Diabetess mellitus is a heterogenous disease characterized by remarkably high degrees of glucose in the blood stream. This common chronic upset is caused by ( 1 ) insulin resistance/inadequate sensitiveness 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 of import 1s are:
Type 1 diabetes mellitus ( T1DM ) : insulin dependant ; this type of diabetes consequences from the organic structure ‘s incapableness to bring forth insulin.
Type 2 diabetes mellitus ( T2DM ) : non-insulin dependant ; this type of diabetes consequences from the failure of the cells to utilize insulin suitably.
Gestational diabetes: occurs among pregnant adult females with no history of diabetes before. It may develop to T2DM.
T2DM is characterized either by low secernment of insulin or the cells ignore the insulin. The faulty sensitiveness of these cells to insulin is believed to affect the insulin receptor. T2DM is one of the most common chronic diseases and is associated with comorbidities, such as fleshiness, high blood pressure, lipemia and cardiovascular disease, which taken together, consist the ‘Metabolic Syndrome ‘ ( Jain and Saraf, 2008 ) . It is a disease with multi-factorial causes affecting the interactions of familial susceptibleness and environmental factors. It consequences from combined defects in insulin secernment from the pancreatic ?-cells and peripheral insulin opposition which is the loss of an appropriate response to insulin at normal degrees ( Ridderstrale et al. , 2008 ) . T2DM is often non diagnosed until complications appear because the effectivity of early diagnosing through showing of symptomless persons has non been established ( Engelgau et al. , 2000 ) . The prevalence of T2DM continues to increase around the universe every bit good as in Malaysia. Harmonizing to the Third National Health and Morbidity Survey 2006 ( 3rd NHMS ) , in Malaysia, the prevalence of the T2DM for grownups aged 30 old ages old and supra now stood at a astonishing 14.9 % . In other words, 1 in every 6 grownups has T2DM.The incidence of T2DM is the highest among Indian ethnic at 19.9 % for those aged 30 old ages and supra. The chronic nature of T2DM seems to do inauspicious blow on the stricken population taking to patient mortality, morbidity and reeling wellness attention costs to the states. Six categories of unwritten agents are now approved by the US Food and Drug Administration for the intervention of T2DM: sulfonylureas and meglitinides ( both secretagogues ) , nateglinitides, biguanides ( Glucophage ) , ?-glucosidase inhibitors ( acarbose and miglitol ) , and thiazolidinediones ( rosiglitazone and pioglitazone ) ( Donner, 2006 ) . One of the major factors that altered the hazard to diabetes susceptibleness and the inefficiency of anti-diabetic drugs in order to keep normal blood glucose degree is the single familial fluctuation.
Symptoms ‘ of T2DM:
Chronic weariness
Excessive piss production
Excessive thirst and increased fluid ingestion
Blurred vision
Itch of external genital organ
Lethargy
Excessive intestine motions
Genetic and acquired factors lending pathogenesis of T2DM
Surveies suggested that T2DM has both familial and environmental constituents and a complex form of heritage ( Zhou et al. , 2005 ) . Familial fluctuation frequently influences cistron look by different mechanisms such as changing rate of written text or splice or transcript stableness ( Schadt et al. , 2003 ) . Harmonizing to American Diabetes Association ( ADA ) , T2DM has a outstanding familial footing than type 1, yet it besides depends more on environmental factors. The conducive familial factors are frequently multiple, interacting with each other and environmental factors in a complex manner.
Hazard factors of T2DM:
Fleshiness
Sedentary life style
Unhealthy eating wonts
Aging
High blood force per unit area and high cholesterin
Family history and familial factors
History of gestational diabetes
ENTER SLIDE BY FUAD
Those with first-degree relations enduring from T2DM have a higher hazard of developing the disease. In general, the hazard of kids with T2DM parents is 1 in 7 if the parents were diagnosed earlier age 50 and 1 in 13 if diagnosed after age 50. Harmonizing to ADA, some scientists believe that a kid ‘s hazard is greater when the parent with T2DM is the female parent. If both parents have T2DM, the kid ‘s hazard is about 1 in 2. Examples of the cistrons that is significantly associated with developing T2DM ; TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX ( Lyssenko et. al. , 2008 ) . KCNJ11 ( K inside rectifying channel, subfamily J, member 11 ) , encodes the islet ATP-sensitive K channel Kir6.2, and TCF7L2 ( written text factor 7-like 2 ) regulates proglucagon cistron look and therefore the production of glucagon-like peptide-1 ( Rother et. al. , 2007 ) . Understanding the familial factors associated with T2DM will supply of import hints to the pathogenesis of type 2 diabetes, therefore, bettering the direction of diabetes in Malaysia.
