Showing papers in "Diabetes-metabolism Research and Reviews in 2008"

Practical guidelines on the management and prevention of the diabetic foot: based upon the International Consensus on the Diabetic Foot (2007) Prepared by the International Working Group on the Diabetic Foot.

Abstract: 1Department of Endocrinology, University Hospital of Malmö, S-205 02 Malmö, Sweden 2International Working Group on the Diabetic Foot (IWGDF), Heemsteedsedreef 90, 2102 KN Heemstede, The Netherlands 3Department of Internal Medicine, Spaarne Hospital Hoofddorp, Hoofddorp, The Netherlands 4Department of Internal Medicine, Division of Endocrinology. University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands

Vascular disease and diabetes: is hypoglycaemia an aggravating factor?

Abstract: Acute hypoglycaemia provokes profound physiological changes affecting the cardiovascular system and several haematological parameters, principally as a consequence of sympatho-adrenal activation and counter-regulatory hormonal secretion. Many of these responses have an important role in protecting the brain from neuroglycopenia, through altering regional blood flow and promoting metabolic changes that will restore blood glucose to normal. In healthy young adults the cardiovascular effects are transient and have no obvious detrimental consequences. However, some of the effected changes are potentially pathophysiological and in people with diabetes who have developed endothelial dysfunction, they may have an adverse impact on a vasculature that is already damaged. The acute haemodynamic and haematological changes may increase the risk of localized tissue ischaemia, and major vascular events can certainly be precipitated by acute hypoglycaemia. These include myocardial and cerebral ischaemia and occasionally infarction. Established diabetic retinopathy often deteriorates after strict glycaemic control is instituted, the latter being associated with a threefold increase in frequency of severe hypoglycaemia, and enhanced exposure to mild hypoglycaemia. The possible mechanisms underlying these hypoglycaemia-induced effects include haemorrheological changes, white cell activation, vasoconstriction, and the release of inflammatory mediators and cytokines. The concept that acute hypoglycaemia could aggravate vascular complications associated with diabetes is discussed in relation to evolving comprehension of the pathogenesis of atherosclerosis and blood vessel disease.

The diabetic foot: grand overview, epidemiology and pathogenesis

Abstract: This review assesses the progress that has been made over the last quarter century in our understanding of the pathogenesis of diabetic foot problems as well as in their management. Some recent exciting developments are highlighted. This is followed by a brief discussion on the epidemiology and causal pathways to diabetic foot disease.

Diabetic foot osteomyelitis: a progress report on diagnosis and a systematic review of treatment.

Abstract: The International Working Group on the Diabetic Foot appointed an expert panel to provide evidence-based guidance on the management of osteomyelitis in the diabetic foot. Initially, the panel formulated a consensus scheme for the diagnosis of diabetic foot osteomyelitis (DFO) for research purposes, and undertook a systematic review of the evidence relating to treatment. The consensus diagnostic scheme was based on expert opinion; the systematic review was based on a search for reports of the effectiveness of treatment for DFO published prior to December 2006. The panel reached consensus on a proposed scheme that assesses the probability of DFO, based on clinical findings and the results of imaging and laboratory investigations. The literature review identified 1168 papers, 19 of which fulfilled criteria for detailed data extraction. No significant differences in outcome were associated with any particular treatment strategy. There was no evidence that surgical debridement of the infected bone is routinely necessary. Culture and sensitivity of isolates from bone biopsy may assist in selecting properly targeted antibiotic regimens, but empirical regimens should include agents active against staphylococci, administered either intravenously or orally (with a highly bioavailable agent). There are no data to support the superiority of any particular route of delivery of systemic antibiotics or to inform the optimal duration of antibiotic therapy. No available evidence supports the use of any adjunctive therapies, such as hyperbaric oxygen, granulocyte-colony stimulating factor or larvae. We have proposed a scheme for diagnosing DFO for research purposes. Data to inform treatment choices in DFO are limited, and further research is urgently needed.

Correlation between vitamin D3 deficiency and insulin resistance in pregnancy

Abstract: Background The serum level of 25-hydroxyvitamin D deficiency has long been suspected as a risk factor for glucose intolerance and perhaps 1,25-dihydroxyvitamin D has a role in the regulation of insulin secretion. This study investigates the relation between 25-hydroxyvitamin D concentrations and insulin resistance in pregnant women. Methods A cross-sectional study was conducted on 741 pregnant women referred to five educating hospital clinics. Universal screening was performed with a GCT-50 g, and those with plasma glucose levels ≥ 7.2 mmol/L were diagnosed as GDM if they had an impaired GTT-100 g based on Carpenter and Coustan criteria. The levels of insulin and C-peptide were measured during OGTT-100 g test. The homeostasis model assessment index (HOMA) equation was used as the insulin resistance index. The concentrations of 25-hydroxyvitamin D, and PTH were also measured. Results Total prevalence of vitamin D deficiency (<25 nmol/L) was found in 70.6% of pregnant women. Prevalence of severe vitamin D deficiency (<12.5) in GDM patients was higher than in normoglycaemic pregnancies. The regression model revealed a strong correlation between the HOMA index and serum levels of vitamin D. Conclusions These results show that a positive correlation of 25(OH) vitamin D concentrations with insulin sensitivity and vitamin D deficiency could be a confirmative sign of insulin resistance. Copyright © 2007 John Wiley & Sons, Ltd.

