Epigenome-wide association study of DNA methylation in maternal blood leukocytes with BMI in pregnancy and gestational weight gain.

OBJECTIVES: We aimed to discover CpG sites with differential DNA methylation in peripheral blood leukocytes associated with body mass index (BMI) in pregnancy and gestational weight gain (GWG) in women of European and South Asian ancestry. Furthermore, we aimed to investigate how the identified sites were associated with methylation quantitative trait loci, gene ontology, and cardiometabolic parameters. METHODS: In the Epigenetics in pregnancy (EPIPREG) sample we quantified maternal DNA methylation in peripheral blood leukocytes in gestational week 28 with Illumina's MethylationEPIC BeadChip. In women with European (n = 303) and South Asian (n = 164) ancestry, we performed an epigenome-wide association study of BMI in gestational week 28 and GWG between gestational weeks 15 and 28 using a meta-analysis approach. Replication was performed in the Norwegian Mother, Father, and Child Cohort Study, the Study of Assisted Reproductive Technologies (MoBa-START) (n = 877, mainly European/Norwegian). RESULTS: We identified one CpG site significantly associated with GWG (p 5.8 × 10-8) and five CpG sites associated with BMI at gestational week 28 (p from 4.0 × 10-8 to 2.1 × 10-10). Of these, we were able to replicate three in MoBa-START; cg02786370, cg19758958 and cg10472537. Two sites are located in genes previously associated with blood pressure and BMI. DNA methylation at the three replicated CpG sites were associated with levels of blood pressure, lipids and glucose in EPIPREG (p from 1.2 × 10-8 to 0.04). CONCLUSIONS: We identified five CpG sites associated with BMI at gestational week 28, and one with GWG. Three of the sites were replicated in an independent cohort. Several genetic variants were associated with DNA methylation at cg02786379 and cg16733643 suggesting a genetic component influencing differential methylation. The identified CpG sites were associated with cardiometabolic traits. GOV REGISTRATION NO: Not applicable.

Higher frequency of hospitalization but lower relative mortality for pandemic influenza in people with type 2 diabetes.

BACKGROUND: There is limited evidence linking type 2 diabetes (T2D) to influenza-related complications. OBJECTIVES: To test a set of research questions relating to pandemic influenza vaccination, hospitalization and mortality in people with and without T2D. METHODS: In this population-based cohort study, we linked individual-level data from several national registers for all Norwegian residents aged 30 years or more as of January 2009. People with or without T2D at baseline (n = 2 992 228) were followed until December 2013. We used Cox regression to estimate adjusted hazard ratios (aHRs). RESULTS: Pandemic influenza hospitalization was more common in individuals with T2D (aHR = 2.46, 95% CI 2.04-2.98). The mortality hazard ratio associated with hospitalization for pandemic influenza was lower in people with T2D (aHR = 1.82, 95% CI 1.21-2.74) than in those without T2D (aHR = 3.89, 95% CI 3.27-4.62). The same pattern was observed when restricting to 90-day mortality (aHR = 3.89, 95% CI 1.25-12.06 amongst those with T2D and aHR = 10.79, 95% CI 7.23-16.10 amongst those without T2D). The rate of hospitalization for pandemic influenza was 78% lower in those vaccinated compared to nonvaccinated amongst people with T2D (aHR = 0.22, 95% CI 0.11-0.39), whilst the corresponding estimate for those without T2D was 59% lower (aHR = 0.41, 95% CI 0.33-0.52). Mortality was 25% lower in those vaccinated compared to nonvaccinated amongst people with T2D (aHR = 0.75, 95% CI 0.73-0.77), whilst the corresponding estimate for those without T2D was 9% (aHR = 0.91, 95% CI 0.90-0.92). CONCLUSIONS: There may have been a lower threshold for pandemic influenza hospitalization for people with T2D, rather than more severe influenza infection. Our combined results support the importance of influenza vaccination amongst people with T2D, especially during pandemics.

