The relationship between prescribed pre-operative knee-extensor exercise dosage and effect on knee-extensor strength prior to and following total knee arthroplasty: a systematic review and meta-regression analysis of randomized controlled trials.

OBJECTIVE: The aim of this systematic review was to evaluate the relationship between prescribed knee-extensor strength exercise dosage in pre-operative exercise intervention and the effect on knee-extensor muscle strength prior to and following TKA. Additional meta-analyses report the effect of pre-habilitation on outcomes prior to and following TKA. DESIGN: A systematic literature search was performed including RCT's evaluating the effect of pre-operative exercise prior to and following TKA. Meta-regression analysis was performed to evaluate the dose-response relationship between prescribed exercise dose and the pooled effect, measured as standardized mean difference (SMD). The prescribed exercise dose was quantified using a formula accounting for as many exercise descriptors as possible. Risk of bias in the included trials was assessed using the Cochrane Risk of Bias Tool. RESULTS: Twelve trials with 616 patients were included. Meta-regression analysis showed no relationship between prescribed pre-operative knee-extensor exercise dosage and change in knee-extensor strength neither prior to (slope 0.0005 [95%CI -0.007 to 0.008]) or 3 months following TKA (slope 0.0014 [95%CI -0.006 to 0.009]). Prior to TKA, a moderate effect favoring pre-operative exercise for increase in knee-extensor strength was found (SMD 0.50 [95%CI 0.12 to 0.88]), but not at 3 months following TKA (SMD -0.01 [95%CI -0.45 to 0.43]). Risk of bias was generally assessed as unclear. CONCLUSION: Meta-regression analysis of existing trials suggests no relationship between the prescribed pre-operative knee-extensor exercise dosage and the change in knee-extensor strength observed prior to and following TKA. Pre-operative exercise including knee-extensor muscle strength exercise increased knee-extensor strength moderately prior to but not 3 months following TKA. PROTOCOL REGISTRATION: PROSPERO ID (CRD42018076308) (http://www.crd.york.ac.uk/PROSPERO/).

Effect of extended scope physiotherapists assessments in orthopaedic diagnostic setting: a systematic review.

BACKGROUND: Patients with musculoskeletal diseases can potentially be assessed by an extended scope physiotherapist (ESP) instead of by an orthopaedic surgeon (OS). OBJECTIVES: To evaluate the effectiveness of the diagnostic musculoskeletal assessment performed by ESP compared to OS. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, PEDro and reference lists of included studies and previous reviews were searched in November 2015. ELIGIBILITY CRITERIA: Studies were included if they evaluated adults with a musculoskeletal disease referred to an outpatient orthopaedic clinic where a diagnostic assessment had been conducted by an ESP. DATA EXTRACTION: Data were extracted using a customised data extraction sheet. Two reviewers using checklists evaluated methodological independently. RESULTS: We included one randomised controlled trial and 31 observational studies. Diagnostic agreement between ESPs and OSs was 65 to 100% across studies. Health care cost savings for diagnostic assessments performed by ESPs were 27 to 49% compared to OSs. Overall, 77 to 100% of the patients were satisfied with the ESP assessment. Results were comparable on diagnostic agreement, cost and satisfaction in studies with high, moderate and low risk of bias. LIMITATIONS: Risk of bias in the included studies. CONCLUSION AND IMPLICATION OF KEY FINDINGS: Diagnostic assessments performed by ESP may be as beneficial as or even better than assessment performed by OSs in terms diagnostic agreement, costs and satisfaction. However, the methodological quality was generally too low to determine the clear effectiveness of ESP assessment, and more high quality studies are needed. Systematic review registration number: PROSPERO CRD42014014229.

Prevalence of depressive disorder among patients with fibromyalgia: Systematic review and meta-analysis.

BACKGROUND: It is acknowledged that fibromyalgia (FM) as a medical (rheumatological) disorder and major depressive disorder (MDD) as a mental disorder often co-occurs, but the inconsistency is prevailing at study-level and no overall estimate of the co-occurrence exist. AIMS: This systematic review and meta-analysis aimed to estimate the overall point- and life-time prevalence of MDD among FM patients based on structured clinical interviews (SCI); and to estimate the point-prevalence of MDD among FM patients based on screening symptom scales (SSS). METHOD: The electronical databases MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and PsycINFO were searched for papers that reported on prevalence of MDD among FM patients. Eligible studies were included in a random effects meta-analysis pooling the prevalence of depression. RESULTS: The literature search identified 11 eligible studies for the meta-analysis. For SCI, the overall pooled point-prevalence (PP) was 25% (95% CI 19 to 31%), and life-time prevalence (LP) was 65% (95% CI 59 to 71%). When estimating the PP with self-administered SSS the overall pooled PP was 45% (95% CI 32 to 59%), and a single clinician-administered SSS yielded a PP of 23% (95% CI 10 to 41%). There was low inconsistency for the SCI and high inconsistency for the SSS. CONCLUSION: One fourth of all FM patients had MDD, and more than half experienced MDD during their life-time according to clinician-administered instruments. Prevalence of MDD was almost twice as high when using self-administered symptom scales and may be likely to overestimate the co-occurrence.

