Neurovascular microcirculatory vasodilation mediated by C-fibers and Transient receptor potential vanilloid-type-1 channels (TRPV 1) is impaired in type 1 diabetes.

Microvascular dysfunction may have an early onset in type 1 diabetes (T1D) and can precede major complications. Our objectives were to assess the endothelial-dependent (acetylcholine, ACh; and post-occlusive hyperemia, PORH), non-endothelial-dependent (sodium nitroprusside, SNP) and neurovascular-dependent (local heating, LH and current induced vasodilation, CIV) microcirculatory vasodilation in T1D patients compared with matched control subjects using a laser speckle contrast imager. Seventeen T1D patients - matched with 17 subjects according to age, gender, Body-Mass-Index, and smoking status - underwent macro- and microvascular investigations. The LH early peak assessed the transient receptor potential vanilloid type 1 channels (TRPV1) mediated vasodilation, whereas the plateau assessed the Nitirc-Oxyde (NO) and endothelium-derived hyperpolarizing factor (EDHF) pathways. PORH explored sensory nerves and (EDHF), while CIV assessed sensory nerves (C-fibers) and prostaglandin-mediated vasodilation. Using neurological investigations, we observed that C-fiber and A-delta fiber functions in T1D patients were similar to control subjects. PORH, CIV, LH peak and plateau vasodilations were significantly decreased in T1D patients compared to controls, whereas there was no difference between the two groups for ACh and SNP vasodilations. Neurovascular microcirculatory vasodilations (C-fibers and TRPV 1-mediated vasodilations) are impaired in TD1 patients whereas no abnormalities were found using clinical neurological investigations. Clinicaltrials: No. NCT02538120.

Aging effect on microcirculation: A multiscale entropy approach on laser speckle contrast images.

PURPOSE: It has long been known that age plays a crucial role in the deterioration of microvessels. The assessment of such deteriorations can be achieved by monitoring microvascular blood flow. Laser speckle contrast imaging (LSCI) is a powerful optical imaging tool that provides two-dimensional information on microvascular blood flow. The technique has recently been commercialized, and hence, few works discuss the postacquisition processing of laser speckle contrast images recorded in vivo. By applying entropy-based complexity measures to LSCI time series, we present herein the first attempt to study the effect of aging on microcirculation by measuring the complexity of microvascular signals over multiple time scales. METHODS: Forearm skin microvascular blood flow was studied with LSCI in 18 healthy subjects. The subjects were subdivided into two age groups: younger (20-30 years old, n = 9) and older (50-68 years old, n = 9). To estimate age-dependent changes in microvascular blood flow, we applied three entropy-based complexity algorithms to LSCI time series. RESULTS: The application of entropy-based complexity algorithms to LSCI time series can differentiate younger from older groups: the data fluctuations in the younger group have a significantly higher complexity than those obtained from the older group. CONCLUSIONS: The effect of aging on microcirculation can be estimated by using entropy-based complexity algorithms to LSCI time series.

Evidence for a vasomotor cyclo-oxygenase dependent mechanism of sensitization at the cutaneous level.

AIMS: Current-induced vasodilation (CIV) is an axon-reflex response observed during monopolar current application such as iontophoresis. Cyclo-oxygenase derivates (COD) participate in CIV and act as sensitizing agents at the anodal level. Mechanisms involved during cathodal current application (CCA) are partially unknown. In a randomized double-blind crossover trial, we tested in 16 healthy subjects (i) the influence of the inter-stimulation interval (I-I) by comparing CIV following all-at-once 10 s CCA against 2 × 5 s CCA with intervals ranging from15 s-16 min and (ii) the participation of COD in CIV using 1 g aspirin or placebo intake. METHODS: Measurements were repeated 2 h and 14 days after treatment. Laser Doppler flowmetry assessed cutaneous blood flow, reported in multiples of baseline. RESULTS: Before treatment, peak vasodilation 10 min after the last current application (CVCstim2 ) increased compared with baseline whatever the I-I. Increase in CVCstim2 from baseline was greater for the 4 min (9.4 (5.3, 10.9) times; median (1(st) percentile, 3(rd) percentile)) and higher I-Is compared with all-at-once delivery (3.0 (2.1, 4.3) times, P < 0.05). The response was similar after placebo but aspirin abolished this vasodilation (increase by 1.2 (1.1, 1.3) times for all-at-once delivery and by 1.5 (1.3, 1.7) ± 0.3 times for 4 min interval, 2 h after aspirin intake) that recovered after 14 days. CONCLUSIONS: This confirms the participation of COD in CIV with CCA and their sensitizing action. This model can represent an attractive way to study the axon-reflex and sensitizing function of COD in humans.

