Insulin resistance in type 2 diabetes role of fatty acids wiki,jan de witte klok,cfg investment services ltd,m&p 9 performance parts - Plans Download


Science, Technology and Medicine open access publisher.Publish, read and share novel research. Beta-Cell Function and FailureSoltani Nepton1[1] Physiology Department, Faculty of Medicine, Hormozgan University of Medical Science, Iran1.
Russ HA, Sintov E, Anker-Kitai L, Friedman O, Lenz A, Toren G, Farhy C, Pasmanik-Chor M, Oron-Karni V, Ravassard P, Efrat S. Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti R, Ng T, Jin T, Zhang H, Lu WY, Feng ZP, Prud'homme GJ, Wang Q. Pathway for the movement of acetyl-CoA units from within the mitochondrion to the cytoplasm.
SLC16A1 protein (also called the monocarboxylic acid transporter 1, MCT1) and transport across the outer mitochondrial membrane involves a voltage-dependent porin transporter. The synthesis of squalene, from FPP, represents the first cholesterol-specific step in the cholesterol synthesis pathway. This first reaction in this two-step cyclization is catalyzed by the enzyme, squalene epoxidase (also called squalene monooxygenase). As a result, a greater amount of cholesterol is converted to bile acids to maintain a steady level in circulation. Prevention of beta cell dysfunction and apoptosis by adenoviral gene transfer of rat insulin-like growth factor 1. ICV brain glibenclamide suppresses counterregulatory responses to brain glucopenia in rats: evidence for a role for brain KATP channels in hypoglycemia sensing. The function of CA(2+) channel subtypes in exocytic secretion: new perspectives from synaptic and non-synaptic release. Prevention of beta cell dysfunction and apoptosis activation in human islets by adenoviral gene transfer of the insulin-like growth factor I.
Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities. Effect of the administration of Psidium guava leaves on lipid profiles and sensitivity of the vascular mesenteric bed to phenylephrine in STZ-induced diabetic rats.
Insulin-Producing Cells Generated from Dedifferentiated Human Pancreatic Beta Cells Expanded In Vitro.
Due to its important role in membrane function, all cells express the enzymes of cholesterol biosynthesis.
Pyruvate transport across the inner mitochondrial membrane requires a heterotetrameric transport complex (mitochondrial pyruvate carrier) consisting of the MPC1 gene and MPC2 gene encoded proteins. The HMGCS1 gene is located on chromosome 5p14–p13 and is composed of 12 exons that generate two alternatively spliced mRNAs, both of which encode the same 520 amino acid protein. This is due to the fact that, as depicted in the pathway Figure above, several intermediates in the pathway can be diverted to the production of other biologically relevant molecules.
In the second step, this epoxide intermediate is converted to lanosterol through the action of the enzyme lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase). The original designation for these enzymes was ACAT for acyl-CoA: cholesterol acyltranferase. The INSIG1 gene is located on chromosome 7q36 and is composed of 7 exons that generate three alternatively spliced mRNAs encoding three isoforms of Insig-1. In addition to the cleavage-activation of SREBP transcriptional activity, S2P is involved in pathways that regulate cellular responses to endoplasmic reticulum stress, primarily the unfolded protein response, UPR. Il ne se manifeste par la survenue soudaine de l ’ hyperglycemie, progression rapide de l'acidocetose diabetique, et la mort a moins traites par l ’ insuline.
