Clinical manifestations type 2 diabetes mellitus,jump to cure diabetes 2014 bogota,cfg yapma cs go - PDF 2016


Acanthosis nigricans is a skin condition that causes a dark discoloration in body folds and creases. Neuropathy means damage to the nerves that run throughout the body, connecting the spinal cord to muscles, skin, blood vessels, and other organs. The first step in de novo pyrimidine biosynthesis (Figure-1) is the synthesis of Carbamoyl phosphate from bicarbonate and glutamine in a multistep process, requiring the cleavage of two molecules of ATP. Carbamoyl phosphate reacts with aspartate to form Carbamoyl aspartate in a reaction catalyzed by Aspartate Transcarbamoylase (Figure-1).Carbamoyl aspartate cyclizes to form Dihydro orotate, which then gets oxidized by Dihydro orotate dehydrogenase in the presence of NAD+ to form orotate. Orotidylate is then decarboxylated to form uridylate (UMP), a major pyrimidine nucleotide that is a precursor to RNA. This disorder usually appears in the first year of life and is characterized by growth failure, developmental retardation, megaloblastic anemia, and increased urinary excretion of Orotic acid. The diagnosis of this disorder is suggested by the presence of severe Megaloblastic anemia with normal serum B12 and Folate levels and no evidence of TC-II deficiency (Transcobalamine- II). Uridine treatment is effective because Uridine can easily be converted into UMP by omnipresent tissue kinase, thus allowing UTP, CTP, and TMP to be synthesized and feedback inhibit further Orotic acid production. Increased excretion of orotic acid, uracil, and uridine accompanies a deficiency in liver mitochondrial ornithine transcarbamoylase (reaction 2, Figure 2). Figure-2- Showing the  block at the level of Ornithine transcarbamoylase that results in diffusion of carbamoyl phosphate to cytoplasm to be utilized in the pathway of pyrimidine bio synthesis causing Orotic aciduria. The orotic aciduria that accompanies Reye syndrome probably is a consequence of the inability of severely damaged mitochondria to utilize carbamoyl phosphate, which then becomes available for cytosolic overproduction of orotic acid. 1) Allopurinol  is an alternative substrate for orotate phosphoribosyltransferase (reaction 5, Figure-1), competes with orotic acid. 2) 6-Azauridine, following conversion to 6-azauridylate, also competitively inhibits orotidylate decarboxylase (reaction 6, Figure-1), enhancing excretion of orotic acid and orotidine. 3) The anticancer drug 5-fluorouracil is also phosphoribosylated by orotate phosphoribosyl transferase. Type 2 Diabetes Mellitus is a chronic and systemic metabolic disorder distinguished by high blood glucose (hyperglycemia), insulin resistance, and insulin deficiency. The individual with Type 2 Diabetes typically goes undiagnosed for years because the onset is gradual and signs of hyperglycemia is not noticed.
The long-term presence of type 2 diabetes impacts the large and small blood vessels and nerves throughout the body. The insulin signaling pathway refers to the complex biological process of insulin reacting with target cells such as muscle, fat, or liver cells and the resulting intracellular effects that result, leading to various functional effects observed at the multicellular level. Insulin works by binding its specific receptor on cell surfaces throughout the body, such as on liver, muscle or adipose cells.[5] The insulin receptor is a tyrosine kinase protein that undergoes autophosphorylation of its tyrosine residues that located on its cytoplasmic face once activated by insulin.
In total, the activation of the PI3K subpathway mediates several insulin-induced responses including GLUT4 activation, glycogen synthesis by inhibiting CSK-3 phosphorylation, and lipogenesis by up-regulation of fatty-acid synthase gene expression.
MAPK is other main subpathway that is activated after IRS-1 and 2 phosphorylation that begins with small adaptor proteins Grb2 and SHP2 that lead to further substrate activation downstream. Insulin-mediated Glucose transport is primarily accounted for through the translocation of glucose transporters to the plasma membrane, most of which is GLUT4 within muscle and adipose cells.
Most of glucose that enters human muscle in response to insulin is desposited as Glycogen (see Carbohydrate Storage: Glycogen for more information).
The biochemical process of glycolysis reverses many of the steps of Glycogenesis with different enzymes[64]. The Immune System of the human body is comprised of two different systems, the aquired immune system and innate immune system. The innate immune system is the body’s first-line of defense against invaders including infections and physical or chemical injury. Research has shown that circulating concentrations of acute-phase reactants is increased in type 2 diabetic patients when compared to nondiabetic subjects.