[Endothelial function: role, assessment and limits]. / La fonction endothéliale : rôle, méthodes d'évaluation et limites.

For several years, detecting and preventing cardiovascular diseases have become a major issue. Different methods have been developed to evaluate endothelial function. Endothelial dysfunction is one of the first steps leading to atherosclerosis. This review presents an insight into endothelial function, the interests of its assessment and methods for studying endothelial function. To date, the vascular endothelium must be considered as a specific organ with its own functions that contribute to the homeostasis of the cardiovascular system. Endothelial dysfunction typically corresponds to a decrease of nitric oxide NO bioavailability. Biological or physico-chemical methods may be used to assess dysfunction. Biological methods allow measuring NO metabolites and pro-inflammatory and vasoconstrictor mediators released by the endothelium. The physico-chemical methods include intra-coronary injections, plethysmography, flow-mediated dilation (FMD), digital plethysmography and optical techniques using laser (laser Doppler single-point, laser Doppler imager, laser speckle contrast imaging) that can be coupled with provocation tests (iontophoresis, microdialysis, post-ischemic hyperemia, local heating). The principle of each technique and its use in clinical practice are discussed. Studying endothelial dysfunction is a particularly promising field because of new drugs being developed. Nevertheless, assessment methodology still needs further development to enable reliable, non-invasive, reproducible, and inexpensive ways to analyze endothelial dysfunction.

Relevance of laser Doppler and laser speckle techniques for assessing vascular function: state of the art and future trends.

In clinical and research applications, the assessment of vascular function has become of major importance to evaluate and follow the evolution of cardiovascular pathologies, diabetes, hypertension, or foot ulcers. Therefore, the development of engineering methodologies able to monitor noninvasively blood vessel activities-such as endothelial function-is a significant and emerging challenge. Laser-based techniques have been used to respond-as much as possible-to these requirements. Among them, laser Doppler flowmetry (LDF) and laser Doppler imaging (LDI) were proposed a few decades ago. They provide interesting vascular information but possess drawbacks that prevent an easy use in some clinical situations. Recently, the laser speckle contrast imaging (LSCI) technique, a noninvasive camera-based tool, was commercialized and overcomes some of the LDF and LDI weaknesses. Our paper describes how-using engineering methodologies-LDF, LDI, and LSCI can meet the challenging clinician needs in assessing vascular function, with a special focus on the state of the art and future trends.

Cutaneous microvascular functional assessment during exercise: a novel approach using laser speckle contrast imaging.

Cardiovascular diseases are often revealed during exercise and are associated with cutaneous blood flow (CBF) dysfunction. Studies of CBF during exercise are consequently of interest. Laser speckle contrast imaging (LSCI) allows for non-contact and real-time recording of CBF at rest. We tested whether LSCI could allow the study of CBF during a cycling exercise using a specific signal treatment procedure that removes movement-induced artefacts from the LSCI raw signal. We recorded the baseline CBF and peak post-occlusive reactive hyperaemia (PORH) from the cutaneous forearm using LSCI and the mean blood pressure before and during cycling (80 W at 70 rpm) in nine healthy subjects. We determined the cross-correlation coefficient r between LSCI traces obtained before and during cycling and before and after a specifically designed signal processing technique. The results are presented as the median (25th-75th centile) and expressed as the cutaneous vascular conductance (laser speckle perfusion units (LSPU) per millimetre of mercury). Cross-correlation r increased from 0.226 ± 0.140 before to 0.683 ± 0.170 after post-processing. After signal processing, the peak PORH during exercise was reduced [0.38 (0.30-0.52) LSPU/mmHg] compared with the peak PORH during the non-exercise phase [0.69 (0.63-0.74) LSPU/mmHg, p < 0.01], whereas no difference was found between the baseline values. With adequate signal processing, LSCI appears valuable for investigating CBF during exercise. During constant-load lower limb cycling exercise, the upper limb peak PORH is reduced compared with the peak PORH during non-exercise. The underlying mechanisms warrant further investigations in both healthy (trained) subjects and diseased (e.g., coronary heart disease) patients.