Beta cells (?-cells)Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association, 14(18), 2002; San Francisco, California. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association, 17, 2002; San Francisco, California. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association, 14(18), 2002, San Francisco, California. Effect of oral magnesium sulfate administration on blood pressure and lipid profile in streptozocin diabetic rat.Eur J Pharmacol. The MVK gene is located on chromosome 12q24 and is composed of 12 exons that generate three alternatively spliced mRNAs. The IDI1 gene is located on chromosome 10p15.3 and is composed of 7 exons that encode a 284 amino acid protein that is localized to the peroxisomes. The synthesis of squalene is catalyzed by the NADPH-requiring enzyme, farnesyl-diphosphate farnesyltransferase 1 (commonly called squalene synthase). These 11 different FDFT1-encoded mRNAs collectively synthesize five different isoforms of farnesyl-diphosphate farnesyltransferase 1. Squalene epoxidase is derived from the SQLE gene which is located on chromosome 8q24.1 and is composed of 12 exons that encode a protein of 574 amino acids. However, this conflicts with the official ACAT enzymes, ACAT1 and ACAT2 which are acetyl-CoA acetyltransferases 1 and 2. The human SREBP-1a protein (1147 amino acids) predominates in the spleen and intestines while the SREBP-1c protein (1123 amino acids) predominates in liver, adipose tissue, and muscle. The INSIG2 gene is located on chromosome 2q14.2 and is composed of 7 exons that encode a 225 amino acid protein. They make up 65-80% of the cells in the islets.The Islets diameter is about 50 to 300 micrometers. Program and abstracts of the 62nd Scientific Sessions of the American Diabetes Association; 14(18), 2002, San Francisco, California.
Extracts on insulin release from in situ isolated perfused rat pancrease in newly modified isolation method: the role of Ca and K channels.
Phosphomevalonate kinase is also a peroxisomal enzyme and it is derived from the PMVK gene.
The IDI2 gene is located on the same chromosomal region as the IDI1 gene but is composed of only 5 exons and encodes a 227 amino acid protein. Farnesyl diphosphate synthase is derived from the FDPS gene which is located on chromosome1q22 and is composed of 11 exons that generate five alternatively spliced mRNAs that, together, encode three different isoforms of the enzyme. Lanosterol synthase is derived from the LSS gene which is located on chromosome 21q22.3 and is composed of 25 exons that generate four alternatively spliced mRNAs which together generate three distinct isoforms of the enzyme.
These latter two enzymes are thiolases discussed in the Lipolysis and Fatty Acid Oxidation page. The SREBF2 gene is located on chromosome 22q13 and is composed 23 exons that encode a 1141 amino acid protein. A major function of PCSK9 is the endosomal degradation of the LDL receptor (LDLR), thereby reducing the recyling of the LDLR to the plasma membrane.
The PMVK gene is located on chromosome 1q22 and is composed of 6 exons that encode a 192 amino acid protein.
This effect of PCSK9 leads to a reduced ability of the liver to remove IDL and LDL from the blood contributing to the potential for hypercholesterolemia. The potential for the pharmaceutical benefits of the interference in the activity PCSK9 was recognized by a confluence of several studies. These cells are surrounded by alpha cells that secrete glucagon, smaller numbers of delta cells that secrete somatostatin, and PP cells or F cells that secrete pancreatic polypeptide. Patients with a specific form of familial hypercholesterolemia not due to mutations in the LDLR gene were shown to have severe hypercholesterolemia due to mutations in the PCSK9 gene resulting in hyperactivity of the enzyme. All of the cells communicate with each other through extracellular spaces and through gap junctions. In addition, it was found that in certain individuals with low serum LDL levels there was an association with the inheritance of nonsense mutations in the PCSK9 gene which result in loss of PCSK9 activity.
This arrangement allows cellular products secreted from one cell type to influence the function of downstream cells.
Hypercholesterolemic patients taking another cholesterol-lowering drug while simultaneously utilizing either of these new PCSK9 inhibitors saw further reductions in serum LDL levels of betweeen 55% and 77%.