The Insulin Resistance Atherosclerosis Study (IRAS)[37] investigated the relationships insulin resistance, cardiovascular risk factors, and cardiovascular disease in a multiethnic population across varying statuses of glucose tolerance. Research indicates that increased ROS levels are associated with altered mitochondrial morphology in both myotubes cultured in high glucose conditions and in diet-induced diabetic mice.[16] In addition, increased oxidative stress in mitochondria may contribute to increased lipid peroxidation and damage to cell membranes and DNA. Apoptosis is a genetically directed process of cell self-destruction marked by the fragmentation of nuclear DNA.[45] It is a form of cell death during which a programmed sequence of events leads to the elimination of cells without releasing harmful substances into the surrounding area.
Evidence suggests that the release of cytochrome c from the mitochondria results from direct action of ROS on cardiolipin, a mitochondrial phospholipid which is located in the inner mitochondrial membrane.[17][52][53] During the early phase of apoptosis, mitochondrial ROS production is stimulated and cardiolipin is oxidized (loses electrons). Although HbA1c is directly related to blood glucose levels, it is important to realize that blood glucose and HbA1c are not the same.


A portion of the metabolic stress seen in Type 2 Diabetes may originate from myocellular fat storage. A four month study investigating the relationship between insulin sensitivity (IS) and IMCL content in Zucker diabetic fatty rats (ZDF) confirmed the relationship between IS and IMCL content seen in humans. AMPK is a protein kinase, that combines signals to monitor and balance both systemic and cellular energy. At times of high energy demand the ? subunit rapidly responds to changes in the AMP to ATP ratio to maintain energy balance. AMPK is activated by physical activity in such a way that increased intensity results in increased activation. Reduction of AMPK activity promotes the development of insulin resistance and glucose intolerance, disturbs muscle energy balance during exercise, and decreases mitochondrial biogenesis (mitochondria’s ability to make ATP).[33] In insulin-resistant rodents, increased AMPK activity has been linked with improved blood glucose homeostasis, lipid profile and blood pressure. Angiotensin II increases gene expression after selective intra-arterial adenovirus delivery in a rabbit model assessed using in vivo SSTR2-based reporter imaging.
Singh SP1, Ravoori MK1, Dixon KA2, Han L1, Gupta S2, Uthamanthil R3, Wright KC4, Kundra V5,6,7. Hepatopancreatoduodenectomy for local recurrence of cholangiocarcinoma after excision of a type IV-A congenital choledochal cyst: a case report. Surgical resection is the only curative treatment for biliary tract cancer (BTC); however, the recurrence rate remains high even after curative resection.
Early testing, new medical treatments and improvements in diabetic control are protective measures. The usual form of hereditary Orotic aciduria is the buildup of Orotic acid due to the deficiency in one or both of enzymes that convert it to UMP.
This reaction is catalyzed by Carbamoyl phosphate synthetase -II (CPS-II). Carbamoyl phosphate synthetase-II  primarily uses glutamine as a source of ammonia.
At this stage, orotate couples to ribose, in the form of 5-phosphoribosyl-1-pyrophosphate (PRPP), a form of ribose activated to accept nucleotide bases. All of these end products normally act in some way to feedback inhibit the initial reactions of pyrimidine synthesis.
Excess carbamoyl phosphate exits to the cytosol, where it stimulates pyrimidine nucleotide biosynthesis.
Orotate phosphoribosyltransferase (reaction 5, Figure 1) converts the drug allopurinol  to a nucleotide (Oxypurinol ribonucleotide).
Individuals commonly experience visual blurring, neuropathic complications, infections, fatigue and significant blood lipid abnormalities.[2][12] Type 2 Diabetes is typically diagnosed when the patient is receiving medical care for another problem.
Chronic hyperglycemia can lead to macrovascular disease, which affects the arteries supplying the heart, brain, and lower extremities.[2] Type 2 diabetes is also associated with the development of microvascular pathologies in the retina, renal glomerulus, and peripheral nerves. Through PKB’s isoforms ?, ?, and ?, it plays role in mediating glycogen synthase kinase-3, metabolic actions of insulin, and Glut4 translocation.[8][66] It is debated whether PKB plays a significant role in insulin resistance with diabetes. Mounting evidence has shown that PI3k and PKB activation participate in the stimulation of p70 S6k. Insulin increases the transporters’ cycle to and from the cell surface by promoting exocytosis and inhibiting endocytosis. Insulin causes stable Glycogen Synthase (GS) activation by causing dephosphorylation at multiple sites within the enzyme.
Through these three subpathways, the insulin signaling pathway promotes GS and glycogen synthesis.