Phenotypic and genotypic differences between Indian and Scandinavian women with gestational diabetes mellitus.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia. METHODS: Eighty-five GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N = 398, Finnish) and STORK/STORK-G (N = 780, Norwegian). RESULTS: Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women, was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased GDM risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations. CONCLUSIONS: Gestational diabetes mellitus is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences.

Diabetes prevalence among older people receiving care at home: associations with symptoms, health status and psychological well-being.

AIMS: To determine the prevalence of diabetes among older people receiving care at home, and to explore differences in sociodemographic and clinical characteristics, symptoms, health status, quality of life and psychological well-being between diabetes categories defined as HbA1c ≥ 48 mmol/mol (6.5%) and/or self-report. METHODS: A community-based sample of 377 people receiving care at home in Western Norway participated in a cross-sectional survey. Instruments included the MMSE-NR, Symptom Check-List, WHO Quality of Life-BREF (WHOQOL-BREF, global items), EuroQol EQ-5D-5L/EQ-5D-VAS and WHO-Five Well-Being Index (WHO-5). Participants were grouped into four categories: no diabetes, self-report only, HbA1c ≥ 48 mmol/mol (6.5%) and self-report, and HbA1c ≥ 48 mmol/mol (6.5%) only. RESULTS: Median age (IQR) was 86 (81-91) years and 34% of the sample were men. We identified 92 people (24%) with diabetes. Diabetes was more prevalent in men than women (34% vs. 20%, age-adjusted P = 0.005). Among people with diabetes, 14% were unaware of their diagnosis. There were significant differences in symptoms between the diabetes categories, with more symptoms (abnormal thirst, polyuria, genital itching, nausea, excessive hunger, perspiring, cold hands/feet, daytime sleepiness) among the groups with elevated HbA1c . Significant differences in WHO-5, WHOQOL-BREF and EQ-5D-5L between diabetes categories were identified, with the poorest scores in the group with undiagnosed diabetes. CONCLUSIONS: A high percentage of people with diabetes receiving care at home are unaware of their diagnosis. Diabetes deserves increased case-finding efforts and allocation of resources towards those receiving care at home to alleviate symptoms and the burden of inadequate diabetes care.

Ethnic differences in postpartum weight retention: a Norwegian cohort study.

OBJECTIVE: To explore ethnic differences in weight retention 14 weeks postpartum. DESIGN: Population-based cohort study. SETTING: The STORK Groruddalen Study. POPULATION: A multi-ethnic cohort of healthy pregnant women attending primary antenatal care at three public Child Health Clinics, in Oslo, Norway (n = 642). METHODS: An explanatory linear regression was performed to model the relationship between ethnicity and postpartum weight retention. Forward selection of 12 explanatory factors was used to adjust for potential confounding factors, based on univariate analysis and adjusted R(2) . MAIN OUTCOME MEASURE: Postpartum weight retention. RESULTS: Unadjusted mean postpartum weight retention was 2.3 (4.9) kg for women from Western Europe and varied from 3.7 (3.5) to 6.3 (4.7) kg among the five ethnic minority groups. The proportion of women in the highest quintile (postpartum weight retention >8.5-24.4 kg) significantly differed by ethnicity (P < 0.01 for the proportion of women from South Asia, the Middle East and Africa compared with Western Europeans). Women from all ethnic minority groups had a higher relative increase in weight from pre-pregnancy to postpartum (P < 0.01) compared with Western Europeans. After adjustments for significant exposures, women from the Middle East retained 2.0 kg (95% CI: 1.0-3.0), South Asia 2.8 kg (91.9-3.6), and Africa 4.4 kg (3.1-5.8) more than Western Europeans (P < 0.01). CONCLUSIONS: Significantly more women with an ethnic origin from South Asia, the Middle East and Africa had high postpartum weight retention compared with Western European women.

Weight gain, total fat gain and regional fat gain during pregnancy and the association with gestational diabetes: a population-based cohort study.