Effects of 6 months supervised physical training on muscle strength and aerobic capacity in patients undergoing Roux-en-Y gastric bypass surgery: a randomized controlled trial.

Obesity and physical inactivity are major health problems. Roux-en-Y gastric bypass (RYGB) surgery results in significant weight loss and reduces obesity-related morbidity and mortality. Physical activity lowers the risk of cardiovascular disease and premature death. The aims of this study were to elucidate the effects of RYGB followed by 6 months of supervised physical training on physical capacity. In a randomized controlled trial, 60 participants eligible for RYGB were randomized 6 months post-surgery to either two weekly physical training sessions for 26 weeks (INT) or a control group (CON). Aerobic capacity (VO2 max), muscle strength (MS) of the shoulder and hip and physical function were measured pre-surgery and 6, 12 and 24 months post-surgery. RYGB per se decreased MS in all tested muscle groups, had no effects on VO2 max but improved physical function. After the intervention, INT had a significant 0.33 L min-1 increase in VO2 max compared to CON (95% CI: 0.07-0.57, P = 0.013). Furthermore, MS in the hip adductor increased significantly with 13 N (95% CI: 3.6-22.4, P = 0.007) and a between-group difference was found in the Stair Climb Test (0.46 repetitions [95% CI: 0.02-0.91, P = 0.042]). The effects were not maintained at follow-up. Supervised physical training following RYGB improved VO2 max, hip MS and physical function, but the positive effects were not maintained at follow-up. While activities of daily life may become easier as a result of RYGB, the observed extensive post-operative loss of MS requires more attention to increase the patient's physical capacity prospectively.

Adrenaline and cortisol levels are lower during nighttime than daytime hypoglycaemia in children with type 1 diabetes.

AIM: We investigated children's counter regulatory hormone profiles during a hyperinsulinaemic hypoglycaemic clamp procedure at day and night. METHODS: In 2013, we assessed the counter regulatory response to hypoglycaemia in eight outpatients with type 1 diabetes, recruited from the Herlev Hospital, Denmark, at a mean age of 9.6 ± 2.3 years. Hyperinsulinaemic 80 mU/m2 /min clamps were performed with a stepwise reduction in plasma glucose from euglycaemia (7-9 mmol/L) to hypoglycaemia (<3.5 mmol/L) and the glucose nadir (≤2.2 mmol/L) during the day and night. Adrenaline, cortisol, glucagon and growth hormone levels were assessed. RESULTS: Adrenaline and growth hormone levels were higher during the day versus the night (p = 0.04 and p = 0.01, respectively). However, at the glucose nadir, the level of adrenaline was lower during the night than the day (0.6 ± 0.2 versus 1.9 ± 0.5 nmol/L, p = 0.016) and cortisol was lower during the day than the night (42 ± 15 versus 319 ± 81 nmol/L, p = 0.016). No differences were demonstrated for glucagon and growth hormone levels based on the same criteria. CONCLUSION: The adrenaline response was blunted during nocturnal iatrogenic hypoglycaemia in our study cohort, and no increase in cortisol levels was demonstrated.

Hidradenitis suppurativa and electrocardiographic changes: a cross-sectional population study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease, recently associated with metabolic syndrome, subclinical atherosclerosis and increased risk of cardiovascular disease. OBJECTIVES: To investigate the hitherto unknown electrocardiographic (ECG) changes associated with HS, which have recently been associated with significant cardiovascular burden. METHODS: Data were obtained from the cross-sectional Danish General Population Study (GESUS). HS diagnosis was based on a validated self-reported questionnaire; 404 individuals met the HS diagnosis criteria and 19 001 controls without HS were identified. Severity of HS was staged according to a modified Hurley score. The ECG parameters of heart rate (HR), PR interval, QRS duration, JTc interval and QTc interval were obtained from 12-lead resting ECGs. We investigated the difference in means by unpaired t-test or anova. RESULTS: HR was significantly higher [mean difference 2·3 beats per min (bpm), 95% confidence interval (CI) 1·2-3·4; P < 0·01] when adjusting for age and sex, but when adjusting for multivariates, there was no significant difference (0·3 bpm, 95% CI -0·7 to 1·4; P = 0·52). Severe HS was significantly associated with increased HR across all models (2·9 bpm, 95% CI 0·7-5·1; P = 0·01). Mean QRS duration was significantly shorter in the group with mild HS but not in the groups with moderate and severe HS. CONCLUSIONS: Mean resting HR in patients with severe HS was significantly higher compared with controls. Given that resting HR is associated with increased risk of all-cause and cardiovascular mortality, and that patients with HS have increased risk of cardiovascular events, this finding is potentially important, easily testable and intervenable.