The effectiveness of footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in diabetes: a systematic review

Abstract: Background Footwear and offloading techniques are commonly used in clinical practice for the prevention and treatment of foot ulcers in diabetes, but the evidence base to support this use is not well known. The goal of this review was to systematically assess the literature and to determine the available evidence on the use of footwear and offloading interventions for ulcer prevention, ulcer treatment, and plantar pressure reduction in the diabetic foot. Methods A search was made for reports on the effectiveness of footwear and offloading interventions in preventing or healing foot ulcers or reducing plantar foot pressure in diabetic patients published prior to May 2006. Both controlled and uncontrolled studies were included. Assessment of the methodological quality of studies and data extraction was independently performed by two reviewers. Interventions were assigned into four subcategories: casting, footwear, surgical offloading and other offloading techniques. Results Of 1651 articles identified in the baseline search, 21 controlled studies were selected for grading following full text review. Another 108 uncontrolled and cross-sectional studies were examined. The evidence to support the use of footwear and surgical interventions for the prevention of ulceration is meagre. Evidence was found to support the use of total contact casts and other non-removable modalities for treatment of neuropathic plantar ulcers. More studies are needed to support the use of surgical offloading techniques for ulcer healing. Plantar pressure reduction can be achieved by several modalities including casts, walkers, and therapeutic footwear, but the diversity in methods and materials used limits the comparison of study results. Conclusions This systematic review provides support for the use of non-removable devices for healing plantar foot ulcers. Furthermore, more high-quality studies are urgently needed to confirm the promising effects found in both controlled and uncontrolled studies of footwear and offloading interventions designed to prevent ulcers, heal ulcers, or reduce plantar pressure.

A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes.

Abstract: The outcome of management of diabetic foot ulcers is poor and there is uncertainty concerning optimal approaches to management. We have undertaken a systematic review to identify interventions for which there is evidence of effectiveness. A search was made for reports of the effectiveness of interventions assessed in terms of healing, ulcer area or amputation in controlled clinical studies published prior to December 2006. Methodological quality of selected studies was independently assessed by two reviewers using Scottish Intercollegiate Guidelines Network (SIGN) criteria. Selected studies fell into the following categories: sharp debridement and larvae; antiseptics and dressings; chronic wound resection; hyperbaric oxygen (HBO); reduction of tissue oedema; skin grafts; electrical and magnetic stimulation and ultrasound. Heterogeneity of studies prevented pooled analysis of results. Of the 2251 papers identified, 60 were selected for grading following full text review. Some evidence was found to support hydrogels as desloughing agents and to suggest that a systemic (HBO) therapy may be effective. Topical negative pressure (TNP) may promote healing of post-operative wounds, and resection of neuropathic plantar ulcers may be beneficial. More information was needed to confirm the effectiveness and cost-effectiveness of these and other interventions. No data were found to justify the use of any other topically applied product or dressing, including those with antiseptic properties. Further evidence to substantiate the effect of interventions designed to enhance the healing of chronic ulcers is urgently needed. Until such evidence is available from robust trials, there is limited justification for the use of more expensive treatments and dressings.

How hypoglycaemia can affect the life of a person with diabetes

Abstract: Hypoglycaemia is the commonest side-effect of insulin treatment for diabetes, and is the single greatest barrier to achieving and maintaining good glycaemic control. Severe hypoglycaemia (requiring assistance for recovery) is associated with significant morbidity and is feared by most people with type 1 diabetes and their families. It causes stress and anxiety and may influence self-management and glycaemic control. The annual prevalence of severe hypoglycaemia is around 30% in people with type 1 diabetes, and is higher in those with risk factors such as strict glycaemic control, impaired awareness of hypoglycaemia and increasing duration of diabetes. It is also common during sleep (nocturnal hypoglycaemia). Neurological manifestations include coma, convulsions, transient hemiparesis and stroke, while reduced consciousness and cognitive dysfunction may cause accidents and injuries. Cardiac events may be precipitated such as arrhythmias, myocardial ischaemia and cardiac failure. Hypoglycaemia can affect all aspects of life, including employment, driving, recreational activities involving exercise, and travel, and measures should be taken in all of these situations to avoid this potentially dangerous side-effect of insulin therapy.

Genistein and daidzein prevent diabetes onset by elevating insulin level and altering hepatic gluconeogenic and lipogenic enzyme activities in non-obese diabetic (NOD) mice.

