Current Diabetes Reviews - Volume 2, Issue 4, 2006

In contrast to the accumulation of fat in the gluteo-femoral region, the accumulation of fat around abdominal viscera and inside intraabdominal solid organs is strongly associated with obesity-related complications like Type 2 diabetes and coronary artery disease. The association between visceral adiposity and accelerated atherosclerosis was shown to be independent of age, overall obesity or the amount of subcutaneous fat. Recent evidence revealed several biological and genetic differences between intraabdominal visceral-fat and peripheral subcutaneous-fat. Such differences are also reflected in their contrasting roles in the pathogenesis of obesity-related cardiometabolic problems, in either lean or obese individuals. The functional differences between visceral and the subcutaneous adipocytes may be related to their anatomical location. Visceral adipose tissue and its adipose-tissue resident macrophages produce more proinflamatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) and less adiponectin. These cytokines changes induce insulin resistance and play a major role in the pathogenesis of endothelial dysfunction and subsequent atherosclerosis. The rate of visceral fat accumulation is also different according to the individual's gender and ethnic background; being more prominent in white men, African American women and Asian Indian and Japanese men and women. Such differences may explain the variation in the cardiometabolic risk at different waist measurements between different populations. However, it is unclear how much visceral fat reduction is needed to induce favorable metabolic changes. On the other hand, peripheral fat mass is negatively correlated with atherogenic metabolic risk factors and its selective reduction by liposuction does improve cardiovascular risk profile. The increasing knowledge about body fat distribution and its modifiers may lead to the development of more effective treatment strategies for people with/or at high risk for Type 2 diabetes and coronary artery disease. These accumulating observations also urge our need for a new definition of obesity based on the anatomical location of fat rather than on its volume, especially when cardiometabolic risk is considered. The term “Metabolic Obesity”, in reference to visceral fat accumulation in either lean or obese individuals may identify those at risk for cardiovascular disease better than the currently used definitions of obesity.

Insulin resistance in skeletal muscle is a major hallmark of type 2 diabetes and an early detectable abnormality in the development of this disease. The cellular mechanisms of insulin resistance include impaired insulin-mediated muscle glycogen synthesis and increased intramyocellular lipid content, whereas impaired insulin activation of muscle glycogen synthase represents a consistent, molecular defect found in both type 2 diabetic and high-risk individuals. Despite several studies of the insulin signaling pathway believed to mediate dephosphorylation and hence activation of glycogen synthase, the molecular mechanisms responsible for this defect remain unknown. Recently, the use of phosphospecific antibodies in human diabetic muscle has revealed hyperphosphorylation of glycogen synthase at sites not regulated by the classical insulin signaling pathway. In addition, novel approaches such as gene expression analysis and proteomics have pointed to abnormalities in mitochondrial oxidative phosphorylation and cellular stress in muscle of type 2 diabetic subjects, and recent work suggests that impaired mitochondrial activity is another early defect in the pathogenesis of type 2 diabetes. This review will discuss the latest advances in the understanding of the molecular mechanisms underlying insulin resistance in human skeletal muscle in type 2 diabetes with focus on possible links between impaired glycogen synthase activity and mitochondrial dysfunction.

Metabolic syndrome, also known as the insulin resistance syndrome (IRS), dysmetabolic syndrome or syndrome X, is a burgeoning global epidemic. This constellation of risk factors, namely glucose intolerance, hypertension, dyslipidemia (high triglyceride and low HDL cholesterol), central obesity, pro-inflammatory and prothrombotic state, culminating to the development of premature cardiovascular and renal disease, has significant impact on life expectancy, societal productivity and quality of life. The underlying mechanism of this complex syndrome remains to be elucidated. In recent years, light has been shed on the roles of neuroendocrine system and adipocytokines on the pathogenesis of IRS. In this review, we summarize the possible links between insulin and various hormones (growth hormones (GH), catecholamines, glucocorticoids and sex hormones), partly mediated through visceral adiposity and adipocytokines (notably adiponectin, leptin, resistin, visfatin, tumor necrosis factor α (TNF-α), interleukin-6 (IL-6)) in the pathogenesis of this syndrome.