A new laser Doppler flowmeter prototype for depth dependent monitoring of skin microcirculation.

Laser Doppler flowmetry (LDF) is now commonly used in clinical research to monitor microvascular blood flow. However, the dependence of the LDF signal on the microvascular architecture is still unknown. That is why we propose a new laser Doppler flowmeter for depth dependent monitoring of skin microvascular perfusion. This new laser Doppler flowmeter combines for the first time, in a device, several wavelengths and different spaced detection optical fibres. The calibration of the new apparatus is herein presented together with in vivo validation. Two in vivo validation tests are performed. In the first test, signals collected in the ventral side of the forearm are analyzed; in the second test, signals collected in the ventral side of the forearm are compared with signals collected in the hand palm. There are good indicators that show that different wavelengths and fibre distances probe different skin perfusion layers. However, multiple scattering may affect the results, namely the ones obtained with the larger fibre distance. To clearly understand the wavelength effect in LDF measurements, other tests have to be performed.

Incidence and characteristics of lower limb amputations in people with diabetes.

AIMS: To estimate the incidence, characteristics and potential causes of lower limb amputations in France. METHODS: Admissions with lower limb amputations were extracted from the 2003 French national hospital discharge database, which includes major diagnoses and procedures performed during hospital admissions. For each patient, diabetes was defined by its record in at least one admission with or without lower limb amputation in the 2002-2003 databases. RESULTS: In 2003, 17 551 admissions with lower limb amputation were recorded, involving 15 353 persons, which included 7955 people with diabetes. The crude incidence of lower limb amputation in people with diabetes was 378/100 000 (349/100 000 when excluding traumatic lower limb amputation). The sex and age standardized incidence was 12 times higher in people with than without diabetes (158 vs. 13/100 000). Renal complications and peripheral arterial disease and/or neuropathy were reported in, respectively, 30% and 95% of people with diabetes with lower limb amputation. Traumatic causes (excluding foot contusion) and bone diseases (excluding foot osteomyelitis) were reported in, respectively, 3% and 6% of people with diabetes and lower limb amputation, and were 5 and 13 times more frequent than in people without diabetes. CONCLUSIONS: We provide a first national estimate of lower limb amputation in France. We highlight its major impact on people with diabetes and its close relationship with peripheral arterial disease/neuropathy and renal complications in the national hospital discharge database. We do not suggest the exclusion of traumatic causes when studying the epidemiology of lower limb amputation related to diabetes, as diabetes may contribute to amputation even when the first cause appears to be traumatic.

Mutations in the ABCC8 gene can cause autoantibody-negative insulin-dependent diabetes.

Activating mutations in genes KCNJ11 and ABCC8, which form the ATP-sensitive K+channel (K(ATP) channel), have been shown to cause transient or permanent neonatal diabetes. We describe here a rather different phenotype: two cases of adult diabetic patients-considered and treated as insulin-dependent diabetic patients since adolescence-who, in fact, turned out to be heterozygous for an ABCC8 mutation and able to successfully discontinue insulin while taking sulphonylurea treatment.

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

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.

Diabetic foot osteomyelitis.

