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The Journal of Diabetic Foot Complications The Journal of Diabetic Foot Complications, 2012; Volume 4, Issue 2, No. Diabetes mellitus (DM) is a global epidemic, and diabetic foot ulcer (DFU) is one of its most serious and costly complications.
Diabetic foot infection (DFI) treatment accounts for up to one-quarter of all diabetic admissions in both Europe and the United States making it the single most common reason for DM-related hospital admission 6.
Recognizing this predictable progression, the solution includes developing structured screening tools to identify those at risk and implementing both standardized education and prevention protocols. Diabetic peripheral neuropathy results from degenerative changes of axons and affects all nerve fibers, but at different times.
The first notion to consider is that vascular disease of the diabetic foot always results from tight and obliterative atherosclerosis in the large limb vessels and not from, as is most commonly believed, microvascular disease 21.
Once the protective layer of skin is broken, the deep tissues are exposed to bacterial colonization 28.
Staphylococcus aureus and ß-hemolytic streptococci are the first microorganisms to colonize and acutely infect breaks in the skin.
Assuming that the qualitative microbiology remains constant, the probability of wound infection increases as the microbial load increases to a critical level.
All of these complex interactions have been systematized by the wound infection continuum 34.
In the acute wound setting, once the protective barrier is broken, the physiologic process of healing is immediately set in motion (Figure 3). In this classic model 35 wound healing is divided into three sequential but overlapping phases: (1) the inflammatory phase, (2) the proliferative phase (re-epithelialization, granulation, and neo-angiogenesis), and (3) the remodeling phase (extracellular matrix remodeling). The inflammatory phase starts with injury-related subendothelial collagen-mediated platelet activation. The proliferation phase begins at 72 hours, as recruited fibroblasts migrate inward from the wound margins over the fibrin matrix established during the inflammatory phase.
Chronic wounds are wounds that, following the orderly and timely repair process, fail to establish a sustained anatomic and functional result 39. Recognizing important risk factors and making a logical treatment-oriented assessment of DFIs requires a consistent and thorough diagnostic approach. Based on the present literature 25,44, the presence of both pulses in the foot, in combination with the absence of intermittent claudication, renders significant PAD unlikely. Although the PEDIS classification system suggests the use of toe pressures or TcPO2 to exclude clinically relevant vascular disease 44, the complexity and cost of its use precludes its generalized application outside of clinical studies.
The International Working Group on the Diabetic Foot has proposed consensus criteria 55 for diagnosing diabetic foot osteomyelitis (Table 1) that remain to be validated in a properly designed trial.
In the absence of suspected osteomyelitis, bacteriological sampling, which must be done after mechanical debridement and cleansing of the wound with gauze soaked in sterile physiological saline, is indicated if a DFI ≥ Grade 2 is clinically confirmed. Although research continues to improve wound-healing modalities and show promising options for the future, the importance of prevention cannot be overemphasized. When treating a DFI, the multidisciplinary team must consider the need for hospitalization, prioritize the treatment and drainage of any invasive infection, and perform limited debridement if necrosis is present. When used after adequate debridement in a well-vascularized bed, NPWT prepares the wound for closure by secondary intention or skin graft. Hospitalization is the first decision to make regarding patients with a DFI, and determining its necessity requires considering many aspects. Invasive infection drainage should be the first-line treatment for all ulcers, especially those associated with abscesses complicated by compartmental syndrome, extensive necrosis, or necrotizing cellulitis. If the lesion is healing and the patient is tolerating the empirical regimen, then there may be no reason to change, even if some or all of the isolated organisms are resistant to the agents used.
Other factors that must be taken into account when selecting an antibiotic regimen are the route of administration (oral vs.
The presence of bone infection substantially alters the approach to therapy, but there are no validated or well-accepted guidelines for treating diabetic foot osteomyelitis 29,60. In the case of critical ischemia, once the infection has been controlled, revascularization must be immediately considered.
Drainage and debridement (surgical, mechanical, sharp, etc.) are two different but complementary surgical procedures. The presence of clotted vessels, stringy fascia, or tendon indicates that the tissue is not viable and should be removed and shaved down to shiny hard tendon or fascia.
Wet-to-dry dressings, hydrotherapy, biotherapy, and other topical debriding agents provide alternative options to surgical debridement. NPWT includes a family of devices consisting of specialized dressings, including adhesive drape and open-cell foam, cut to fill the wound defect and capable of transmitting constant or intermittent pressure throughout the wound using a feedback control mechanism. Excessive physiopathological exudate in DFIs can be detrimental because it contains an imbalance of matrix metalloproteases (MMPs) and their inhibitors (TIMPs).
Several subsequent studies have demonstrated NPWT’s effectiveness in DFIs, particularly to treat osteomyelitis and soft tissue infections 65,91-93, when used in conjunction with adequate debridement and appropriate antibiotics. No intervention is likely to be successful if the wound is not protected against external trauma; therefore, complete and permanent off-loading of the wound must be ensured as strictly as possible. Slideshare uses cookies to improve functionality and performance, and to provide you with relevant advertising. AbstractType 2 diabetes is a serious and common chronic disease resulting from a complex inheritance-environment interaction along with other risk factors such as obesity and sedentary lifestyle. T2DM patients are more susceptible to different forms of both short- and long-term complications. Statistically, about 50% of people with diabetes remain undiagnosed and approximately 20-30% patients usually have already developed complications before being diagnosed [157]. T2DM and its related complications impose heavy health burdens worldwide and there have been not effective measures to fully cope with the diseases.
Preventing disease and detecting disease early, if it occurs, are important to living a healthy life.
In a study of middle-aged and older people with type 2 diabetes, declines in thinking and memory that are often linked to later dementia happened faster in those who were depressed compared to those who were not.
Both diabetes and depression have been found to raise the risk of Alzheimer’s disease and other forms of dementia later in life.
More than one-quarter of Americans older than age 65 have diabetes, according to the Centers for Disease Control and Prevention. To assess the role of depression in cognitive decline among older diabetes patients, Sullivan’s team looked at data on nearly 3,000 people over age 55 with type 2 diabetes and risk factors for cardiovascular events.
Tests of cognitive abilities were given to all participants at the study’s beginning, and again at 20 months and 40 months.
Researchers determined whether an individual was depressed using a 9-question form patients filled out themselves.
Yet, the researchers report in JAMA Psychiatry, depression was linked to greater cognitive decline regardless of other risk factors.
He and Sullivan both cautioned, however, that the role of depression in cognitive decline may be complex. Depression itself is associated with increases in stress hormones, inflammation and other processes that could directly contribute to cognitive decline, Sullivan said. One implication of this study, Nathanson said, is that primary care physicians would do well to pay attention to and treat depression in people with chronic illnesses like diabetes.
Main Outcomes and Measures  Mixed-effects statistical models were used to analyze cognitive test outcomes incorporating depression as a time-dependent covariate.
Conclusions and Relevance  Depression in patients with type 2 diabetes was associated with greater cognitive decline in all domains, across all treatment arms, and in all participant subgroups assessed. A Pragmatist's Guide for LivingIt's easy to make a financial decision based on what you need right now, but making an informed choice will benefit you in the long run.
The study looked at the effects of consuming an almond-enriched diet as it relates to the progression of type 2 diabetes and cardiovascular disease in adults with pre-diabetes. The Diet: The study population was randomly divided into either the group consuming almonds or the control group. Overall, this study suggests that consuming an ADA-recommended diet consisting of 20% of the total calories from almonds for 16 weeks is effective in improving LDL cholesterol levels and measures of insulin sensitivity in individuals with pre-diabetes.(4) Nutrients in almonds, such as fiber and unsaturated fat, have been shown to help maintain healthy cholesterol levels and increase insulin sensitivity, both of which help to prevent the development of type 2 diabetes and reduce the risk of cardiovascular disease. There are an estimated 171 million diabetic patients worldwide and this number is expected to double by the year 20301. In the longer term, costs are even higher as DFUs have recurrence rates of up to 70% in centers of excellence, resulting in repeated interventions and progressive disability7.
Different countries and healthcare systems have implemented such approaches to diabetic foot care, some with reported success 4 and others with reported failure 8.
