Targ Elgzyri

Impact of an Exercise Intervention on DNA Methylation in Skeletal Muscle From First-Degree Relatives of Patients With Type 2 Diabetes

To identify epigenetic patterns, which may predispose to type 2 diabetes (T2D) due to a family history (FH) of the disease, we analyzed DNA methylation genome-wide in skeletal muscle from individuals with (FH+) or without (FH−) an FH of T2D. We found differential DNA methylation of genes in biological pathways including mitogen-activated protein kinase (MAPK), insulin, and calcium signaling (P ≤ 0.007) and of individual genes with known function in muscle, including MAPK1, MYO18B, HOXC6, and the AMP-activated protein kinase subunit PRKAB1 in skeletal muscle of FH+ compared with FH− men. We further validated our findings from FH+ men in monozygotic twin pairs discordant for T2D, and 40% of 65 analyzed genes exhibited differential DNA methylation in muscle of both FH+ men and diabetic twins. We further examined if a 6-month exercise intervention modifies the genome-wide DNA methylation pattern in skeletal muscle of the FH+ and FH− individuals. DNA methylation of genes in retinol metabolism and calcium signaling pathways (P < 3 × 10−6) and with known functions in muscle and T2D including MEF2A, RUNX1, NDUFC2, and THADA decreased after exercise. Methylation of these human promoter regions suppressed reporter gene expression in vitro. In addition, both expression and methylation of several genes, i.e., ADIPOR1, BDKRB2, and TRIB1, changed after exercise. These findings provide new insights into how genetic background and environment can alter the human epigenome.

Factors related to outcome of neuroischemic/ischemic foot ulcer in diabetic patients

OBJECTIVES Peripheral vascular disease (PVD) is an important limiting factor for healing in neuroischemic or ischemic diabetic foot ulcer. The purpose of this study was to identify factors related to healing in patients with diabetes with foot ulcers and severe PVD. METHODS Patients with diabetes with a foot ulcer, consecutively presenting at a multidisciplinary foot center with a systolic toe pressure <45 mm Hg or an ankle pressure <80 mm Hg were prospectively included, followed according to a preset program, and with the exception of specified exclusions, subjected to angiography offered vascular intervention when applicable. All patients had continuous follow-up until healing or death irrespective of the type of vascular intervention. RESULTS One thousand one hundred fifty-one patients were included. Eighty-two percent had a toe pressure <45 mm Hg and 49% had an ankle pressure <80 mm Hg. Eight hundred one patients (70%) underwent an angiography. Out of these, 63% had vascular intervention, either percutaneous transluminal angioplasty (PTA; 39%) or reconstructive surgery (24%). Nine percent of the patients had one or more complications after angiography. PTA was multisegmental in 46% and to the crural arteries in 46%. Reconstructive surgery was distal in 51%. Age (P < .001), renal function impairment (P = .005), congestive heart failure (P = .01), number and type of ulcer (P < .001), and severity of PVD (P = .003) affected the outcome of ulcers. PTA and reconstructive vascular surgery increased the probability of healing without amputation (odds ratio [OR], 1.77 and 2.05, respectively). CONCLUSION Probability of ulcer healing is strongly related to comorbidity, extent of tissue involvement, and severity of PVD in patients with diabetes with severe PVD.

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.

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.

The effects of GH replacement therapy on cardiac morphology and function, exercise capacity and serum lipids in elderly patients with GH deficiency

objectives  To assess effects of GH replacement therapy on cardiac structure and function, exercise capacity as well as serum lipids in elderly patients with GH deficiency (GHD).

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

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.

Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity

Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10−5) and 49 expression–insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment–insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10−4). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10−6) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016–0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r2 = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10−3). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.

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

Diabet. Med. 29, e377–e381 (2012)

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.

Relation between cycling exercise capacity, fiber-type composition, and lower extremity muscle strength and muscle endurance.

Segerström, ÅB, Holmbäck, AM, Hansson, O, Elgzyri, T, Eriksson, K-F, Ringsberg, K, Groop, L, Wollmer, P, and Thorsson, O. Relation between cycling exercise capacity, fiber-type composition, and lower extremity muscle strength and muscle endurance. J Strength Cond Res 25(1): 16-22, 2011-The aim of the study was to determine the relation between peak oxygen uptake (&OV0312;o2peak), peak work rate (WRpeak), fiber-type composition, and lower extremity strength and endurance during a maximal incremental cycle test. Thirty-nine healthy sedentary men, aged 30-46, participated in the study. Subjects performed a maximal incremental cycle test and isokinetic knee extension (KE) and flexion (KF) strength and endurance tests at velocities of 60 and 180°·s−1. Muscle biopsies were taken from m. vastus lateralis and analyzed for fiber-type composition. A significant correlation existed between KE strength and &OV0312;o2peak and WRpeak. Also, KF endurance correlated significantly to &OV0312;o2peak and WRpeak. The KE endurance correlated significantly to WRpeak (rp = 0.32, p < 0.05) and almost significantly to &OV0312;o2peak (rp = 0.28, p = 0.06). Stepwise multiple regression analyses showed that KE strength, KF endurance, and the percentage of type I fibers could explain up to 40% of the variation in &OV0312;o2peak and WRpeak. The performance of sedentary subjects in a maximal incremental cycle test is highly affected by knee muscle strength and endurance. Fiber-type composition also contributes but to a smaller extent.