XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Standards of Medical Care in Diabetes

Epidemiology of cardiovascular disease in chronic renal disease

Glucose control and vascular complications in veterans with type 2 diabetes

Cytokines act as pleiotropic polypeptides regulating inflammatory and immune responses through actions on cells. They provide important signals in the pathophysiology of a range of diseases, including diabetes mellitus. Chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Inflammatory cytokines, mainly IL-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic nephropathy. In this context, cytokine genetics is of special interest to combinatorial polymorphisms among cytokine genes, their functional variations, and general susceptibility to diabetic nephropathy. Finally, the recognition of these molecules as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.

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The Role of Inflammatory Cytokines in Diabetic Nephropathy

Objective: This is the first part of a bipartite review that summarizes the rising knowledge on the molecular mechanisms underlying the action of advanced glycation endproducts (AGEs) and their contribution to diabetic complications and vascular disease. While the first part presented here focusses on AGE formation, the second part will describe the AGE-protein/receptor interactions and their role in mediating AGE-dependent intracellular signalling. Results: Nonenzymatic glycation, in which reducing sugars are covalently attached to free amino groups and ultimately form AGEs, has been found to occur during normal aging and at accelerated rate in diabetes mellitus. Oxidation, accompanying glycation in vivo, further supports chemical modifications. AGE formation and protein crosslinking are irreversible processes that alter the structural and functional properties of proteins, lipid components and nucleic acids. AGE modifications do not only change the physicochemical properties of the afflicted molecules, but also induce cellular signalling, activation of transcription factors and subsequent gene expression in vitro and in vivo. Conclusions: AGEs elicit a wide range of cell-mediated responses that might contribute to the pathogenesis of diabetic complications, vascular and renal disease and Alzheimer's disease. Substances that inhibit AGE formation, reduce oxidative stress or destroy already formed crosslinks may limit the progression of disease and may offer new tools for therapeutic interventions in the therapy of AGEs mediated disease.

AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept

The accelerated formation of advanced glycation end products (AGEs) and the overexpression of transforming growth factor beta (TGF-beta) have both been implicated in the pathogenesis of diabetic microvascular and macrovascular complications. Previous studies in our laboratory have demonstrated that the vascular changes in diabetes include hypertrophy of the mesenteric vasculature. To examine the role of AGEs in this process, streptozotocin-induced diabetic rats and control animals were randomized to receive aminoguanidine, an inhibitor of AGE formation, or no treatment. Animals were studied at 7 d, 3 wk, and 8 mo after induction of diabetes. When compared with control animals, diabetes was associated with an increase in mesenteric vascular weight and an increase in media wall/lumen area. By Northern analysis, TGF-beta1 gene expression was increased 100-150% (P < 0.01) and alpha1 (IV) collagen gene expression was similarly elevated to 30-110% compared to controls (P < 0.05). AGEs and extracellular matrix were present in abundance in diabetic but not in control vessels. Treatment of diabetic rats with aminoguanidine resulted in significant amelioration of the described pathological changes including overexpression of TGF-beta1 and alpha1 (IV) collagen. These data implicate the formation of AGEs in TGF-beta overexpression and tissue changes which accompany the diabetic state.

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Vascular hypertrophy in experimental diabetes. Role of advanced glycation end products.

Background
Some previous observations suggest that insulin resistance and glucose metabolism disturbances are frequent complications of chronic kidney disease. However, there are no conclusive studies on other indices of the effectiveness of insulin action in end-stage renal disease (ESRD) patients, including chronically hemodialysed (HD) ones.

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Homeostatic model assessment indices in evaluation of insulin resistance and secretion in hemodialysis patients

Background: Nephropathy is a major cause of morbidity and mortality in diabetic patients. Current treatments include optimization of glycemic and blood pressure control, but more innovative strategies are needed for the prevention and treatment of diabetic nephropathy. Objectives: To review emerging therapies for diabetic nephropathy. Methods: This paper discusses the molecular mechanisms of diabetic nephropathy and the potential therapeutic interventions. Results/conclusion: New therapies, including those targeting the accumulation of advanced glycation end products (AGEs) and reactive oxygen species (ROS) generation, are likely to feature in future treatment regimens. Other approaches that at this stage do not appear to be progressing include the glycosaminoglycan sulodexide and the protein kinase C-beta (PKC-β) inhibitor, ruboxistaurin.

Agents in development for the treatment of diabetic nephropathy.

BACKGROUND The purpose of this study was to investigate microvascular perfusion in insulin-dependent diabetic patients at various locations on the foot, and to determine which part of the foot is most sensitive to microangiopathic changes. All the parameters of postocclusive reactive hyperemia calculated from multichannel laser Doppler recordings were also evaluated to find the most valuable measure for diabetes examination. MATERIAL/METHODS Our study involved 65 subjects divided into four subgroups: male and female controls, and male and female IDDM patients without overt complications. The measurements were performed with a multichannel laser Doppler perfusion monitor using surface probes located in the distal parts of the lower limbs. The occlusion test was performed using a cuff located on the limb above the knee. Multivariate discriminatory analysis was used to evaluate the data. RESULTS The most valuable data were obtained by recordings from the laser-Doppler probes located on the hallex and the base of the little toe. The maximum hyperemic response for both sex subgroups was significantly lower in the diabetic patients. The time to peak flow was higher in male diabetics. The half-time for hyperemia was significantly longer in the male diabetic patients. CONCLUSIONS The females showed smaller changes in foot perfusion than the males, probably due to protection by estrogens. The best locations for perfusion measurement are the most distal, especially the hallex and the base of the little toe. The most valuable parameters of postocclusive hyperemia were maximum response, time to peak flow, and half-time of hyperemia.

Mariusz Jasik

Papers

Vascular hypertrophy in experimental diabetes. Role of advanced glycation end products.

Homeostatic model assessment indices in evaluation of insulin resistance and secretion in hemodialysis patients

Agents in development for the treatment of diabetic nephropathy.

Microcirculation in the diabetic foot as measured by a multichannel laser Doppler instrument.

Diabetes and hypertension. Australian Diabetes Society position statement