Diabetes mellitus is a heterogeneous disease characterized by unusually high levels of glucose in the bloodstream. This common chronic disorder is caused by (1) insulin resistance/inadequate sensitivity of cells to the action of insulin and/or (2) low production of insulin by the pancreas. There are few types of diabetes, but the most important ones are:
Type 1 diabetes mellitus (T1DM): insulin dependent; this type of diabetes results from the body's incapability to produce insulin.
Type 2 diabetes mellitus (T2DM): non-insulin dependent; this type of diabetes results from the failure of the cells to use insulin appropriately.
Gestational diabetes: occurs among pregnant women with no history of diabetes before. It may develop to T2DM.
T2DM is characterized either by low secretion of insulin or the cells ignore the insulin. The defective sensitivity of these cells to insulin is believed to involve the insulin receptor. T2DM is one of the most common chronic diseases and is associated with comorbidities, such as obesity, hypertension, hyperlipidemia and cardiovascular disease, which taken together, comprise the 'Metabolic Syndrome' (Jain and Saraf, 2008). It is a disease with multi-factorial causes involving the interactions of genetic susceptibility and environmental factors. It results from combined defects in insulin secretion from the pancreatic β-cells and peripheral insulin resistance which is the loss of an appropriate response to insulin at normal levels (Ridderstrale et al., 2008). T2DM is frequently not diagnosed until complications appear because the effectiveness of early diagnosis through screening of asymptomatic individuals has not been established (Engelgau et al., 2000). The prevalence of T2DM continues to increase around the world as well as in Malaysia. According to the Third National Health and Morbidity Survey 2006 (3rd NHMS), in Malaysia, the prevalence of the T2DM for adults aged 30 years old and above now stood at a staggering 14.9%. In other words, 1 in every 6 adults has T2DM.The incidence of T2DM is the highest among Indian ethnic at 19.9% for those aged 30 years and above. The chronic nature of T2DM seems to cause adverse blow on the afflicted population leading to patient mortality, morbidity and staggering health care costs to the nations. Six classes of oral agents are now approved by the US Food and Drug Administration for the treatment of T2DM: sulfonylureas and meglitinides (both secretagogues), nateglinitides, biguanides (metformin), α-glucosidase inhibitors (acarbose and miglitol), and thiazolidinediones (rosiglitazone and pioglitazone) (Donner, 2006). One of the major factors that altered the risk to diabetes susceptibility and the inefficiency of anti-diabetic drugs in order to maintain normal blood glucose level is the individual genetic variation.
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Symptoms' of T2DM:
Excessive urine production
Excessive thirst and increased fluid consumption
Itching of external genitalia
Excessive bowel movements
Genetic and acquired factors contributing pathogenesis of T2DM
Studies suggested that T2DM has both genetic and environmental components and a complex pattern of inheritance (Zhou et al., 2005). Genetic variation often influences gene expression by different mechanisms such as altering rate of transcription or splicing or transcript stability (Schadt et al., 2003). According to American Diabetes Association (ADA), T2DM has a prominent genetic basis than type 1, yet it also depends more on environmental factors. The contributing genetic factors are often multiple, interacting with each other and environmental factors in a complex mode.
Risk factors of T2DM:
Unhealthy eating habits
High blood pressure and high cholesterol
Family history and genetic factors
History of gestational diabetes
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Those with first-degree relatives suffering from T2DM have a higher risk of developing the disease. In general, the risk of children with T2DM parents is 1 in 7 if the parents were diagnosed before age 50 and 1 in 13 if diagnosed after age 50. According to ADA, some scientists believe that a child's risk is greater when the parent with T2DM is the mother. If both parents have T2DM, the child's risk is about 1 in 2. Examples of the genes that is significantly associated with developing T2DM; TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX (Lyssenko et. al., 2008). KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11), encodes the islet ATP-sensitive potassium channel Kir6.2, and TCF7L2 (transcription factor 7-like 2) regulates proglucagon gene expression and thus the production of glucagon-like peptide-1 (Rother et. al., 2007). Understanding the genetic factors associated with T2DM will provide important clues to the pathogenesis of type 2 diabetes, thus, improving the management of diabetes in Malaysia.
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The basic rule of pharmacology is drug molecule must exert chemical influence on one or more cellular constituents to initiate pharmacological response. There are four types of regulatory proteins that act as drug targets; enzymes, carrier molecules, ion channels and receptors. Understanding the pathogenesis of T2DM will help to unleash new and better treatment for this disease.
