The numbers of incident of diabetes is increasing worldwide and it becomes the tenth leading cause of death. Diabetes mellitus is the chronic metabolic disorder of carbohydrates, fats and proteins. This usually occur due to beta cell dysfunction and insulin deficiency resulting in hyperglycemia. The increased morbidity and mortality in diabetes is caused by impaired wound healing which is one of the serious complications of diabetes and lead to chronic wounds and limb amputation.
Wound healing is a complex process and it is the restoration of normal tissue architecture.Regulation of metalloproteinases (MMPs) and transforming growth factor-β (TGF-β) play a central role in wound healing. Normal wound healing proccess is the orderly sequences of cells and tissue responces which are arranged into 4 steps. They are homeostasis, inflammation, proliferation and remodelling.
Factors that affected the wound healing in diabetes are over production of TNF-α, growth factor, MMPs, increase apoptosis, excessive degradation of ECM and prolong inflammation. By knowing the mechanism and complications, the morbidity and mortality can be reduced and new theraputic stratigies can be developed.
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The number of incidents of diabetes is increasing worldwide and common among tenth leading cause of death directly or indirectly. Researchers expect that the affected numbers will be projected to double in the next 20 years ( Wild.,2004).
Diabetes mellitus is the chronic metabolic disorder which is characterized by hyperglycemia due to absolute or relative deficiency of insulin or resistance to insulin action. Insulin is required for glucose uptake in skeletal muscle and adipose tissue. When there is abscence of insulin, the metabolism of carbohydrate, proteins and fats are impaired and this lead to siginificant disturbance of water and electrolyte homeostasis.
Diabetes can be classified into type 1 diabetes, type 2 diabetes, other specific types of diabetes like maturity onset of diabetes of the young and the gestational diabetes. Among them, type-1 and type-2 are the major types of diabetes. These two major types of diabetes have different pathogenic mechanism and metabolic characteristics.
Role of insulin, glucose and pancreatic beta cell
Insulin is secreated from beta cells of pancreatic islets. In the beta cells of pancreatic islets, insulin is synthesized and stored in granules before it is secreated. When the blood glucoes level is increased, insulin is released immediately and severed as pro-insulin in endoplasmic reticulum and stored as active form in secretory granules. When the beta cells reach the portal blood flow, the newly released insulin goes to the liver first (Jansson.,1983). In liver, it inhibits hapatic glucose production ( Michael.,et al,2000). Insulin is an major anabolic hormone. It is necessary for transmembrane transport of glucose and amino acids. It indirectly supresses the blood glucose level by decreasing glucagon which transforms glycogen to glucose in liver and skeletal muscles which are mediated by the glucose transporter (GLUT-4). It promotes conversion of glucose to triglycerides and synthesis of protein , glycogen and nucleic acid. It inhibits the activity of hormone sensitive lipase.
Normal blood glucose level plays an important role of in human because glucose is secreated from the liver and it enters into the circulation where it is spplemented by intestinal absorption after meals and glucose uptake by skeletal muscles. For regulation of homeostasis, these mechanisms should be in balance. As glucose is metabolic fuel, a continuous supply of glucose is needed for the brain to function. In a normal person, blood glucose level rises after meals. In this condition, insulin is released and it makes the glucose to normoglycemic levels within an hour. In a diabetes individual, there is an abnormal rise in blood glucose level and it cannot reach normal glucose level. This is because of the absolute lack of pancreatic insulin release or from impaired target tissue response to insulin ,or both.
To secrete insulin, the beta cells depend on changes in membrane potential and variations in blood glucose as they are more active given electrical signals. Two types of iron channels which contain in the beta cells, K+-ATPase channels and L-typed Ca2+ channels which are essential in the process of insulin secretion. Due to high intracellular ADP levels which stimulates the activity in the channel, the K+-ATPase channels are active when glucose concentrations are low. As for L-typed Ca2+channels, they are especially important for exocytosis of granules containing insulin because they mediate the Ca2+ influx to release insulin quickly. The K+-ATPase channel is important to keep up the normal blood glucose concentration. It can be seen in the case of severe hypoglycemia in children with PHHI.
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Dysfunction of beta cell is common in type-2 diabetes patients. These are inadequate action and secreation of insulin in them. The levels of insulin is apparently lower in them than the healthy individuals. Therefore, the lower in insulllin level and inadequate function of beta cells are the key features of diabetes. Moreover, researchers have indicated that insulin secretory defect in type-2 diabetes is the result of impairment of insulin secretion, which is not the result of insufficient beta cell mass. In addition, genetics background, age and obesity are the risk factors like the former is laid on the effects of the latter ones, type-2 diabetes can be resulted.