This is true even though, in some cases, the wound may have closed over before DFI presentation 9.Numerous observational studies have indicated that DFUs have a multifactorial nature. The non-myelinated autonomic nerve fibers are affected first, resulting in autosympathectomy with consequent medial artery calcification (Mönckeberg calcification), microvascular thermoregulatory dysfunction, and arteriovenous shunting 16. This confusion results from the theoretical conclusion that diabetic multifactorial microvascular insufficiency applies to the foot; however, even the almost universal basal membrane thickening is not likely to be present in the foot capillaries 22. Qualitative and quantitative aspects of wound microbiology are critical determinants of the wound outcome (Figure 2). Chronic wounds develop a more complex polymicrobial microbiology, including aerobic Gram-negative rods and anaerobes. This concept describes the effects of increasing bacteria quantity and diversity in wound tissue, and their relationship to the quality of the host’s immune response. Wound healing is divided into three sequential but overlapping phases: (1) the inflammatory phase, (2) the proliferative phase (re-epithelialization, granulation, and neoangiogenesis), and (3) the remodeling phase (extracellular matrix remodeling). This complexly orchestrated biochemical cascade is characterized by signature events and cells, and their molecular regulators 36. Initially stimulated by bFGF and PDGF, fibroblasts begin to synthesize and deposit extracellular matrix (ECM) components (the provisional matrix).
The current thinking is that imbalances exist in the molecular environment of these chronic nonhealing wounds.
Although it was not developed as a guide for daily management or to predict the outcome of an individual patient, it considers all the potentially useful information obtained from the clinical history, foot examination and diagnostic exams.
The presence of both pulses in the foot, in combination with the absence of intermittent claudication, renders significant PAD unlikely.
On the contrary, if one or two pulses are absent, clinically relevant PAD is more likely; however, pulses can be absent because of edema, making additional objective vascular assessment necessary to exclude PAD or to grade it if it is present 46.
When used in clinical practice, the formal revascularization decision is based on information from previous clinical tests and duplex ultrasonography (B mode, color flow, and spectral Doppler analysis) 48.
Loss of protective sensation in the affected foot is defined as absent light pressure sensation at two out of three sites on the plantar side of the foot (plantar aspect of hallux, first metatarsal, and fifth metatarsal), as described in the International Consensus on the Diabetic Foot 15. The size could be evaluated using a precise technique (planimetry or grid technique), however, this is not always possible in clinical practice. These scans are more sensitive but rather nonspecific, especially in neuropathic patients 10. Bacteriological sampling is indicated if a diabetic foot infection (DFI) corresponding to PEDIS Grades ≥2 has been clinically confirmed. However, it should be noted that many of these tests lack the ability to provide a definitive diagnosis, and clinical correlation is always required. The clinically predictable progression from DFU to DFI, present in 85% of amputation cases 63, highlights the importance of implementing an integrated, standardized prevention and treatment protocol. The multidisciplinary team must consider draining invasive infections, debriding necrosis, and promptly starting empirical antibiotic therapy, followed by complete and appropriate vascular reconstruction. The assessment of vascular supply adequacy as well as a complete and appropriate vascular reconstruction follows. A wound that fails to improve within 2 to 4 weeks should prompt the clinician to consider alternative and adjunctive therapies (assuming appropriate attention to debridement, infection, ischemia, offloading, and nutritional status).
Patients with severe infection (Grade 4), deep wounds, suspected bone and joint involvement, and severe ischemia (gangrene) should be hospitalized.
Randomized clinical trials have shown that systemic antibiotics (including the most recently available agents) are of clinical value in DFI 10,66 and, as in the majority of infectious diseases, they must be provided as early as possible.
When culture and sensitivity results are available, these should be considered to select a narrower-spectrum antibiotic therapy and complete the course of therapy. This is well illustrated by the Sidestep study 69, in which a favorable clinical response to ertapenem was noticed in patients in whom Enteroccus spp. Classically, bone resection in chronic osteomyelitis was considered essential to a cure 60.
Ideally, revascularization should be done at the same time as the formal debridement procedure. Soft, grey bone is necrotic and should be resected to reveal clean, hard bone with punctuated bleeding at the surface.
Unfortunately, they are less definitive and controllable, require prolonged and repeated applications, and delay the application of other therapies 82. NPWT has proven its effectiveness in various diabetic foot wounds in several randomized, controlled studies 83-85; however, most of these studies have not addressed the preoperative infectious status, and few have addressed the use of NPWT in DFI.
NPWT increases the diffusion gradients, which facilitates the removal of excess interstitial fluid and infectious materials and improves blood flow as well as consequent metabolic waste evacuation.
A new strategy to amplify the bioburden control using a modified NPWT system with an infusion port to intermittently instill antimicrobial agents has been developed 94, but it has not been properly investigated in the clinical setting. Many types of devices can off-load the infected wound, but it is important to choose one that permits easy inspection. Lab of Molecular Immunology, Zhejiang Provincial Center for Disease Control and Prevention, 3399 Binsheng Road, Hangzhou, 310051, China;2.
Risk Factors Contributing to Type 2 Diabetes and Recent Advances in the Treatment and Prevention.
Type 2 diabetes and its complications constitute a major worldwide public health problem, affecting almost all populations in both developed and developing countries with high rates of diabetes-related morbidity and mortality. There are two primary forms of diabetes, insulin-dependent diabetes mellitus (type 1 diabetes mellitus, T1DM) and non-insulin-dependent diabetes mellitus (type 2 diabetes mellitus, T2DM). Analysis of recent statistical data reveals that T2DM has several new epidemiological characteristics. Genetic component: Although we have not completely elucidated the pathophysiology of T2DM so far, it is the case that the disease has a major genetic component.
As shown in Figure 2, the complications include macrovascular diseases (hypertension, hyperlipidemia, heart attacks, coronary artery disease, strokes, cerebral vascular disease, and peripheral vascular disease), microvascular diseases (retinopathy, nephropathy, and neuropathy) and cancers.Cardiovascular disease. Biguanides: Biguanides are one of the major classes of antidiabetic drugs, among which metformin is the most common drug used in the first line therapy for diabetes mellitus [91]. When T2DM patients cannot be well controlled by lifestyle and single oral antidiabetic drugs, it may be necessary to consider combination therapy with two or more antidiabetic drugs such as a thiazolidinedione plus metformin or a dipeptidyl peptidase-4 (DPP-4) inhibitor plus metformin [115, 116].
An alternative screening approach is thus urgently required for the earlier diagnose of T2DM. Nowadays, physical inactivity has been considered as one of the biggest public health problems worldwide [176]. The main cause of the diabetes epidemic is the interaction between genetic and environmental risk. Mark Sullivan, professor of psychiatry at the University of Washington and lead author of the study, told Reuters Health in an email. An estimated 6.5 million Americans in this age group suffer from depression, according to the National Alliance for Mental Illness.
One test measured psychomotor speed, or how long it takes the brain to register a stimulus, process it and respond. These included age, gender, race, obesity, smoking, alcohol use, previous cardiovascular events, as well the types of diabetes and heart disease medications the participants were taking. Mark Nathanson, director of the geriatric psychiatry fellowship at Columbia College of Physicians and Surgeons in New York, who was not involved in the study.
But the array of other diseases that often go along with diabetes may also harm cognition and promote depression. Depression might be an early symptom of vascular disease in the brain, which later develops into dementia.
Future randomized trials will be necessary to determine if depression treatment can lower the risk of cognitive decline in patients with diabetes. After 16 weeks of consuming either an almond-enriched or regular diet, both of which conformed with American Diabetes Association (ADA) recommendations, the group that consumed an almond-enriched diet showed significantly improved LDL cholesterol levels and measures of insulin sensitivity, risk factors for heart disease and type 2 diabetes.
However, it adds a new dimension to the existing research because it shows almond consumption not only aids in disease management, but may also help reduce the risk  of certain chronic diseases. Once the protective layer of skin is broken, deep tissues are exposed to bacterial infection that progresses rapidly. It is well established that insulin deficiency (absolute or relative) is the basis of the biochemical abnormalities that lead to the organic complications of diabetes mellitus 12 (namely, neuropathy) and the biological deficits of tissue healing and regeneration. Neuropathy (with alterations in motor, sensation, and autonomic functions) plays the central role and causes ulcerations due to trauma or excessive pressure in a deformed foot without protective sensibility.
Mönckeberg calcification, unlike atherosclerosis, does not reduce the arterial internal diameter. DM is associated with a near 3-fold increased risk of accelerated atherosclerosis, which is histologically identical to that seen in the non-diabetic population 23. Chronic wounds develop a more complex polymicrobial microbiota, including aerobic Gram-negative rods and anaerobes.
