Exercise training decreases pancreatic fat content and improves beta cell function regardless of baseline glucose tolerance: a randomised controlled trial

Aims/hypothesis

Pancreatic fat accumulation may contribute to the development of beta cell dysfunction. Exercise training improves whole-body insulin sensitivity, but its effects on pancreatic fat content and beta cell dysfunction are unclear. The aim of this parallel-group randomised controlled trial was to evaluate the effects of exercise training on pancreatic fat and beta cell function in healthy and prediabetic or type 2 diabetic participants and to test whether the responses were similar regardless of baseline glucose tolerance.

Methods

Using newspaper announcements, a total of 97 sedentary 40–55-year-old individuals were assessed for eligibility. Prediabetes (impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes were defined by ADA criteria. Of the screened candidates, 28 healthy men and 26 prediabetic or type 2 diabetic men and women met the inclusion criteria and were randomised into 2-week-long sprint interval or moderate-intensity continuous training programmes in a 1:1 allocation ratio using random permuted blocks. The primary outcome was pancreatic fat, which was measured by magnetic resonance spectroscopy. As secondary outcomes, beta cell function was studied using variables derived from OGTT, and whole-body insulin sensitivity and pancreatic fatty acid and glucose uptake were measured using positron emission tomography. The measurements were carried out at the Turku PET Centre, Finland. The analyses were based on an intention-to-treat principle. Given the nature of the intervention, blinding was not applicable.

Results

At baseline, the group of prediabetic or type 2 diabetic men had a higher pancreatic fat content and impaired beta cell function compared with the healthy men, while glucose and fatty acid uptake into the pancreas was similar. Exercise training decreased pancreatic fat similarly in healthy (from 4.4% [3.0%, 6.1%] to 3.6% [2.4%, 5.2%] [mean, 95% CI]) and prediabetic or type 2 diabetic men (from 8.7% [6.0%, 11.9%] to 6.7% [4.4%, 9.6%]; p?=?0.036 for time effect) without any changes in pancreatic substrate uptake (p?≥?0.31 for time effect in both insulin-stimulated glucose and fasting state fatty acid uptake). In prediabetic or type 2 diabetic men and women, both exercise modes similarly improved variables describing beta cell function.

Conclusions/interpretation

Two weeks of exercise training improves beta cell function in prediabetic or type 2 diabetic individuals and decreases pancreatic fat regardless of baseline glucose tolerance. This study shows that short-term training efficiently reduces ectopic fat within the pancreas, and exercise training may therefore reduce the risk of type 2 diabetes.

Trial registration

ClinicalTrials.gov NCT01344928

Funding

This study was funded by the Emil Aaltonen Foundation, the European Foundation for the Study of Diabetes, the Finnish Diabetes Foundation, the Orion Research Foundation, the Academy of Finland (grants 251399, 256470, 281440, and 283319), the Ministry of Education of the State of Finland, the Paavo Nurmi Foundation, the Novo Nordisk Foundation, the Finnish Cultural Foundation, the Hospital District of Southwest Finland, the Turku University Foundation, and the Finnish Medical Foundation.

     

High dose intravenous methylprednisolone pulse therapy versus oral prednisone for thyroid-associated ophthalmopathy

PURPOSE: To compare the effectiveness of intravenous (i.v.) methylprednisolone pulse therapy and oral prednisone when used as the initial treatment of patients with mild or moderate thyroid-associated ophthalmopathy. METHODS: Thirty-three consecutive patients with thyroid-associated ophthalmopathy in Helsinki and Turku University Hospitals were randomly assigned either i.v. methylprednisolone pulse therapy (group A, n = 18) or oral prednisone (group B, n = 15). Treatment outcomes were measured by subjective changes in the grade of diplopia and quantitatively in several ophthalmic variables at 3 and 12 months. Any decision to proceed with additional treatment at 3 months was made on clinical grounds. The study was open in respect of both the initial treatment and the need for additional therapy. RESULTS: No significant differences in the grade of diplopia, proptosis or soft tissue activity scores were noted between groups A and B from 0 to 3 months. However, group A required additional forms of therapy at 3 months less frequently than did group B (p = 0.038). CONCLUSIONS: Our data suggest that i.v. methylprednisolone pulse therapy and oral prednisone are equally effective as initial treatments for thyroid-associated ophthalmopathy where diplopia, proptosis and signs of soft tissue inflammation are concerned. When additional treatment is required, i.v. methylprednisolone pulse therapy may be more effective than oral prednisone. However, the study's limitations meant that any decision to give additional treatment after the initial therapy was made on clinical grounds.     