Types of diabetes mellitus
Type-1 diabetes can be seen in about 10% ot the cases and juvenile onset. It is insulin dependent and previously termed insulin-dependent diabetes mellitus(IDDM). It is an auto immune disease mediated by T-cell. There is also beta cells destruction. The signs and symptoms are fatigue, polyuria, polydipsia, tachycardia, hypotension, hypothermia and loss of weight. Insulin injection is usually given as a treatment. Maintaining of normal blood glucose level delays the onset of secondary complication.
Type-2 is diabetes is about 90%of the cases and maturity onset. It is non-insulin dependent and previously termed non-insulin dependent diabetes mellitus (NIDDM). The risk factors consist of genetics and lifestyle such as obesity, greater longerity, unsatisfactory diet, sedentary lifestlyle and increasing urbanistaion. Type-2 diabetes is more complex than type-1 diabetes because there is a combination of resistance to insulin action in liver and muscle causing the impairment of the pancreatic beta-cell funtion insulin resistance and abnormal insulin secretion. When this happens, there may be hyperinsulinaemia. The symptones are usually dry mouth, polyuria, nacturia, hyperphagia, hypertension and mood changes, fatigye and irratability. The treatments are dietary and/or lifestyle modification, oral anti-diabetic agents and insulin injections.
Maturity onset diabetes of the young (MODY) is a hereditary forms of diabetes caused by mutations in a autosomal dominant gene distrupting insulin production. It is a monogenic disease unlike polygenic type-1 and type-3 diabetes.
Gestational diabetes usually occour during pregnancy characterized by hyperglycemia for the first time. Most of the women suffer this disease in repeated pregnancy and can give rise permenent diabetes.
Complication of diabetes
Nowadays, the morbidity and mortality of diabetes are higher due to the development of complications of diabetes which consist of both macrovascular and microvascular, including impaired wound healing process. This lead to diabetic foot ulcer in 15% of all diabetes patient (Reiber et al 1999) and 84% of the diabetic patients undergoes lower leg amputation (Giurini,2005). Microvasular complications such as peripheral neuorpathy, diabetes retinopathy, diabetes nephropathy and macrovascular complication such as myocardial infarction, stroke and vascular disease occur due to atherosclerosis in cerebral, coronary and peripjeral arteries (Tchaikovski and Waltenberger., 2007) . Diabetic nephropathy occurs due to defective neruonal metabolism and impaired nerve blood flow (Purves.et.al ., 2001). Impaired woind healing is depend upon the inflammatory phase, growth factor production, ECM regulation and tissue remodeling by MMPs (Lobmann et al ., 2002). These complications are arise due to the metabolism of 4 main pathways such as increased polyol pathwau flux, advanced glycation end products (AGEs) , activation of PKC pathway and increased hexoamins pathway flux ( Tchaikovski and Waltenberger ., 2007).
Fingure-1 Complications of Diabetes Mellitus.
Normal wound healing
Wound healing is the restoration of normal tissue architecture. It is a complex process of cells consisting of proliferation, differentian, production of granulation tissue, infammation and tissue remodelling which are regulated by metalloproteinase, cytokines and growth factors ( Singer ., 1999). Presence of hair follicle, diabetes mellitus and oestrogen are the factors that influence wound healing. Normal wound healing takes places in 4 major phases which area arranged into orderly sequences of cell and tissue response ( Whitney., 2005).
Step 1 : Bleeding occurs at hte injury site immediatelyafter the injury. There is platelet aggregation which leads to form blood clot to stop bleeding. Release of cytokines and growth factors in this region trigger an inflammatory response.
Step 2 : After several hours, a scab has formed and cells of the stratum germinatirum are migratin along the edges of the wound. Neutrophils chemotatic substances and macrophages are removing the debris and more of these cells are arriving via the enchanced circulation. Clothing around the edges of the affected are pratically isolates the region.
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Step 3 : One week after the injury, the scab has been undermined by epidermal cells migrating over the meshwork produced bu fibroblast activity. Phagocytic activity around the site has almost ended, and the fibrin clot is disintegrating.
Step 4 : After several weeks, the scab has been shed, and the epidermis is complete. A shallow depressions marks the injury site, but fibroblasts in the dermis continue to create scar tissue that will gradually elevate the overlying epidermis.
Fingure-2 Mechanisms of wound healing in healthy people versus people with diabetes.