OBJECTIVE: In a multi-ethnic population-based study, we investigate the change in indicators of adiposity (being weight gain and gain of total fat, truncal fat and mean skinfold thickness) from early pregnancy to 28 weeks of gestation overall and across ethnic groups, and explore the association between the change in indicators of adiposity and gestational diabetes (GDM). DESIGN: Weight, skinfold thickness and bioelectrical impedance analysis were performed twice in 728 pregnant women in gestational week 15 (visit 1) and week 28 (visit 2). GDM was defined by the modified International Association of Diabetes in Pregnancy Study Group (IADPSG) criteria (1-hour glucose not available). RESULTS: An increase in all indicators of adiposity gave increased odds ratios (OR) for GDM. After adjusting for pre-pregnant body mass index, a 0.14 kg per week (one standard deviation (s.d.)) increase in truncal fat gave an OR of 1.31 (95% CI 1.10-1.56), while a 0.21 kg per week (one s.d.) weight gain gave an OR of 1.23 (95% CI 1.04-1.46) for GDM. The ORs for the indicators of adiposity remained after additional adjustments for insulin resistance in early pregnancy. When combining the effects of an ethnic origin, 0.14 kg per week (one s.d.) truncal fat gain and 4.7 kg m(-2) (one s.d.) increased pre-pregnant BMI the OR for South Asians was 5.9 (3.5-10.0) versus 2.1 (1.6-2.8) for Europeans. CONCLUSION: Weight gain and gain of total fat mass, mean skinfold thickness and especially truncal fat were all positively associated with GDM. South Asians, in particular, should be encouraged to avoid an excessive weight gain during pregnancy to reduce risk of GDM.

Objectively recorded physical activity in early pregnancy: a multiethnic population-based study.

This study aimed to compare objectively recorded physical activity (PA) levels and walking steps among pregnant women. Cross-sectional data from a multiethnic cohort (n = 823) of pregnant women consisting of 44% from Western countries, 24% from South Asia, 14% from Middle East, and 18% from other countries. PA and steps were recorded by the activity monitor SenseWear™ Pro3 Armband. A total of 678 women were included in the analysis. Western women walked significantly more steps and had higher moderate-to-vigorous-intensity physical activity (MVPA) levels compared with South Asian women per weekday and weekend day. Interaction terms (P = 0.008) between ethnicity (Western vs South Asian) and parity, and education, respectively, were identified: having ≥ 1 children was positively associated with steps during weekends in South Asians in contrast to Western women. Having <12 years education was associated with more MVPA time among South Asians in contrast to Western women. South Asian women are prone to low levels of PA during pregnancy and South Asian women without children and with higher education may have an elevated risk for an inactive lifestyle during pregnancy.

Objectively recorded physical activity and the association with gestational diabetes.

The aim of this population-based study was to assess the association between objectively recorded physical activity (PA) in early gestation and gestational diabetes mellitus (GDM) identified at 28 weeks of gestation in a multi-ethnic cohort of healthy pregnant women in Oslo, Norway. In total, 759 women were included. In early gestation (<20 weeks), light-, moderate-, and vigorous-intensity PA and number of steps were objectively recorded (SenseWear™ Armband Pro3), and self-reported PA, demographics, and anthropometrics were collected. The 75-g oral glucose tolerance test was performed at 28 weeks of gestation. Women with GDM had fewer objectively recorded steps (mean 7964 steps/day vs 8879 steps/day, P < 0.001) and minutes of moderate-to-vigorous-intensity PA (median 62 min/day vs 75 min/day, P = 0.004) in early gestation than women without GDM. Additionally, 30% of women with GDM compared with 44% (P < 0.001) of women without GDM self-reported regular PA before pregnancy. The significant inverse association between objectively recorded steps per day in early gestation and GDM persisted after adjustment for ethnic origin, weeks of gestation, age, parity, pre-pregnancy BMI, early life socioeconomic position, and self-reported regular PA before pregnancy. The adjusted odds ratio for GDM decreased 19% per standard deviation (3159 steps) increase in objectively recorded steps per day (P = 0.039). Daily life PA in early gestation measured as steps/day was associated with lower risk of GDM.