Gram-negative bacilli, mainly Enterobacteriaceae, are found in many patients with chronic or previously treated infections, and Pseudomonas aeruginosa is specifically associated with wounds treated with wet dressings 29. In complex extremity wounds, this critical level has been established by Breidenbach et al. This complexly orchestrated biochemical cascade is characterized by signature events and cells, and their molecular regulators. In recent years, the scientific study of wound healing has progressed greatly making it impossible to summarize all the current knowledge in this article.
This initially results in vasoconstriction and the formation of a fibrin clot, which becomes the pathway for cellular influx and the primary foundation for collagen deposition 37. ECM is composed of fibrinous elements (collagen, elastin and structural glycoproteins) and glycosaminoglycans (chondroitin sulfate, hyaluronic acid and dermatan sulfate), which attract large amounts of water and sodium collagen.
Although classically described at the end of the proliferative phase, it actually begins concurrently with the formation of the granulation tissue and continues until the tissue reaches maturation. That is, when the scales are tipped towards high levels of MMPs and proinflammatory cytokines along with senescent cells, there is a low mitogenic activity that invariably results in chronicity 40.
Various systems have been proposed to classify DFUs, but none have gained widespread acceptance. Consequently, the use of this systematic examination ensures that important aspects are not overlooked. The ultrasonographic exam is a good, noninvasive method for delineating the peripheral arteries and enables the distinction of high-flow functional arteriopathy.
The properly calibrated 10-gram monofilament is an objective and simple instrument used to screen the diabetic foot for loss of protective sensation and has shown to be a significant and independent predictor of likely lower extremity amputations in the diabetic population 50.
Instead, wound size and depth can be estimated by multiplying the largest diameter by the perpendicular largest diameter 44. Further qualitative definitions of clinical interest should also be considered: cellulitis (infection of the subdermis), necrotizing cellulitis (infection-related tissue necrosis of the subdermis and dermis), necrotizing fasciitis (infection with involvement of the superficial fascia, presenting as sloughing of the skin and a violaceous color of the integument, without pus or abscess), wet gangrene (infection associated with blackish necrotic tissues), and osteomyelitis (infection of the bone). The initial imaging studies should be plain radiographs, as they often show characteristic pathological findings in established cases. Combining bone scans with other scintigraphic techniques, such as white blood cell scans (Indium-111 leukocyte scans or other variations), improves specificity, although these tests are rarely used because they are expensive and time consuming 59.
While tissue biopsy and fluid aspirate are considered the gold standard for diagnosing wound infection 28, such invasive tests are infrequently performed for superficial wounds or in many practice settings, such as outpatient clinics, due to concerns about enlarging the ulcer or inducing pain 28,62.
Mechanical debridement and wound cleansing with gauze soaked in sterile physiological saline must precede sampling. In this disease-management program, prevention strategies should be delivered by family physicians and diabetologists using structured screening tools at defined intervals, with high-risk patients referred to multidisciplinary foot care teams for treatment.
A biomechanically sound surgical reconstruction, with or without amputation, must be considered part of the treatment plan to minimize the risk of recurrent ulceration.
They often may require surgical intervention (debridement, drainage, bone resection, or possibly urgent revascularization), fluid resuscitation, and metabolic derangement regulation through strict glycemic control (usually using insulin therapy). However, as authoritative guidelines emphasize 10,11 and a recent systematic review confirms 67, no particular antimicrobial regimen has been shown to be superior to others in DFI treatment. If the lesion is healing and the patient is tolerating the empirical regimen, there may be no reason to change, even if some or all of the isolated organisms are resistant to the agents used.
The parenteral route should be used for severe infections, in the neuroischemic foot, when the agents used cannot be administered orally, or when the patient’s state is incompatible with oral therapy. This routine, however, has recently been disputed 72 because radical surgical solutions (such as transmetatarsal amputations) may result in altered biomechanics, with a consequent higher risk of reulceration. In other cases, revascularization can be deferred and proposed secondarily, especially in cases of delayed healing. This surgical procedure is particularly important in deep infections of the plantar surface of the foot, where infection spreads through the tendon sheaths of the toe flexor muscles located in the compartment between the superficial fascia and the arch of the foot. Debridement should be performed as soon as possible, bearing in mind that in neuroischemic ulcers, formal debridement other than drainage of infection should only be performed after or during revascularization procedures. Be that as it may, recent physiopathological and clinical evidence justifies its use as a useful adjunct to the management of DFIs 65. Whether NPWT actually reduces the bacterial load is debatable, however, its clinical effectiveness in DFIs has been demonstrated.
In DFIs, there are no contraindications to NPWT, but special care should be taken to cover exposed blood vessels, prosthesis, or bone with natural tissues or several layers of fine-meshed, non-adherent synthetic material 64. NPWT should be applied immediately after the revascularization procedure and formal debridement, while the patient is in the operating room.

In inpatients, either bed rest or wheelchair use (keeping the affected leg horizontal) is preferred 10,11. Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310014, China;3.
T2DM is the most common form of DM, which accounts for 90% to 95% of all diabetic patients [1] and is expected to increase to 439 million by 2030 [2]. Firstly, diabetes keeps a steady increase in developed countries, such as United States and Japan. Higher concordance rates are found among monozygotic (96%) than dizygotic (DZ) twins in some [11, 12] but not all [13] twin studies, which has been a compelling evidence of a significant genetic component in T2DM.
Meanwhile, many of these loci are also therapeutic targets for the extensively used pharmaceuticals of T2DM, for example, KCNJ11 and PPARG2 are targets of sulphonylurea and thiazolidinedione classes of drugs widely used for the treatment of T2DM, respectively [36, 37].
Cardiovascular disease is a primary cause of mortality and morbidity in both prediabetes and T2DM, the potential mechanism for which is oxidative stress that has important effects on atherogenesis and may contribute to low-density lipoprotein (LDL) oxidation [76]. Metformin has been proven to be efficacious in lowering blood glucose, increasing insulin sensitivity, reducing cardiovascular [92] and hypoglycemia risk [93], and is the only hypoglycemic agent to improve macrovascular outcomes [94] and to reduce mortality rates in T2DM patients [95].
At present, a variety of risk assessment tools based on selfassessed, biochemical measures or genetic markers have been developed for the prediction of T2DM, which are more practical and valuable than conventional blood glucose screening test, so that interventions can be applied to those with impaired glucose tolerance to delay the onset of T2DM.Prediction models with noninvasive measures.
It is demonstrated that physical activity may contribute to 30-50% reduction in the development of T2DM [177].
Maintaining or improving your health is important - and a focus on regular preventive care, along with following the advice of your doctor, can help you stay healthy. Eighteen percent were depressed at the start of the study, 16 to 17 percent were depressed at 20 and 40 months and five percent had scores indicating depression at all three time points. Addition of demographic and clinical covariates to models did not significantly change the cognitive decline associated with depression. Patients with DFUs frequently require amputations of the lower limbs and, in more than half the cases, infection is the preponderant factor.
A DFU is any full-thickness wound below the ankle in a diabetic patient, irrespective of duration. 9, however, even with the best of preventive care, 9% of patients with DM will still develop a DFI, with the consequent risk of amputation.
It has also been established that perfect and persistent glycemic control, with either insulin or oral agents, stop 13 and probably regress 14 these complications. Once the protective layer of skin is broken, deep tissues are exposed to bacterial colonization. Noninvasive flow studies 17 have demonstrated a hyperperfusion of the foot, especially of the deep tissues, while transcutaneous oxygen pressure (TcPO2) measurements have shown a relative epidermal ischemia as a result of the microvascular dysfunction and arteriovenous shunting 18. This underlines the importance of identifying and aggressively managing associated vascular risk factors, such as obesity, cigarette smoking, dyslipidemia, hypertension, and sedentary behavior 24. Intrinsic traumas are also easily understood as they result from foot deformities (foot drop, equinus, hammertoes, and prominent plantar metatarsal heads) and consequent altered foot biomechanics 4. Consequently, we will only describe the process of wound healing to the degree necessary for the clinician to apply this basic science to selecting treatment interventions and understanding their expected outcomes.
Vasoconstriction also promotes a hypoxic and acidotic wound space (secondary to anaerobic metabolism), which stimulates vascular endothelial growth factor (VEGF) release and fibroblast infiltration 38.