Impaired Wound Healing
Impaired wound healing is one of the common and serious complications of diabetes melllitus ( Coffman ; et.at. 1984) and it leads to physical inactivity and later gives rise to chronic wounds and lower leg amputation (Lioupis , 2005). In patients with diabetes mellitus, healing mechanism is characterized by reduced tensile strength of wounds and impaired in matrix production and deposition. In diabetes individuals, peripheral neuropathy which decrease sensory nerve functions, finally give rise to impaired healing ( Ferguson .et al, 1996).
A perisitent inflammatory phase is significant in wounds with diabetes and there is also delay in mature granulation tissue formation ( Jeffcoated , et.al , 2004). In non-healing wound, hyperglycemia which lead to increase the formation of advanced glycation end-products (AGE) plays a role (Goova et.al ., 2001). There are many factors which impaired the wound healing in diabetes. These include impaired growth factor production, prolong inflammatory phase, response to angiogensis, regulation of ECM components and their remodelling by MMPS, increased formation of granulation tissues, function of macrophage which remove the debris and bacteria and bacteria and alteration in fibroblast appotosis (Rai et.al . 2005).
In regulation of ECM, there are 2 major classes of regulators of Ecm which are growth factors and matrix metallo proteinases (MMPs) ( Greenhalgh , 1996).
Growth factors which impaired wound healing in diabetes
In regulating of wound healing, growth factors take part in central role. One of their main function is not to take too much time for inflammatory phase and can enter quickly into phases of formation of granulation tissue. Sometimes in this kinds of woind shows defects in tyoe and amount of growth factors. Among the growth factors, inflammatory growth factors like TNF-β, IL-β and IL-6 can be seen in chronic ulcers and burns and their levels are increased.
Increased neutrophil infiltration and protease activity alteration occur due to the prolonged inflammatory phase result in tissue destruction rathe than repair. In diabetic wound, reduced in growth factors like PDGF and TGF-β are responsible for tissue repair ( Loot et.al , 2002). But in some GF, tissue destruction is due to receptor level and which are not because of the concentration of growth factors ( Goldman , 2004).
There is a complex mechanism between connective tissue growth factor ( CTGF) and TGF-β. Gene expression of CTGF and protein levels are regulated by TGF-β and CTGF stimulates the binding of the receptor, Type-2 TGF-β receptor, to the TGF-β (GoreHyer et al, 2002). During normal woud healing process, TGF-β level is increased and CTGF gene and protein levels are also rise to promote wound healing. But in chronic wound of the diabetes, receptor level falls and cannot undergo gene expression and GF bound to protein macromolecules and fibrin deposition is not happen on the woind ( Falanga , 1993).
MMPs which impaired wound healing in diabetes
To form a mature wound tissue, ECM degradation remodelling should be regulated and maintained in healing process. ECM is mainly degraded by MMPs which are Zinc-dependent endopeptidase. There are 25 MPPs, 24 of which are found in mammals (parks et al., 2004) and 4-sub-divisions. They are collagenases, stromelysin, gelatinase and membrane-type MMPs.
MMPs are expressed at low level in the normal tissue. Its production and activation increases when tissue remodeling is required. MMPs are also important in wound healing in scar resorption and other wound healing responses, such as inflammation and re-epithelialization. Degradation of Ecm components occur almost completely when they act together (Lobomann et.al ., 2002).
MMP 1, 3, 7 and 9 regulates both chemokine activity and establishment of chemotatic gradient during the inflammatory phase. MMP 1, 7, 9 and 10 are required for cell migration. MMPs are also required for cell proliferation during this phase and TIMPs regulates the angiogenesis for the maintenance of granulation tissue. Finally, MMP3 is required for wound contraction.
MMPs action are increased on healing of chronic diabetes wound than acute healing wound upto 30 times ( Wall et.al ., 2002). Not only growth factors but also changes in MMPs level and other protein degrading enzymes can delayed healing process in diabetic ulcers (Armstrong and Jude ., 2002). In diaberic individuals, excessive degradtion of newly formed ECM can be seen due to changes on activation and expression of MMPs ( Trengrove et al , 1999). Persistant increased on MMPs concentration can be seen in diabetic rephropathc ulcer than traumatic wound.
Transforming Growth Factor-β (TGF-β), multifunctional cytokine, plays a central role on wound healing and tissue repair. It increases the MMPs sunthesis and decreasis matrix degadation. Latent TGF-β activates within 1 hour wounding and 2nd wave follows several days later. The realative abundance of TGF-β isoforms is critical to shifting the balance between scarring and scar-free healing of cutaneous wound. In Diabetes, the chronic dermal ulcer shows excessive proteolytic activity and degradation of ECM. Chronic dermal wounds have high MMP-2 and MMP-9. Plasma glucose concentration modulates TGF-β so that in type 2 DM patients have twice the level of circulating TGf-β. There is high incidence of squamous cell carcinoma in chronic leg ulcers.
