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Abstract Diabetes mellitus Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects of insulin secretion and/or increased cellular resistance to insulin. Diabetes mellitus is classified into type 1, type 2, gestational and other specific types Manifested by polyuria, polydepsia and polyphagia. Diagnosed by FPG ≥126 mg/dl (7.0 mmol/l) = provisional diagnosis of diabetes. 2-h post load glucose ≥200 mg/dl = provisional diagnosis of diabetes. Symptoms of hyperglycemia and casual plasma glucose ≥ (200 mg/dL). Glycated hemoglobin (Hb A1C) ≥ 6.5%. Screening is recommended to obese, hypertensive,family history of diabetes or gestational diabetes and dyslipidemia. Complications of diabetes include acute complications as DKA, HONK and hypoglycemia. and chronic complications in form of microangiopathy as retinopathy, nephropathy and neuropathy. and macroangiopathy as coronary heart disease strokes and peripheral arterial disease. Treatment of diabetes includes: 1- Patient education about the disease nature and ideal food and possible complications. 2- Diet patient should be educated about ideal food weight control. 3- Exercise has beneficial effects for diabetics and good glycemic control. 4- Oral drugs include biguanides as metformin which is recommended in all type 2 diabetics but has high incidence of GIT complaint. And sulphonylureas which is potent drugs with more incidence of hypoglycemia. Also TZDs which is good option in treatment. And alpha glucosidase inhibitors but it is a weak drugs can be combined with any other medications. With new drugs GLP 1 analogue and DPP4 inhibitors which is excellent drugs with high safety profile but expensive. Oral drugs can be combined with insulin if oral drugs failed alone. 5- Insulin therapy which is the treatment of type 1 and some cases of type 2 diabetes insulin has several preparations in market with several treatment regimens for easy control of hyperglycemia. Apoptosis Apoptosis is the process of Programmed cell death. 145 The alternative to apoptotic cell death is necrosis, which is considered to be a toxic process where the cell is a passive victim and follows an energyindependent mode of death. There is many differences between apoptosis and necrosis regarding provoking stimuli, morphologic changes, inflammatory response, cell fate and molecular changes. Apoptosis activation occurs through caspases or caspase independent Caspase activation occurs through 3 ways they are the death receptor (extrinsic) and mitochondrial (intrinsic), and the third is an intrinsic pathway involving the endoplasmic reticulum. The caspases involved in apoptosis are subdivided into initiator caspases (2, 8, 9, 10) and effector caspases. Apoptosis manifests in two major execution programs downstream of the death signal: the caspase pathway and organelle dysfunction. When caspases activated caspase cascade runs end with execution of the cell. Granzyme B: There is an accessory method of triggering apoptosis by the serine protease granzyme B Apoptosis is regulated by proapoptotic mediators which cause positive induction and antiapoptotic mediators which cause negative induction Regulators of mitochondrial apoptosis are Apoptosis-relevant proteins of the OMM are the VDAC and Bcl-2 members. The adenine nucleoside translocator is situated in the IMM. Activation of the pro-apoptotic molecule BAX appears to involve subcellular translocation and dimerization. The BH3-domain BIM also translocates to the mitochondria following certain apoptotic stimuli. the BH3-domain-only molecule BAD is phosphorylated on two serine sites. Following TNFα or Fas treatment, BID, a BH3-domain-only molecule is cleaved at its amino terminus. Abnormalities in cell death regulation can be a significant component of diseases such as cancer, autoimmune lymphoproliferative syndrome, AIDS, ischemia, and neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis. Some conditions feature insufficient apoptosis whereas others feature excessive apoptosis. potential methods of anti-apoptotic therapy includes stimulation of the IAP (inhibitors of apoptosis proteins) family of proteins, caspase inhibition, PARP (poly [ADP-ribose] polymerase) inhibition, stimulation of the PKB/Akt (protein kinase B) pathway, and inhibition of Bcl-2 proteins. Apoptosis assays can be classified into Cytomorphological alterations, DNA fragmentation, Detection of caspases, cleaved substrates, regulators and inhibitors, Membrane alterations, Detection of apoptosis in whole mounts and Mitochondrial assays. Apoptosis & diabetes mellitus Diabetes mellitus is one of the most common non-communicable diseases. Pancreatic B-cell loss by apoptosis appears to play an important role in the development of insulin deficiency and the onset and/or progression of the disease. β-Cell apoptosis is a key event contributing to the pathogenesis of type 1 diabetes mellitus. induction of B-cell apoptosis by death receptors through studies in type 1 diabetes As a result, macrophages and cytotoxic T lymphocytes have been accused of dealing the lethal blow to B-cells Studies from autopsies of subjects affected by Type 2 diabetes demonstrated that in some, although not all individuals with diabetes, there is a marked decrease in beta cells mass free fatty acids, glucose, sulfonylurea, and the islet cell hormone termed amylin can cause beta-cell apoptosis. This suggests that PCD may also be involved in the pathogenesis of Type 2 diabetes. New and convincing data indicating that increased apoptosis rather than decreased neogenesis or replication may be the main mechanism leading to reduced B-cell mass in type 2 diabetics. Cytokines, lipotoxity, and glucotoxity are three main stimuli for beta-cell apoptosis. Replication of somatic cells including B-cells occurs at a limited rate in adulthood, B-cell apoptotic death is likely to occur at a slow rate, which is compatible with the slow development of diabetes. (GLP-1) has recently been found to have antiapoptotic properties. This new property of GLP-1 has clinical relevance for the treatment of patients with overt DM, possible prevention of DM during the stage of impaired glucose tolerance. In both animal models and in Type 2 diabetes patients Imatinib seems to improve glycemic control, possibly via an insulin sensitizing effect. B-cell death is a common event in MODY. Renal apoptosis in diabetic nephropathy are scarce and scattered, but both the intrinsic and extrinsic apoptotic pathway seems to be involved. Diabetes causes apoptosis of neural and vascular cells in the retina. Apoptosis plays an important role in the healing process, Apoptosis of matrix-producing cells at this stage may interfere with the ability to produce enough matrix and limit repair. Cardiomyocyte apoptosis causes a loss of contractile units which reduces organ function and provokes cardiac remodeling which increase incidence of heart failure. New strategies to prevent B cell apoptosis include: (1) to remove stimuli from the islet and keep it in a safety environment; (2) to attenuate the apoptotic stimuli and stop the apoptosis at an early stage; (3) to block the pathway of apoptosis and stop the process; (4) to change the balance between pro and anti-apoptosis and reverse the cellular apoptotic process. |