Fragile X founder effects and new mutations in Finland

The apparent associations between fragile X mutations and nearby microsatellites may reflect both founder effects and microsatellite instability. To gain further insight into their relative contributions, we typed a sample of 56 unrelated control and 37 fragile X chromosomes from an eastern Finnish population for FMR1 CGG repeat lengths, AGG interspersion patterns, DXS548, FRAXAC1, FRAXE and a new polymorphic locus, Alu-L. In the controls, the most common FMR1 allele was 30 repeats with a range of 20 to 47 and a calculated heterozygosity of 88%. A strong founder effect was observed for locus DXS548 with 95% of fragile X chromosomes having the 21 CA repeat (196 bp) allele compared to 17% of controls, while none of the fragile X but 69% of controls had the 20 repeat allele. Although the FRAXAC1 locus is much closer than DXS548 to FMR1 (7 kb vs. 150 kb), there was no significant difference between fragile X and control FRAXAC1 allele distributions. The FRAXE repeat, located 600 kb distal to FMR1, was found to show strong linkage disequilibrium as well. A newly defined polymorphism, Alu-L, located at ∼40 kb distal to the FMR1 repeat, showed very low polymorphism in the Finnish samples. Analysis of the combined loci DXS548-FRAXAC1- FRAXE showed three founder haplotypes. Haplotype 21-19-16 was found on 27 (75%) of fragile X chromosomes but on none of controls. Three (8.4%) fragile X chromosomes had haplotypes 21-19-15, 21-19-20, and 21-19-25 differing from the common fragile X haplotype only in FRAXE. These could have arisen by recombination or from mutations of FRAXE. A second haplotype 21-18-17 was found in four (11.1%) fragile X chromosomes but only one (1.9%) control. This may represent a more recent founder mutation. A third haplotype 25-21-15, seen in two fragile X chromosomes (5.6%) and one (1.9%) control, was even less common and thus may represent an even more recent mutation or admixture of immigrant types. Analysis of the AGG interspersions within the FMR1 CGG repeat showed that 7/8 premutation chromosomes lacked an AGG whereas all controls had at least one AGG. This supports the hypothesis that the mutation of AGG to CGG leads to repeat instability and mutational expansion. © 1996 Wiley-Liss, Inc.     

Deletion in the FMR1 gene in a fragile-X male

The pathogenesis of Fragile-X syndrome is a consequence of absence of the FMR1 gene product associated with expansion of the CGG repeat and abnormal methylation of this and a CpG island 250 bp proximal to the CGG repeat located at exon 1 in the FMR1 gene. While this is usually the case, some suspected Fragile-X syndrome patients have been described with a mutation other than CGG expansion. We describe here an affected Fragile-X male, who was found to be mosaic of a full mutation of the CGG expansion and a deletion in the FMR1 gene. The patient's phenotype is probably mainly due to the effect of the full mutation of the repeat sequence. Thus, the influence of the deletion is difficult to evaluate. © 1996 Wiley-Liss, Inc.     

A nationwide survey of mortality in acromegaly

CONTEXT: Increased mortality in acromegaly has been confined to those with posttreatment basal GH of 2.5 microg/liter or greater, but the impact of IGF-I and pituitary radiotherapy on mortality has remained controversial. OBJECTIVE: The purpose of this nationwide survey was to examine the all-cause mortality of patients with acromegaly and evaluate the impact of treatment outcome and mode of treatment on survival. DESIGN, SETTING, AND PATIENTS: All-cause mortality of all patients with acromegaly diagnosed during January 1980 and December 1999 in the five university hospitals of Finland was followed up by the end of 2002 (12.5 +/- 5.6 yr) and compared with that of the general population by using age- and gender-adjusted standardized mortality ratios (SMRs). Logistic regression analysis was used to investigate factors related to mortality within the survey population. MAIN OUTCOME MEASURE: Mortality was the main outcome measure. RESULTS: Of the 334 patients, 56 (16.8%) had died during follow-up. SMR of the patients was 1.16 [confidence interval (CI) 0.85-1.54, not significant (NS)]. However, patients with basal serum GH concentration 2.5 microg/liter or greater (SMR 1.63, CI 1.10-2.35, P < 0.001) measured 5.2 +/- 4.4 yr after the initial treatment, and those irradiated (SMR 1.69, CI 1.05-2.58, P < 0.001) showed excess mortality. In a multivariate model, the effect of radiotherapy was of borderline significance only (P = 0.083). Posttreatment IGF-I levels, available for 72.2% of the patients, did not have impact on mortality. CONCLUSIONS: The posttreatment basal GH concentration less than 2.5 microg/liter in acromegalic patients is associated with a normal lifespan. Excess mortality is confined to poorly controlled patients and possibly those who have received conventional radiotherapy.     

