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There are many challenges might be faced by human beings day by day. The lifestyle keep changing, the technologies bring up numerous inventions and solutions that assist humans to live much more better than before. Nowadays, scientists show lots of new techniques and used group of mechanisms to solve variety of health defects in people's life. In recent days it has been a special concern in the prevalence of variety of chronic disorders like obesity, diabetes mellitus and cardiovascular diseases. Indeed one of most progressing in science is the discovery of how to treat chronic disorders such as obesity and diabetes mellitus (DM) 1,15. As it been known that the obesity is one of the major health problem in developing countries that resulting because of diet changes and less exercise efforts.
There are two main types of diabetes:- type 1 insulin-dependent diabetes mellitus ( T1DM), and type 2 noninsulin-dependent diabetes mellitus (T2DM) 2.
Type Two diabetes mellitus (T2DM) :-
T2DM known as non-insulin-dependent diabetes mellitus (NIDDM) as well as adultonset diabetes. It occurs because the body does not counter suitably to insulin and cause a combination resistance and insufficient secretion of insulin. T2DM is the most common one in which occur in about 90-95% of all cases of DM.
1.1-The progress of T2DM is occur in different stages:-
The primer stage occurs due to the resistance of insulin as the body do not respond to its secretion even if the insulin do attach normally to the liver and muscles' receptors but special mechanisms avoid the insulin from shifting glucose inside these cells to be used by cells whenever it is needed. However, the majority of individuals with diabetes produce normal or slight high as it eventually that amount is sufficient to tolerate that resistance.
Fig 1: Type two diabetes. After the digestion of food in the stomach, the pancreas produce increase amount of insulin, however, when glucose inter the blood stream and because of the obesity, there is no response for the massive production of insulin, thereby the glucose increase in the blood, and cause diabetes. The image adopted from: http://savvyhealthfitness.com/get-healthy/diabetes/type-2-diabetes-lifestyle-diabetes.
In afterwards stage, the pancreas become not capable to synthesize enough amount of insulin to defeat that fight of resistance as the original consequence of this stage is usually an irregular elevation of glucose level after a meal. Ultimately, elevated level of glucose harms beta cells, thus severely decline production insulin, result in complete diabetes. Therefore, obvious by fasting hyperglycaemia in which high glucose levels are there in the blood.
Fig. 2. Progress of type 2 diabetes: Insulin
resistance in fat/muscle cells and impaired insulin secretion represent
the core defects in type 2 diabetes. ( adopted from http://www.deo.ucsf.edu/types-of-diabetes/type-2.html)
Recently, an increase incidence of a variety of chronic metabolic disorders like obesity, T2DM a risen massively in the individual's life. A half century and over the facts from epidemiological, experimental, and clinical experiments isolates, there is an optimistic relationship among nutritional ingestion with fat source and risk of diseases and yet in a very recent years have been recognized by the researchers in which physical inactive lifestyle open mal-adaptations that leads to chronic illnesses7,56.
Fig 3: The development of obesity and insulin resistance occur due to the response of genes for the insulin resistance as it increased by fat and calories intake with less of excise effort. That elevation due to increase demands of β-cells of the pancreas as these cells if working normally, the more efforts from their side may increase according to the demanded situation of insulin resistance of the body causing a case of compensatory hyperinsulinaemia and the upholding of normal glucose tolerance. However, liable β-cells have a risk of genetically determination in which an arrangement of elevated secretary demand and determine of environmental results in dysfunction and decline of β cells intensity causing a progressive impairment of glucose intolerance. Thereby, T2DM and hepatocyte nuclear factor are the result 54.
There are a lot of clinical conditions and turbulences among insulin resistant hyperglycaemia beside the obesity like disturbances in adiponectin and some of secretion of cytokines by adipocytes, hyperglycaemia parallel among hyperinsulinaemia, dyslipidaemia, mainly assorted through the increase of low density lipoprotiens (LDL) of triglycerides and the reduce amount of high density lipoprotiens (HDL), non-alcoholic fatty liver, arterial hypertension, particularly associated with fatness increase in fibrinogen, disturbances in endothelial cell function, microalbuminuria, conditions by an elevation of C-Reactive Protien (CRP) and of low-grade inflammatory markers 41.