Insulin resistance is a relevant risk factor for the major cardiovascular events, caused by severe atherosclerotic involvement of coronary, cerebral and lower limb blood vessels. One of the alterations accounting for this increased cardiovascular risk is the impairment of platelet function, explained, at least in part, by the reduced sensitivity to the physiological and pharmacological anti-aggregating agents. In the first part of this review, we will focus our attention on the physiological mechanisms involved in the attenuation of platelet response and on their impairment in insulin resistance, considering in particular: i) the reduced sensitivity to insulin and other substances acting via intracellular cyclic nucleotides; ii) the altered intracellular ionic milieu with elevated cytosolic Ca2+, iii) the increase of oxidative stress, which elicits isoprostane production from arachidonic acid. Therapeutic guidelines recommend a multifactorial prevention including antiplatelet drugs, even though the protective effect of antiplatelet therapy in both obese and type 2 diabetic patients has not been completely clarified so far. Furthermore, some reports show a decreased sensitivity to the platelet antiaggregating effect of acetylsalicylic acid in obesity and type 2 diabetes mellitus. These defects explain why antiplatelet therapy for both chronic atherosclerotic vascular disease and acute coronary syndromes should be specifically tailored in obese, insulin resistant subjects, especially in the presence of type 2 diabetes mellitus. Thus, in the second part of this review we performed a critical overview of the clinical trials on anti-aggregating agents carried out in subjects with metabolic syndrome and type 2 diabetes mellitus.

Diabetic foot disease is a major health problem, which concerns 15% of the 200 million patients with diabetes worldwide. Major amputation, above or below the knee, is a feared complication of diabetes. More than 60% of nontraumatic amputations in the western world are performed in the diabetic population. Many patients who undergo an amputation, have a history of ulceration. Major amputations increase morbility and mortality and reduce the patient's quality of life. Treatment of foot complications is one of the main items in the absorption of economic and health resources addressed to the diabetic population. It is clear that effective treatment can bring about a reduction in the number of major amputations. Over recent years, we have seen a significant increase in knowledge about the physiopathological pathways of this complication, together with improvements in diagnostic techniques, but above all a standardized conservative therapeutic approach, which allows limb salvage in a high percentage of cases. This target has been achieved in specialized centers. An important prelude to diabetic foot treatment is the differing diagnosis of neuropathic and neuroischemic foot. This differentiation is essential for effective treatment. Ulceration in neuropathic foot is due to biomechanical stress and high pressure, which involves the plantar surface of toes and metatarsal heads. Treatment of a neuropathic plantar ulcer must correct pathological plantar pressures through weight bearing relief. Surgical treatment of deformities, with or without ulcerations, is effective therapy. A neuropathic ulcer that is not adequately treated can become a chronic ulcer that does not heal. An ulcer that does not heal for many months has a high probability of leading to osteomyelitis, for which treatment with antibiotics is not useful and which usually requires a surgical procedure. Charcot neuroarthropathy is a particular complication of neuropathy which may lead to fragmentation or destruction of joints and bones. A well-timed diagnosis of Charcot neuroartropathy is essential to avoid deformities of chronic evolution. In the diabetic population peripheral vascular disease (PVD) is the main risk factor for amputation. If peripheral vascular disease is ignored, surgical treatment of the lesion cannot be successful. In diabetic patients, PVD is especially distal, but often fully involves the femoral, popliteal and tibial vessels. It can be successfully treated with either open surgical or endovascular procedures. Infection is a serious complication of diabetic foot, especially when neuroischemic: phlegmon or necrotizing fascitis are not only limb-threatening problems, but also life-threatening ones. In this case, emergency surgery is needed. Primary and secondary prevention of foot ulceration is the main target. Prevention programs must be carried out to highlight risk factors, lowering amputation incidence.