In diabetic wounds, a persistent inflammatory phase is commonly witnessed at histopathology, which is associated with a delay in the formation of mature granulation tissue and a reduction in wound tensile strength 41. The International Working Group of the Diabetic Foot developed the PEDIS classification system 44, which presents internationally applicable guidelines that can reliably predict the outcome of diabetic foot management 45. If a possible revascularization is considered, intra-arterial digital subtraction angiography is conducted to properly visualize the arteries of the feet and evaluate the feasibility of revascularization 49.
The PEDIS classification system considers the use of a 128-Hz tuning fork applied to the dorsum of the hallux at the base of the proximal phalanx to evaluate the presence or absence of vibration sensation.
To definitively categorize the patient into one of these groups different diagnostic procedures are indicated.
However, because they are relatively insensitive in the first two weeks, additional imaging studies may be necessary.
Plain radiographs should be the initial imaging study, because in established cases, they often show characteristic pathological findings (cortical erosion, periosteal reaction, and mixed lucency and sclerosis). Superficial swabbing of the wound is discouraged, but swabbing the base of the ulcer is acceptable if it is the only possible option 11. Tissue biopsy and fluid aspirate are considered the gold standard for diagnosing wound infection, but deep swabbing of the wound is acceptable in special circumstances. Even when using these well-defined interfaces, less than 20% of patients are referred to specialized diabetic foot clinics 64. Superficial ulcers without residual ischemia can usually be treated on an outpatient basis. Superficial ulcers without residual ischemia can usually be treated on an outpatient basis with repeated debridement, off-loading, and oral antibiotics. The initial empirical antibiotic therapy in DFIs should aim to cover the most common pathogens and should be based on the known epidemiology of DFIs. On the other hand, if the infection is not responding then the treatment should be changed to cover all of the isolated organisms. This may be due to either the disruption of microbial synergy or the differential importance of individual virulence potential.
In all other cases, outpatient oral therapy is recommended, provided that regular medical follow-up can be ensured. Published nonrandomized case series on nonsurgical treatment with a prolonged (3 to 6 months) course of antibiotics have reported clinical success in 65% to 80% of cases 10,73. In these later cases, the criterion for revascularization should consider the patient’s status performance, the potential for cicatrization, the site of the lesions, and the quality of the arterial distal runoff.
This compartment serves as a non-expandable box, resulting in a compartment syndrome that leads to ischemia and tissue necrosis. Finally, but importantly, a number of studies 65,95,96 suggest that adding NPWT as part of a wound management strategy results in shortened hospital stays and a higher percentage of limb salvage, with consequent decreased overall medical costs.
For the first 2 or 3 days, a continuous suction mode of 125 mmHg should be used and the dressing should be changed every 12 to 24 hours, at which time the wound should be carefully evaluated for any residual necrotic material and subsequent debridement should be performed, if appropriate 64,97. According to a meta-analysis 98, G-CSF treatment might reduce the duration of hospitalization, the risk of lower-limb amputation, and other infection-related invasive intervention, but it does not appear to have a significant effect on the duration of intravenous antibiotic treatment, the resolution of infection, or the rate of wound healing. Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan. Multiple risk factors of diabetes, delayed diagnosis until micro- and macro-vascular complications arise, life-threatening complications, failure of the current therapies, and financial costs for the treatment of this disease, make it necessary to develop new efficient therapy strategies and appropriate prevention measures for the control of type 2 diabetes.
And it is worthy of note that T2DM has become a serious issue at an alarming rate in developing countries. Prevention of premature cardiovascular events involves complex interactive treatments with antihypertensives, lipid-lowering agents, and routine low-dose aspirin administration [77].Diabetic neuropathy. The glucose-lowering effect of metformin is mainly through reducing hepatic glucose output such as gluconeogenesis and glycogenolysis, and increasing insulin-stimulated glucose uptake and glycogenesis in skeletal muscle [96]. Insulin, the most effective anti-hyperglycemic agent, was discovered by Banting and Best in 1921. Physical activity interventions can improve glucose tolerance and reduce the risk of T2DM [178], because it simply help achieve weight loss [179]. Whereas most antidiabetic agents have shown beneficial effects when used as monotherapy or combination therapy, they are also associated with negative effects, such as weight gain, hypoglycemia, gastrointestinal effects or cardiovascular disease. A third test measured executive functioning, or how the brain uses memories to plan actions, pay attention and inhibit inappropriate behavior.
Given the challenges of treating these complex infections, this paper aims to provide a hospital-based framework for the diagnosis and treatment of diabetic foot infections (DFIs). Based on current studies, the annual population-based incidence is 1 to 4% with a prevalence of 4 to 10%, and the estimated lifetime risk is 25% 2. This partial failure of prevention strategies supports the need to develop a framework for diagnosing and treating patients with suspected DFIs. DFUs result from a complex interaction of two major risk factors: neuropathy and peripheral vascular disease.
Infection is facilitated by DM-related immunological deficits, especially in terms of neutrophils, and rapidly progresses to the deep tissues. The major difference in the diabetic population is the distribution of disease, which tends to be symmetrical with a more distal (tibio-peroneal) involvement and a predominance of long segment occlusions and calcification 25.
These foot deformities result from the atrophy induced by motor neuropathy of the foot’s intrinsic muscles. There are exceptions to this rule of thumb, however, as various organisms have different intrinsic virulence potentials.
In the second stage of the inflammatory phase, leukocytes attracted by chemotaxis, supplant platelets as the dominant cell type. This new microenvironment, with ECM-embedded fibroblasts coated with a layer of fibronectin, constitutes the scaffolding for the subsequent neo-angiogenesis and re-epithelization.
Collagenase and other MMPs degrade Type III collagen, and Type I collagen fibrils are then laid down parallel to the wound lines of tension in an organized fashion, with strong cross-linking and bundle construction, replacing the lost tissue with an increased tensile strength 35.
Continuous bacterial infection 42 and increased advanced glycation end-product (AGE) formation 43 limit the cytokine (mainly TGF-ß)-mediated switch to the later granulation tissue formation phase. Thus, in clinical practice, the formal revascularization decision is based on information from previous clinical tests and duplex ultrasonography (B mode, color flow and spectral Doppler analysis). Unfortunately, because of the arterial media calcification observed in up to one-third of diabetic patients, this technique has limited usefulness in this special population 47. Magnetic resonance (MR) angiography and computed tomography (CT) angiography, performed without direct arterial injection and without iodinated contrast agent injection for MR angiography, can be alternatives to classic arteriography, especially for distal and calcified lesions.
Although both tests have similar sensitivities for evaluating protective sensation loss, and combining modalities appears to increase specificity 51, we consider that, for practical purposes, the 128-Hz tuning fork should be reserved for clarifying equivocal results on the Semmes-Weinstein 10-gram monofilament test in DFI cases.
All patients should have a complete blood count with differential, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) testing and, ideally, procalcitonin (PCT) testing. Magnetic resonance (MR) imaging, which has a very high sensitivity for bone and deep soft-tissue infections, is preferred to nuclear medicine scans.
However, they are relatively insensitive, particularly in the first two weeks after infection when no changes are frequently found. Independent of the sampling method, specimens must be placed in transport medium and be sent to the microbiology laboratory as quickly as possible. Microbiologists and clinicians working in close collaboration must interpret the results, while taking into consideration the collection conditions, transport time, transport conditions, and the type of bacteria isolated.
When a DFI patient presents to the care team, a multidisciplinary management strategy should be rapidly implemented (Figure 7). In other ulcers, formal debridement should be completed and, as accumulating evidence indicates, negative pressure wound therapy (NPWT) should be included in the treatment pathway 65. They should subsequently be refined according to initial response and elements of the patient assessment 29. If the infection is worsening despite susceptibility of the isolated microorganisms, the fastidious organisms may have been missed on culture and a revised debridement should be conducted. On the other hand, if the infection is not responding then treatment should be changed to cover all the isolated organisms.
The optimal duration of antibiotic therapy has not been clearly established, but it could be 1 to 2 weeks for simple forms and 2 to 4 weeks for moderate to severe forms of skin and soft tissue infections. While optimal therapy requires obtaining bone for culture, initial empirical therapy should virtually always cover Staphylococcus aureus, which causes most infections.