These clinical cases comprise an evidence diagnostic tests so to get a measurable evaluation of insulin resistance by either a metabolic or mathematical procedures of testing and measuring the resistance to insulin indirectly. Finding out a diagnosis of insulin resistance funds a good clue for treatment by controlling individuals' lifestyle habits and the utilization of sensitizers for insulin like tiazolidinediones, acarbose, incretins, or incretin enhancers 42-43.
1.2- How does insulin resistance occur? :-
Insulin as it is known to be a polypeptide hormone produced by the pancreas. Its resistance known as the state in which the body synthesize insulin but can not benefit from it in a proper way. The digestive system made the glucose as a final product and send to the cell via the blood stream ' blood glucose' and that process in known as glucose clearance. The function of the pancreas is to produce insulin to ease taking up the glucose by the cells of the body and use glucose for energy.
Fig 4: Insulin glucose metabolism adopted from: http://www.diabetesdaily.com/wiki/File:Insulin_glucose_metabolism.jpg
When resistance of insulin occurs, the body muscles, fat, and liver hepatocytes do not show a proper response to the insulin and so the body needs massive amount of insulin to ease glucose to pass inside the cells. However, the pancreas produce huge amount of insulin but fails to maintain with the body's requirement of insulin.
Therefore, an increase amount of glucose remains in the blood, and cause diabetes. There are lots of individuals with resistance of insulin have elevated levels of both insulin as well as glucose in the bloodstream at the same period of time.
1.3 - General Features of Insulin Signalling and Control of Metabolic Roles:-
Events from several researches provides essentials actions carried out on phospholipid- signalling methods that used via insulin to initiate variety of protein kinases which founds to be vital in interceding the metabolic effects of insulin. Interestingly, in recent decade more knowledge arising regarding how these lipid-dependant protein kinases roles through the action of insulin and how they fail to operate well in case of insulin resistance5,55.
It is well known that insulin adjusts the blood glucose via the activation of insulin receptor substrat-1 (IRS-1) dependent phosphatidylinositol n3-kinase (PI3K) and that occurs by the elevation of PI-3,4,5- triphosphate (PIP3) and triggers atypical protein kinase C (aPKC) as well as protein kinase B (PKB/AKt) 3. Using the insulin receptors, the insulin is initiated, as these receptors take an action in the phosphorylation of tyrosine residues on IRS-1, IRS-2m Cb1 and other protein signal transducing molecules substances like Pleckstrin homology (PH) and Src homology-2 (SH2) domains 4,5,6,57.
Phosphorylation of tyrosine of the above proteins guides attaching to SH2 domains of the subunit PI3K of p85 and that takes place by activation of the subunit catalytic of the p110 alters PI-4,5-(PO4)2 towards PIP3. Moreover, GRB2 turns on the pathway of extracellular receptor-activated kinase (ERK). At the site of juxtaposition with 3 phosphoinositide-dependent protein kinase-1 (PDK1), the substance of PIP3 motivates the downstream effectors which is responsible for controlling variety of metabolic processing like glucose transporter 4 (Glut4) translocation in the direction of the membrane of the plasma and glucose transport in muscle and adipose tissues where synthesis of glycogen in muscle, adipocytes, and liver. The following figure (fig 5) explains that mechanism.
Fig 5: Insulin signalling in muscle and adipocytes.
In skeletal muscle, IRS-1, via PI3K, controls aPKC and PKB activation. In adipocytes, both IRS-1 and IRS-2, via PI3K, control aPKC and PKB activation. In both muscle and adipocytes, aPKC and PKB stimulates the translocation of Glut4 , the glucose transporters to the plasma membrane. Insulin signalling to IRS-1, PI3K, aPKC, and PKB is impaired in simple obesity and diabetes. Obviousely, the activation of aPKC by PIP3 is impaired in simple obesity and diabetes adopted from: (Rnholm and Zierath, 2005).