As an example, insulin secreted from beta cells can suppress glucagon secretion.A neurovascular bundle containing arterioles and sympathetic and parasympathetic nerves enters each islet through the central core of beta cells. The arterioles branch to form capillaries that pass between the cells to the periphery of the islet and then enter the portal venous circulation.2. Beta cells functionsInsulin is synthesized as preproinsulin in the ribosomes of the rough endoplasmic reticulum in the beta cells (fig 1). FDFT1: farnesyl-diphosphate farnesyltransferase 1 (more commonly called squalene synthase). Preproinsulin is then cleaved to proinsulin, which is transported to the Golgi apparatus where it is packaged into secretory granules located close to the cell membrane. Proinsulin is cleaved into equimolar amounts of insulin and C-peptide in the secretory granules. The process of insulin secretion involves fusion of the secretory granules with the cell membrane and exocytosis of insulin, C-peptide, and proinsulinInsulin is a hormone that controls the blood glucose concentration. The liver maintains the base-line glucose level, but the beta cells can respond quickly to spikes in blood glucose by releasing some of its stored insulin while simultaneously producing more. The response time is very quick.Figure 1Mouse pancreatic islet as seen by light microscopy.
Glucagon is labeled in red and the nuclei in blueApart from insulin, beta cells release C-peptide, a consequence of insulin production, into the bloodstream in equimolar amounts. Amylin's metabolic function is now somewhat well characterized as an inhibitor of the appearance of nutrient [especially glucose] in the plasma. Whereas insulin regulates long-term food intake, increased amylin decreases food intake in the short term.GABA (? amino butyric acid) is produced by pancreatic beta cell. GABA released from beta cells can act on GABA Areceptor in the ? cells, causing membrane hyperpolarization and hence suppressing glucagon secretion.
An impaired insulin-Akt-GABAA receptors glucagon secretory pathway in the islet may be an underlying mechanism for unsuppressed glucagon secretion, despite hyperglycemia, in diabetic subjects. Some studies demonstrated that beta cells also express GABA A receptors, forming an autocrine GABA signaling system. However, the role of this autocrine GABA signaling in the regulation of beta cell functions remains largely unknown.
Zinc can keep insulin molecules together in the beta cells.Beta cells must have zinc to function.
Mechanisms of insulin secretion from beta cellsThe secretion of insulin from pancreatic beta cells is a complex process involving the integration and interaction of multiple external and internal stimuli.
Thus, nutrients, hormones, neurotransmitters, and drugs all activate or inhibit insulin secretion.
The primary stimulus for insulin release is the beta-cell response to changes in glucose concentration.
First-phase insulin release occurs within the first few minutes after exposure to an elevated glucose level; this is followed by a more permanent second phase of insulin release. Of particular importance is the observation that first-phase insulin secretion is lost in patients with type 2 diabetes. In the K (ATP) channel-dependent pathway, glucose stimulation increases the entry of extrinsic Ca2+ through voltage-gated channels by closure of the K (ATP) channels and depolarization of the beta cell membrane. While in the GTP-dependent pathway, intracellular Ca2+ is elevated by GTP-dependent proteins and augments the Ca2+-stimulated release. Secretagogues and insulin secretion inhibitors act at intermediate steps of these signaling pathways and influence the process of insulin exocytosis.
Several researchers have investigated this intricate mode of known secretagogue action using isolated islets as an in vitro model.
To quote a few; imidazoline antagonists of alpha 2-adrenoreceptors increase insulin release in vitro by inhibiting ATP-sensitive K+ channels in pancreatic beta cells.
Some researchers have evaluated the properties of sulphonylurea receptors (SUR) of human islets of Langerhans.
They studied the binding affinity of various oral hypoglycaemic agents to the receptor and also tested insulinotropic action of the drugs on intact human islets. This binding potency order was parallel with the insulinotropic potency of the evaluated compounds. Some investigators have shown an insulinotropic effect of Triglitazone (CS-045) and have shown its mode of action to be distinct from glibenclamide (a sulphonylurea drug). A-4166, a derivative of D-phenylalanine, evokes a rapid and short-lived hypoglycaemic action in vivo. Some studies showed S21403, a meglitinide analogue to be a novel insulinotropic tool in the treatment of type 2 diabetes, as it affected cationic fluxes and the drugs secretary responses displayed favourable time course of prompt, and not unduly prolonged, activation of beta cells. Some studies demonstrated that tetracaine (an anaesthetic) stimulates insulin secretion by release of intracellular calcium and for the first time elucidated the role of intracellular calcium stores in stimulus-secretion coupling in the pancreatic beta cells. JTT-608, is a nonsulphonylurea oral hypoglycaemic agent which stimulates insulin release at elevated but not low glucose concentrations by evoking PKA-mediated Ca2+ influx.4.
