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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. The materials contained on this website are provided for general information purposes only and do not constitute medical, legal, financial or other professional advice on any subject matter. 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. 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. All tips, guides and recommendations are followed at your own risk and should be followed up with your own research. 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].
Pyruvate then enters the mitochondria and is decarboxylated to acetyl-CoA, which enters the tricarboxylic acid cycle. The tricarboxylic acid cycle proper begins with a condensation of acetyl-CoA and oxaloacetate, to form citrate, a reaction catalysed by citrate synthase.
NAD-linked isocitrate dehydrogenase then oxidatively decarboxylates isocitrate to form ?-ketoglutarate. How do we become resistant to insulin and what causes our beta cells to fail?Insulin resistance can develop as a result of fat cells releasing more pro-inflammatory chemicals such as IL-6, and fewer anti-inflammatory chemicals such as adiponectin. The ?-ketoglutarate is oxidised to succinyl-CoA in a reaction catalysed by ?-ketoglutarate dehydrogenase. Succinyl-CoA synthase then catalyses the conversion of succinyl-CoA to succinate, with the concomitant phosphorylation of GDP to GTP. That is not what some of my textbooks say, which claim that type 2 diabetes has a stronger genetic component than type 1 diabetes.
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].
Unfortunately their authors have been lazy and taken the fact that type 2 diabetes runs in families as evidence of a genetic link.


It is all to do with the fact that people in the same family follow a similar dietary pattern, and often a similar exercise pattern as well.
Malate exits the mitochondria to the cytoplasm where it is subsequently oxidised to pyruvate concomitant with the production of NADPH by cytosolic malic enzyme. In fact type 1 diabetes has a much stronger genetic component with a few genes on chromosome 6 being responsible for much of the susceptability. In type 2 diabetes a large number of genes are associated with risk and none particularly strongly.What happens in the diabeticThere are some tissues in our body that let glucose in without insulin. Citrate then exits the mitochondrion to the cytoplasm where it is converted back to oxaloacetate and acetyl-CoA by ATP-citrate lyase. Oxaloacetate is converted by cytosolic malate dehydrogenase to malate before being converted to pyruvate by malic enzyme. Fat and muscle cells contain GLUT-4 transporters, which don't allow much glucose in without insulin being present.
The brain on the other hand has a lot of GLUT-3 transporters, which allow appreciable amounts of glucose in without insulin being present.Tissues which let in glucose without insulin are found in the eye, kidneys, peripheral nervous system as well as the liver, ovaries and seminal vesicles. The unfortunate result for these cells is that they can accumulate too much glucose over time.
The NADPH oxidase complex in the plasma membrane is also activated through protein kinase C, which is activated by fatty acid derived signalling molecules.
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].
However, those cells in the eyes, kidneys and in our peripheral circulation accumulate sorbitol, which causes swelling of the cells due to osmotic pressure. 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. 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].
Most of these complications result from raised levels of glucose in cells which do not rely on insulin to obtain it. In particular some cells lining capillaries and nerves in the kidneys, eyes and limbs are vulnerable. 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. 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]. Several lines of evidence indicated that there is no hyperglycemia without beta-cell dysfunction [13,14].
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].
As a result they leak proteins which ultimately result in constriction of the blood vessels supplying the kidney. In the phase which precedes overt diabetes the decline of beta-cell function is slow but constant (2% per year) [19].
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]. Since the brain uses sugar as its main energy source it goes to plan B which is creating ketones, which can provide energy also.
Too many ketones acidify our blood and cause excess urination, thirst, vomiting and tummy pain.
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. Ultimately severe dehydration, swelling of the brain and coma can occur, which is why hospitalisation is often needed. This is a serious complication of type 1 diabetes. 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].
However, it is uncommon with type 2 as some insulin is normally available.Curing diabetes naturallyExercising more and consuming foods that do not raise blood sugar levels is the key to reversing diabetes. This reflects a genetic predisposition for beta-cell defect, whereas the subsequent beta-cell failure may be a consequence of concomitant environmental conditions.
While it becomes harder to regain full health the longer you have had diabetes, when first diagnosed, the vast majority of people have the potential to completely cure themselves of the condition.The correct dietThe modern western diet is the main cause of diabetes.
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]. For instance on one of my GI lists I have a baked potato with a GI of 111, greater than pure glucose while peanuts are listed with a GI of just 7, which implies that foods containing the East Asian sauce, satay would be very low GI. 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]. So in other words the GI is not an absolute value, but just a guideline. Sometimes it is more realistic to consider the glycaemic load or GL of a food, which takes account of the amount of a food you eat. Obviously one Cornflake (GI=93) is not going to raise blood sugar as much as a whole can of baked beans (GI=40), but a small bowl of them probably will.Foods that are normally low GI can be eaten as the main part of a diet for someone with diabetes. These include meat, fish, eggs, dairy as well as nuts, seeds, most vegetables and some fruits. 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.