The Significance of Diabetes (why diabetes is important?):-
It is vital to detect T2DM in early stages to avoid its major problems and complications that follows later on. T2DM has a silence and asymptomatic period and interferences are there in which an established valuable outcome on clinically meaningful effects and screening procedures -in good extant are secure, satisfactory, sensitive and specific.
Several biological digressions that might create insulin resistance and a non utilization of glucose.
The structure of lipid cell membrane in known to be impermeable to mono-saccharides sugars, therefore, the glucose requires a helper of biological transport structure that has a specialized proteins ease its transportation. Their main job is to supply physiological accord of delivery of glucose to the cell for advance metabolism29-30. Glucose metabolism is a complex process and has to undergo in a multistage in order to be completed so to give the desire energy for the body system. However, this action has to be carried out a long with other specialized regulatory systems. Physiologically, there is a measurable coordination subsists throughout the action of the molecular intracellular glucose transport system (CGT) along with intermediate glucose plasma metabolism. For instance, as discussed earlier, insulin plays the major role in regulation of the this relationship 30-31.
In DM, this regulation and management shut off and the utilization of glucose via the tissues is stopped even though the presence of hyperglycaemia. The major reason for that defect is due to the deficiency of insulin and its resistance 32-33. Therefore, as that disturbances occurs, a shortage of insulin regulatory function on the cells and tissues take place and diminish transport of cellular glucose and its the utilization and cause an abnormalities of the pathway of insulin signalling34-38.
The appearing relationship linking glycaemia and the concentration serum insulin cover the feature of a known changeable. Moreover, the point of the relationship among glycaemia and cellular glucose consumption is independently diverse however, is reserved inside a constricted physiological array in individuals who are healthy 39-40.
2.1- The role of skeletal Muscles in Health and Disease
There is about 55% of skeletal muscles comprise the body mass49, in which they take a part in metabolism of fundamental body energy and substrate proceeds. In fact, in about 80% ,the skeletal muscles known to be an insulin- stimulated glucose uptake in a fit person and that percentage decline to the half in case of insulin- resistance individuals 50. This indicates the significant of the peripheral tissues in the clearance of glucose and specifies that the skeletal muscles are the most vital location of the insulin resistance noticed in case of obesity and T2DM as the skeletal muscles shows a feature of plasticity adjusting to many external sources of stressors like routine level of contractile action and availability of substrates 49. Referring to a surgical techniques in the late of 1960s ease for the researchers to identify the morphological structure of skeletal muscles through the histological and biochemical techniques and interestingly, it has been found that these muscles possess multiple myofibres differs un their contractile features. The myfibers categorized to be slow twitch and fast twitch fibres, and the fast twitch known to be responsible for metabolic potentials especially in sedentary individuals where the activities of oxidative and glycolytic enzymes in majority of fibres is large in a considerable amount to accumulate the metabolism aerobically and non aerobically51. On the other hand, the entire body insulin sensitivity associates with the proportion of slow twitch oxidative fibres, precisely the insulin-stimulated glucose transport that found to be in great amount in skeletal muscle enriched within these slow twitch fibres. Hence the priming muscles increase speed of glucose transport and oxidative metabolism 49. Therefore, the proportion of glycolytic action and the activity of oxidative enzymes in the skeletal muscles in case of T2DM and obese individuals is connected to the confliction of insulin52.
2.2- Treatment for Diabetes.
Looking for treatment for T2DM is one of the essential solutions to stop its complications and adverse progressions. One of the most complications during the treatment of diabetes is hypoglycaemia as it cause a bad adverse effect of diabetes treatment, persuaded by increase exogenous insulin or increase endogenous insulin via the results of treatment with insulin secretagogues11.
