. Oxaloacetate is converted by cytosolic malate dehydrogenase to malate before being converted to pyruvate by malic enzyme. The renewal of mitochondria through the process of biogenesis is vital for maintaining mitochondrial integrity, and a diminished capacity for organelle biogenesis has been implicated in the pathogenesis of several diseases such as aging, neurodegeneration, as well as type 2 diabetes [1, 5]. Additionally, muscle mitochondrial metabolism is regulated by a group of morphogenesis machinery proteins which are important for mitochondrial fusion and fission events and also for their independent effects on bioenergetics, programmed cell death, and autophagy [6]. Defects in mitochondrial biogenesis and morphogenesis factors can impair enzyme activity and reduce the oxidative capacity of the cell leading to insufficient oxidation of lipids and increased intramyocellular lipid (IMCL) levels.
The inability of mitochondria to utilize these substrates along with their accumulation within muscle has been associated with impaired insulin signaling pathways and reduced glucose uptake [7]. Elevated IMCLs, in association with the increased production of lipid metabolites such as acyl coenzyme A (CoA), diacylglycerol (DAG), ceramides, and reactive oxygen species (ROS) [2, 8], can affect insulin signaling and contribute to insulin resistance associated with type 2 diabetes. The NADPH oxidase complex in the plasma membrane is also activated through protein kinase C, which is activated by fatty acid derived signalling molecules. Additionally, skeletal muscle from individuals with type 2 diabetes have a higher percentage of type II fibers and a lower percentage of type I fibers when compared to control individuals [9, 10].
These events result in an enhanced ratio of ATP to ADP in the cytoplasm, which determines the closure of the ATP-sensitive K+ channels, depolarization of the plasma membrane, influx of extracellular Ca2+ and activation of exocytosis which takes place in several stages including recruitment, docking, priming, and fusion of insulin granules to the beta-cell plasma membrane [1,6,7]. Type II fibers have a reduced capacity to oxidize fat [11] and possess unique properties that have been shown to potentiate mitochondrial hydrogen peroxide production and oxidative stress [12].
Two independent studies, using diazoxide for maintaining the ATP-sensitive K+ channels in the open state or mice in which the ATP-sensitive K+ channels were disrupted, indicated that glucose –stimulated insulin secretion can also occur independently of ATP-sensitive K+ channels activity [8].Under physiological conditions, there is a hyperbolic relation between insulin secretion and insulin sensitivity.
Therefore, there are likely multiple factors that contribute to the stress environment that intensify the mitochondrial dysregulation observed in type 2 diabetes. Classically, glucose-stimulated insulin secretion is characterized by a first phase, which ends within a few minutes, and prevents or decreases glucose concentration and a more prolonged second phase in which insulin is released proportionally to the plasma glucose [9].In addition, it has been demonstrated that the release of insulin is oscillatory, with relatively stable rapid pulses occurring at every 8-10 minutes which are superimposed on low-frequency oscillations [10]. The multiplicity of mitochondrial functions has made it a logical target for the study of metabolic diseases, and, given that skeletal muscle represents the major site of insulin-stimulated glucose utilization in the body [13, 14], dysregulation of mitochondria is closely associated with insulin resistance and the pathogenesis of type 2 diabetes in muscle. In this paper, we will first discuss key pathways involved in the regulation of mitochondria, with specific attention given to organelle biogenesis, as well as mitochondrial fusion and fission events and their contribution to metabolic perturbations in muscle. Place of beta-cell dysfunction in natural history of type 2 diabetesT2DM is a progressive condition caused by genetic and environmental factors that induce tissue insulin resistance and beta-cell dysfunction. In the second part, current therapeutic interventions will be described, with the focus on those related to stimulating mitochondrial biogenesis.2. Based on the United Kingdom Prospective Diabetes Study (UKPDS) and on the Belfast Diabetes Study, it is estimated that at diagnosis of T2DM, beta-cell function is already reduced by 50-60% and that this reduction of beta-cell function seems to start with 10-12 years before the appearance of hyperglycemia [11,12].
Mitochondrial BiogenesisSkeletal muscle is a malleable tissue and can adapt to alterations in energy status and substrate supply in part via its ability to increase the number of mitochondria. Several lines of evidence indicated that there is no hyperglycemia without beta-cell dysfunction [13,14]. Mitochondrial biogenesis is induced by numerous physiological, environmental, and pharmacological stimuli and results from the transcription and translation of genes both in the nuclear and the mitochondrial genomes [15, 16]. In most subjects with obesity-induced insulin resistance developing increased insulin secretion, insulin gene expression and beta-cell mass, these compensatory mechanisms can succeed to maintain glucose homeostasis and avoidance of diabetes mellitus [13-15].


