Relationship between insulin sensitivity and gene expression in human skeletal muscle.

BACKGROUND: Insulin resistance (IR) in skeletal muscle is a key feature of the pre-diabetic state, hypertension, dyslipidemia, cardiovascular diseases and also predicts type 2 diabetes. However, the underlying molecular mechanisms are still poorly understood. METHODS: To explore these mechanisms, we related global skeletal muscle gene expression profiling of 38 non-diabetic men to a surrogate measure of insulin sensitivity, i.e. homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: We identified 70 genes positively and 110 genes inversely correlated with insulin sensitivity in human skeletal muscle, identifying autophagy-related genes as positively correlated with insulin sensitivity. Replication in an independent study of 9 non-diabetic men resulted in 10 overlapping genes that strongly correlated with insulin sensitivity, including SIRT2, involved in lipid metabolism, and FBXW5 that regulates mammalian target-of-rapamycin (mTOR) and autophagy. The expressions of SIRT2 and FBXW5 were also positively correlated with the expression of key genes promoting the phenotype of an insulin sensitive myocyte e.g. PPARGC1A. CONCLUSIONS: The muscle expression of 180 genes were correlated with insulin sensitivity. These data suggest that activation of genes involved in lipid metabolism, e.g. SIRT2, and genes regulating autophagy and mTOR signaling, e.g. FBXW5, are associated with increased insulin sensitivity in human skeletal muscle, reflecting a highly flexible nutrient sensing.

Changes in daily nursing needs and self-care capability of people with diabetes after in-hospital treatment for foot complications: A descriptive study.

AIM: A limited number of studies discuss the changes in patients' self-care skills and needs for assisted self-care after discharge from in-patient treatment due to diabetes foot ulcer-related complications. The aim of this study was to examine the ability to perform self-care and needs for assisted nursing interventions at hospital discharge, compared to pre-admission, for people with diabetes admitted and treated for foot ulcer-related complications. DESIGN: Retrospective patient record study. METHODS: A retrospective assessment was done on the medical records of a total of 134 patients with diabetes consecutively admitted to a specialist in-patient unit due to foot ulcer complications, between 1 November 2017 and 30 August 2018. Data on daily self-care needs and home situations at admission and discharge were recorded. RESULTS: The median age was 72 years (38-94), 103 (76.9%) were men and 101 (73.7%) had diabetes type 2. The median length of admission was 10 days (2-39). Infection was the most common cause of admission (51%), with severe ischaemia in 6%, and a combination of both in 20% of patients. Surgical treatment was performed in 22% and vascular intervention in 19% of patients. The percentage of patients discharged to their home without assistance was 48.1% compared to 57.5% before admission, discharge to home with assistance was 27.4% versus 22.4% before admission and 9.2% were discharged to short-term nursing accommodation versus 6% before admission. Three patients died during their stay in hospital. The need for help with medications increased from 14.9% of patients at admission to 26.7% at discharge and for mobility assistance from 23.1% to 35.9%. Social services at home were increased in 21.4% of patients at discharge.

Diabetic Neuropathy Assessed with Multifrequency Vibrometry Develops Earlier than Nephropathy but Later than Retinopathy.