Abstract: Background Non-obese diabetic (NOD) mice are regarded as being excellent animal models of human type 1 diabetes or insulin dependent diabetes (IDDM). This study investigated the beneficial effects of genistein and daidzein on IDDM, an autoimmune disease. Methods Female NOD mice were divided into control, genistein (0.02%, w/w) and daidzein (0.02%, w/w) groups. Blood glucose level, plasma biomarkers, hepatic glucose and lipid regulating enzyme activities and pancreas immunohistochemistry analysis were examined after a 9-week experimental period. Results Blood glucose levels of genistein and daidzein groups were 40 and 36% of control value at the end of study (9th week). The genistein and daidzein supplements increased insulin/glucagon ratio and C-peptide level with preservation of insulin staining β-cell of pancreas in the NOD mice. In the liver, genistein and daidzein supplements resulted in lowering glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities, while increasing two lipogenic enzymes activities, malic enzyme and glucose-6-phosphate dehydrogenase (G6PD), compared to the control group. Significantly, genistein and daidzein supplementation lowered the activities of fatty acid β-oxidation and carnitine palmitoyltransferase (CPT) in these mice. Genistein and daidzein also improved plasma triglyceride and free fatty acid (FFA) concentrations compared to the control group. Conclusions These results suggest that genistein and daidzein play important roles in regulation of glucose homeostasis in type 1 diabetic mice by down-regulating G6Pase, PEPCK, fatty acid β-oxidation and CPT activities, while up-regulating malic enzyme and G6PD activities in liver with preservation of pancreatic β-cells. The supplementation of genistein and daidzein are seemingly helpful for preventing IDDM onset. Copyright © 2007 John Wiley & Sons, Ltd.

Advanced glycation end products and diabetic foot disease.

Abstract: Diabetic foot disease is an important complication of diabetes. The development and outcome of foot ulcers are related to the interplay between numerous diabetes-related factors such as nerve dysfunction, impaired wound healing and microvascular and/or macrovascular disease. The formation of advanced glycation end products (AGEs) has been recognized as an important pathophysiological mechanism in the development of diabetic complications. Several mechanisms have been proposed by which AGEs lead to diabetic complications such as the accumulation of AGEs in the extracellular matrix causing aberrant cross-linking, the binding of circulating AGEs to the receptor of AGEs (RAGE) on different cell types and activation of key cell signalling pathways with subsequent modulation of gene expression, and intracellular AGE formation leading to quenching of nitric oxide and impaired function of growth factors. In the last decade, many experimental studies have shown that these effects of AGE formation may play a role in the pathogenesis of micro- and macrovascular complications of diabetes, diabetic neuropathy and impaired wound healing. In recent years also, several clinical studies have shown that glycation is an important pathway in the pathophysiology of those complications that predispose to the development of foot ulcers. Currently, there are a number of ways to prevent or decrease glycation and glycation-induced tissue damage. Although not in the area of neuropathy or wound healing, recent clinical studies have shown that the AGE-breakers may be able to decrease adverse vascular effects of glycation with few side effects.

The biology of chronic foot ulcers in persons with diabetes.

Abstract: Diabetic foot ulcers constitute a major health problem and they are recalcitrant to healing due to a constellation of intrinsic and extrinsic factors. The purpose of this article is to review the potential biological mechanisms that deter healing and perpetuate inflammatory responses in chronic diabetes foot ulcers. The link between hyperglycemia induced oxidative stress and its negative impact on cellular functions are explained. Key evidence related to alteration in tissue perfusion, bacterial balance, sustained proteases and cytokines release, leukocyte function, and growth factor production at the local wound level are summarized.

Gait characteristics of diabetic patients: a systematic review.

Abstract: Patients with diabetes are at higher risk of experiencing fall-related injuries when walking than healthy controls. The underlying mechanism responsible for this is not yet clear. Thus we intend to summarize diabetic patients' gait characteristics and emphasize those which could be the possible underlying mechanisms for increased fall risk. This systematic review aims, in particular, to: (1) evaluate the quality of existing studies which investigate the gait characteristics of diabetic patients, (2) highlight areas of agreement and contradiction in study results, (3) discuss and emphasize parameters associated with fall risk, and (4) propose new orientations and further domains for research needed for their fall risk prevention. We conducted an electronic search of Pedro, PubMed, Ovid and Cochrane. Two authors independently assessed all abstracts. Quality of the selected articles was scored, and the study results summarized and discussed. We considered 236 abstracts of which 28 entered our full text review. Agreement on data quality between two reviewers was high (kappa: 0.90). Authors investigating gait parameters in a diabetic population evaluated in particular parameters either associated with fall risk (speed, step length or step-time variability) or with ulcers (pressure). There is agreement that diabetic patients walk slower, with greater step variability, and present higher plantar pressure than healthy controls. We concluded that diabetic patients present gait abnormalities, some of which can lead to heightened fall risk. To understand its' underlying mechanisms, and to promote efficient prevention, further studies should analyse gait under 'real-life' conditions.

Painful diabetic neuropathy: treatment and future aspects.