Bone infection in the diabetic foot is always a complication of a preexisting infected foot wound. Prevalence can be as high as 66%. Diagnosis can be suspected in two mains conditions: no healing (or no depth decrease) in spite of appropriate care and off-loading, and/or a visible or palpated bone with a metal probe. The first recommended diagnostic step is to perform (and if necessary to repeat) plain radiographs. After a four-week treatment period, if plain radiographs are still normal, suspicion for bone infection will persist in case of bad evolution despite optimized management of off-loading and arterial disease. It is only in such cases that other diagnosis methods than plain radiographs must be used. Staphylococcus aureus is the most common pathogen cultured from bone samples, followed by Staphylococcus epidermidis. Among enterobacteriaceae, Escherichia coli, Klebsiella pneumonia and Proteus sp. are the most common, followed by Pseudomonas aeruginosa. Surprisingly, bacteria usually considered contaminant (as coagulase negative staphylococci (CNS) and Corynebacterium sp.) have been documented to be pathogens in the osteomyelitis of diabetic foot. Traditional approach to treatment of chronic osteomyelitis was by surgical resection of infected and necrotic bone. But new classes of antibiotics have both the required spectrum of activity and the capacity to penetrate and concentrate in the infected bone. Recently, several observations of osteomyelitis remission following non-surgical management with a prolonged course of antibiotics have been published. Lastly, combined approach with local bone excision and antibiotics has been proposed. Prospective trials should be undertaken to determine the relative roles of surgery and antibiotics in managing diabetic foot osteomyelitis.

Insulin therapy for type 2 diabetes: premixed or basal-prandial?

It is logical to begin type 2 insulin therapy with an injection of an intermediate-acting or a long-acting insulin at bedtime, but one should treat to target, i.e. aim at fasting glycaemias lower than 1.20 g/l to obtain an HbA(1c) close to 7%. Nevertheless, basal insulin therapy does not prevent progression to insulin-secretory deficiency. If necessary, recourse should be made to multiple-injection protocols, taking into account postprandial hyperglycaemia. For every level of HbA(1c), the suppression of postprandial hyperglycaemia, 1 point of HbA(1c) can be gained in theory, whereas reducing the fasting glycaemia to values of less than 1.10 g/l reduces HbA(1c) to close to 7%, whatever the initial level of HbA(1c). However, when a diabetic is clearly not controlled, the preprandial acting use of rapid analogues allows the fasting glycaemia to be improved significantly. Inversely, an early treatment with basal insulin, by correcting glucotoxicity, can also decrease postprandial hyperglycaemia. Many industry-sponsored studies comparing insulin therapy regimens show annoying biased interpretations of results. It does not seem pertinent to compare a single injection with two or even three injections, nor to compare an efficient titration with an inefficient titration or to eliminate oral drugs, in particular sulphonylureas combined with a basal insulin. If premix insulins can give satisfactory results in patients who maintain a sufficient residual insulin-secretion, we think it would be preferable to adopt the basal-prandial regimen and a step-by-step escalating therapy. The first stage consists in combining oral therapy with an injection of NPH insulin or a long-acting analogue at bedtime, aiming at a fasting glycaemia of less than 1.20 g/l. In the next stages, a single injection of rapid-acting insulin analogue is added each time. The main advantage of this regimen is to fix a target adapted to each injection and, as a result, to facilitate forced titration of the doses.

Should diabetic patients be asked to test their blood glucose 90 to 120 minutes after the beginning of their meals?

There are three distinct objectives in reducing the post-prandial blood glucose peaks: 1st to reduce the risk of foetal macrosomia in pregnancy, 2nd to reduce cardiovascular morbi-mortality, 3rd to lower the HbA1c. With 6-7 glycaemic controls per day and fractionning their meals, motivated women with gestational diabetes reach this goal. But there is no data today directly proving that post-prandial glycaemia is specifically related to the development of micro and macrovascular complications. So to reduce the cardiovascular risk, there are more arguments in favour of lowering HbA1c or prescribing statins than in prescribing a hypoglycaemic drug acting selectively on post-prandial glycaemia. Lastly, to reduce HbA1c near to the goal of 7%, the most important is to reduce the preprandial glycaemia below 1.20 g/l. The patients must be required to monitor their post-prandial glycaemia 2 hours after the beginning of the meal only when the aim is to lower the HbA1c below 7% or 6.5%, for example during pregnancy, or in case of discrepancy between glycaemia at 8 a.m. and 7 p.m. (below 1.20 g/)l and HbA1c (above 7%). In other cases, in type 2 diabetes, two glycaemias per day, fasting and vesperal, seems sufficient.