Improved health status with insulin degludec compared with insulin glargine in people with type 1 diabetes.

AIMS: The efficacy and safety of insulin degludec (degludec), a new-generation ultra-long-acting basal insulin, was compared with insulin glargine (glargine) in people with Type 1 diabetes mellitus in a 16-week, open-label, randomized trial. Health status, an important aspect of effective diabetes management, was also assessed. METHODS: Degludec (n = 59) or glargine (n = 59) were injected once daily, with insulin aspart at mealtimes. Health status assessment utilized the validated Short Form 36 Health Survey, version 2, which has two summary component scores for mental and physical well-being, each comprising four domains. RESULTS: At study end, HbA(1c) reductions were comparable between groups, but confirmed nocturnal hypoglycaemia was significantly less frequent with degludec [relative rate 0.42 (95% CI 0.25-0.69)], and overall hypoglycaemia numerically less frequent [relative rate 0.72 (95% CI 0.52-1.00)]. After 16 weeks, a significant improvement in Short Form 36 Health Survey mental component score of +3.01 (95% CI 0.32-5.70) was obtained for degludec against glargine, attributable to significant differences in the social functioning [+8.04 (95% CI 1.89-14.18)] and mental health domains [+2.46 (95% CI 0.10-4.82)]. For mental component score, Cohen's effect size was 0.42, indicating a small-to-medium clinically meaningful difference. The physical component score [+0.66 (95% CI -2.30 to 3.62)] and remaining domains were not significantly different between degludec and glargine. CONCLUSIONS: In the context of comparable overall glycaemic control with glargine, degludec improved mental well-being as measured using the mental component score of the Short Form 36 Health Survey. The improvements in overall mental component score and the underlying social functioning and mental health domains with degludec compared with glargine may relate to the observed reduction in hypoglycaemic events.

Irbesartan has no short-term effect on insulin resistance in hypertensive patients with additional cardiometabolic risk factors (i-RESPOND).

AIMS: Intervention studies have shown that angiotensin receptor blockers (ARB) may reduce the incidence of type 2 diabetes mellitus. It is currently unclear whether short-term therapy with ARBs affects metabolic parameters. METHODS: i-RESPOND, a randomised, controlled, multicentre, double-blind study evaluated the effect of 16 weeks of irbesartan vs. hydrochlorothiazide (HCTZ) on insulin resistance as well as on lipid and inflammatory parameters in hypertensive subjects with metabolic syndrome. Patients received irbesartan (150 mg/d; n = 211) or HCTZ (12.5 mg/d; n = 215), titrated to 300 mg/day and 25 mg/day respectively. In a second part of the study (weeks 16-28), patients initially randomised to irbesartan received additional HCTZ and vice versa. RESULTS: At week 16 both irbesartan and HCTZ had no effect on insulin resistance measured by the Matzuda index and beta-cell function. Similarly, in the second part of the study (week 16-28) no differences between irbesartan and HCTZ with respect to glucose metabolism were observed. However, irbesartan induced beneficial changes in high-sensitivity-C-reactive protein (hs-CRP) (irbesartan: -5.5 +/- 5.2%; HCTZ + 19.9 +/- 6.5%, p = 0.0024) and in urinary albumin/creatinine ratio (ACR) (irbesartan: -13%; HCTZ + 9%; p = 0.0041) compared with HCTZ despite a similar decrease in blood pressure in both treatment groups. Irbesartan and HCTZ were well tolerated and adverse events were comparable. CONCLUSION: Irbesartan did not show significant favourable effects on insulin resistance compared with HCTZ in this study; however, may have beneficial effects on inflammation and microalbuminuria in hypertensive patients with metabolic syndrome.

Long-term glycaemic effects of pioglitazone compared with placebo as add-on treatment to metformin or sulphonylurea monotherapy in PROactive (PROactive 18).

