Reconstructive vascular surgery and the extent of tissue damage due to diabetic foot ulcers relates to risk of new ulceration in patients with PAD.

OBJECTIVE: There is limited information regarding new ulceration following the healing of ischaemic foot ulcers in diabetic patients. Our aim is to study new ulcerations in the same foot as the previous ulcer(s) in patients with diabetes and severe peripheral artery disease (PAD). METHOD: Patients with diabetes and severe PAD who healed from previous ulcer(s) (Wagner grade 1-5, at or below the ankle), were recruited for the prospective study from the time of healing of their ulcer. Patients were followed up regarding new ulceration, and their treatments and ulcer status noted either directly or on examination of medical records. RESULTS: We analysed the data on 602 patients with diabetes and severe PAD with healed foot ulcers, either primarily (n=443, 74%) or after minor amputation (n=159, 26%). Of these 51% (n=305) had revascularisation before healing from the previous ulcer, 34% (n=202) developed a new ulcer on the same foot within 15 months (range 0-106). Amputation was required by 22% (n=45) of patients, with a new ulcer on the same foot. The median survival time of all patients (n=602) was 54 months. By regression analysis, a low maximal Wagner grade for the previous ulcer and reconstructive vascular surgery was related to a decreased risk of developing new ulcers in the same foot. CONCLUSION: Patients with diabetes and ischaemic foot ulcers have a high-risk for developing new ulcers and amputation in the same foot after healing. The extent of tissue involvement in the previous ulcer and reconstructive vascular surgery affected the risk for development of new ulcers.

Early revascularization after admittance to a diabetic foot center affects the healing probability of ischemic foot ulcer in patients with diabetes.

OBJECTIVES: There is limited information about whether time from recognition of decreased perfusion to revascularization affects the probability of healing in a patient with a diabetic foot ulcer. The aim of the present study was to examine whether time to revascularization after referral to a multidisciplinary foot center was related to the outcome of foot ulcers in patients with diabetes and severe peripheral arterial disease (PAD). METHODS: Patients with diabetes, a foot ulcer, and a systolic toe pressure <45 mmHg or an ankle pressure <80 mmHg were prospectively included at the foot center, and considered for revascularization according to a preset protocol. All patients underwent invasive revascularization, either percutaneous transluminal angioplasty (PTA) or reconstructive vascular surgery. All patients had continuous follow-up until healing or death irrespective of the type of revascularization. RESULTS: A total of 478 patients were included (age 74 [range 66-80] years, 60% males), of whom 315 patients (66%) had PTA, and 163 (34%) had reconstructive surgery. Of the 478 patients, 217 (45%) healed primarily, 88 (19%) healed after a minor amputation, 76 (16%) healed after a major amputation and 92 patients (19%) died unhealed. The median time from inclusion in the study to revascularization was 8 weeks (3-18 weeks). Time to vascular intervention within 8 weeks (p < .001), maximum Wagner grade reached <3 (p < .001), absence of peripheral edema (p = .033), and presence of intermittent claudication (p = .001) were related to a higher probability of healing. CONCLUSIONS: Time to revascularization and extent of tissue damage were related to the probability of healing of ischemic foot ulcer in patients with diabetes over time. In the presence of a decreased perfusion in a patient with diabetes and a foot ulcer not only revascularization per se but also timing of revascularization is important for the possibility of healing without a major amputation.

Outcome of ischemic foot ulcer in diabetic patients who had no invasive vascular intervention.

OBJECTIVE/BACKGROUND: There is limited information regarding outcome in patients not available for revascularisation. Our aim was to identify factors related to ulcer healing in diabetic patients with severe peripheral arterial disease who were not available for revascularisation. METHODS: Diabetic patients with a foot ulcer, consecutively presenting at a multidisciplinary foot centre with systolic toe pressure <45 mmHg or an ankle pressure <80 mmHg were prospectively included. Patients who received revascularisation were excluded. All patients had continuous follow-up until healing or death. RESULTS: Out of 602 patients (median age: 76 years) included in this study, 50% healed either primarily (76%) or with a minor amputation (24%). Seventeen percent of patients healed after major amputation and 33% died unhealed. By regression analysis, rest pain, impaired renal function, ischemic heart disease, cerebral vascular disease, extent of tissue destruction, and ankle pressure >50 mmHg affected the outcome of the ulcers. CONCLUSION: Diabetic patients with ischemic foot ulcers not available for revascularisations are not excluded from healing without major amputation. Factors strongly related to outcome were co-morbidity, severity of peripheral arterial disease, and extent of tissue destruction. Our findings reinforce the need for a classification system considering these factors at decision-making for vascular intervention.

Telomere length in blood and skeletal muscle in relation to measures of glycaemia and insulinaemia.

