Diabetes are related to the development ofDiabetes are related to the development of

mellitus (DM) is a group of metabolic disorders distinguished by hyperglycemia
resulting from failures in insulin action, insulin secretion, or both. Insulin
is a hormone secreted by the beta cells (?-cells) of the pancreas, which is essential
for utilizing of glucose from digested food as an energy source. The chronic
hyperglycemia of DM is referred to long-term dysfunction, damage and failure of
several organs, especially the kidneys, hearts, nerves, eyes, and blood vessels (ADA, 2014).

     Various pathogenic processes are related
to the development of DM. These range from pancreatic ?-cells autoimmune destruction
with consequent insulin insufficiency and abnormalities in insulin action (ADA, 2014).

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     The first widely accepted classification
of DM was published by World Health Organization (WHO) in 1980. The 1980
Expert Committee proposed two major classes of diabetes mellitus, type 1
diabetes mellitus and type 2 diabetes mellitus (WHO, 1980).




Type 1 Diabetes Mellitus (T1DM):

     This form of diabetes, formerly
called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes,
results from a cellular-mediated autoimmune destruction of the ?-cells of the pancreas.
Onset most often appears in childhood, but it can also develop in adults in
their late 30s and early 40s (ADA, 2014). The mechanisms that lead to ?-cell
destruction are still not completely understood but it is more accepted that
the selective destruction of ?-cell is interposed by cytotoxic T-cells and by certain
cytokines (Graham et al., 2012).


     In this type of diabetes, the rate of ?-cell destruction is widely
variable, being slow in others, mainly adults, and rapid in some individuals, mainly
infants and children (ADA, 2014). Patients with this form often become relied on insulin for survival
and are at risk for ketoacidosis (Willis et al., 1996).


Type 2 Diabetes Mellitus (T2DM):

     This type of diabetes, formerly
known as non-insulin-dependent diabetes mellitus (NIDDM), is an expression used
for persons who have insulin resistance and usually have relative insulin insufficiency.
It usually exists in individuals over 40 and is called adult onset diabetes
mellitus. T2DM frequently goes not diagnosed for many years since the
hyperglycemia appears gradually and at earlier stages is often not severe
enough for the patient to notice any of the classic symptoms of diabetes (ADA, 2014).



     The risk of progressing
this type of diabetes increases with obesity, age, and lack of physical activity
and it exists more frequently in individuals with hypertension or dyslipidemia and
in women with prior gestational diabetes mellitus (GDM) (ADA, 2014). T2DM also requires continuous medical care
and multifactorial risk reduction strategies to normalize blood glucose levels
and prevent or minimize acute and long-term microvascular or macrovascular complica­tions
(DeFronzo et al., 2015).


     Many T2DM individuals need
exogenous insulin in the later stages of the disease since endogenous insulin secretion
becomes insufficient to maintain acceptable levels of glycemia despite ongoing
therapy with other anti-diabetic agents (Ma et al., 2012).


     Although insulin resistance
is considered the initiating event in the pathogenesis of T2DM, pancreatic ?-cell
dysfunction is an indispensable condition for the development of the disease
and hyperglycemia does not become apparent until there is severe ?-cell
dysfunction (Tripathy and Chavez, 2010). Several factors contribute to ??cell dysfunction, including ageing,
genetic abnormali­ties, lipotoxicity, glucotoxicity, insu­lin resistance
leading to ??cell stress and reactive oxygen stress (DeFronzo et al.,






T2DM and Insulin Resistance (IR):

     Insulin is a
pleiotropic hormone secreted from ?-cells of pancreas and has different
functions including enhancing of nutrient transport into cells, modification of
enzymatic activity and regulation of energy homeostasis. These functions of
insulin are done across a variety of insulin target tissues; skeletal muscle, liver
and adipose tissue (Zeyda and Stulnig, 2009).


     In skeletal muscle, insulin enhances glucose
uptake by stimulating translocation of the glucose transporter 4 (GLUT4) to the plasma membrane. In the liver,
insulin inhibits gluconeogenesis
by reducing key enzyme activities resulting in decreasing of hepatic
glucose production. In adipose
tissue, insulin reduces lipolysis thereby decreasing free fatty acid (FFA)
efflux from adipocytes (Zeyda and Stulnig, 2009).


     These metabolic effects of insulin are mediated by a complex
insulin-signaling cascades (Figure 1.1), that is initiated when insulin
binds to its receptor on the cell membrane of target tissues, leading to phosphorylation
and activation of insulin receptor substrate (IRS) proteins that are associated
with the activation of two main signaling pathways: the Ras-mitogen-activated
protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase
(PI3K)-AKT/protein kinase B (PKB) pathway.


     The phosphorylated IRS-1 activates
PI3K which converts phosphatidylinositol 4,5-bisphosphate (PIP2) to
phosphatidylinositol 3,4,5-trisphosphate (PIP3) which thereby activates various
phosphoinositide-dependent protein   kinase 1(PDK1) and recruits Akt to the cell
Ultimately, these signalling events result in
the translocation of GLUT 4 to the plasma membrane, resulting in an increase in
glucose uptake. The MAPK pathways are not implicated in mediating metabolic
actions of insulin but in stimulating mitogenic and growth effects of insulin including
the activation of genes that are involved in cell growth, thereby promoting
inflammation and atherogenesis (Jung and Choi, 2014).


Figure (1.1) Schematic view of insulin signaling pathway in adipose tissue (Jung
and Choi, 2014).

Abbreviations: IRS-1: insulin
receptor substrate, MAPK: mitogen-activated protein kinase, PDK:
phosphoinositide-dependent protein kinase 1, PI3K: phosphatidylinositol
3-kinase, PIP2: phosphatidylinositol 4,5-bisphosphate, PIP3:
phosphatidylinositol 3,4,5-trisphosphate, PKB: protein kinase B, MEK:

mitogen-activated protein/extracellular
signal-regulated kinase kinase.


resistance (IR), a central feature of T2DM, is believed to be the
underlying mechanism for the metabolic syndrome (Guo, 2014). By definition, IR
is an impairment of insulin action which causes the impairment of glucose
uptake in muscle and the increase of endogenous glucose production by the liver
resulting in hyperglycemia (Kim et al., 2008). The defect
in insulin action occurs in multiple tissues, including adipocytes, liver, and
skeletal muscle. In insulin-resistant individuals, insulin-stimulated glucose
disposal is impaired in skeletal muscle due to impaired insulin signaling and
multiple intracellular defects in glucose metabolism. Similar defects in
insulin signaling in the adipocytes and liver have been reported