The aquired immune system is your immunity your body build up from being exposed to foreign invaders, and the innate immune system is the body's natural unspecific defense against new foreign invaders that the body has not built up immunity against. Participants demonstrated normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or type 2 diabetes mellitus.[37] Measures of insulin sensitivity and insulin secretion were obtained from all participants during two 4-hour visits, occurring approximately one week apart. Increased levels of ROS are a likely cause in a variety of pathophysiological conditions, including type 2 diabetes.[16] Oxidative stress to the mitochondria can come from many sources.
The amount of hemoglobin that forms HbA1c depends on the amount of glucose that hemoglobin is exposed to over time.[22],[23] For example, hemoglobin exposed to high levels of glucose for long periods of time results in greater amounts of glycation. The Diabetes Control Card is a quick reference for patients diagnosed with diabetes to assess glucose control.
In muscle tissue, lipids are stored as either extramyocellular lipids (EMCL) or intramyocellular lipids (IMCL).
An obese Zucker diabetic fatty rat has significantly higher IMCL concentrations than its lean counterpart.
AMPK phosphorylates TBC1D1 which increases activity of GLUT4, resulting in increased glucose uptake.


There are limited data regarding the effectiveness of surgical resection for recurrent BTC. Either orotate phosphoribosyl transferase and orotidylate decarboxylase both are defective, or the decarboxylase alone is defective. A different enzyme mitochondrial carbamoyl phosphate synthase I catalyzes the first step of urea synthesis (Figure-2). Orotate reacts with PRPP to form orotidylate (Orotate mono phosphate), a pyrimidine nucleotide. Specially, the lack of CTP inhibition allows Aspartate Transcarbamoylase to remain highly active.
Confirmation of the diagnosis, however, requires assay of the Transferase and decarboxylase enzymes in the patient’s erythrocytes . Raf phosphorylates MEK, a dual-specificity kinase of tyrosine and threonine that activates mitogen-activated protein kinase (MAPK).
It has been shown that tyrosine kinase activity and IRS-1-protein phosphorylation are two essential processes in normal glucose transport.
PKB has also been shown to directly inhibit GSK-3, a well-known inhibitor of GS, thereby promoting GS. Ezymes responsible for Glycogenolysis 1 through 3 respectively: Glycogen phosphorylase, Phosphoglutomutase, Phosphoglutomutase, and Glucose-6 Phosphotase. ROS are produced in larger amounts by islet cells from patients with type 2 diabetes than by those from non-diabetic patients.[17] Although some ROS are produced in the peroxisomes, the major source of ROS production in cells is the mitochondria. This is directly related to continuous breakdown and replacement of erythrocytes in the body. EMCL is metabolically static, but IMCL stores are built up, mobilized, and used within hours. This results in more and more production of Orotic acid which gets accumulated and is excreted in urine excessively.
The MAPK pathway is well known within the insulin signaling cascade, but is not very sensitive to insulin or involved in most of the hormone’s important metabolic responses.[8] The MAPK subpathway has some evidence showing it functions to exert feedback regulation on the PI3k subpathway and is involved in the process of insulin resistance. The PI3k subpathway functions to mediate glut4 activation, glycogen synthesis, and lipogenesis.
Within these pathways, PI3k, PKB, and the atypical PKCs play an particularly key roles in the process of glucose uptake into cells. MAPK has been implicated in activating GS through phosphorylation of p90 Ribosomal S6 kinase 2 (p90 rsk2) and glycogen bound protein phosphatase-1 (PP1G) downstream. The later branch is implicated GS promotion by inhibition of the well-established inhibitor of GS, GSK-3.
During times of high glucose uptake, increased amounts of glucose-6-phosphate (G6P) leads to an increase in glycogen synthesis.
They carry information to the brain about shape, movement, texture, warmth, coolness or pain from special sensors in the skin and from deep in the body. In contrast, the downstream constituents of PKB such as p70 S6k have been shown to have no immediate effects on glucose uptake.
PP1G has many phosphorylation sites that insulin has been shown to augment, but its exact role in GS promotion is not fully understood. The MAPK subpathway may serve to regulate the PI3k subpathway and may be involved in insulin resistance, but more research is needed to prove this. Indirect activators (metformin, dinitrophenol (DNP), and rotenone) work by increasing AMP:ATP ratio, compound C works by inhibiting activation of AICAR. These nerves have functions such as controlling the pace of heartbeats, maintaining blood pressure, and controlling sweating.Some symptoms of neuropathy occur when the nerve fibers are lost. If the loss affects the sensory fiber, it can cause loss of feeling and of the loss of functions not normally under conscious control like digestion.Neuropathy symptoms can also be caused by nerves that are damaged or are healing. These symptoms include prickling, tingling, burning, aching or sharp jabs of needle-like pain. There are signs of the increased nerve activity that occurs in damaged or healing nerves.For more interesting and very important health related and medical articles, click on the links below1.



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