AIMS: Skeletal muscle is a major metabolic organ and plays important roles in glucose metabolism, insulin sensitivity and insulin action. Muscle telomere length reflects the myocyte's exposure to harmful environmental factors. Leukocyte telomere length is considered a marker of muscle telomere length and is used in epidemiologic studies to assess associations with ageing-related diseases where muscle physiology is important. However, the extent to which leucocyte and muscle telomere length are correlated is unknown, as are their relative correlations with glucose and insulin concentrations. The purpose of this study was to determine the extent of these relationships. METHODS: Leucocyte and muscle telomere length were measured by quantitative real-time polymerase chain reaction in participants from the Malmö Exercise Intervention (n = 27) and the Prevalence, Prediction and Prevention of Diabetes-Botnia studies (n = 31). Participants in both studies were free from Type 2 diabetes. We assessed the association between leucocyte telomere length, muscle telomere length and metabolic traits using Spearmen correlations and multivariate linear regression. Bland-Altman analysis was used to assess agreement between leucocyte and muscle telomere length. RESULTS: In age-, study-, diabetes family history- and sex-adjusted models, leucocyte and muscle telomere length were positively correlated (r = 0.39, 95% CI 0.15-0.59). Leucocyte telomere length was inversely associated with 2-h glucose concentrations (r = -0.58, 95% CI -1.0 to -0.16), but there was no correlation between muscle telomere length and 2-h glucose concentrations (r = 0.05, 95% CI -0.35 to 0.46) or between leucocyte or muscle telomere length with other metabolic traits. CONCLUSIONS: In summary, the current study supports the use of leucocyte telomere length as a proxy for muscle telomere length in epidemiological studies of Type 2 diabetes aetiology.

Immigrants from the Middle-East have a different form of Type 2 diabetes compared with Swedish patients.

AIMS: To compare the clinical characteristics of Type 2 diabetes (T2DM) between immigrants from the Middle-East and Swedish patients. METHODS: The study group included 450 consecutive patients with T2DM, 379 Swedish-born aged 61 +/- 12 years and 71 patients originally from the Middle-East aged 50 +/- 11 years from the diabetes clinic of Malmo University Hospital. RESULTS: Onset of diabetes had occurred 12 years earlier in the Middle-East immigrants compared with the Swedish-born patients (43 +/- 10 vs. 55 +/- 12 years, P < 0.001). Immigrants had lower fasting serum C-peptide [0.7 (0.1-2.6) vs. 0.9 (0.1-4.0) nmol/l, P = 0.013], lower homeostasis model assessment (HOMA)-beta[1.7 (0.1-9.1) vs. 2.7 (0.1-59.0), P = 0.010], lower HOMA-IR [0.4 (0.02-1.19) vs. 0.4 (0.01-2.8), P = 0.005] than the Swedish group. A first-degree family history of diabetes was reported in 61% of immigrants, compared with 47% of Swedish-born (P = 0.022). CONCLUSIONS: Immigrants from the Middle-East have an earlier onset, stronger family history and more rapid decline of pancreatic B-cell function than Swedish patients, suggesting that they have a different form of T2DM compared with Swedish patients.

Can duplex arterial ultrasonography reduce unnecessary angiography?

OBJECTIVE: To assess the value of arterial duplex ultrasound, which assesses the location and severity of arterial disease, in determining whether invasive vascular intervention is required. METHOD: A total of 166 consecutive diabetic patients presenting at a multidisciplinary foot clinic with severe peripheral vascular disease, with or without a foot ulcer, were included in this prospective study. The choice of vascular intervention was based on the results of a duplex ultrasound examination. Subjects were followed up for two years, and their clinical management, vascular assessments and interventions given, and patient outcomes were recorded in a specially designed protocol. RESULTS: Based on findings of the duplex ultrasound, it was recommended that 55 patients (33%) should undergo angioplasty (percutaneous transluminal angioplasty [PTA] and/or subintimal recanalisation), 64 patients (39%) diagnostic angiography and 47 patients (28%) medical treatment only, thereby avoiding unnecessary angiography and its potential complications. Diagnostic angiography was recommended when the duplex ultrasound results were inconclusive. Fifty-two of the 55 patients recommended angiography with simultaneous angioplasty had an angiography; of these, 42 (81%) then had an angioplasty. Fifty-seven of the 64 patients with inconclusive results had an angiography. Of these, 23 (40%) subsequently had angioplasty, only 10 (18%) had reconstructive surgery and 24 (42%) had a diagnostic angiography only. CONCLUSION: Arterial duplex ultrasound may assist evaluations of the need for and type of invasive vascular intervention in patients with an ischaemic diabetic foot. It can thus help avoid diagnostic angiographies that do not result in vascular intervention. However, such decision-making remains at the discretion of the vascular surgeon and radiologist.

Less pronounced response to exercise in healthy relatives to type 2 diabetic subjects compared with controls.