The current revascularization options for the DM patient include conventional open surgery and endovascular interventions, which are not mutually exclusive and are often combined. Once the infection is controlled and the wound is stable, the suction mode should be changed to an intermittent cycle of 5 minutes on and 2 minutes off.
As there is insufficient evidence to recommend a specific wound dressing or any type of wound healing agent for DFIs, we agree with the National Institute of Health and Clinical Excellence (NICE) guidelines 11 that advise the multidisciplinary team to consider their clinical assessment of the wound, the patient’s preference, clinical circumstances, and acquisition cost. Systemic HBOT has also been proposed, as infection and ischemia are considered the two main indications for this procedure. Herein, we summarize our current understanding about the epidemiology of type 2 diabetes, the roles of genes, lifestyle and other factors contributing to rapid increase in the incidence of type 2 diabetes.
T2DM mostly results from the interaction among genetic, environmental and other risk factors. It is predicted that T2DM will continue to increase in the next twenty years, and more than 70% of the patients will appear in developing countries, with the majority of them being 45-64 years old [7]. The susceptibility loci of T2DM have been discovered by genome-wide association studies (GWAS) since early 2007 [15-21]. We thus need to expand our current biological knowledge to completely understand and control T2DM.Lifestyle factor correlation. Diabetic neuropathy may be associated with foot ulcers, amputations, non-healing skin wounds, and sexual dysfunction [12]. In addition, it is demonstrated that metformin has important roles in activating AMP-activated protein kinase (AMPK) which acts on the expression of hepatic gluconeogenic genes [97] and decreasing progression of impaired glucose tolerance in T2DM patients [98].
FINDRISC (Finnish Diabetes Risk Score) questionnaire, the most commonly used method [160], is designed to self-assess the risk on the basis of seven questions, which has a good validity in the prediction of future diabetes onset over a 10-year period [158].
With increasing incidence of T2DM, searching an ideal therapy becomes one of the top priorities in combating this disease. According to a study published by the Eurodiale study group 3, approximately 58% of DFU patients will become clinically infected. This assumes special importance in DFIs that require hospitalization, as strategies have proven efficacy in reducing morbidity, mortality, psychological distress, and financial costs10.
Neuropathy, both symmetric and bilateral, plays the main role with varying degrees of alterations in autonomic, sensory, and motor functions.
When femoral disease is present, it tends to be diffuse with no single dominant focal lesion 23.
Anaerobes are rarely the sole pathogen, but they often participate in a mixed infection with aerobes, especially in cases of deep tissue infection 30.
A good example is ß-hemolytic streptococci which is able to induce tissue damage at 102 CFU per gram of tissue, while greater counts of less pathogenic organisms may be of little clinical significance 32. Neutrophils are the first to begin bactericidal activities, using inflammatory mediators and oxygen free-radical metabolites. Initially directed by fibroblasts that express keratinocyte growth factor-2 (KGF-2) and interleukin-6 (IL-6), and later by nitric oxide (NO) and IL-6 self-expression, keratinocytes at the wound edges migrate laterally along the basal membrane and both proliferate and differentiate to produce the epidermis 36. This results in prolonged inflammation and increased neutrophil infiltration with consequent protease activity. The complexity and cost of toe pressure or TcpO2 use precludes their generalized application outside clinical studies. On the other hand, more complex techniques, such as systolic toe-pressure measurement or TcPO2, were better predictors of healing in several studies 25. The cause and severity gradation of protective sensory loss are difficult to evaluate and do not provide clinically useful information 15, consequently, they are not considered necessary. However, caution must be exercised when interpreting laboratory tests, as no marker is sufficiently sensitive and specific to confirm the diagnosis of DFI and tests are often misleading, even in the case of severe lesions 19. The gold standard for diagnosing osteomyelitis remains histopathology of a positive culture from a properly obtained bone specimen. Furthermore, they are nonspecific, because they do not permit the differential diagnosis of noninfectious neuro-osteoarthropathy 58.
Despite its high cost, this imaging test has gained wide acceptance in the management of patients with DFI 60, as it can also be used for surgical planning.
Assuming that there are no completely reliable microbiological methods to distinguish between pathogenic and nonpathogenic microorganisms at the present time, microbiologists and clinicians must collaborate closely to interpret the results. As previously described, evidence suggests that this reduces the incidence of major amputation.
Accumulating evidence also suggests that negative pressure wound therapy (NPWT) should be included in the treatment pathway. The severity of infection is essential in determining the appropriate antibiotic regimen 10.
If the infection is worsening despite the isolated microorganisms’ susceptibility, the possibility that fastidious organisms were missed on culture should be taken in account and a revision of debridement should be done. Cost is also an important consideration, and antibiotic therapy should proceed as indicated by the clinical situation and severity of the infection, with the lowest cost. The traditional recommendations of initial parenteral therapy may be outdated by the introduction of newer agents with excellent oral bioavailability 29.
Open surgical techniques include endarterectomy for local lesions and peripheral bypass for long occlusions. 87 showed that NPWT use resulted in enhanced granulation tissue formation with improved bacterial clearance compared with control dressings.
The dressings should then be changed every 24 to 48 hours, as this has been shown to increase blood flow and improve granulation 86. Its use was recently analyzed in a systematic review 99 of five RCTs in which it was associated with a reduction in major amputations, but not in minor amputations or time to heal.
Furthermore, loss of first-phase of insulin release, abnormal pulsatility of basal insulin secretion, and increased glucagon secretion also accelerate the development of T2DM [4, 5].
Then, numerous GWAS conducted in different countries and ethnic groups have reported linkage signals at the same or different chromosomes with T2DM, and have successfully identified approximately 75 susceptibility loci related to T2DM.
A wide variety of lifestyle factors are also of great importance to the development of T2DM, such as sedentary lifestyle [38], physical inactivity [39], smoking [40] and alcohol consumption [41]. The neuropathy results in loss of protective sensation in the feet, which leads to callous formation, ulceration and other injury, and may also result in the infection of the skin (e.g. It is worthy of note that metformin should be used cautiously in elderly diabetic patients owing to the concern of lactic acidosis, gastrointestinal (GI) effects such as nausea, vomiting diarrhea and flatulence, the reduction of calorie intake, and weight loss. Insulin therapy can provide effective glycemic control even when oral antidiabetic medicines are inadequate, and can improve many of the metabolic abnormalities in T2DM patients. The other approach is based on the data which are routinely available to the general practitioner, for example, the CRS or the QDScore® (ClinRisk, Leeds, UK) [161-163]. To date, several therapeutic strategies have been developed, such as the use of SGLT2 inhibitors, DPP-4 inhibitors and GPR40 agonists.
We stress the need for a clinical diagnosis of DFIs and the importance of microbiological evaluation for antibiotic therapy guidance. Patients with DM frequently require minor or major amputations of the lower limbs (15 to 27%) and in more than 50% of cases, infection is the preponderant factor 4. Despite the publication of different clinical guidelines for DFI management, there is still practical variation in inpatient management 10,11. Playing a secondary role is peripheral vascular disease resulting from atherosclerosis (Figure 1).
Contrary to the classical conceptualization, it is of the utmost importance to recognize that most diabetic persons have adequate circulation necessary for a cure 17.
These mixed infections provide an optimal opportunity for microbial synergy, which increases the net pathogenic effect and hence the severity of infection 28.
A third critical factor is the efficacy of the host’s immune response in dealing with wound microflora. As these begin to wane, circulating monocytes, attracted by TGF-ß and PDGF, enter the wound and mature into tissue macrophages. In turn, keratinocytes direct neo-angiogenesis at the wound edge by expressing VEGF, which is upregulated by NO. In these patients, the most sensible sign of infection is often recalcitrant hyperglycemia despite regular anti-hyperglycemic regimens. Newer techniques, such as positron emission tomography (PET) scans, appear promising, but their role is as yet undefined 61. They must also take into account the collection conditions transport time, transport conditions, and the type of bacteria isolated. Assuming that debridement, infection, ischemia, offloading, and nutritional status are addressed, a wound that fails to improve within 2 to 4 weeks should prompt the clinician to consider alternative and adjunctive therapies.
Patients with mild infections who have not previously received antibiotic therapy usually have an infection caused by only one or two species of bacteria 68, and an antibiotic regimen should almost always include an agent active against Staphylococcus aureus and Streptococcus spp.