Percutaneous transluminal angioplasty in severe diabetic foot ischemia: outcomes and prognostic factors.

OBJECTIVES: To evaluate the outcomes of severe ischemic diabetic foot ulcers for which percutaneous transluminal angioplasty (PTA) was considered as the first-line vascular procedure. Factors associated with successful PTA were sought. RESEARCH DESIGN AND METHODS: In 32 consecutive diabetic patients with foot ulcers and severe limb ischemia, PTA was performed if feasible; if not, primary bypass grafting was done when feasible. All patients were followed until healing or for at least one year. Patients with worsening ulcers after PTA underwent bypass grafting. Clinical and angiographic factors influencing outcomes after PTA were sought by univariate and multivariate analysis. RESULTS: PTA was done in 25 of the 32 (78%) patients, and considered clinically successful in 13 (52%). After 1 year, the healing rate was 70% and the limb salvage rate 90%. Successful PTA was significantly associated with a higher post-PTA transcutaneous oxygen pressure (P = 0.03) and presence of at least one patent pedal vessel (P = 0.03) in the univariate analysis; only a patent pedal vessel was significant in the multivariate analysis. CONCLUSION: Primary PTA in diabetic patients with severe ischemic foot ulcers provides similar outcomes to usual results obtained in severe ischemia in absence of diabetes. The presence of one patent pedal vessel on arteriography before PTA is the best prognostic factor.

PPAR-gamma-agonists' renal effects.

PPAR-gamma ligands, including thiazolidinediones, have recently become clinically available for treating insulin-resistant diabetes mellitus. Accumulating evidence suggests that these drugs not only significantly improve insulin sensitivity but also may have antiproteinuric effects in genetically obese diabetic rodents and patients with type II diabetes and diabetic nephropathy. Moreover, troglitazone reduced expression of ECM proteins and transforming growth factor-beta in glomeruli from streptozotocin-induced diabetic rats. Many other properties including antiproteinuric, hemodynamic, and antihypertensive effects in insulin-dependent diabetes mellitus suggest that PPAR-gamma ligands might have a direct, beneficial renal effect, independent of their capacity to improve glucose tolerance. Besides their antidiabetic effects, thiazolidinediones have been shown to lower blood pressure in diabetic patients with hypertension and patients with diabetic nephropathy through multiple mechanisms. Several studies showed the efficacy of PPAR-gamma agonists to ameliorate the progression of glomerulosclerosis. The effect is independent of insulin effects and could only be partially due to lipid effects. These renal protective effects of PPAR-gamma agonists suggest that they may provide a novel intervention strategy to prevent vascular and glomerular sclerosis.

Review article: an unexpected virus-host interaction--the hepatitis C virus-diabetes link.

There is now consistent epidemiological evidence for an association between chronic hepatitis C and diabetes. Important, although so far limited longitudinal data, have documented an increased risk for diabetes in patients infected by hepatitis C virus (HCV) especially in those with metabolic risk factors such as a high BMI and older age. HCV encoded proteins might alter insulin signalling thus explaining impaired insulin sensitivity and the occurrence of glycaemic dysregulation even before the cirrhotic stage. The consequences of the association between diabetes and HCV infection are an increased liver fibrosis stage and faster fibrosis progression rate. This article reviews recent human and experimental data on the HCV-diabetes association.

Anemia and diabetes.

World Health Organization statistics identify 150 million people with diabetes mellitus worldwide and suggest that this figure may double by 2025. In countries with a western lifestyle, the number of patients admitted for renal replacement therapy with diabetes as a co-morbid condition has increased significantly up to three to four times in a period of 10 years. Diabetes and renal failure are thus tightly linked diseases, and so is anemia. However, whether anemia may be worsened and/or directly, at least in part, caused by diabetes is not clearly elucidated yet. In this article, we review the prevalence, pathophysiology and consequences of anemia in diabetic patients.