AIMS: To assess the long-term glycaemic effects, concomitant changes in medications and initiation of permanent insulin use (defined as daily insulin use for a period of > or = 90 days or ongoing use at death/final visit) with pioglitazone vs. placebo in diabetic patients receiving metformin or sulphonylurea monotherapy at baseline in the PROspective pioglitAzone Clinical Trial in macroVascular Events (PROactive). METHODS: In PROactive, patients with Type 2 diabetes and macrovascular disease were randomized to pioglitazone (force titrated to 45 mg/day) or placebo, in addition to other existing glucose-lowering therapies. In a post-hoc analysis, we categorized patients not receiving insulin at baseline and treated by oral monotherapy into two main cohorts: add-on to metformin alone (n = 514) and sulphonylurea alone (n = 1001). The follow-up averaged 34.5 months. RESULTS: There were significantly greater reductions in glycated haemoglobin (HbA(1c)) with pioglitazone than with placebo and more pioglitazone-treated patients achieved HbA(1c) targets, irrespective of the baseline oral glucose-lowering regimen and despite a decrease in the use of other glucose-lowering agents. Approximately twice as many in the placebo groups progressed to permanent insulin use than in the pioglitazone groups across the two cohorts: 3.4% for pioglitazone and 6.5% for placebo when added to metformin monotherapy and 6.3% and 14.8%, respectively, when added to sulphonylurea monotherapy. The overall safety of both dual therapies was good. CONCLUSIONS: Intensifying an existing oral monotherapy regimen to a dual oral regimen by adding pioglitazone resulted in sustained improvements in glycaemic control and reduced progression to insulin therapy. The efficacy and safety of adding pioglitazone to either metformin monotherapy or sulphonylurea monotherapy were good.

Long-term glycaemic control with metformin-sulphonylurea-pioglitazone triple therapy in PROactive (PROactive 17).

AIMS: We assessed the long-term glycaemic effects and the safety profile of triple therapy with the addition of pioglitazone vs. placebo in patients with Type 2 diabetes treated with combined metformin-sulphonylurea therapy in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive). METHODS: In a post-hoc analysis, we identified patients treated with metformin plus sulphonylurea combination therapy and not receiving insulin at baseline (n = 1314). In those patients, we compared the effects of pioglitazone (force-titrated to 45 mg/day, n = 654) vs. placebo (n = 660) on glycated haemoglobin (HbA(1c)) reduction, concomitant changes in medications and initiation of permanent insulin use (defined as daily insulin use for a period of > or = 90 days or ongoing use at death/final visit). RESULTS: Significantly greater reductions in HbA(1c) and greater proportions of patients with HbA(1c) at target were noted with pioglitazone vs, placebo, despite a decrease in the use of other oral glucose-lowering agents. There was an approximate twofold increase in progression to permanent insulin use in the placebo group vs. the pioglitazone group: 31.1 vs. 16.1%, respectively, when added to combination therapy. The overall safety of the metformin-sulphonylurea-pioglitazone triple therapy was good. CONCLUSIONS: Intensifying an existing dual oral therapy regimen to a triple oral regimen by adding pioglitazone to the classical metformin-sulphonylurea combination resulted in sustained improvements in glycaemic control and reduced progression to insulin therapy. The advantages and disadvantages of adding pioglitazone instead of adding basal insulin should be assessed further.

Insulin-induced weight gain and cardiovascular events in patients with type 2 diabetes. A report from the DIGAMI 2 study.