Understanding these basic principles behind choosing an antibiotic regimen is more important than knowing particular antibiotic regimens, and each hospital should have epidemiology-based antibiotic guidelines for DFI management. For bypass surgery, a single segment of the greater saphenous vein is the best conduit, although acceptable results have been obtained with prosthetic grafts that do not cross the knee 74. The debridement process involves physically excising necrotic material and debris until normal tissue appears, thus enabling wound healing and removing a reservoir of potential pathogens 79.
In other studies 88, NPWT reduced the bacterial count to 104 to 106 per gram of tissue within 4 to 5 days.
Although T2DM patients are generally independent of exogenous insulin, they may need it when blood glucose levels are not well controlled with diet alone or with oral hypoglycemic drugs. Secondly, although advancing age is a risk factor for T2DM, rising rates of childhood obesity have resulted in T2DM becoming more common in children, teenagers and adolescents, which is a serious emerging of the epidemic and a new public health problem of significant proportions [10]. Substantial epidemiological studies have shown that obesity is the most important risk factor for T2DM, which may influence the development of insulin resistance and disease progression [42]. The mechanism underlying the reduction of glucose concentrations by insulin is mainly through suppressing hepatic glucose production, increasing postprandial glucose utilization, and improving abnormal lipoprotein composition. Researches have demonstrated that noninvasive screening tools are more cost-effective than a blood test as a first stage screening, and risk scores show good sensitivity and specificity for the identification of prevalence or incident of impaired glucose regulation or T2DM [164].Prediction models including biochemical measure.
It is widely advocated to keep a daily step, which is an effective self-regulatory strategy to successfully promote increased physical activity. Above all, stem cell educator therapy opened avenues to develop new therapeutic strategies in the treatment of T2DM, with safety and high therapeutic efficacy. Regarding treatment, we propose a multidisciplinary approach prioritizing invasive infection drainage, necrosis debridement, and the prompt start of empirical antibiotic therapy, followed by complete and appropriate vascular reconstruction.

Major amputation is associated with significant morbidity and mortality (ranging from 13 to 40% at 1 year to 39 to 80% at 5 years 2) in addition to immense social, psychological, and financial consequences 5. This paper aims to provide a hospital-based framework for the diagnosis and treatment of DFIs, based on a pathophysiological approach.
In this time frame, in which autonomic dysfunction dominates, there is clinically a pathophysiologically resultant hot and turgid foot. Accordingly, the composition of the polymicrobial wound flora is likely to be more important than the presence of specific pathogens.
In DFUs, infection is facilitated by intrinsic immunological deficits, especially in terms of neutrophil dysfunction. These cells debride the wound on a microscopic level and produce cytokines necessary for the proliferative stage 36.
The vasodilation induced by NO also aids in the movement of inflammatory cells to the site of injury. In our clinical experience, CRP has proven to be a good test in the diagnosis and follow up of serious DFIs. The criterion gold standard for diagnosing osteomyelitis is a characteristic histopathology (acute or chronic inflammatory cells, or necrosis) associated with a positive culture from a properly obtained bone specimen ideally obtained at the time of surgical debridement or by fluoroscopic- or computed tomography-guided percutaneous biopsy 55. These professionals should also have access to other specialist services such as those provided by vascular surgeons and orthopedists 11. A biomechanically sound reconstruction, with or without amputation, should be part of the treatment plan to minimize the risk of recurrent ulceration. Long-term results are good, with 5-year secondary patency rates >70% and limb salvage rates of 75 to 85% 75. 10 that only additional randomized clinical trials can establish protocols for using these expensive and limited resources to treat DFIs. In addition, people with T2DM are often accompanied by complications, such as cardiovascular diseases, diabetic neuropathy, nephropathy, and retinopathy. Nearly 90% of diabetic patients develop T2DM mostly relating to excess body weight according to the World Health Organization (WHO, 2011).
They remain effective until they reach their targets when used alone or combined with other anti-hyperglycemic drugs [1], but they are dependent on the presence of enough β cells with sufficient functional reserve.
Moreover, insulin therapy can improve insulin sensitivity and β-cell secretary function by the reduction of hyperglycemia, thus decreasing or eliminating the effects of glucose toxicity. Biochemical testing plays an essential role in the identification of individuals with high risk for developing T2DM [165, 166]. For people who have difficulty in walking because of joint problems, other forms of physical activity, for example, cycling, swimming or gym-based activities, should be encouraged.Healthy eating. For severe DFIs, we suggest that negative pressure wound therapy (NPWT) be included in the treatment pathway. Signs or symptoms of vascular compromise are observed in 40 to 50% of all patients with the vast majority having neuroischemic ulcers, and only a minority of patients have purely ischemic ulcers 15.
In comparison, culture results from associated soft tissue wounds or sinus tracts do not reliably correlate with those taken from bone 60. Long-standing or severe DFIs need extended coverage to include commonly isolated Gram-negative bacilli, Enterococcus spp., and anaerobes. Although it’s not currently advisable for most clinically infected chronic wounds, it may have a role in specific circumstances 70. 89 showed that despite the clear beneficial effects of NPWT, bacterial colonization increased significantly within the range of 104 to 106 per gram of tissue during prolonged therapy.
If these treatments fail or are not considered, amputation remains the only option in cases of severe infection, especially in the neuroischemic foot. Diabetes and its associated complications lower the quality of people's lives and generate enormous economic and social burdens [6].
Sexual dysfunction usually occurs in young-aged diabetic patients because of oxidative stress in cavernous tissues [78].Diabetic nephropathy.
The major acute adverse reaction of sulphonylureas is higher rate of hypoglycemia [101], especially in older adults with impaired renal function, hepatic dysfunction, and those with poor oral intake, or alcohol abuse, or caloric restriction and so on [102]. Diabetes prevention studies have demonstrated that diet composition is another important factor to prevent the development of T2DM. Sensory neuropathy begins with poorly tolerated tactile allodynia and thermal hyperalgesia. Recognizing the insensibility of classical signs and laboratory tests for the diagnosis of DFI and that various factors suggest the presence of DFI in the absence of these classical signs 53, Lipsky et al.
The application of any topical antibiotic should always be preceded by formal debridement and may be considered for a properly managed wound with subclinical infection that is failing to heal or to help in the removal of biofilms, which have been implicated in persistent infections 71. This treatment modality has a number of advantages over bypass surgery, particularly its low morbidity and mortality rate. Diabetic nephropathy is one of the most important microvascular complications, whose earliest manifestation is the presence of minute amounts of urinary protein (microalbumin) which can not be detected in routine urinalysis, but is detectable by specific testing.
Sulphonylurea-induced hypoglycemia may be exacerbated by interaction with a variety of drugs, such as aspirin, oxidase inhibitors, and phenylbutazone [1]. Insulin has four injectable forms, including rapid acting, short acting, intermediate acting and long acting, among which the long acting forms are least likely to cause hypoglycemia.Insulin analogues have different pharmacokinetic profiles, compared to that of regular insulin, and their onset and duration of action range from rapid to prolonged. Epidemiological studies have suggested that the risk of diabetes can be increased or decreased owing to dietary factors. Scientific evidence suggests, but does not prove, that eating 1.5 ounces per day of most nuts, such as almonds, as part of a diet low in saturated fat and cholesterol may reduce the risk of heart disease.
It is our hope that this protocol will improve the hospital management of DFIs and, ultimately, the prognosis of DFI patients. As progressively thicker myelinated fibers are affected this progresses to an objective loss of sensation and proprioceptive dysfunction 20.
However, the restenosis rate is relatively high, especially in below-the-knee procedures for which it is as high as 50% over a 5-year period 76.
They should implement the technique that best matches their specialist expertise and clinical experience, the patient’s preference, and the site of the ulcer 11. 90, in which NPWT was compared with conventional moist dressing therapy and did not significantly decrease the total bacterial load. If the detection can be done in the earlier phase, the progression of nephropathy can be prevented. At present, rapid-acting insulin analogues (insulin lispro and insulin aspart) and long-acting insulin analogues (insulin glargine and detemir) are available [118]. The dietary factors which may increase the diabetes risk are consuming excessive amounts of refined grains, sugar-sweetened beverages, red and processed meat and alcohol, and those with the opposite effects are the intake of whole-grain cereal, vegetables, dairy, legumes, nuts, independently of body weight change [181-183].A large number of prevention studies concerning dietary factors have been conducted in many countries during the past several years.
Motor neuropathy results from the axonal degeneration of the large motor myelinated fibers.