BACKGROUND: Diabetes is associated with systemic complications. Prevalence of diabetic nephropathy, and retinopathy, in type 1 diabetes mellitus (T1DM) is declining, but it is not known if this is true also for diabetic neuropathy. AIM: To investigate the relationship between large fibre diabetic neuropathy and other diabetic complications. MATERIALS AND METHODS: Neuropathy, defined here as large fibre neuropathy, was assessed by measuring vibration perception thresholds at four different frequencies on the sole of the foot, using a standard VibroSense Meter and/or neuropathic symptoms, in 599 individuals with T1DM. Retinopathy status was graded using the International Clinical Disease Severity Scale. Grade of albuminuria and previous history of any macrovascular complications were registered. RESULTS: Diabetic individuals without retinopathy had similar vibration thresholds as age- and gender-matched control participants without diabetes, whereas those without microalbuminuria had higher thresholds than controls. Two individuals out of 599 (0.3%) had microalbuminuria, but not retinopathy or neuropathy, and 12/134 (9%) without retinopathy had signs of neuropathy. Totally 119/536 (22%) of the patients without microalbuminuria had neuropathy. Vibration thresholds increased with the rising severity of retinopathy and grade of albuminuria. In a multinomial logistic regression analysis, neuropathy was associated with retinopathy (OR 2.96 [1.35-6.49], p=0.007), nephropathy (OR 6.25 [3.21-12.15]; p=6.7×10-8) and macrovascular disease (OR 2.72 [1.50-4.93], p=0.001). CONCLUSIONS: Despite recent changes in the incidence of diabetic complications, the onset of large fibre neuropathy follows that of retinopathy but precedes the onset of nephropathy in T1DM.

Transient increase in glucose variability during Ramadan fasting in patients with insulin-treated type 2 diabetes: A preliminary study.

AIM: We aimed to examine the effect of Ramadan fasting on interstitial glucose control and variability before, during, and after Ramadan in type 2 diabetes patients receiving insulin therapy. METHODS: Participants received a flash glucose monitoring (FGM) system one week before Ramadan that was removed on the sixth or seventh day (pre- and early Ramadan periods) of Ramadan and a second FGM system one week before the end of Ramadan that was removed one week after the end of Ramadan (late and post-Ramadan periods). Fasting blood samples were collected during the pre-, early, and late Ramadan study visits and tested for HbA1c, serum creatinine, and plasma glucose levels. RESULTS: Thirty-four patients were prospectively included. The standard deviation and coefficient of variation of glucose concentrations were higher in the early Ramadan period than in the pre-Ramadan period, but did not differ in the late or post-Ramadan periods. Changes in the early Ramadan period were restricted to males and patients aged <55 years. No significant changes were observed in the average glucose level, glucose management indicator, time in range, time in hyperglycemia, or time in hypoglycemia at any time point. CONCLUSIONS: Ramadan fasting in patients with insulin-treated type 2 diabetes is associated with an initial increase in glucose variability that quickly returned to pre-Ramadan levels. Ramadan fasting was not associated with any significant changes in glycemic control measures.

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.

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

The aim of the study was to determine the relation between peak oxygen uptake V(O2)peak), 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 V(O2)peak and WRpeak. Also, KF endurance correlated significantly to V(O2)peak and WRpeak. The KE endurance correlated significantly to WRpeak (rp = 0.32, p < 0.05) and almost significantly to V(O2)peak (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 V(O2) 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.

Healing below the ankle is possible in patients with diabetes mellitus and a forefoot gangrene.

BACKGROUND: Forefoot gangrene in patients with diabetes is a severe form of foot ulcers with risk of progress and major amputation. No large cohort studies have examined clinical characteristics and outcome of forefoot gangrene in patients with diabetes. The aim was to examine clinical characteristics and outcome of forefoot gangrene in patients with diabetes admitted to a diabetic foot centre. METHODS: Patients with diabetes and foot ulcer consecutively presenting were included if they had forefoot gangrene (Wagner grade 4) at initial visit or developed forefoot gangrene during follow-up at diabetic foot centre. Patients were prospectively followed up until final outcome, either healing or death. The median follow-up period until healing was 41 (3-234) weeks. RESULTS: Four hundred and seventy-six patients were included. The median age was 73 (35-95) years and 63% were males. Of the patients, 82% had cardiovascular disease and 16% had diabetic nephropathy. Vascular intervention was performed in 64%. Fifty-one patients (17% of surviving patients) healed after auto-amputation, 150 after minor amputation (48% of surviving patients), 103 had major amputation (33% of surviving patients) and 162 patients deceased unhealed. Ten patients were lost at follow-up. The median time to healing for all surviving patients was 41 (3-234) weeks; for auto-amputated, 48 (10-228) weeks; for minor amputated, 48 (6-234) weeks; and for major amputation, 32 (3-116) weeks. CONCLUSION: Healing without major amputation is possible in a large proportion of patients with diabetes and forefoot gangrene, despite these patients being elderly and with extensive co-morbidity.