The importance of KATP channelsThe KATP channels play an integral role in glucose-stimulated insulin secretion by serving as the transducer of a glucose-generated metabolic signal (ie, ATP) to cell electrical activity (membrane depolarization).
Thus, like neurons, beta cells are electrically excitable and capable of generating Ca2+ action potentials that are important in synchronizing islet cell activity and insulin release.
In addition to being signal targets for glucose, KATP channels are the targets for sulfonylureas, which are commonly prescribed oral agents in the treatment of type 2 diabetes. The sulfonylurea receptor belongs to a superfamily of ATP-binding cassette proteins and contains the binding site for sulfonylurea drugs and nucleotides. Evans, MD, Yale University Medical School, New Haven, Connecticut, and colleagues have suggested that glucose sensing in the brain during hypoglycemia may be mediated by KATP channels located in brain hypothalamic neurons. Thus, these molecules may also serve as new therapeutic targets for the restoration of impaired hypoglycemia awareness and glucose counterregulation in type 1 diabetes.5. Voltage-dependent Ca2+ channels: Novel regulatorsExtracellular Ca2+ influx through L-type voltage-dependent Ca2+ channels (VDCC) raises free cytoplasmic Ca2+ levels and triggers insulin secretion.
The structure of the VDCC is complex and consists of 5 subunits: alpha1, alpha2, beta, gamma, and delta units. The alpha subunit constitutes the ion-conducting pore, whereas the other units serve a regulatory role. Previous work has identified that isoforms of alpha1 subunits interact with exocytotic proteins. More recently, using the yeast hybrid screening method, a novel protein, Kir-GEM, interacting with the beta3 isoform of the VDCC, has been identified by Seino and colleagues.
Furthermore, it has been determined that Kir-GEM inhibits alpha ionic activity and prevents cell-surface expression of alpha subunits. The investigators have proposed that in the presence of Ca2+, Kir-GEM binds to the beta isoform, and this interaction interferes in the trafficking or translocation of alpha subunits to the plasma membrane. Novel cAMP signaling pathways of insulin releaseThe incretins are another set of factors that are important hormonal regulators of insulin secretion.
The incretins are polypeptide hormones released in the gut after a meal that potentiate insulin secretion in a glucose-dependent manner.
Due to their dependence on ambient glucose for action, they are emerging as important new therapeutic agents to promote insulin secretion without accompanying hypoglycemia (a common complication of sulfonylurea treatment).Unlike sulfonylureas, incretins act by activating Gs (a G-protein that activates adenylyl cyclase) to increase cAMP in beta cells. Typically, the main mechanism of action of cAMP is by activation of an enzyme called protein kinase A (PKA) that, in turn, phosphorylates other substrates to turn on (or off) vital cell functions. Then, using molecular reagents that antagonize the effects of cAMPS, they observed that incretin-potentiated insulin secretion is attenuated. These results provide a mechanism whereby cAMP can directly promote exocytosis of insulin granules without activation of PKA (ie, a PKA-independent pathway), and thereby provide additional molecular targets for therapeutic intervention.7.
Beta cell dysfunction and apoptosisType one diabetes: Islet beta-cells are almost completely destroyed when patients with type 1 diabetes are diagnosed.
In the absence of a defect in beta-cell function, individuals can compensate indefinitely for insulin resistance with appropriate hyperinsulinemia, as observed even in obese populations.
However, when allowance is made for the hyperglycaemia and the fact that glucose stimulates insulin secretion, it becomes apparent that the insulin levels in diabetic patients are lower than in healthy controls and inadequate beta-cell function therefore represents a key feature of the disease.