PTEN gene encodes a protein known as phosphatase and tensin homolog. The PTEN protein modifies other proteins and fats (lipids) by removing phosphate groups, which consist of three oxygen atoms and one phosphorus atom; an activity that classified the PTEN protein as a type of enzyme called a phosphatase (http://ghr.nlm.nih.gov/gene=pten). It acts as a tumor suppressor gene by regulating the cycle of cell division, keeping the cells from growing and dividing in an uncontrolled way. PTEN has also been proven to dephosphorylate position D-3 of PtdIns 3,4,5-P3 which is an important second messenger involved in insulin and growth actor signaling. Undeniably, PI 3-kinase activation and subsequent 3' phosphoinositide formation is required and in some cases, it is enough to trigger many of the biological actions of insulin.
The receptor for insulin is embedded in the plasma membrane. The insulin receptor (IR) is made of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains infiltrate through the plasma membrane. When insulin binds to the α-subunits, it stimulates the tyrosine kinase activity of the β-subunits, thus, activating the catalytic activity of the receptor. Phosphorylations of few intracellular proteins (e.g. Shc, IRS-1, IRS-2, IRS-3, IRS-4, and other proteins) occur, which in turn alters their activity, thereby generating a biological response. The activated IRkinase transduces the insulin signal by activating pathways such as the Ras-Raf-MEK-ERK, the PI3K-PDK-AKT, the c-Cbl-Glut4, the PI3K-Rab4-Glut4 and the PI3K-Rac-MEKK1-MKK4-JNK pathways (http://www.sigmaaldrich.com/life-science/your-favorite-gene-search/pathway-overviews/insulin-receptor-pathway.html). Tyrosine phosphorylation of the IRS and Shc proteins allows them to serve as docking proteins that interact with signaling molecules containing Src homology 2 domains (White et. al., 1994), including PI1 3-kinase (Nakashima et. al., 2000).
The phosphoinositide 3-kinases (PI 3-kinases), are ubiquitos, lipid kinase composed of a heterodimer that is responsible for the regulation of many cellular processes; cell growth, motility, proliferation and survival (http://www.calbiochem.com/insulin). PI 3-kinase activation is required for a number of insulin stimulated effects, ranging from stimulation of glucose transport, glycogen synthesis, and membrane ruffling to mitogenesis, although the precise function of phosphatidylinositol (PtdIns) products in eliciting these responses is currently unknown (Kotani et. al., 1995 and Jhun et. al., 1994). A recent discovery done by a group of researchers from California found out that adenovirus-mediated expression of the 3' phosphatidyl Inisotol phosphatase, PTEN, in 3T3-L1 adipocytes, significantly inhibits insulin-induced GLUT4 translocation (35%), glucose uptake (36%), and membrane ruffling (50%), all of which are dependent on PI 3-kinase activity. Glucose homeostasis in maintained by the ability of insulin to stimulate translocation of GLUT4 glucose transporters to the cell surface, thus increasing the rate of glucose uptake into muscle and adipose tissue. It has been clearly demonstrated that PI 3-kinase activation is both necessary and sufficient for these actions(Egawa et. al., 1999 and Martin et. al., 1994).
New approach in the treatment of T2DM
The sympathetic nervous system has several classes of adrenergic receptors (adrenoreceptors) which can be distinguished pharmacologically. The adrenergic receptors (adrenoreceptors) are a class of G protein-coupled receptors that uses catecholamines (neurotransmitters), especially noradrenalin and adrenalin (http://en.wikipedia.org/wiki/Adrenergic_receptor). There are two families of adrenoreceptors; α and β receptors. β adrenoreceptors can be subdivided into three subgroups, β1, β2 and β3, based on the affinities for adrenergic agonists and antagonists. β3 is located predominantly in adipose tissue and is responsible for the regulation of lipolysis in adipose tissue (Ferrer-Lorente et. al., 2005) and thermogenesis in skeletal muscle (Rang 2003). Obesity is the major risk factor for T2DM and cardiovascular disease. Most obese people have difficulty to control their eating habit by food constriction alone. Thus by treating obesity, the major risk of T2DM, the risk of acquiring T2DM is decreases. Activation of β3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis (Fisher et. al., 1998). This indicates that the stimulation of β3 adrenergic receptors has the potential to greatly decrease body weight and consequently, reduce the risk of diabetes-related complications. However, a report by Elbein et. al., in 1996 concluded that β3 adrenergic receptor locus does not play an important role in T2DM susceptibility or in the insulin resistance syndrome among members of families with a strong predisposition to T2DM. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus β3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a β3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue (Fisher et. al., 1998). These data propose the promise of β3 agonists in the treatment of human obesity, thereby preventing related illnesses such as diabetes and cardiovascular disease.
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