The one vegetable that has a high GI is the potato (this includes the sweet potato), and the fruits with a high GI include ripe bananas, dates and raisins.
Glucolipotoxicity differs from beta-cell exhaustion, which is a reversible phenomenon characterized by depletion of insulin granules due to prolonged exposure to secretagogues.
Generally speaking fruits from warm climates have a higher GI than those from more temperate climates. 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].
For instance if you exercise soon after consuming the food then some of the blood sugar it creates will be taken up by your muscle cells. Increased fatty acids in the pancreas leads to intrapancreatic accumulation of triglycerides [55]. If you combine it with other foods of much lower GI or eat a small portion of it you will also find your blood sugar does not rise as far.Timing foodsIn general if you exercise then you will reduce your blood sugar level. 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].
A 30 minute exercise stint before food will allow you to get away with a higher overall glycaemic load. Equally if you do some light exercise soon after a large meal you can lower the peak which your blood sugar will reach.In general it is best to leave some time between any meal and completely sedentary activity such as bed or watching the TV. 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]. Kids get it about right when they automatically rush about after a meal, often to the frustration of their bloated parents.


PDX-1 is affected in its ability to translocate to the nucleus, whereas MafA is affected at the level of its expression [61].
A bit of housework, gardening or short walk are often quite effective at making a real dent in your blood sugar readings.Treating diabetes with drugsIt really is best to avoid the need for drugs. Free fatty acid impairs insulin gene expression only in the presence of hyperglycemia [62]. I would always advise making concerted efforts to control blood sugar levels with increases in exercise and changes to the diet.
Palmitate affects both insulin gene expression and insulin secretion, unlike oleate which affects only insulin secretion [63].
Many people find they can come off drugs completely when they do this properly.For those who cannot control their blood sugar levels without drugs then it is sensible to take them. The cumulative effect over time of high blood sugar levels is extremely damaging, and this is why so many diabetics suffer from amputations, blindness, heart attacks and strokes.Blood sugar lowering agentsThe main one is perhaps Metformin which lowers the amount of sugar your liver produces. Thiazilienediones such as Rosiglitazone increase insulin sensitivity of the tissues and glucosidase inhibitors such as Acarbose reduce absorption of glucose from the gut. Endoplasmic reticulum stressThe endoplasmic reticulum is responsible for the protein synthesis, being involved in protein translation, folding and assessing quality before protein secretion. All these drugs will be more or less effective in different people depending on how their diabetes is affecting them. Measuring blood sugar levelsDiabetes is diagnosed using criteria that are arbitrary. There are several ways that are used to measure blood sugar problems:Fasted blood sugar level - FBGThis measures blood sugar levels after not eating anything for at least 8 hours. 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].
However, this value will vary depending on factors such as stress, recent exercise and illness. 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]. Secondly their muscles get used to using fat as a fuel place of glucose and so more glucose is left in the blood. In diabetic state, the proteins from the mitochondrial inner membrane are decreased, and also may exist transcriptional changes of the mitochondrial proteins [89]. If you come into this category the measure below could be more useful to you.Long term blood sugar controlTo assess this we measure the amount of glycosylated haemoglobin - HbA1c, in your red blood cells. 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. Haemoglobin - Hb, is the protein found in red blood cells that is responsible for carrying oxygen to your tissues. 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]. In good health somewhere between 3-5% of our haemoglobin is in the HbA1c form.Red blood cells live for an average of 120 days. There are a number of factors that can skew the measurement:People with healthy low blood sugar have longer lived red blood cells that may survive for an average of 150 days.
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].
In this case a high end reading for HbA1c does not imply bad blood sugar control.Diabetics with high blood sugar levels have red blood cells that live shorter lives than average, typically around 90days.
Persistent oxidative stress mediates beta-cell failure through several different mechanisms, including:Decreased insulin secretion. It may be a better measure than HbA1c, and gives an indication of blood sugar levels over the previous 2-3 weeks(5).Glucose challenge or OGTTThe oral glucose tolerance test - OGTT is a measure of our response to consuming 75g of glucose in one hit. 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]. It is unrealistic as most people never consume such a large and purified amount of glucose.
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].
For most people achieving the low GI meal involves limiting the amount of starchy carbohydrates they eat.
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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