The events of hypoglycaemia appears to cause an impaired nutrient liberation to the brain and cause a down regulation of many markers of neuronal plasticity and elevate the quantity of toxicity with neuro- glutamate12-14. Despite that majority of hypoglycemia is mild and self manageable, an extra severity of hypoglycemia may need hospitalization and lead to coma and damage of the brain because of hypoglycaemic effects and this lead to injure of blood-brain barrier integrity14. Moreover, the probable effects of severe hypoglycaemia on the hazard of succeeding dementia have not assessed at a residents height yet.
The morbidity with cardiovascular diseases was more with patients who have T2DM compared with those with no T2DM16-17. Elevation of the rigidity of the arterials showed higher risk of cardiovascular actions in variety of population19-20. Clinical trials shows that changes in lifestyle delayed the development of T2DM21. Moreover, best medical treatment like using β-blocking agents may possibly diminish arterial stiffening22. Involvements of exercise in short term enhances the balance of glucose and insulin sensitivity, thereby improve the stiffness of the arteries that found in young healthy individuals23-25.
In an early studies done by the diabetes control and complications trial research group in 1993, a more standardized valuable result of extensive treatment in patients with diabetes, the thorough treatment dense the attuned danger for the development of serious complications, hence effectively holds-up the inception and deliberates the developments of diabetic retinopathy, nephropathy, and neuropathy15.
Yet, there is no clear picture gives a wide image if a large-arterial elasticity in diabetes patients could be changed. Moreover, an elevated serum liptin might predict-in an independent way the condition of cardiovascular measures27. In addition, the insulin resistance with chronic inflammations may also associated and cause severe arteries' damages. In fact, there is could be a reduction of that risk can be achieved along with an equal chance of atherosclerosis failure and improved diabetics' prospects in those with DM. The long term physical implement effects on arterial stiffness and longer term of exercise involvements can decrease the series rate if patients are welling to enthuse to contribute exercise program28.
2.3- The effect of exercise as a possible treatment for Diabetes:
Diversity of previous evidence of epidemiological, experimental and clinical tracks illustrate a positive relationship between dietary intake with full fat consumption and risk of chronic diseases like DM44. While the Centres for Disease Control in United States a rise a matter in which the inactive style of life without exercise is the definite reason of numerous of chronic diseases 46.In fact, it has been known and considered that controlling diet along with medication is one of the three keystones of therapy for diabetes45. It is very apparent to the researchers that habitual physical exercise is essential for T2DM individuals as this physical movements exercises may give their body the beneficial possessions on metabolic risks factors to avoid any complications due to diabetes in future47. In this comportment, the non-pharmacological character of body actions improves diabetes therapeutically.
Seeing that the most important goals of treatment for diabetes is to diminish hyperglycaemia and accumulation of fats, the chronic hyperglycemia is connected with major long-standing worries like the bad damage to kidneys, nerve, eyes and vessels of blood48.
As the exercise known to be the source of energy production in the muscles when they are contracting. That energy derivative is obtained because of the metabolism of lipids and carbohydrates as the carbohydrates are broken down from muscle glycogen. This broken down and the gaining of the energy are depend upon variety of factors such as pre-exercise controlling diet, the type of muscles' fibres, the time of the practicing exercise, the intensity of exercise and existing of glycogen levels in the muscles. The up-taking of glucose in the skeletal muscles ease a function of liberation and trans-membrane glucose from the intestinal space to the inner parts of the adipocytes. For instance, the exercise intercedes the transportation of glucose by an insulin-like properties as the two of the stimuli elevate glucose transportation by encountering in the definite Glut4 to the membrane of the plasma. Interestingly, while the exercise enhances the transportation of glucose, there is no need for the involvement of insulin signalling. However, there are lot of signalling mechanisms have been projected to relate exercise to intervention of Glut4 translocation. Very clear to the researchers that an increase in the intracellular calcium through the action of depolarization of membrane is a causative factor to initiate the up-take of glucose while the muscles are contacting. Through out the dependent of the persistence of a mechanism that controlled by energy, it has been stated that the transportation of glucose while skeletal muscles are controlled is more dependent on the intensity progress of how regular a stimulation is present55. During the period of exercise, the metabolic tense may be observed, so the glucose transportation may be regulated and maintained. In this circumstance, the 5'-AMP-activated protein kinase (AMPK) has been known to participate in mediating exercise- persuaded muscle transportation of glucose.