AIM: We investigated whether insulin treatment-induced weight gain was accompanied by increased cardiovascular (CV) mortality and morbidity in the second Diabetes Insulin Glucose in Acute Myocardial Infarction (DIGAMI 2) study. METHODS: We studied the 865 patients who survived during 12 months without any change in their glucose-lowering (GL) therapy. They were divided into four subgroups according to GL treatment: group I, no pharmacological GL treatment (n = 99); group II, oral hypoglycaemic agents (n = 250); group III, new insulin treatment (n = 245) and group IV, insulin before inclusion continued during the first year of follow up (n = 271). RESULTS: Patients who started on insulin (group III) experienced an average body weight increase of 2.3 (1.5-3.2) kg during the first year of treatment, whereas weight remained unchanged in groups I, II and IV. The incidence of non-fatal reinfarction was higher in group III compared with the other groups (hazard ratio (HR) = 2.5, p = 0.011) and CV mortality was higher in group IV (HR = 2.4, p = 0.003). When the subjects were grouped in quartiles according to maximal body weight increase, those in the lowest quartile experienced the highest CV mortality. Each kilogram increase in weight reduced the risk for CV death with 6%. The incidence of reinfarction did not differ between quartiles. CONCLUSIONS: Initiation of insulin treatment after myocardial infarction was associated with a significant increase in weight and incidence of reinfarction. The increase in weight did, however, not explain the increased rate of reinfarction.

Comparison of genetic risk in three candidate genes (TCF7L2, PPARG, KCNJ11) with traditional risk factors for type 2 diabetes in a population-based study--the HUNT study.

UNLABELLED: We studied the impact of genetic and traditional risk factors for type 2 diabetes in a large, population-based study from Nord-Trøndelag county in Norway (HUNT), in both cross-sectional and prospective design. MATERIAL AND METHODS: 65,905 individuals participated in the HUNT study. We studied a randomly selected group of 869 individuals with self-reported diabetes or non-fasting serum glucose >or=11.1 mmol/L and 2,080 non-diabetic control subjects with non-fasting serum glucose <5.5 mmol/L. Four candidate polymorphisms in the three genes TCF7L2 (rs12255372 and rs7903146), PPARG (rs1801282), KCNJ11 (rs5219) and traditional risk factors were studied. RESULTS: Risk alleles of the TCF7L2 gene showed increased risk of diabetes even when controlled for traditional diabetes risk factors (diabetes in family, waist circumference, physical activity, BMI, SBP and total and HDL-cholesterol) in both a cross-sectional and prospective setting (cross-sectional: rs12255372 OR 1.61 (1.31-1.99), rs7903146 OR 1.48 (1.20-1.83) and prospective: rs12255372 OR 1.59 (1.22-2.07), rs7903146 OR 1.47 (1.11-1.93)). The risk alleles of TCF7L2 indicated impaired beta-cell function in patients and control subjects. The population attributable risks for diabetes with TCF7L2 risk alleles were 15 % and with diabetes in a first-degree relative 31 %. CONCLUSION: The risk alleles of the TCF7L2 gene (rs12255372 and rs7903146) were strongly associated with type 2 diabetes, even after controlling for traditional risk factors in both a cross-sectional and prospective setting. These risk alleles were associated with indices of reduced beta-cell function.

Global mRNA sequencing of human skeletal muscle: Search for novel exercise-regulated myokines.

OBJECTIVE: Skeletal muscle is an important secretory organ, producing and releasing numerous myokines, which may be involved in mediating beneficial health effects of physical activity. More than 100 myokines have been identified by different proteomics approaches, but these techniques may not detect all myokines. We used mRNA sequencing as an untargeted approach to study gene expression of secreted proteins in skeletal muscle upon acute as well as long-term exercise. METHODS: Twenty-six middle-aged, sedentary men underwent combined endurance and strength training for 12 weeks. Skeletal muscle biopsies from m. vastus lateralis and blood samples were taken before and after an acute bicycle test, performed at baseline as well as after 12 weeks of training intervention. We identified transcripts encoding secretory proteins that were changed more than 1.5-fold in muscle after exercise. Secretory proteins were defined based on either curated UniProt annotations or predictions made by multiple bioinformatics methods. RESULTS: This approach led to the identification of 161 candidate secretory transcripts that were up-regulated after acute exercise and 99 that where increased after 12 weeks exercise training. Furthermore, 92 secretory transcripts were decreased after acute and/or long-term physical activity. From these responsive transcripts, we selected 17 candidate myokines sensitive to short- and/or long-term exercise that have not been described as myokines before. The expression of these transcripts was confirmed in primary human skeletal muscle cells during in vitro differentiation and electrical pulse stimulation (EPS). One of the candidates we identified was macrophage colony-stimulating factor-1 (CSF1), which influences macrophage homeostasis. CSF1 mRNA increased in skeletal muscle after acute and long-term exercise, which was accompanied by a rise in circulating CSF1 protein. In cultured muscle cells, EPS promoted a significant increase in the expression and secretion of CSF1. CONCLUSION: We identified 17 new, exercise-responsive transcripts encoding secretory proteins. We further identified CSF1 as a novel myokine, which is secreted from cultured muscle cells and up-regulated in muscle and plasma after acute exercise.