Abstract: Around one of three diabetic patients is affected by distal symmetric polyneuropathy (DSP) which represents a major health problem, as it may present with partly excruciating neuropathic pain and is responsible for substantial morbidity and increased mortality. Treatment is based on four cornerstones: (1) multifactorial intervention aimed at (near)-normoglycaemia and reduction in cardiovascular risk factors, (2) treatment based on pathogenetic mechanisms, (3) symptomatic treatment, and (4) avoidance of risk factors and complications. Among the pathogenetic treatments only α-lipoic acid and epalrestat are available for treatment in several countries. Neuropathic pain, which is present in 8-26% of diabetic patients, exerts a substantial impact on the quality of life, particularly by causing considerable interference in sleep and enjoyment of life. Non-pharmacologic options such as nerve or muscle stimulation should always be given consideration. Among the centrally acting analgesic drugs for many years mainly the tricyclic antidepressants (TCA), carbamazepine, gabapentin, and opioids have been used to treat neuropathic pain. More recently, significant pain relief has been reported in clinical trials of painful diabetic neuropathy using agents such as the dual selective serotonin noradrenaline reuptake inhibitor (SNRI), duloxetine and the anticonvulsant pregabalin, a specific modulator of the α 2 δ subunit of the voltage-dependent calcium channels. A promising new anticonvulsant is lacosamide. In future, drug combinations might also include those aimed at symptomatic pain relief and quality of life on one hand and improvement or slowing the progression of the underlying neuropathic process on the other hand.

Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant?

Abstract: We have been interested in the metabolic effects of ingested fuels, both in normal subjects and in people with type 2 diabetes. Recently, we have become interested in the regulation of glucose production and the regulation of gluconeogenesis in particular. We are not aware of a recent comprehensive review of these topics. Therefore, we have reviewed the currently available literature. The pertinent papers obtained from a Medline search of the words gluconeogenesis, glycogenolysis, hepatic glucose output, as well as papers from our personal files, form the basis of this review. In order to analyse the data, it also was necessary to review the relevant methodology used in determining gluconeogenesis. Pathway diagrams have been included with this review in order to illustrate and highlight key aspects of the methodologies. Current data support the hypothesis that the rate of glucose appearance changes but the rate of gluconeogenesis remains remarkably stable in widely varying metabolic conditions in people without diabetes. In people with diabetes, whether gluconeogenesis remains unchanged is at present uncertain. Available data are very limited. The mechanism by which gluconeogenesis remains relatively constant, even in the setting of excess substrates, is not known. One interesting speculation is that gluconeogenic substrates substitute for each other depending on availability. Thus, the overall rate is either unaffected or only modestly changed. This requires further confirmation.

Early infant feeding and risk of type 1 diabetes mellitus—a nationwide population-based case–control study in pre-school children

Abstract: Background The evidence on the role of environmental factors in the development of type 1 diabetes is conflicting. Reducing potential bias and the variety of exposures, we investigated the association between type 1 diabetes risk and nutritional and environmental exposures in pre-school children. Methods This nationwide population-based case–control study included 760 cases under 5 years of age newly diagnosed with type 1 diabetes during 1992–1995. From the general population, 1871 controls were randomly selected and individually matched on age ( ± 1 year), sex, and residence. Information on infant diet, foetal, perinatal and socio-economic factors, and familial diabetes was obtained by a parent-administered questionnaire. Data were analysed by multiple conditional logistic regression. Results Duration of breastfeeding and age at introduction of bottle-feeding were inversely associated with type 1 diabetes risk according to a dose-response relationship (trend test p 40 years, and low birth weight were found more frequently among diabetic than among control children. Current cow's milk consumption, higher social status, and a larger family were associated with a reduced diabetes risk. Up to one half of the diabetic cases in the population could be attributed to modifiable exposures. Conclusions Our findings indicate that infant feeding is associated with type 1 diabetes risk and that a considerable part of new type 1 diabetic cases is potentially preventable. Copyright © 2007 John Wiley & Sons, Ltd.

1,25-Dihydroxyvitamin D improved the free fatty-acid-induced insulin resistance in cultured C2C12 cells.