Amputation-free survival in patients with diabetic foot ulcer and peripheral arterial disease: Endovascular versus open surgery in a propensity score adjusted analysis.

AIMS: The aim of the present study was to compare outcomes of endovascular surgery versus open vascular surgery in patients with diabetic foot ulcer (DFU) and peripheral arterial disease (PAD). METHODS: Between 1984 and 2006, 1151 patients with DFU were admitted to the diabetic foot care team. Three hundred seventy-six patients with 408 limbs were consecutively included at a multidisciplinary foot center, 289 limbs were treated with endovascular surgery and 119 limbs with open vascular surgery first strategy. A propensity score adjusted analysis was performed to compare outcomes for type of revascularization. RESULTS: Major amputation rates at 3 years were 17.0% and 16.8% (p = 0.97) and mortality at 3 years were 43.1% and 46.5% (p = 0.55) after endovascular surgery and open vascular surgery, respectively. In the propensity score adjusted analysis, patients undergoing endovascular surgery first had similar outcomes in terms of major amputation, mortality, combined major amputation/mortality compared to those undergoing open vascular surgery. Longer time to intervention (p = 0.003) was associated with increased major amputation rate in the multivariable Cox regression analysis. CONCLUSION: The endovascular surgery first and open vascular surgery first strategies were associated with similar long-term results in a large cohort of patients with DFU and PAD undergoing revascularization. Rapid revascularization reduces the risk of amputation.

Improved metabolic control using glucose monitoring systems leads to improvement in vibration perception thresholds in type 1 diabetes patients.

AIMS: Few studies have examined how improved metabolic control might influence vibration perception thresholds (VPTs). The aim of this study was to evaluate if improved HbA1c can influence vibration thresholds in adults with type 1 diabetes (T1DM). METHODS: VPTs were investigated at six frequencies (4-125 Hz) using VibroSense Meter in the sole of the foot at two occasions in 159 T1DM patients, at the heads of the first and fifth metatarsal bones, i.e. MTH1 and MTH5, respectively. The participants were divided into three groups: group A: HbA1c improved by more than 1 mmol/mol (n = 95), group B: HbA1c deteriorated by more than 1 mmol/mol (n = 48) and group C: HbA1c unchanged (± 1 mmol/mol) (n = 16) compared to baseline. RESULTS: In group A, the mean z-score, reflecting the combined effect of all VPTs, improved being lower at the follow-up than at the baseline [0.2 (- 0.3 to 1.2) vs. -0.1 (- 0.7 to 0.8), p = 0.00002]. VPTs improved at 4 and 64 Hz at both MTH1 (metatarsal head 1) and MTH5. The VPTs at 125 Hz frequency improved at MTH5, but not at MTH1. No significant differences were seen in group B or group C. CONCLUSIONS: Lower HbA1c and lower VPTs in T1DM patients were associated with improved VPT, suggesting a reversible effect on nerve function by improved metabolic control.

Initial increase in glucose variability during Ramadan fasting in non-insulin-treated patients with diabetes type 2 using continuous glucose monitoring.