Risk factors for clinical stress fractures in male military recruits: a prospective cohort study

This prospective study was aimed at evaluating risk factors for symptomatic stress fractures among 179 Finnish male military recruits, aged 18 to 20 years. The subjects were studied in the very beginning of the military service of 6 to 12 months in summer. Bone mineral content (BMC) and density (BMD) were measured by dual energy X-ray absorptiometry (DXA) at the lumbar spine and at the hip and heel ultrasound investigation was performed. Blood was sampled for determination of serum total and free testosterone, total and free estradiol, sex hormone-binding globulin (SHBG), procollagen type I N propeptide, total and carboxylated osteocalcin, tartrate-resistant acid phosphatase 5b, 25-hydroxyvitamin D (25-OHD), and intact parathyroid hormone (iPTH), as well as for studying the XbaI and PvuII polymorphisms of the estrogen receptor gene and the CAG repeat polymorphism of the androgen receptor gene. Urine was collected for the determination of N-terminal cross-linking telopeptide of type I collagen. Muscle strength was measured and Cooper's test was performed. Current exercise, smoking, calcium intake, and alcohol consumption were recorded using a questionnaire. During military service, 15 men experienced a stress fracture, diagnosed with X-ray in 14 and with nuclear magnetic resonance in one man. Those who experienced a fracture were taller than those who did not (P = 0.047). The result of Cooper's test was worse in the fracture group than in the non-fracture group (P = 0.026). Femoral neck and total hip BMC and BMD, adjusted for age, weight, height, exercise, smoking, and alcohol and calcium intake were lower (P = 0.021-0.041) for the fracture group. Stress fractures associated with higher iPTH levels (P = 0.022) but not with lower 25-OHD levels. Bone turnover markers as well as sex hormone and SHBG levels were similar for men with and without stress fracture. There was no difference in the genetic analyses between the groups. In conclusion, tall height, poor physical conditioning, low hip BMC and BMD, as well as high serum PTH level are risk factors for stress fractures in male Finnish military recruits. Given the poor vitamin D status of young Finnish men, intervention studies of vitamin D supplementation to lower serum PTH levels and to possibly reduce the incidence of stress fractures are warranted.     

Intratonsillar detection of 27 distinct viruses: A cross-sectional study

Palatine tonsils have been observed to harbor several distinct respiratory and herpesviruses in separate studies. In this study, the presence of these viruses in palatine tonsils was comprehensively studied in both children and adults. A cross-sectional analysis of 181 patients (median age 22 years; range, 2.6-66) operated for a benign tonsillar disease was conducted. Real-time polymerase chain reaction was performed to detect 27 distinct viruses in all: eight human herpesviruses, 16 respiratory viruses, parvo B19, and polyoma BK/JC viruses. Clinical characteristics of the patients and underlying conditions were evaluated. In total, 92% of patients had virus detected in tonsils (Epstein-Barr virus 72%, human herpesvirus 7, and 6B 54% and 16%, respectively, enterovirus 18%, parvovirus B19 7% and the rest <4%). No herpes simplex virus 2, varicella zoster virus, polyoma JC virus, parainfluenza-, metapneumo-, or coronaviruses were found. Enterovirus was more common in children and was frequently observed in the presence of HHV6B. None of the viruses showed a positive association to the tonsillar disease. Respiratory symptoms were not associated with the prevalence of viruses. This study comprehensively reports a cross-sectional view of intratonsillar virus infections in elective tonsillectomy patients in a wide age range cohort. Tonsils are a major virus reservoir for distinct herpes and respiratory viruses without a positive association with tonsillar disease or respiratory symptoms.     

Radicicol but not geldanamycin evokes oxidative stress response and efflux protein inhibition in ARPE-19 human retinal pigment epithelial cells

Drug delivery to retinal cells has represented a major challenge for ophthalmologists for many decades. However, drug targeting to the retina is essential in therapies against retinal diseases such as age-related macular degeneration, the most common reason of blindness in the developed countries. Retinal cells are chronically exposed to oxidative stress that contributes to cellular senescence and may cause neovascularization in the most severe age-related macular degeneration cases. Various pre- and clinical studies have revealed that heat shock protein 90 (HSP90) inhibitors, such as geldanamycin and radicicol, are promising drugs in the treatment of different malignant processes. In this study, our goal was to compare the effects of 0.1 microM, 1 microM or 5 microM geldanamycin or radicicol on the oxidative stress response, cytotoxicity, and efflux protein activity (a protein pump which removes drugs from cells) in ARPE-19 (human retinal pigment epithelial, RPE) cells. Our findings indicate that geldanamycin and radicicol increased HSP70 and HSP27 expression analyzed by western blotting. Cellular levels of protein carbonyls were increased in response to 0.1 microM (P=0.048 for 24 h, P=0.018 for 48 h) or 5 microM (P=0.030 for 24 h, P=0.046 for 48 h) radicicol but not to geldanamycin analyzed by ELISA assay. In addition, HNE-protein adducts were accumulated in the RPE cells exposed to 0.1 microM or 5 microM radicicol but not to geldanamycin analyzed by western blotting. However, MTT assay revealed that 5 microM geldanamycin reduced cellular viability 20-30% (P<0.05 for 24 h, P<0.01 for 48 h), but this was not observed at any radicicol concentration in RPE cells. Interestingly, the increased oxidative stress response was associated with efflux protein inhibition (20-30%) when the cells were exposed to 1 microM or 5 microM (P<0.05) radicicol, but not in geldanamycin-treated RPE cells. These novel findings help in understanding the influence of HSP90 inhibition and regulatory mechanisms of drug delivery to retinal cells.