Myostatin in relation to physical activity and dysglycaemia and its effect on energy metabolism in human skeletal muscle cells.

AIM: Some health benefits of exercise may be explained by an altered secretion of myokines. Because previous focus has been on upregulated myokines, we screened for downregulated myokines and identified myostatin. We studied the expression of myostatin in relation to exercise and dysglycaemia in skeletal muscle, adipose tissue and plasma. We further examined some effects of myostatin on energy metabolism in primary human muscle cells and Simpson-Golabi-Behmel syndrome (SGBS) adipocytes. METHODS: Sedentary men with or without dysglycaemia underwent a 45-min acute bicycle test before and after 12 weeks of combined endurance and strength training. Blood samples and biopsies from m. vastus lateralis and adipose tissue were collected. RESULTS: Myostatin mRNA expression was reduced in skeletal muscle after acute as well as long-term exercise and was even further downregulated by acute exercise on top of 12-week training. Furthermore, the expression of myostatin at baseline correlated negatively with insulin sensitivity. Myostatin expression in the adipose tissue increased after 12 weeks of training and correlated positively with insulin sensitivity markers. In cultured muscle cells but not in SGBS cells, myostatin promoted an insulin-independent increase in glucose uptake. Furthermore, muscle cells incubated with myostatin had an enhanced rate of glucose oxidation and lactate production. CONCLUSION: Myostatin was differentially expressed in the muscle and adipose tissue in relation to physical activity and dysglycaemia. Recombinant myostatin increased the consumption of glucose in human skeletal muscle cells, suggesting a complex regulatory role of myostatin in skeletal muscle homeostasis.

The exercise-regulated myokine chitinase-3-like protein 1 stimulates human myocyte proliferation.

AIM: Chitinase-3-like protein 1 (CHI3L1) is involved in tissue remodelling and inflammatory processes. Plasma levels are elevated in patients with insulin resistance and T2DM. We recently showed that CHI3L1 and its receptor protease-activated receptor 2 (PAR-2) are expressed in skeletal muscle. Activation of PAR-2 by CHI3L1 protects against TNF-α-induced inflammation and insulin resistance. However, the effect of exercise on CHI3L1 and PAR-2 signalling remains unknown. The aim of this work was to study the impact of exercise on CHI3L1 production and the effect of CHI3L1/PAR-2 signalling on skeletal muscle growth and repair. METHODS: Three human exercise studies were used to measure CHI3L1 plasma levels (n = 32). In addition, muscle and adipose tissue CHI3L1 mRNA expression was measured in response to acute and long-term exercise (n = 24). Primary human skeletal muscle cells were differentiated in vitro, and electrical pulse stimulation was applied. In addition, myoblasts were incubated with CHI3L1 protein and activation of MAP kinase signalling as well as proliferation was measured. RESULTS: Circulating CHI3L1 levels and muscle CHI3L1 mRNA were increased after acute exercise. In addition, CHI3L1 mRNA expression as well as CHI3L1 secretion was enhanced in electrically stimulated cultured myotubes. Incubation of cultured human myoblasts with CHI3L1 protein leads to a strong activation of p44/42, p38 MAPK and Akt as well as enhanced myoblast proliferation. CONCLUSION: Our findings suggest that CHI3L1 is induced by acute exercise and that CHI3L1/PAR-2 signalling activates myocyte proliferation, which is important for restructuring of skeletal muscle in the response to exercise training.