These gene products are assembled into functional multisubunit complexes within mitochondria and enhance oxidative capacity and ATP production within the cell. In the phase which precedes overt diabetes the decline of beta-cell function is slow but constant (2% per year) [19]. Thus, mitochondria are key regulators of metabolic activity within the cell, and it is these attributes that have made mitochondria a primary focus in the study of metabolic disorders such as type 2 diabetes. After the development of overt hyperglycemia there appears a significant acceleration (18% per year) in beta-cell failure, and the beta-cell function deteriorates regardless of the therapeutic regimen [11,19,20].
In response to a stimulus such as skeletal muscle contractile activity or exercise, intracellular Ca2+ levels, as well as AMP levels, increase leading to the activation of signaling molecules including AMP-activated protein kinase (AMPK).
Consequent deterioration in metabolic equilibrium with increasing levels of glucose and free fatty acids, enhance and accelerate beta-cell dysfunction, lead to beta-cell apoptosis that does not seems to be adequately compensated by regenerative process and subsequent decrease of beta-cell mass.4.
Potential mechanism and modulators of beta-cell failureThe main focus of the present chapter is on potential beta-cell failure mechanisms in T2DM.The initial alterations in beta-cell function are likely to reflect intrinsic defects, whereas the accelerated beta-cell dysfunction which mainly occurs after the development of overt hyperglycemia is the consequence of glucolipotoxicity [21].
This reflects a genetic predisposition for beta-cell defect, whereas the subsequent beta-cell failure may be a consequence of concomitant environmental conditions. Genetic factorsSeveral genes associated with increased risk of developing T2DM have been identified in genome-wide association studies [22].
Genetic variation in this gene obviously affects the beta-cell excitability and insulin secretion [23].HHEX encodes a transcription factor necessary for the organogenesis of the ventral pancreas [49] and two SNPs (rs1111875, rs7923837) in HHEX were found to be associated with reduced insulin secretion [24-26]. SLC30A8 encodes the protein zinc transporter 8, which provide zinc for maturation, storage and exocytosis of the insulin granules [50]. Variants in this gene show to be associated with reduced glucose-stimulated insulin secretion [25,27] and alterations in proinsulin to insulin conversion [42]. GlucolipotoxicityGrowing evidence indicated that long-term elevated plasma levels of glucose and fatty acids contribute to beta-cell function decline, a phenomenon known as glucolipotoxicity.
Glucolipotoxicity differs from beta-cell exhaustion, which is a reversible phenomenon characterized by depletion of insulin granules due to prolonged exposure to secretagogues.
Chronic exposure of beta-cells to hyperglycemia can also induce beta-cells apoptosis by increasing proapoptotic genes expression (Bad, Bid, Bik) while antiapoptotic gene expression Bcl-2 remains unaffected [54].There is a strong relationship between glucotoxicity and lipotoxicity.
Thus, hyperglycemia increases malonyl-CoA levels, leading to the inhibition of carnitine palmitoyl transferase-1 and subsequently to decreased oxidation of fatty acids and lipotoxicity [52]. Increased fatty acids in the pancreas leads to intrapancreatic accumulation of triglycerides [55].
Lim E et al showed that the intrapancreatic fat is associated with beta-cell dysfunction and that sustained negative energy balance induces restoration of beta-cellular function [56].Elevated levels of glucose and saturated fatty acids in beta cells, stimulates AMP-activated protein kinase, which contributes to increased expression of sterolregulatory-element-binding-protein-1c (SREBP1c), leading to increased lipogenesis [57]. Activation of the isoform of protein kinase C (PKC?) by free fatty acids which has been suggested as a possible candidate signaling molecule underlying the decrease in insulin secretion [60].Impaired insulin gene exepression by down-regulation of PDX-1 and MafA insulin gene promoter activity [61].
PDX-1 is affected in its ability to translocate to the nucleus, whereas MafA is affected at the level of its expression [61]. Free fatty acid impairs insulin gene expression only in the presence of hyperglycemia [62]. Palmitate affects both insulin gene expression and insulin secretion, unlike oleate which affects only insulin secretion [63]. Endoplasmic reticulum stressThe endoplasmic reticulum is responsible for the protein synthesis, being involved in protein translation, folding and assessing quality before protein secretion. Accumulation of unfolded and misfolded protein in the endoplasmic reticulum lumen may impose endoplasmic reticulum stress [79,80]. Inflammatory cytokines such as IL-1? and IFN-?, can also cause endoplasmic reticulum stress [72].Endoplasmic reticulum stress induced beta-cell activation of an adaptive system named unfolded protein response by which it attenuates protein translation, increases protein folding and promotes misfolded protein degradation [81,82].