Abstract: Background Epidemiological evidence has indicated that vitamin D deficiency increased the risk of insulin resistance in metabolic syndrome. The present study was conducted to test the hypothesis that 1,25-dihydroxyvitamin D may improve the free fatty-acid (FFA)-induced insulin resistance in muscle cells. Method The insulin resistance of muscle cell model was established by treatment of FFA in differentiated C2C12 cells. Glucose uptake of C2C12 myotubes was analysed by the 3H-labelled 2-deoxyglucose uptake assay. The diameter of myotubes was measured under the condition of glutaraldehyde-induced autofluorescense. Tyrosine phosphorylated insulin receptor substrate 1 (IRS-1) was measured by immunoprecipitation. Serine phosphorylated IRS-1 and protein kinase B (Akt), extracellular signal-related kinase (ERK), c-Jun amino-terminal kinases (JNK) as well as their phosphorylated form were analysed by Western blots. Results Compared with a vehicle-treated group, FFA treatment in myotubes was associated with 70.6% reduction in insulin-mediated uptake of glucose, a five-fold increase in serine phosphorylation of IRS-1, 76.9% decrease in tyrosine phosphorylation of IRS-1 and 81.8% decrease in phosphorylation of Akt. Supplement of 1,25-dihydroxyvitamin D improved the FFA-induced inhibition of glucose uptake in a dose- dependent (p < 0.001) and time-dependent manner (p < 0.01). This was accompanied by increase in tyrosine phosphorylation of IRS-1 and phosphorylated Akt and decrease in serine phosphorylation of IRS-1 (p < 0.001). 1,25-Dihydroxyvitamin D also inhibited the FFA-induced reduction in myotube diameter by 35.3% (p < 0.001). JNK phosphorylation was reduced by 126.7% with treatment of 1,25-dihydroxyvitamin D (p < 0.001). 1,25-Dihydroxyvitamin D had no effect on FFA-induced ERK phosphorylation (p = 0.84). Conclusion 1,25-Dihydroxyvitamin D improved the FFA-induced insulin resistance in muscle cells. Copyright © 2008 John Wiley & Sons, Ltd.

Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome?

Abstract: Hyperinsulinemia as a consequence of insulin resistance causes hyperandrogenemia in women. The objective was to review evidence for the converse situation, i.e. whether androgens adversely influence insulin action. Androgen excess could potentially contribute to the pathogenesis of insulin resistance in women with polycystic ovary syndrome (PCOS), metabolic syndrome/type 2 diabetes, and in obese peripubertal girls. An Entrez-PubMed search was conducted to identify studies addressing the relationship of androgens with metabolic syndrome/type 2 diabetes in women. Studies reporting outcomes of androgen administration, interventions to reduce androgen effects in hyperandrogenemic women, and basic studies investigating androgen effects on insulin target tissues were reviewed. Multiple studies showed associations between serum testosterone and insulin resistance or metabolic syndrome/type 2 diabetes risk in women, but their cross-sectional nature did not allow conclusions about causality. Androgen administration to healthy women was associated with development of insulin resistance. Intervention studies in women with hyperandrogenism were limited by small subject numbers and use of indirect methods for assessing insulin sensitivity. However, in three of the seven studies using euglycemic hyperinsulinemic clamps, reduction of androgen levels or blockade of androgen action improved insulin sensitivity. Testosterone administration to female rats caused skeletal muscle insulin resistance. Testosterone induced insulin resistance in adipocytes of women in vitro. In conclusion, the metabolic consequences of androgen excess in women have been under-researched. Studies of long-term interventions that lower androgen levels or block androgen effects in young women with hyperandrogenism are needed to determine whether these might protect against metabolic syndrome/type 2 diabetes in later life.

Chromium picolinate and biotin combination improves glucose metabolism in treated, uncontrolled overweight to obese patients with type 2 diabetes

Abstract: Background Chromium and biotin play essential roles in regulating carbohydrate metabolism. This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of the combination of chromium picolinate and biotin on glycaemic control. Methods Four hundred and forty-seven subjects with poorly controlled type 2 diabetes (HbA1c ≥ 7.0%) were enrolled and received either chromium picolinate (600 µg Cr+3) with biotin (2 mg), or matching placebo, for 90 days in combination with stable oral anti-diabetic agents (OADs). Major endpoints were reductions in HbA1c, fasting glucose, and lipids. Safety and tolerability were assessed. Results Change in HbA1c was significantly different between treatment groups (p = 0.03). HbA1c in the chromium picolinate/biotin group decreased 0.54%. The decrease in HbA1c was most pronounced in chromium picolinate/biotin subjects whose baseline HbA1c ≥ 10%, and highly significant when compared with placebo (−1.76% vs − 0.68%; p = 0.005). Fasting glucose levels were reduced in the entire chromium picolinate/biotin group versus placebo (−9.8 mg/dL vs 0.7 mg/dL; p = 0.02). Reductions in fasting glucose were also most marked in those subjects whose baseline HbA1c ≥ 10.0%, and significant when compared to placebo (−35.8 mg/dL vs. 16.2 mg/dL; p = 0.01). Treatment was well tolerated with no adverse effects dissimilar from placebo. Conclusions These results suggest that the chromium picolinate/biotin combination, administered as an adjuvant to current prescription anti-diabetic medication, can improve glycaemic control in overweight to obese individuals with type 2 diabetes; especially those patients with poor glycaemic control on oral therapy. Copyright © 2007 John Wiley & Sons, Ltd.

Diabetes classification: grey zones, sound and smoke: Action LADA 1.