Since the main goal for patients with DFI is to obtain sufficient perfusion to control the infection and save the limb, this is significant since this temporary improvement of perfusion can be sufficient enough to promote healing and avoid amputation. Efforts should be made to only remove dead tissue, while preserving as much other viable tissue as possible. There were qualitative differences, however, with nonfermentative Gram-negative bacilli showing a significant reduction and Staphylococcus aureus showing a significant increase.
Several studies have indicated that OSA in T2DM patients is much more prevalent (36%-60%) than in the general population [47, 48].In addition, diet is considered as a modifiable risk factor for T2DM. This is, however, frequently overlooked because of the unawareness that the routine urinalysis lacks sensitivity in detecting microalbuminuria [77].Diabetic retinopath. Long-acting insulin analogues can provide a prolonged duration of action and reduce the risk of hypoglycaemic events, especially nocturnal events [119].When lifestyle changes and oral antidiabetic agents fail to achieve adequate glycemic control in T2DM patients, it is generally required for the patients to initiate insulin therapy.
Among them, triglyceride and high density lipoprotein cholesterol can be easily obtained in clinical practice and can slightly increase the predictive value.
Studies from China, Japan and India aimed at examining the effects of reducing fat, refined carbohydrates and alcohol and increasing fibre intake on the development of T2DM [184-186].
This causes anterior crural muscle atrophy or intrinsic muscle wasting, which leads to foot deformities and consequent altered foot biomechanics with foot pressure redistribution 19. However, it takes up to 28 days after endovascular intervention for the new blood flow to have maximal effect at the wound’s edge, whereas this time frame is reduced to 4 to 10 days after bypass surgery 77. Sharp debridement with a scalpel, scissors, or tissue nippers is the conventional procedure; however, to minimize damage to normal tissue, which sometimes occurs with normal surgical sharp debridement techniques, alternative debridement with a hydrosurgical water knife may be used 81.
This suggests that bacterial burden reduction may occur within the first 4 to 5 days, making subsequent therapy effective in decreasing wound size. Studies have shown that a low-fiber diet with a high glycemic index is positively associated with a higher risk of T2DM [49], and specific dietary fatty acids may affect insulin resistance and the risk of diabetes in varying degrees [50].
The retina is the most vascular region in the body, as it needs high oxygen to convert light into electrical energy in the rods and cones. Numerous reviews introduced the effectiveness of combination therapy with insulin and oral antidiabetic agents in T2DM patients [120, 121]. In particular, fasting plasma glucose can obviously improve the predictive value based on noninvasive measures.Some novel biochemical markers include C-reactive protein, liver enzymes and so on. The Finnish Diabetes Prevention Study (DPS) advocated decreasing total and saturated fat intake and increasing fibre density in the diet [187].
As the disease progresses, the foot becomes clinically insensitive and possibly deformed (claw toes, hammertoes, prominent metatarsal heads, etc.). The results of recent studies 78 indicate that endovascular therapy might take a prominent place in the treatment of PAD, especially in patients with significant comorbidities, and this applies even more to patients with DFI.
In all of the procedures, serial thin slices of tissue should be removed until normal tissue appears.
This was also seen in the first large prospective and randomized study of NPWT use in the treatment of complex clean diabetic foot wounds 83. Total and saturated fat intake is associated with an increased risk of T2DM independently of BMI, but higher intake of linoleic acid has the opposite effect, especially among leaner and younger men [51]. The TZDs have more durable action to regulate hyperglycemia than sulfonylureas and metformin, and do not increase the risk of hypoglycemia when used as monotherapy [1]. In the European Prospective Investigation into Cancer and Nutrition-Potsdam (EPIC-Potsdam) Study, C-reactive protein has not shown added prognostic information beyond the extended prediction model, whereas liver enzymes with concentrations of blood lipids can obviously improve prediction beyond the noninvasive parameters and measures of glycemia [170]. In the Diabetes Prevention Program (DPP), dietary goals were to reduce total fat and energy intake [188]. Antiplatelet therapy should begin preoperatively and continue after an endovascular or surgical procedure 25. Frequent consumption of processed meat, but not other meats, may increase the risk of T2DM after adjustment for BMI, prior weight change, and alcohol and energy intake [51]. In fact, dysglycemia often occurs earlier than the diagnosis of diabetes patients, because nearly 20% of newly diagnosed diabetes patients show evidence of retinopathy [79].Cancers.
TZDs are efficacious in combined therapy with other classes of antidiabetic agents, especially in combination with insulin to reduce the high insulin dosage and improve glycemic control in T2DM [1].
Besides, a risk score from Taiwan shows that white blood cell count can also improve prediction, although the accuracy of the derived score is low [171].Prediction models involving genetic maker.
Soft drinks have also been bounded up with increased risk of T2DM [52] and metabolic syndrome [53], because they are directly associated with BMI [54].Gut metagenome correlation.
Epidemiologic evidence has demonstrated that diabetes may elevate the risk of cancer such as colorectal cancer [80], liver cancer [81], bladder cancer [82], breast cancer [83], kidney cancer [84], which varies depending on the subsites of specific cancers.
Moreover, preliminary clinical studies have demonstrated that TZDs and metformin, two different classes of drugs, can be used together to cooperatively lower blood glucose activity [1].
Although oral antidiabetic agents and insulin are currently used for the treatment of T2DM and have brought about promising outcomes, problems still exist such as inadequate efficacy and adverse effects. A large number of genetic variants have been investigated for the prediction value of T2DM [172, 173], and they marginally improved prediction beyond noninvasive characteristics in those studies. In some recent studies, gut metagenome was shown to be a factor for the development of T2DM [55]. Mechanisms underlying the association of T2DM with cancer risk are as follows: firstly, T2DM and cancers usually share many risk factors such as age, obesity, sedentary lifestyle, smoking, higher intake of saturated fats and refined carbohydrates, and some psychology factors [85]. However, TZDs exhibit several negative effects in the treatment for T2DM, including an increased risk of bladder cancer [105], weight gain and fluid retention leading to edema.
Because the accuracy of prediction relies on many factors such as the number of genes involved, the frequency of the risk alleles, and the risks correlated with the genotypes [174, 175], many additional common variants with small effect sizes or rare variants with stronger effect sizes must be further identified. It has been shown that behavior change interventions can prevent or delay the development of T2DM for people with high risk [190]. Different kinds of gut bacteria may play different roles in maintaining or interacting with their environment.
Even though pioglitazone is well tolerated in the treatment of elderly patients with renal impairment and does not cause hypoglycemia, its use should be avoided in older patients with congestive or class III-IV heart failure. They have been shown to be effective in reducing HbA1c, fasting plasma glucose (FPG), systolic blood pressure, bodyweight, as well as hyperglycaemia [125]. It is always a time-consuming and painstaking project to identify novel diabetes genes by GWAS, which requires many cases for sufficient statistical power to ensure a very modest increase in risk of each risk allele. For instance, the DPS and DPP demonstrated that changes in diet or physical activity could reduce the diabetes incidence by almost 60% in 4 years [98, 191]. Two-stage metagenome-wide association study (MGWAS) suggested that T2DM patients show a moderate degree of gut microbial dysbiosis, with various butyrate-producing bacteria being decreased (Clostridiales sp. Meanwhile, it might promote carcinogenesis directly [86] as it may promote the proliferation of colonic tumors in vitro and in experimental animals [87]. Dapagliflozin, one of the most advanced SGLT2 inhibitors, has been confirmed effective either as monotherapy [126] or as add-on therapy with metformin [127] and insulin [128].
Even though these have been done successfully, it still needs to consider how the information can be provided to patients and whether it will encourage people to adopt healthy lifestyles and medical interventions. Vermunt group took behavior change techniques including motivational interviewing, filling out decisional balance sheets, goal setting, developing action plans, barrier identification, relapse prevention [192].