Emergence of marks
The basic regulation of pharmacological medicine is drug molecule must exercise chemical influence on one or more cellular components to originate pharmacological response. There are four types of regulative proteins that act as drug marks ; enzymes, bearer molecules, ion channels and receptors. Understanding the pathogenesis of T2DM will assist to unleash new and better intervention for this disease.
PTEN cistron encodes a protein known as phosphatase and tensin homolog. The PTEN protein modifies other proteins and fats ( lipoids ) by taking phosphate groups, which consist of three O atoms and one P atom ; an activity that classified the PTEN protein as a type of enzyme called a phosphatase ( hypertext transfer protocol: //ghr.nlm.nih.gov/gene=pten ) . It acts as a tumour suppresser cistron by modulating the rhythm of cell division, maintaining the cells from turning and spliting in an uncontrolled manner. PTEN has besides been proven to dephosphorylate place D-3 of PtdIns 3,4,5-P3 which is an of import 2nd courier involved in insulin and growing histrion signaling. Undeniably, PI 3-kinase activation and subsequent 3 ‘ phosphoinositide formation is required and in some instances, it is adequate to trip 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 fractional monetary units and two beta fractional monetary units linked by disulfide bonds. The alpha ironss are wholly extracellular and house insulin binding spheres, while the linked beta ironss infiltrate through the plasma membrane. When insulin binds to the ?-subunits, it stimulates the tyrosine kinase activity of the ?-subunits, therefore, triping 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 bend alters their activity, thereby bring forthing a biological response. The activated IRkinase transduces the insulin signal by triping tracts 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 tracts ( hypertext transfer protocol: //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 function as docking proteins that interact with signaling molecules incorporating Src homology 2 spheres ( 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 ordinance of many cellular procedures ; cell growing, motility, proliferation and endurance ( hypertext transfer protocol: //www.calbiochem.com/insulin ) . PI 3-kinase activation is required for a figure of insulin stimulated effects, runing from stimulation of glucose conveyance, animal starch synthesis, and membrane ruffling to mitogenesis, although the precise map of phosphatidylinositol ( PtdIns ) merchandises in arousing these responses is presently unknown ( Kotani et. al. , 1995 and Jhun et. al. , 1994 ) . A recent find done by a group of research workers from California found out that adenovirus-mediated look of the 3 ‘ phosphatidyl Inisotol phosphatase, PTEN, in 3T3-L1 adipocytes, significantly inhibits insulin-induced GLUT4 translocation ( 35 % ) , glucose consumption ( 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 excite translocation of GLUT4 glucose transporters to the cell surface, therefore increasing the rate of glucose uptake into musculus 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 attack in the intervention of T2DM
The sympathetic nervous system has several categories of sympathomimetic receptors ( adrenoreceptors ) which can be distinguished pharmacologically. The sympathomimetic receptors ( adrenoreceptors ) are a category of G protein-coupled receptors that uses catecholamines ( neurotransmitters ) , particularly noradrenalin and epinephrine ( hypertext transfer protocol: //en.wikipedia.org/wiki/Adrenergic_receptor ) . There are two households of adrenoreceptors ; ? and ? receptors. ? adrenoreceptors can be subdivided into three subgroups, ?1, ?2 and ?3, based on the affinities for sympathomimetic agonists and adversaries. ?3 is located preponderantly in adipose tissue and is responsible for the ordinance of lipolysis in adipose tissue ( Ferrer-Lorente et. al. , 2005 ) and thermogenesis in skeletal musculus ( Rang 2003 ) . Fleshiness is the major hazard factor for T2DM and cardiovascular disease. Most corpulent people have trouble to command their eating wont by nutrient bottleneck entirely. Therefore by handling fleshiness, the major hazard of T2DM, the hazard of geting T2DM is lessenings. Activation of ?3 sympathomimetic receptors on the surface of adipocytes leads to additions in intracellular camp and stimulation of lipolysis ( Fisher et. al. , 1998 ) . This indicates that the stimulation of ?3 sympathomimetic receptors has the possible to greatly diminish organic structure weight and accordingly, cut down the hazard of diabetes-related complications. However, a study by Elbein et. al. , in 1996 concluded that ?3 adrenergic receptor venue does non play an of import function in T2DM susceptibleness or in the insulin opposition syndrome among members of households with a strong sensitivity to T2DM. With the find of L-755,507, a potent and selective partial agonist for both human and Macaca mulatta ?3 receptors, we now demonstrate that acute exposure of Macaca mulatta monkeys to a ?3 agonist elicits lipolysis and metabolic rate lift, and that chronic exposure additions decoupling protein 1 look in Macaca mulatta brown adipose tissue ( Fisher et. al. , 1998 ) . These informations propose the promise of ?3 agonists in the intervention of human fleshiness, thereby forestalling related unwellnesss such as diabetes and cardiovascular disease.