Healthy first-degree relatives with heredity of type 2 diabetes (FH+) are known to have metabolic inflexibility compared with subjects without heredity for diabetes (FH-). In this study, we aimed to test the hypothesis that FH+ individuals have an impaired response to exercise compared with FH-. Sixteen FH+ and 19 FH- insulin-sensitive men similar in age, peak oxygen consumption (V̇o2 peak), and body mass index completed an exercise intervention with heart rate monitored during exercise for 7 mo. Before and after the exercise intervention, the participants underwent a physical examination and tests for glucose tolerance and exercise capacity, and muscle biopsies were taken for expression analysis. The participants attended, on average, 39 training sessions during the intervention and spent 18.8 MJ on exercise. V̇o2 peak/kg increased by 14%, and the participants lost 1.2 kg of weight and 3 cm waist circumference. Given that the FH+ group expended 61% more energy during the intervention, we used regression analysis to analyze the response in the FH+ and FH- groups separately. Exercise volume had a significant effect on V̇o2 peak, weight, and waist circumference in the FH- group, but not in the FH+ group. After exercise, expression of genes involved in metabolism, oxidative phosphorylation, and cellular respiration increased more in the FH- compared with the FH+ group. This suggests that healthy, insulin-sensitive FH+ and FH- participants with similar age, V̇o2 peak, and body mass index may respond differently to an exercise intervention. The FH+ background might limit muscle adaptation to exercise, which may contribute to the increased susceptibility to type 2 diabetes in FH+ individuals.

Extensive changes in the transcriptional profile of human adipose tissue including genes involved in oxidative phosphorylation after a 6-month exercise intervention.

AIM: Adipose tissue has an important function in total energy homeostasis, and its dysregulation may contribute to lifestyle-related diseases such as type 2 diabetes, cancer and cardiovascular diseases. The aim of this study was to investigate genome-wide mRNA expression in adipose tissue in healthy men before and after an exercise intervention to identify genes or pathways that mediate the beneficial effect of regular exercise. We also investigated the difference in adipose tissue mRNA expression between individuals with or without a family history of type 2 diabetes. METHODS: The 6-month supervised exercise intervention was conducted in 47 healthy men (age 37.8 ± 4.3 years, BMI 28.5 ± 3.6 kg m(-2) ) with a previous low level of physical activity. RNA was analysed using GeneChip Human Gene 1.0 ST arrays (Affymetrix) before and after the exercise. RESULTS: We identified 2,560 significant transcripts differentially expressed before vs. after exercise with a false discovery rate (FDR) < 0.1%, including genes encoding the respiratory chain, histone subunits, small nucleolar RNAs and ribosomal proteins. Additionally, pathways enriched in response to exercise include the ribosome, oxidative phosphorylation, proteasome and many metabolic pathways, whereas the WNT and MAPK signalling pathways were down-regulated (FDR < 5%) after exercise. There were no significant differences in mRNA expression between individuals with or without a family history of type 2 diabetes. CONCLUSION: Exercise increased the expression of genes involved in oxidative phosphorylation, which is the opposite of what has been seen in adipose tissue from elderly or obese individuals with low physical fitness, and our study thereby demonstrates a mechanism for the beneficial effect of exercise.

First-degree relatives of type 2 diabetic patients have reduced expression of genes involved in fatty acid metabolism in skeletal muscle.

CONTEXT: First-degree relatives of patients with type 2 diabetes (FH+) have been shown to have decreased energy expenditure and decreased expression of mitochondrial genes in skeletal muscle. In previous studies, it has been difficult to distinguish whether mitochondrial dysfunction and differential regulation of genes are primary (genetic) or due to reduced physical activity, obesity, or other correlated factors. OBJECTIVE: The aim of this study was to investigate whether mitochondrial dysfunction is a primary defect or results from an altered metabolic state. DESIGN: We compared gene expression in skeletal muscle from 24 male subjects with FH and 26 without FH matched for age, glucose tolerance, VO(2peak) (peak oxygen uptake), and body mass index using microarrays. Additionally, type fiber composition, mitochondrial DNA content, and citrate synthase activity were measured. The results were followed up in an additional cohort with measurements of in vivo metabolism. RESULTS: FH+ vs. FH- subjects showed reduced expression of mitochondrial genes (P = 2.75 × 10(-6)), particularly genes involved in fatty acid metabolism (P = 4.08 × 10(-7)), despite similar mitochondrial DNA content. Strikingly, a 70% reduced expression of the monoamine oxidase A (MAOA) gene was found in FH+ vs. FH- individuals (P = 0.0009). Down-regulation of the genes involved in fat metabolism was associated with decreased in vivo fat oxidation and increased glucose oxidation examined in an additional cohort of elderly men. CONCLUSIONS: These results suggest that genetically altered fatty acid metabolism predisposes to type 2 diabetes and propose a role for catecholamine-metabolizing enzymes like MAOA in the regulation of energy metabolism.