Thus, it prevents additional protein misfolding and further accumulation of unfolded protein; increase the folding capacity of the endoplasmic reticulum to deal with misfolded proteins via the induction of endoplasmic reticulum chaperones. Mitochondrial dysfunction and ROS productionBeta cell mitochondria play a key role in the insulin secretion process, not only by providing energy in the form of ATP to support insulin secretion, but also by synthesising metabolites that can act as factors that couple glucose sensing to insulin granule exocytosis [3].Mitochondrial dysfunction and abnormal morphology occur before the onset of hyperglycemia and play an important role in beta-cell failure [89]. In diabetic state, the proteins from the mitochondrial inner membrane are decreased, and also may exist transcriptional changes of the mitochondrial proteins [89].
Mitochondrial dysfunction, induced by glucolipotoxicity, plays a pivotal role in beta-cell failure and leads to increased ROS production as a result of metabolic stress. Levels of antioxidant enzymes in beta cells are very low (catalase and glutathione peroxide levels were much lower than those of superoxide dismutase), making beta cells be vulnerable to oxidative stress [92].Low concentrations of ROS contribute to increased glucose-stimulated insulin secretion, but only in the presence of glucose-induced elevations in ATP [93]. All these effects are reversible in time after transient increase ROS.Chronic and significant elevation of ROS, resulted from an imbalance between ROS production and scavenging by endogenous antioxidants, may lead to beta-cell failure [95,96]. Persistent oxidative stress mediates beta-cell failure through several different mechanisms, including:Decreased insulin secretion.
Beta-cells lipid accumulation via SREBP1c [108].The antioxidant effect varies depending on the type of exposure of beta cells to ROS. Thus, under beta-cells exposure to low concentrations of ROS, antioxidants lower the insulin secretion [109,110]. Instead, under the glucolipotoxicity, antioxidants increase the insulin secretion and reduce beta cell apoptosis [108].9.
Additionally, beta-cells dysfunction and apoptosis may also be triggered by pro-inflammatory signals from other organs, such as adipose tissue [111,112].
Chronic exposure of beta-cell to inflammatory cytokines, like Il-1?, IFN-? or TNF-?, can cause endoplasmic reticulum stress and the unfolded protein response activation in beta-cells, and also beta-cells apoptosis [72,115]. Because, as indicated by Donath et al, the apoptotic beta-cells can provoke, in turn, an immune response, a vicious cycle may develop [115].
Another cytokine involved in beta-cells dysfunction is the PANcreatic DERived factor (PANDER). There have not been revealed significant effects of adiponectin on basal or glucose-stimulated insulin secretion [112].Leptin is another adipocytokine that may interfere with beta-cell function and survival. In studies on animal model, leptin has been shown to inhibit insulin secretion via activation of ATP-regulated potassium channels and reduction in cellular cAMP level [116], inhibit insulin biosynthesis by activating suppressor of cytokine signalling 3 (SOCS3) [119], suppress acetylcholine-induced insulin secretion [116] and induce the expression of inflammatory genes [120]. Studies performed on human islets indicated that chronic exposure to leptin stimulates the release of IL-1? and inhibits UCP2 expression, leading to beta-cell dysfunction and apoptosis [111]. Other adipocytokines including TNF-?, IL-6, resistin, visfatin may also modulate beta-cell function and survival, although it is unclear whether the amount released into the circulation is sufficient to affect beta-cells [111].10. Islet amyloid polypeptideHuman islet amyloid polypeptide (amylin) is expressed almost exclusively in beta-cells and is costored and coreleased with insulin in response to beta-cells secretagogues.
Glucolipotoxicity causes increased insulin requirement and those lead to increased production of both insulin and amylin. High concentrations of amyloid are toxic to beta-cells and have been implicated in beta-cell dysfunction and apoptosis [121,122].The effect of Islet amyloid polypeptide on beta-cell function is not fully elucidated. Studies in vivo have shown that the islet amyloid polypeptide inhibits the first and second phase of glucose-stimulated insulin secretion, but this occurs only at concentrations of islet amyloid polypeptide above physiological range [77]. Beta-cell failure — Implication for treatmentUnderstanding the causes for beta-cell failure is of capital importance to develop new and more effective therapeutic strategies.Taking into consideration the existence of early beta-cell dysfunction and the significant reduction of beta-cell mass in the natural history of T2DM as well as the progressive character of these pathophysiological modifications, insulin therapy could be an important option for obtaining and maintaining an optimal glycemic control. Several lines of evidence indicated that metformin could improve beta-cell function and survival.
Incubation of T2DM islets with metformin was associated with increased insulin content, insulin mRNA expression and glucose responsiveness, and also with reduced cell apoptosis by normalization of caspase 3 and caspase 8 activities [103]. It has been shown that metformin, and also the PPAR gamma agonists can protect beta-cell from deleterious effects of glucolipotoxicity [126,127].Other therapeutic options for beta-cell protection, such as incretins are actually under debate.




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