TNF-α which impaired wound healing in diabetes
For removing the unnessary cells, apoptosis of cells should be undergo in the later phases of healing process ( Ladin et.al ., 1998). In diabetes, there is the over production of TNF-α, which is important for inflammation and immunity, due to increase apoptosis ( Taylor , 2001). In diabetes mouse model, impaired healing in type-2 diabetes is associated with elerated levels of TNF-α ( Goova et.al ., 2001). Decreased tensile strength of wound is due to exogenous TNF-α ( Buck et.al ., 1996) and impariede cutaneous wound healing which cause decrease in production of collagen are duce to chronic rise in level of TNF-α. TNF-α can be seen not only in Type-1 and Type-2 (Uno et.al ., 2007) but also in diabetic complication. For example, TNF-α level is increased on diabetic nephropathy and retinopathy with both types ( Behl et.al ., 2008).
In diabetes, it increased in TNF-α level and decreased fibroblast proliferation, increased apoptosis and activated the apototic transcription factor, forkhead box O1 ( FOXO-1). When TNF-α is inhibited, we can see reverse process like increase in fibroblast proliferation and decrease in apoptosis.
Among the complications of the diabetes, the development of chronic ulcers of the foots becomes one of the serious complications in 15% of the patients and 84% of the diabetics lead to preceed lower leg amputation.
Firstly, blood glucose levels should be control. Giving oral anti-diabetes and insulin injection, chaning lifestyle and diets will delay the onset of secondary complications. As the normal wound healing process can be divided into 4 phase, impaired wound healing is due to prolong inflammation, production of growth factor and cytokines, degradation of ECM and increase fibroblast apoptosis. In addition, decubitus ulcers and venous ulcers also take part in wound healing of diabetes ( Falanga , 1993).
According of types of ulcers, ischemic or neuropathic treatments may be different (Steed et.al ., 2006). The former one, ischemic ulcers are usually painful and results in arterial insuffiency with fainted pulses and later develop to large-vessel occlusion and surgical revasularization is needed (Akbari et.al ., 2000). Neuropathic ulcers are usually painless and occur at the edges or sole of the foot where there is rich blood supplies. It usuallyaffects sensory and autonomic systems. Treatments include reducing foot bearing pressure, wound debridement, proper wound care, antibacterial therapy, good blood glucose control, diet and lifestyle changes( Dinh and Veves, 2006).
Bioengineering and Technology
New technologies like artificial skin grafts, matrix wound dressings and vacuum-assisted closure devices are used to facilitate the wound healing. In neuropathic and non-neuropathic ulcers, Dermagrafts are used to promote the healing process (Hanft , 2002). ECM proteins like collagen are used to make for the matrix woind dressings. To increase wound healing, a bioengineering technique, vacuum-assisted closure (VAC) where the sub-atmospheric pressure is used for dressings of the wound.
For surgical treatment, lengthing of Achilles tendon is one of the effective treatment for wound healing in diabetes and prevent the repeated occurence in patients with foot deformity and limited dorsiflexion ( Mueller et.al ., 2003).
Maggots were used as non-surgical debridement of wounds. After developing modern antibiotics and surgical technique for wound debridement, the use of maggots was reduced.
2. Future Therapies
Growth factors play a role in every steps of wound healing and they are searched from platelets, macrophages, neutrophils, etc. Among the growth factors, the only growth factor which can use as the treatment for diabetic foot ulcers is PDGF, Becaplermin. It is a recombinant human-platelet-derived growth factor. It comes with gel form and used for neuropathic ulcers with rich blood supply. Nowadays, scientists try to develop new treatment using other growth factors like FGF, VEGF, granulocyte colony-stimulating factor and HGF ( Powell et.al ., 2004).
Neuropeptides, gene therapy and cell-base therapies are development of future therapies for the management of chronic non-healing ulcers. In animal models, stem cells therpy is used to test. Injection of CD34+ improve healing in diabetic mouse with active revascularization. ( Sixan-Loukianova et.al , 2003).
To conclude, understanding of the process of wound healing and pathogenesis of diabetes, we can develop the new treatment like gene therapy and cell therapy. As the diabetes is the 10th leading causes of death worldwide, we can know how to prevent the occurance of the disease, complications of the disease and reduced the morbidity and mortality rate. We also know that how to take care of diabetes wound, to reduce the secondary complcation, we can know how to change our lifestyle and diets. Scientsists also try to develop new therapies for the management of chronic non-healing ulcers in diabetes to reduce the morbidity and mortility rate caused by this condition and to become a pleasant world.