Long-term randomized placebo-controlled double-blind therapeutic comparison of glipizide and glyburide. Glycemic control and insulin secretion during 15 months.

OBJECTIVE: To examine the long-term (15 months) effects on glycemic control and insulin secretion of glipizide and glyburide treatment in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Prospective, randomized, double-blind, placebo-controlled study on 46 NIDDM patients comparing fasting levels and test-meal responses of glucose and insulin during 15 months of follow-up. RESULTS: A comparable reduction in HbA1c levels by both agents versus placebo was observed throughout the study period, but after a marked initial reduction in both sulfonylurea groups, all three groups showed gradually increasing HbA1c levels. However, both glipizide and glyburide achieved and maintained lowered postprandial glucose levels and increased fasting and postprandial insulin levels compared with placebo. CONCLUSIONS: Both glipizide and glyburide may achieve and maintain glycemic reduction and stimulation of insulin secretion during long-term treatment. However, these agents do not prevent the gradual increase in overall glycemia that develops over time in NIDDM patients.

Hyperproinsulinemia of type II diabetes is not present before the development of hyperglycemia.

OBJECTIVE: To examine proinsulin and insulin levels in first-degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Comparison of insulin and proinsulin responses to an oral glucose tolerance test in four groups of individuals: 1) 31 patients with newly diagnosed NIDDM treated with diet alone, 2) 34 first-degree relatives of NIDDM patients with impaired glucose tolerance (IGT), 3) 26 relatives with normal glucose tolerance (NGT), and 4) 30 subjects without a family history of diabetes. RESULTS: Both fasting and post-glucose levels of proinsulin were elevated in patients with diabetes, but not in the relatives with IGT or NGT. Levels of true insulin were highest in the diabetic group, followed by the subjects with IGT, and were lowest among relatives with NGT. Proinsulin levels correlated with glucose levels, suggesting that hyperglycemia is the main stimulus for increased proinsulin secretion. CONCLUSIONS: First-degree relatives of NIDDM patients, who have a high risk of developing diabetes, do not exhibit elevated levels of fasting or glucose-stimulated proinsulin as long as their fasting glucose levels remain normal.

Lifestyle changes may reverse development of the insulin resistance syndrome. The Oslo Diet and Exercise Study: a randomized trial.

OBJECTIVE: To compare and assess the single and joint effect of diet and exercise intervention for 1 year on insulin resistance and the development leading toward the insulin resistance syndrome. RESEARCH DESIGN AND METHODS: An unmasked, randomized 2 x 2 factorial intervention trial was applied with a duration of 1 year for each participant. The trial comprised 219 men and women with diastolic blood pressure of 86-99 mmHg, HDL cholesterol < 1.20 mmol/l, triglycerides > 1.4 mmol/l, total cholesterol of 5.20-7.74 mmol/l, and BMI > 24 kg/m2. Participants were randomly allocated to diet group (n = 35), diet and exercise group (n = 67), exercise group (n = 54), and control group (n = 43). The diet included increased intake of fish and reduced total fat intake. The exercise program entailed supervised endurance exercise three times a week. Baseline cross-sectional changes and 1-year changes in insulin resistance, fasting serum levels of insulin, C-peptide, proinsulin, glucose, and lipids as well as weight, mean blood pressure, and plasminogen activator inhibitor 1 (PAI-1) values were recorded. RESULTS: The cross-sectional results at baseline showed significant correlations between the calculated insulin resistance and BMI (r = 0.54) and correlations between the mean blood pressure (mBP) (r = 0.26) and PAI-1 (r = 0.40). The 1-year diet intervention gave a significant decrease in the calculated insulin resistance from 4.6 to 4.2 and a positive correlation between the changes in insulin resistance and changes in BMI (r = 0.40). The diet and exercise intervention also led to significantly decreased insulin resistance (from 5.0 to 4.0). The exercise intervention did not significantly change insulin resistance. CONCLUSIONS: The cross-sectional and 1-year intervention results supported each other and underscored the important connection between increased BMI and the development leading toward the insulin resistance syndrome.