Abstract: Diseases gain identity from clinical phenotype as well as genetic and environmental aetiology. The definition of type 1 diabetes is clinically exclusive, comprising patients who are considered insulin dependent at diagnosis, whilst the definition of type 2 diabetes is inclusive, only excluding those who are initially insulin dependent. Ketosis-prone diabetes (KPD) and latent autoimmune diabetes in adults (LADA) are each exclusive forms of diabetes which are, at least initially, clinically distinct from type 2 diabetes and type 1 diabetes, and each have a different natural history from these major types of diabetes.KPD can be diagnosed unequivocally as diabetes presenting with the categorical clinical feature, ketoacidosis. In contrast, LADA can be diagnosed by the co-occurrence of three traits, not one of which is categorical or exclusive to the condition: adult-onset non-insulin-requiring diabetes, an islet autoantibody such as glutamic acid decarboxylase autoantibodies (GADA) or cytoplasmic islet cell autoantibodies (ICA), and no need for insulin treatment for several months post-diagnosis. But while some would split diabetes into distinct subtypes, there is a strong case that these subtypes form a continuum of varying severity of immune and metabolic dysfunction modified by genetic and non-genetic factors. This article discusses the nature of disease classification in general, and KPD and LADA in particular, emphasizing the potential value and pitfalls in classifying diabetes and suggesting a need for more research in this area.

Nanomedicine and its potential in diabetes research and practice

Abstract: Nanomedicine involves measurement and therapy at the level of 1-100 nm. Although the science is still in its infancy, it has major potential applications in diabetes. These include solving needs such as non-invasive glucose monitoring using implanted nanosensors, with key techniques being fluorescence resonance energy transfer (FRET) and fluorescence lifetime sensing, as well as new nano-encapsulation technologies for sensors such as layer-by-layer (LBL) films. The latter might also achieve better insulin delivery in diabetes by both improved islet encapsulation and oral insulin formulations. An 'artificial nanopancreas' could be an alternative closed-loop insulin delivery system. Other applications of nanomedicine include targeted molecular imaging in vivo (e.g. tissue complications) using quantum dots (QDs) or gold nanoparticles, and single-molecule detection for the study of molecular diversity in diabetes pathology.

Inflamed adipose tissue, insulin resistance and vascular injury.

Abstract: Type 2 diabetes is the most common metabolic disorder today and has reached epidemic proportions in many countries. Insulin resistance and inflammation play a central role in the pathogenesis of type 2 diabetes and are present long before the onset of the disease. During this time, many of the complications associated with type 2 diabetes are initiated. Of major concern is the two- to fourfold increase in cardiovascular morbidity and mortality in this group compared to a nondiabetic population. Obesity, characterized by enlarged fat cells, and insulin resistance are, like type 2 diabetes, associated with impaired adipogenesis and a low-grade chronic inflammation that to a large extent emanates from the adipose tissue. Both these processes contribute to unfavourable alterations of the circulating levels of several bioactive molecules (adipokines) that are secreted from the adipose tissue, many of which have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and, in addition, have negative effects on the cardiovascular system. Here we review current knowledge of the adipose tissue as an endocrine organ, the local and systemic effects of a chronic state of low-grade inflammation residing in the adipose tissue, and, in particular, the effects of inflammation and circulating adipokines on the vascular wall. Copyright © 2008 John Wiley & Sons, Ltd.

Interprofessional and transdisciplinary teamwork in health care

Abstract: The article focuses on the need for and the characteristics and positive consequences of interdisciplinary teamwork in health care. Interprofessional collaboration is an important element in total quality management. Factors that determine the success of team work are described, such as a management that promotes openness and an administrative organization that promotes interdisciplinary consultation. Other factors have to do with leadership, shared goals and values, meeting management and planning skills, communication, and also the (degree of) knowledge and the (quality of) perception of competences of other health care workers. The shared care plan is stressed as an important tool. In this, the joint planning of goals for intervention and care is essential. Health care workers with different professional knowledge and background have to harmonize their intervention plan according to the competences and goal settings of the other team members. The core of effective interprofessional teamwork is the presence of interprofessional competences such as these. A brief description of the components and performance criteria of the competence of interprofessional collaboration is given.

Thiazolidinediones as anti-inflammatory and anti-atherogenic agents.

Abstract: In the last few years, there has been increasing focus on the impact of interventions on cardiovascular outcomes in patients with type 2 diabetes. Insulin resistance and hyperglycaemia often co-exist with a cluster of risk factors for coronary artery disease, but the underlying mechanisms leading to the development of such vascular complications are complex. The over-production of free radicals in patients suffering from diabetes results in a state of oxidative stress, which leads to endothelial dysfunction and a greater risk of atherosclerosis. Moreover, inflammatory factors which play a critical role in atherothrombosis and plaque rupture are often found to be at elevated levels in this patient population. Thiazolidinediones (TZDs) are now routinely used to manage glucose levels, and have been suggested to influence other cardiovascular risk factors and therefore the pathways leading to macrovascular events. Consequently, recent studies have investigated the anti-inflammatory and anti-atherogenic properties of TZDs. The data available up to the present time, in the context of the emerging cardiovascular outcome profiles of rosiglitazone and pioglitazone, will be discussed here.

Charcot neuro-osteoarthropathy-current standards.