Theoretically, the insulin secretory defect could result from either defects of beta-cell function or a reduction in beta-cell mass. Most quantitative estimates indicate that type 2 diabetes associates with either no change or < 30% reduction in beta-cell mass. Moreover, the secretion defect is more severe than can be accounted for solely by the reduction in beta-cell mass. It therefore appears that the insulin secretory defect in type 2 diabetes does not primarily result from insufficient beta-cell mass but rather from an impairment of insulin secretion.8. Prevention of beta cell dysfunction and apoptosis Islet beta-cells are almost completely destroyed when patients with type 1 diabetes are diagnosed.
The cure of type 1 diabetes requires beta-cell regeneration from islet cell precursors and prevention of recurring autoimmunity. Therefore, beta-cell replacement, regeneration and proliferation emerge as a new research focus on therapy for type 1 diabetes; however, its application is limited by the shortage of pancreas donors. In-vitro expansion of human cadaveric islet beta cells represents an attractive strategy for generation of abundant beta-like cells. Human beta cells patent a very low proliferation capacity in vivo, and intact isolated islets cultured in suspension do not proliferate, although they remain functional for months. When islets are allowed to attach, limited replication of beta cells can be induced by growth factors or extracellular matrix components before the beta-cell phenotype is lost. Previous accepting of the determinants of tissue mass during adult life is still rudimentary.
Insights into this problem may suggest novel approaches for the treatment of neoplastic as well as degenerative diseases. In the case of the pancreas, elucidating the mechanisms that govern ? cell mass will be important for the design of regenerative therapy for both type 1 and type 2 diabetes, diseases characterized by an insufficient mass of ? cells. It is clear that ? cell mass increase during pregnancy and in insulin-resistant states, but evidence on the ability of ? cells to regenerate from a severe, diabetogenic injury is conflicting.
Igf1 has been shown to influence ?-cell apoptosis, and both Igf1 and Igf2 increase islet growth; Igf2 does so in a manner additive with fibroblast growth factor 2. Some study showed that IGF-1 can protect beta-cells from the destruction of apoptosis factors and promoting beta-cell survival and proliferation. Interleukin-1beta (IL-1 beta) is a potent pro-inflammatory cytokine that has been shown to inhibit islet beta cell function as well as to activate Fas-mediated apoptosis in a nitric oxide-dependent manner. Furthermore, this cytokine is effective in recruiting lymphocytes that mediate beta cell destruction in type one diabetes. IGF-I has been shown to block IL-1beta actions in vitro.Glucagon like peptide 1 (GLP-1) is a potent insulin secretagogue released by L-cells of the distal large intestine in response to meal ingestion and, together with glucose-dependent insulinotropic polypeptide (GIP), account for 90% of the incretin effect. GLP-1 also inhibits glucagon secretion, delays gastric emptying, and promotes weight loss by its appetite-suppressant effect. GLP-1 analogs also stimulate islet neogenesis and ?-cell replication and inhibit islet apoptosis. The gluco-incretin hormones GLP-1 and GIP can protect beta-cell against apoptosis induced by cytokines or glucose and free fatty acids.
Increases in cAMP levels, for instance as stimulated by GLP-1 or GIP action, potentiate glucose-stimulated insulin secretion by both protein kinase A (PKA)-dependent and independent mechanisms; they also stimulate gene transcription through PKA dependent phosphorylation of the transcription factor CREB. Studies of mice with beta-cell specific inactivation of either receptor indicated that the insulin receptor was important for compensatory growth of the beta-cells in response to insulin resistance whereas the IGF-1 receptor was involved in the control of glucose competence. GLP-1 enhances beta cell function with an increase in the ability to secrete insulin and restore first phase insulin release.
Within the pancreas, GLP-1 expands ?-cell mass via promotion of ?-cell growth and reduction of ?-cell death.?-Aminobutyric acid (GABA), a prominent inhibitory neurotransmitter, is present in high concentrations in ?-cells of islets of Langerhans. The GABA shunt enzymes, glutamate decarboxylase (GAD) and GABA transaminase (GABA-T) have also been localized in islet ?-cells.