Besides, hyperinsulinemia may increase the level of IGF-1 which has mitogenic and antiapoptotic actions on cancer cells [88], and the plasma or serum level of IGF-1 is also positively correlated with the risk of cancers [89, 90]. They inhibit intestinal mucosal enzyme (α-glucosidase) which converts complex polysaccharides into monosaccharides, thus decreasing carbohydrate absorption. Adverse effects observed in the treatment of T2DM patients with dapagliflozin include genital infections and the occurrence of breast and bladder cancer [129]. However, barriers existed for the achievement of lifestyle change, one of which is continuity. A study showed that seven of the T2DM-enriched KEGG orthologues markers were associated with oxidative stress resistance, including nitric oxide reductase (K02448), putative iron-dependent peroxidase (K07223), cytochrome c peroxidase (K00428), catalase (K03781), peroxiredoxin (K03386), Mn-containing catalase (K07217), and glutathione reductase (NADPH) (K00383), which were not seen in control-enriched KEGG orthologues markers [58]. Voglibose can significantly improve glucose tolerance [108] and acarbose (precose) would reduce the risk of cardiovascular diseases such as acute myocardial infarction in T2DM [109]. For the weight loss and dietary improvement, it is considerably difficult to resist temptation to snacks, which needs to seek good techniques to control internal and external stimuli [193]. In addition, it was found that 14 KEGG orthologues markers, which were markedly up-regulated in T2DM patients, were related to drug resistance. Side effects such as abdominal bloating, diarrhea and flatulence are always observed after the use of this class of drugs. They are effective in the protection of pancreatic β cells and promotion of normal glucagon secretion, thus inhibiting the progression of T2DM. Examples for the stimulus control are encouraging people to avoid cues for snacks storage [193] and to engage in social support [194, 195].
DPP-4 inhibitors are well tolerated because they play pivotal roles in cardiovascular protection and anti-arteriosclerotic action, with few gastrointestinal side effects and weight neutrality [131]. We can also identify future high-risk situations through monitoring psychological causes and habitual behavior.Obesity management. They are secreted from intestinal endocrine cells, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1).
Obesity is one of the most important risk factors for T2DM, whose basic cause is an imbalance between energy intake and expenditure [196]. Incretin-based therapy is ideal for T2DM management because of its efficacy, good tolerability, low risk of hypoglycemia, and weight loss [111]. A recent research shows that vitamin D deficiency may have negative effects on glucose intolerance, insulin secretion and T2DM [62], either directly via vitamin D receptor (VDR) activation or indirectly via calcemic hormones and also via inflammation [63, 64]. GLP-1 receptor agonists are effective in the regulation of glucose metabolism, such as stimulating insulin production, inhibiting glucagon release, slowing nutrient absorption, and increasing feelings of satiety [94]. Lixisenatide can activate the GLP-1 receptor, thus contributing to increasing insulin secretion, inhibition of glucagon secretion and decreasing gastrointestinal motility to promote satiety [136]. WHO has identified several lifestyle-improving factors to avoid obesity risk, including increased intake of high dietary fiber, reduced intake of energy-dense, micronutrient-poor foods and regular physical activity. Furthermore, vitamin D has influence on the insulin sensitivity by controlling calcium flux through the membrane in both β cells and peripheral insulin-target tissues [66]. Because this class of agents is not specifically designed for older diabetic patients, there is no statistical difference in efficacy and safety profiles between elderly and younger patients [113]. In the GetGoal study program, HbA1c, FPG, and postprandial plasma glucose (PPG) were effectively decreased by the use of lixisenatide. Weight reduction may have effects on diabetes incidence, as seen in the DPP study, each kilogram of weight loss is correlated with a 16% reduction in the development of T2DM [199]. In addition, vitamin D supplementation is recognized as a promising and inexpensive therapy, which may decrease the risk of T2DM and improve glycemic parameters in T2DM patients [67].
Furthermore, lixisenatide reduced bodyweight and had therapeutic effects on glycemia when used as monotherapy or combined therapy with insulin and oral antidiabetic drugs. Weight reduction thus seems to be beneficial in the prevention of T2DM, at least in the short term [200].
Foods with low energy density, such as vegetables and fruits, are advised to increase satiety so that they can reduce total energy intake and achieve weight reduction [201]. Menaquinone-4 (vitamin K2) is considered as the active form of vitamin K in the bone tissue and functions in maintaining bone quality [68] and also as a transcriptional regulator of bone-specific genes that acts through steroid and xenobiotic receptors (SXRs) to promote expression of osteoblastic markers [69].
The stimulation of GPR40 with FFAs leads to insulin secretion through β-cell-specific signaling pathway, which can be inhibited by the treatment with small interfering RNA [138].
A meta-analysis suggests that a habitual energy imbalance of about 50-100 kcal per day may contribute to the gradual weight gain [202], however, modest and sustained changes in lifestyle could lighten or reverse this status [202]. A large number of chemical compounds which can act as GPR40 agonists exhibit glucose-dependent insulin secretion in vitro and in vivo, among which TAK-875 can reduce fasting plasma glucose and HbA1c levels in clinical trials [139].
It is, therefore, more acceptable for people to change gradually in diet or activity rather than dramatically. Because poor glycemic control and bone quality may occur when vitamin K is deficient, it is cardinal to exclude vitamin K deficiency in T2DM patients. Recently, Tanaka and his colleagues reported three novel GPR40 agonists AS2031477, AS1975063 and AS2034178, which could improve both acute glucose-dependent insulin secretion and chronic whole-body glucose metabolism [140].
These strategies require further investigations for the establishment of efficient prevention and control of T2DM.
Several preclinical and clinical observations show that vitamin K2 has effects on bone quality and subsequent bone mechanical strength in T2DM patients independently of increasing BMD (bone mineral density) [71, 72]. Among these GPR40 agonists, AS2034178 has been shown to reduce microvascular complications, thus it has a therapeutic potential to improve the prognosis of T2DM patients. It is also suggested that vitamin K2 may improve osteocyte density and lacunar occupancy by viable osteocytes in the cortical bone of glucocorticoid-treated or sciatic neurectomized rats [73, 74]. In addition, vitamin K2 may down-regulate bone turnover and stimulate lamellar bone formation, and prevent an increase in bone resorption with maintaince of bone formation and prevent a decrease in lamellar bone formation in glucocorticoid-treated rats [75].
Further studies are required for the comprehensive assessment of the role of vitamin K in the development of T2DM.In summary, the above-mentioned susceptibility loci and other influencing factors of T2DM are shown in Figure 1.
In the body, nearly 90% of NO is converted to nitrate (NO3-), a stable end-product of NO [141]. It has been demonstrated that NO3- and nitrite (NO2-) may have some therapeutic implications, such as decreasing blood pressure [142], reducing oxidative stress [143], and reducing oxygen consumption during exercise. It is also demonstrated that inorganic nitrate therapy can reduce visceral fat accumulation, lower serum triglycerides and normalize a disturbed glucose tolerance in eNOS deficient mice [144].
These findings suggest the roles of NO3- and NO2- in the prevention and treatment of T2DM for reduced weight in long-term NO3- therapy [145]. Stem cell educator therapy, a novel technology, is designed to control or reverse immune dysfunctions [148].
The procedure includes: collection of patients' blood circulating through a closed-loop system, purification of lymphocytes from the whole blood, co-culture of them with adherent cord blood-derived multi-potent stem cells (CB-SCs) in vitro and administration of the educated lymphocytes (but not the CB-SCs) to the patient's circulation [149] (Fig. These changes indicate that inflammation plays a pivotal role in the pathogenesis of T2DM and its complications.
Salicylates and interleukin-1 antagonists are the representative drugs with immunomodulatory effects in the treatment of T2DM patients, which can lower blood glucose levels and reduce severity and prevalence of the associated complications [152, 153]. A variety of antioxidants, such as vitamins, supplements, plant-derived active substances and drugs with antioxidant effects, have been used for oxidative stress treatment in T2DM patients. Vitamin C, vitamin E and β carotene are ideal supplements against oxidative stress and its complications [76]. For example, vitamin C can decrease fasting plasma insulin and HbA1c level, improve insulin action, and β carotene may reduce oxidative LDL [156]. Plants which contain substances with antioxidant properties such as monoterpenes, cinnamic acids, coumarins, flavonoid, diterpenes, phenylpropanoids, triterpenes, tannins and lignin can provide therapeutic effects in the treatment of T2DM [76]. Drugs with antioxidant properties, for example, α-lipoic acid and carvedilol, also have antioxidant effects in T2DM [156].

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  1. Lapuli4ka

    Bought a complete blog filled failed on a low carb.


  2. BoneS

    Advantage of a high-fibre diet is a lower incidence of constipation although Atkins.


  3. nazli

    Bananas or potatoes but from eating.


  4. su6

    Total carb consumption, though success with.