Abstract: It is extremely important to have a high index of suspicion for Charcot neuro-osteoarthropathy (CN) and to encourage early presentation of the patient. This should be followed by a rapid diagnosis and early intervention, and with such a modern approach many CN can now be healed and deformity prevented. CN can be divided into two phases: acute active phase and chronic stable phase. The acute active phase includes those patients presenting early with normal X-ray and those presenting later with deformity and radiological changes of CN. The acute phase is characterized by unilateral erythema and oedema. The foot is at least 2 degrees C hotter than the contralateral foot. Patients should have initially an X-ray examination which, at this time, may be normal. We then proceed to two investigations: initially a technetium diphosphonate bone scan, which will detect early evidence of bone damage and also locate the site of this damage. If the result of the bone scan is positive, we would proceed to magnetic resonance imaging (MRI) examination, which would describe in more detail the nature of the bony damage. The aim of treatment is immobilization in a plaster cast until there is no longer evidence on X-ray of continuing bone destruction, and the foot temperature is within 2 degrees C of the contralateral foot. An alternative treatment is a prefabricated walking cast, such as the Aircast. A randomized controlled study of a single 90 mg pamidronate infusion has shown a significant reduction of the markers of bone turnover and skin temperature in treated, compared with control subjects although the fall in skin temperature was similar in both groups. There was a similar finding in a recent study with alendronate. Calcitonin has also been used in the acute stage and there was a more rapid transition to the stable chronic phase in the treated group compared with controls. In the chronic stable phase, the foot is no longer warm and red. There may still be oedema but the difference in skin temperature between the feet is usually less than 2 degrees C. The X-ray shows fracture healing, sclerosis and bone remodelling. The patient must now be rehabilitated and gradually moved from cast treatment to suitable footwear. The patient needs close observation to detect any relapse, which will be evident from further swelling and heat in the foot. Careful rehabilitation is always necessary after a long period in a cast.

Benfotiamine exhibits direct antioxidative capacity and prevents induction of DNA damage in vitro

Abstract: Background Complications in diabetes mellitus are partially mediated by enhanced formation of reactive oxygen species. Among the factors involved in reactive oxygen species formation, advanced glycation end products play a key role. Owing to a reduced activity of the enzyme transketolase, which requires diphosphorylated thiamine (vitamin B1) as cofactor, an accumulation of those deleterious glucose metabolites especially in diabetic patients can be observed. Benfotiamine, a lipophilic thiamine diphosphate prodrug, prevented early renal and retinal changes in animal studies, and reduced neuropathic pain in clinical studies. Several mechanisms for these activities have been described. We investigated for the first time direct antioxidant abilities of benfotiamine. Additionally, a potential DNA protective effect of benfotiamine was analysed. Methods Oxidative stress was detected by flow cytometry, antioxidative capacity was measured with the ferric reducing ability of plasma (FRAP) assay, two endpoints for genomic damage were assessed: the comet assay and the micronucleus test, and the expression and activity of transketolase was quantified. Results Benfotiamine prevented oxidative stress induced by the mutagen 4-nitroquinoline-1-oxide (NQO), the uremic toxin indoxyl sulfate, and the peptide hormone angiotensin II in three different kidney cell lines. Cell-free experiments showed a direct antioxidant effect of benfotiamine, which might account for the protective effect. Oxidative DNA damage, induced by angiotensin II, was completely prevented by benfotiamine. Incubation with benfotiamine increased transketolase expression and activity in the cells. Conclusions Benfotiamine shows a direct antioxidant action. This effect of benfotiamine may be involved in the improvement of diabetic late complications, including peripheral neuropathy. Copyright © 2008 John Wiley & Sons, Ltd.

Neuropathy: mobility and quality of life

Abstract: In summary, diabetes is increasingly becoming a disease of elderly people. Some of the under-appreciated complications such as impaired physical functioning, increased risk for falls and fractures need to be more addressed in the future. When evaluating a patient with peripheral neuropathy, it is also important to pay attention to the possibility of deficits in postural stability and lower extremity functioning. Impairments in lower extremity physical functioning are key contributors to loss of physical independence and have a major impact on quality of life. Increasing awareness of disability as a potentially modifiable complication should become a health priority for people with diabetes. Early results of interventions to improve physical functioning are promising and need to be further explored within clinical practice.

Charcot neuro-osteoarthropathy

Abstract: The classical neurotraumatic and neurotrophic theories for the pathogenesis of the acute Charcot neuro-osteoarthropathy (CN) in diabetes, do not address certain key features of the disease. These features include the facts that the condition usually affects just one side, that it is self-limiting, and that it is also very uncommon. Similarly, it is not known to what extent the condition may depend, as suggested by Jean-Martin Charcot, on pre-morbid osteopenia. Recent advances in understanding the mechanisms underlying the pathogenesis of osteopenia and osteoporosis and the central role of the RANKL/OPG signalling system have, however, suggested the possible involvement of other factors in the evolution of the disease. Specifically, it has been suggested that acute CN may be triggered in a susceptible individual by any event that leads to localized inflammation in the affected foot. This local inflammation leads to a vicious cycle in which there is increasing inflammation, increasing expression of RANKL, and increasing bone breakdown. The likely central role for the RANKL/OPG pathway suggests new possibilities for future treatments.