Resistin was initially identified as a protein, secreted by adipocytes, which inhibits insulin action and adipose differentiation. The three proteins homologous to resistin were termed resistin-like molecules (RELM)α, β and γ . Resistin and RELMα are abundantly expressed in adipose, but RELMβ and RELMγ are secreted mainly from the gut. Recently, resistin and RELMs were reported to be associated with inflammation. For example, RELMα , viewed as an inflammation-related protein, was originally identified in broncho-alveolar lavage fluid obtained from animals with experimentally induced pulmonary inflammation. RELMβ is also related to bacterial colonization, but RELMβ injection or hepatic overexpression of RELMβ induced insulin resistance. RELMγ isolated from rat nasal respiratory epithelium was found to be altered by cigarette smoke. Thus, resistin and RELMs could be useful for assessing the inflammatory condition in vivo. On the other hand, whether the serum resistin or RELM concentration is strongly related to insulin resistance remains unclear. However, taking recent studies showing a close relationship between inflammation and insulin resistance in diabetes into consideration, these proteins may have interactive roles linking inflammation and insulin resistance, both of which major involvement in the progression of atherosclerosis. If so, the serum resistin or RELM concentration may be a good marker of atherosclerotic risk. In addition, these proteins or unidentified receptors are potential therapeutic targets for the treatment of diabetes and prevention of atherosclerosis. These possibilities merit further study.

Rheumatological manifestations of Diabetes Mellitus may be classified in: non articular, articular and bone conditions. Among non articular conditions, diabetic cheiroarthropathy, frequent in type I diabetes, the most important disorder related to limited joint mobility, results in stiff skin and joint contractures. Adhesive capsulitis of the shoulder, flexor tenosynovitis, and Duputryen's and Peyronie's diseases are also linked to limited joint mobility. Diffuse skeletal hyperostosis, due to calcification at entheses, is frequent and early, particularly in type 2 diabetes. Neuropathies cause some non articular conditions, mainly neuropathic arthritis, a destructive bone and joint condition more common in type I diabetes. Algodistrophy, shoulder-hand and entrapment syndromes are also frequent. Mononeuropathy causes diabetic amyotrophy, characterised by painless muscle weakness. Among muscle conditions, diabetic muscle infarction is a rare, sometimes severe, condition. Among articular conditions, osteoarthritis is frequent and early in diabetes, in which also chondrocalcinosis and gout occur. Rheumatoid arthritis (RA) and diabetes I have a common genetic background and the presence of diabetes gives to RA an unfavourable prognosis. Among bone conditions, osteopenia and osteoporosis may occur early in type 1 diabetes. Contrarily, in type 2 diabetes, bone mineral density is similar or, sometimes, higher than in non diabetic subjects, probably due to hyperinsulinemia.

Diabetic retinopathy (DR) is the leading cause of catastrophic loss of vision. Each year, DR darkens the lives of 12,000 to 24,000 diabetic patients in the United States, and more than 4,000 patients in Japan. Clinically, hyperglycemia induces proliferative changes in DR synergistically with other risk factors for vascular diseases. Methyl- enetetrahydrofolate reductase (MTHFR) is an enzyme involved in remethylation of homocysteine to methionine. A polymorphic mutation (C677T) in the MTHFR gene leads to impaired enzyme activity, resulting in hyper- homocysteinemia as an independent risk factor for macroangiopathy. Recently, more and more attention has been paid to the involvement of hyperhomocysteinemia in the progression of DR, a serious microangiopathic complication of diabetes. Clinical studies have demonstrated that MTHFR gene polymorphism can contribute to the progression of DR, especially in the patients with blood glucose poorly controlled. Furthermore, accumulating evidence suggests that homocysteine activates vascular inflammation through inflammatory cytokines, including VEGF. These data imply that the decrease in plasma homocysteine could prevent the development and progression of DR. We also propose the possibility of personalized medicine for diabetes mellitus based on a better understanding of MTHFR gene polymorphism and its ramifications, which might cast new light on diabetic retinopathy.