There are no studies evaluating the glucose variability in different periods of Ramadan fasting in patients with type 2 diabetes using continuous glucose monitoring (CGM). This study examined the effect of Ramadan fasting on interstitial glucose (IG) variability in early,- late-, and post-Ramadan compared to pre-Ramadan days in non-insulin-treated type 2 diabetes patients. Participants had a CGM system connected 2 or 3 days before Ramadan start, which was removed on the third or fourth day of Ramadan. CGM performance continued for a total of 6 days. A second CGM performance started on the 27th or 28th day of Ramadan and ended on the 4th or 5th post-Ramadan day. First, CGM recordings were divided into pre-Ramadan and early-Ramadan CGM, and second recordings into late-Ramadan and post-Ramadan. At each visit, blood pressure, body weight, and waist circumference were measured, and fasting blood samples were collected for HbA1c and plasma glucose. All patients received recommended Ramadan education before Ramadan. Thirty-three patients (mean age 55.0 ± 9.8 years, 73% males) were prospectively included. IG variability, estimated as mean amplitude of glycaemic excursions (MAGE), increased significantly in early-Ramadan compared to pre-Ramadan (P = 0.006) but not in late-Ramadan and post-Ramadan recording days. Only patients on >2 anti-diabetic drugs (n = 16, P = 0.019) and those on sulphonylureas (n = 14, P = 0.003) showed significant increase in MAGE in early-Ramadan. No significant changes were seen in coefficient of variation, time in range, time in hyperglycaemia, or time in hypoglycaemia. Except for an initial increase in glucose variability, fasting Ramadan for patients with non-insulin-treated type 2 diabetes did not cause any significant changes in glucose variability or time in hypoglycaemia during CGM recording days compared to non-fasting pre-Ramadan period.

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; r(2) = 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.

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.

Exercise capacity in relation to body fat distribution and muscle fibre distribution in elderly male subjects with impaired glucose tolerance, type 2 diabetes and matched controls.

BACKGROUND: The aim of this study was to examine the impact of insulin sensitivity and muscle fibre composition to exercise capacity in individuals with type 2 diabetes (T2D), impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). METHODS: Thirty-nine male patients with T2D, 44 male subjects with IGT and 58 subjects with NGT matched for age, weight and body mass index (BMI) participated in the study. Insulin sensitivity was obtained with hyperinsulinemic-euglycemic clamps, muscle fibre distribution with a biopsy and exercise capacity from an incremental exercise test. Anthropometric measurements as height, weight, waist and hip circumference were performed. RESULTS: There were small differences between groups in waist hip ratio (WHR) with significance attained between NGT and T2D. There was a progressive reduction in exercise capacity, both expressed as VO(2peak) and work rate from subjects with NGT to IGT to T2D. Multiple regression analysis with VO(2peak) as dependent variable showed insulin sensitivity to be the most important factor followed by Type I fibres. WHR and capillary density also influenced the variance of VO(2peak). CONCLUSION: Exercise capacity is independently related to insulin sensitivity, muscle fibre composition and WHR in subjects with NGT, IGT and T2D who are matched for age and BMI.

Basic Management of Diabetes Mellitus: Practical guidelines.

Diabetes mellitus is a major health problem associated with microvascular and macrovascular complications, leading to increased morbidity and mortality. It is rapidly growing worldwide with a huge economical and social burden. Although prevention and treatment of diabetes and its complications play a key role in reducing its morbidity and mortality, they require an integrated team approach at national and international levels. Early diagnosis, correct treatment, and effective follow-up are essential in any health care system to prevent complications of diabetes and ensure patients' well being.

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). PATIENTS AND METHODS: Thirty-one patients (six females, 25 males), aged 60-79 years (mean 68 years) with GHD on stable cortisone and thyroxine substitution were studied. All men with gonadotropin deficiency had testosterone and one woman had oestrogen replacement. They were randomized in a double-blind manner to GH or placebo treatment for 6 months, followed by another 12 months GH (Humatrope, Eli Lilly & Co, Uppsala, Sweden). GH dose was 0.017 mg/kg/week for 1 month and then 0.033 mg/kg/week divided into daily subcutaneous injections at bedtime. Echocardiography, exercise capacity tests and serum lipid measurements were performed at 0, 6, 12 and 18 months. RESULTS: During the 6-month placebo-controlled period there were no significant changes in the placebo group, but in the GH-treated group there was a significant increase in IGF-I to normal levels for age, with median IGF-I from 6.9 to 18.5 nmol/l, increase in resting heart rate and maximal working capacity. During the open GH study, IGF-I increased from 8.7 to 19.2 nmol/l at 6 months and 18.8 nmol/l at 12 months (P