Circulating advanced glycation end products (AGEs) and soluble form of receptor for AGEs (sRAGE) are independent determinants of serum monocyte chemoattractant protein-1 (MCP-1) levels in patients with type 2 diabetes.

Abstract: Background Atherosclerosis is an inflammatory disease. Monocyte chemoattractant protein-1 (MCP-1) is an essential chemokine responsible for the recruitment of monocytes to inflammatory lesions in the vasculature, an initial step of atherosclerosis. Since serum levels of MCP-1 are higher in patients with type 2 diabetes, inhibition of MCP-1 may be a novel therapeutic target for prevention of accelerated atherosclerosis in diabetes. However, little is known about the regulation and determinants of serum MCP-1 levels in patients with diabetes. In this study, we examined the determinants of serum MCP-1 levels in type 2 diabetic patients. Methods Eighty-six consecutive outpatients with type 2 diabetes (36 male and 50 female; mean age 68.4 ± 9.6) underwent a complete history and physical examination, determination of blood chemistries, MCP-1, tumour necrosis factor-α, adiponectin, advanced glycation end products (AGEs), and soluble form of receptor for AGEs (sRAGE). We examined the association between MCP-1 levels and those in anthropometric, metabolic and inflammatory variables in these subjects. Results Univariate regression analysis showed that serum levels of MCP-1 were positively associated with AGEs (r = 0.386, p < 0.001) and sRAGE (r = 0.315, p < 0.001). After adjusting for age and sex, AGEs (p < 0.001) and sRAGE (p < 0.05) still remained significant. Conclusion The results demonstrate for the first time that circulating levels of AGEs and sRAGE are independent determinants of serum MCP-1 levels in patients with type 2 diabetes. Our present observations suggest the AGEs-RAGE system may be mainly involved in the elevation of MCP-1 in type 2 diabetic patients. Copyright © 2007 John Wiley & Sons, Ltd.

Decreased in vivo oxidative stress and decreased platelet activation following metformin treatment in newly diagnosed type 2 diabetic subjects.

Abstract: Background In type 2 diabetes, metformin reduces cardiovascular risk beyond the effect of glycaemic control. Since oxidative stress and the consequent enhanced platelet activation contribute to accelerated atherosclerosis in diabetes, we hypothesized that metformin could reduce oxidative stress in this condition. Methods We randomized 26 newly diagnosed type 2 diabetic subjects to assume either metformin (M, n = 13) or gliclazide (G, n = 13) for 12 weeks. Drugs were titrated as needed to achieve good glycaemic control. Before and after treatment, we determined blood glucose, insulin, HbA1c, vitamin A and E levels and 8-iso-PGF2α and 11-dehydro-thromboxane B2 urinary excretion, an in vivo oxidative stress and a thromboxane-dependent platelet activation marker, respectively. Results Notwithstanding a comparable improvement in metabolic control, 8-iso-PGF2α (M from 708 ± 32 to 589 ± 45 pg/mg cr, p < 0.001; G from 646 ± 80 to 665 ± 79, pg/mg cr, p = ns) and 11-dehydro-thromboxane B2 (M from 2190 ± 196 to 1753 ± 150 pg/mg cr, p < 0.05; G from 2048 ± 202 to 1923 ± 223, pg/mg cr, p = ns) urinary excretion decreased after metformin but not after gliclazide treatment. After metformin, vitamin A and E levels significantly increased while they remained unchanged after gliclazide. Conclusions These data suggest that metformin could improve oxidative stress, preserve antioxidant function and restrain platelet activation in type 2 diabetes. Copyright © 2007 John Wiley & Sons, Ltd.

Therapeutic education of diabetic patients

Abstract: Therapeutic patient education is a patient-centred approach, focussed on patients' needs, resources, values and strategies. It allows patients to improve their knowledge and skills not only concerning their illness but also their treatment. It brings a better quality of life, a greater therapeutic compliance and a reduction in complications. The most difficult part of therapeutic patient education occurs when patients must change their behaviour. Motivational interviewing and cognitive-behavioural approaches contribute greatly here and allow both the preparation and support of patients during progressive 'step by step' change. The work on resistance to change is fundamental, and ambivalence when faced with the choice of a new way of life must be measured, discussed and negotiated. Patients become partners and we become 'coaches'. The negotiation of objectives must allow patients to choose their own strategies, which normally should cost them the least possible, psychologically, and bring them the maximum benefit. The efficiency of therapeutic patient education no longer needs to be proved: 80% less amputations over 10 years in diabetic patients; 50% maintenance of weight loss over 5 years, etc. In conclusion, therapeutic education is part of a humanistic medical approach centred on patients; it allows them to be active participants in their own treatment with the aim of improving their quality of life and therapeutic compliance, as well as reducing potential complications. Thus, health care professionals teach, inform, train, negotiate with, motivate and accompany patients in the long-term follow-up of their illness.