2.4- Exercise Provoke an Elevation in Muscle Mitochondria:-
Patience exercise motivate the muscle mitochondria so to be activated biogenically 49. That activation verified by the expression of mitochondrial proteins and that effect is maintained by repetition of exercise as the training develops the competence of the exercise, leading to higher intensities of exercise can be manage for a longer period of time. This lead to a progressive elevation in the mitochondrial muscles and last to a peak where no mitochondrial muscles stimulated by the physical exercise.
An increase of muscles mitochondria results in elevation of exercise capability and endurance by dropping off the homeostasis disturbance during sub-maximal exercise. This caused by dipping of the ATP, creatine phosphate and glycogen and slight elevation of Adenosine monophosphate (AMP), inorganic phosphate and lactate on a specified intensity of submaximal exercise49. Interestingly, the dysfunction of mitochondrial role has been correlated with T2DM and insulin resistance, hence that dysfunction direct to a diminution in the volume of lipids essential for oxidation, therefore, allowing the building up of fatty acids along with other metabolites in skeletal muscles53. Moreover, in case of T2DM individuals there is less mitochondria (about 30% less than the normal) present in their muscles comparing with those who are sensitive to insulin, and that is related to the obesity they suffer from which cause the insulin-resistance syndrome49.
2.5- Rule of AMPK Activity:-
AMPK plays a vital detector role of cellular vigour charge. The main impression of it is that the system of AMPK guards humans cells through the action of arising an alarm when low energetic fuel source system is detected. Thereby, during the activation, AMPK cut off the consumption of ATP anabolic rotes and switches on the production of ATP catabolic routes. That action occur by phosphorylation of involvement of a wide range of enzymes and by the action of gene expression55.
There are two main catalytic AMPK subunits known: the α1 isoform that is widely allocated in many tissues of the body and the α2 isoform which is known to be the primary articulated in skeletal muscles, liver and heart.
The maintenance of AMPK action occurs by different ways (see fig 6). The master initiation activity of AMPK is takes place because of an elevation of AMP/ATP rate plus a decline in the phosphocreatine/creatine rate.
Via AMPK kinases (AMPKKs), AMPK is activated by the action of phosphorylation on Thr172 of the α catalytic subunit.
Fig 6: AMPK activity is controlled by allosteric features plus through phosphorylation and dephosphorylation of AMPK via the AMPKK upstream as well as phosphatase [probably the protein phosphatase 2C (PP2C)], correspondingly55. AMPK plays a role in activation of both AMPKK and AMPK, however, the action of strapping of AMP to AMPK creates AMPK as a more potent substrate of AMPKK and a week one for PP2C. for instance, the level of glycogen inside the muscles could slow down the action of AMPKK as well as AMPK in low possibility, in spite of that it cannot be disqualified that the cause of glycogen is minor to the earlier time of glucose submerging within the cell. The action of activating and inhibiting features of AMPK are shown by arrow and black ovals in that order, while the dotted lines shows that the possibility outcomes on AMPK in which is not fully clarifies 55.
As same as AMPK, the AMPKK initiated by AMP, however, there isn't any regulation of it by phosphocreatine. When AMP is bind to AMPK, that results in holding up of the enzyme a more reliable substrate for AMPKK, as well as a poorer and undependable substrate foe suppression of protein phosphatises.
Glycogen for instance can play a role in regulation of AMPK in skeletal muscles. In crease level of glycogen inside the muscles may arise via exercise or even by controlling diet. And possibly prior exercise. That lead to association with low initial and slimming down of 5 -amino-4-imidazolecarboxamide-riboside (AICAR)- stimulated-α2AMPK activity in compression with skeletal mussels when there is less or standard glycogen level. Vitally, this glycogen effects on the AMPK is independent of any variations in the concentration of the adenine nucleotide as furthermore noticed in case of regulators of AMPK like metformin and hyperosmolarity55.