With the recent demonstration that the 64,000-Mr antigen associated with insulin-dependent diabetes mellitus is GAD, there isincreased interest in understanding the role of GABA in islet functions. Only a small component of ?-cell GABA is contained in insulin secretory granules, making it unlikely that GABA, co-released with insulin, is physiologically significant. Our immunohistochemical study of GABA in ?-cells of intact islets indicates that GABA is associated with a vesicular compartment distinctly different from insulin secretory granules. Physiological studies on the effect of extracellular GABA on islet hormonal secretion have had variable results. The most compelling evidence for GABA regulation of islet hormone secretion comes from studies on somatostatin secretion, where it has an inhibitory effect.
Some researchers present new evidence demonstrating the presence of GABAergic nerve cell bodies at the periphery of islets with numerous GABA-containing processes extending into the islet mantle.
This close association between GABAergic neurons and islet ?- and ?-cells strongly suggests that GABA inhibition of somatostatin and glucagon secretionis mediated by these neurons. New evidence indicates that GABA shunt activity is involved in regulation of insulin secretion. These new observations provide insight into the complex nature of GABAergic neurons and ?-cell GABA in regulation of islet function. Our study showed that GABA exerts has protective and regenerative effects on islet beta cells and reverses diabetes. GABA therapy increased beta cell proliferation and decreased beta cell apoptosis, which in turn increase beta cell mass and induced the reversal of hyperglycemia in the different kind of mice. Our data suggest that GABA exerts has ani-inflammatory effects, and is directly inhibitory to T cells and macrophages.Magnesium deficiency has recently been proposed as a novel factor implicated in the pathogenesis of the diabetic complications.
Photochemical analysis of those herbs have revealed the presence of flavonoids, which include quercetin and its derivatives. It is concluded that quercetin, a flavonoid with antioxidant properties brings about the regeneration of the pancreatic islets and probably increases insulin release in streptozocin-induced diabetic rats.Connective tissue growth factor (CTGF), to induce adult ? cell mass expansion. Some study showed that CTGF is required for embryonic ? cell proliferation3, and that CTGF overexpression in embryonic cells increases ? cell proliferation and ? cell mass. The mouse pancreas develops from ventral and dorsal evaginations of the posterior foregut endoderm at embryonic day, a process dependent on the transcription factors Pdx1 and Ptf1. Differentiation of all pancreatic endocrine cell types (?, ?, ? and PP) is dependent on the transcription factor, neurogenin 3 (Ngn3). Ngn3 expression is controlled by a variety of factors, including the Notch signaling pathway and the transcriptional regulators pancreatic and duodenal homeobox 1 (Pdx1), SRY-box 9 (Sox9) and hepatic nuclear factor 6 (Hnf6). Although ? cell neogenesis begins, these early insulin-positive cells do not contribute to mature islets. Instead, endocrine cells that will go on to contribute to the mature islets begin to differentiate period known as the secondary transition. Although several factors have been identified that play a role in the regulation of embryonic and neonatal ? cell proliferation.
One cell cycle regulator that does play a role in embryonic ? cell proliferation is the cell cycle inhibitor, p27Kip1. Inactivation of p27Kip1 during embryogenesis results in an increase in ? cell proliferation and subsequently ? cell mass. There was no change, however, in early postnatal ? cell proliferation, suggesting that p27Kip1 is not crucial to postnatal proliferation.As mentioned above Pdx1expressed in multipotent pancreatic progenitors in the early stages of pancreas development, but, Pdx1 expression becomes enhanced in insulin-positive cells and is found at only low levels in exocrine cells. This expression pattern is maintained into adulthood and Pdx1 plays a critical rolein maintenance of the mature ? cell phenotype.
Inactivation of Pdx1 in embryonic insulin-expressing cells results in a dramatic decrease in ? cell proliferation at late gestation, leading to decreased ? cell mass at birth and early onset diabetes.



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