Impact of a daily exercise dose on knee joint cartilage - a systematic review and meta-analysis of randomized controlled trials in healthy animals.

OBJECTIVE: To investigate the impact of a daily exercise dose on cartilage composition and thickness, by conducting a systematic review of randomized controlled trials (RCTs) involving healthy animals. METHODS: A narrative synthesis of the effect of a daily exercise dose on knee cartilage aggrecan, collagen and thickness was performed. A subset of studies reporting sufficient data was combined in meta-analysis using a random-effects model. Meta-regression analyses were performed to investigate the impact of covariates. RESULTS: Twenty-nine RCTs, involving 64 comparisons, were included. In the low dose exercise group, 21/25 comparisons reported decreased or no effect on cartilage aggrecan, collagen and thickness. In the moderate dose exercise group, all 12 comparisons reported either no or increased effect. In the high dose exercise group, 19/27 comparisons reported decreased effect. A meta-analysis of 14 studies investigating cartilage thickness showed no effect in the low dose exercise group (SMD -0.02; 95% CI -0.42 to 0.38; I2 = 0.0%), large but non-significant cartilage thickening in the moderate dose exercise group (SMD 0.95; 95% CI -0.33 to 2.23; I2 = 72.1%) and non-significant cartilage thinning in the high dose exercise group (SMD -0.19; 95% CI -0.49 to 0.12; I2 = 0.0%). Results were independent of analyzed covariates. The overall quality of the studies was poor because of inadequate reporting of data and high risk of bias. CONCLUSIONS: Our results suggest that the relationship between daily exercise dose and cartilage composition, but not necessarily cartilage thickness, may be non-linear. While we found inconclusive evidence for a low daily dose of exercise, a high daily dose of exercise may have negative effects and a moderate daily dose of exercise may have positive effects on cartilage matrix composition in healthy animals.

Arthroscopic surgery for degenerative knee: systematic review and meta-analysis of benefits and harms.

OBJECTIVE: To determine benefits and harms of arthroscopic knee surgery involving partial meniscectomy, debridement, or both for middle aged or older patients with knee pain and degenerative knee disease. DESIGN: Systematic review and meta-analysis. MAIN OUTCOME MEASURES: Pain and physical function. DATA SOURCES: Systematic searches for benefits and harms were carried out in Medline, Embase, CINAHL, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to August 2014. Only studies published in 2000 or later were included for harms. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials assessing benefit of arthroscopic surgery involving partial meniscectomy, debridement, or both for patients with or without radiographic signs of osteoarthritis were included. For harms, cohort studies, register based studies, and case series were also allowed. RESULTS: The search identified nine trials assessing the benefits of knee arthroscopic surgery in middle aged and older patients with knee pain and degenerative knee disease. The main analysis, combining the primary endpoints of the individual trials from three to 24 months postoperatively, showed a small difference in favour of interventions including arthroscopic surgery compared with control treatments for pain (effect size 0.14, 95% confidence interval 0.03 to 0.26). This difference corresponds to a benefit of 2.4 (95% confidence interval 0.4 to 4.3) mm on a 0-100 mm visual analogue scale. When analysed over time of follow-up, interventions including arthroscopy showed a small benefit of 3-5 mm for pain at three and six months but not later up to 24 months. No significant benefit on physical function was found (effect size 0.09, -0.05 to 0.24). Nine studies reporting on harms were identified. Harms included symptomatic deep venous thrombosis (4.13 (95% confidence interval 1.78 to 9.60) events per 1000 procedures), pulmonary embolism, infection, and death. CONCLUSIONS: The small inconsequential benefit seen from interventions that include arthroscopy for the degenerative knee is limited in time and absent at one to two years after surgery. Knee arthroscopy is associated with harms. Taken together, these findings do not support the practise of arthroscopic surgery for middle aged or older patients with knee pain with or without signs of osteoarthritis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014009145.

Arthroscopic surgery for degenerative knee: systematic review and meta-analysis of benefits and harms.

OBJECTIVE: To determine benefits and harms of arthroscopic knee surgery involving partial meniscectomy, debridement, or both for middle aged or older patients with knee pain and degenerative knee disease. DESIGN: Systematic review and meta-analysis. MAIN OUTCOME MEASURES: Pain and physical function. DATA SOURCES: Systematic searches for benefits and harms were carried out in Medline, Embase, CINAHL, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to August 2014. Only studies published in 2000 or later were included for harms. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials assessing benefit of arthroscopic surgery involving partial meniscectomy, debridement, or both for patients with or without radiographic signs of osteoarthritis were included. For harms, cohort studies, register based studies, and case series were also allowed. RESULTS: The search identified nine trials assessing the benefits of knee arthroscopic surgery in middle aged and older patients with knee pain and degenerative knee disease. The main analysis, combining the primary endpoints of the individual trials from three to 24 months postoperatively, showed a small difference in favour of interventions including arthroscopic surgery compared with control treatments for pain (effect size 0.14, 95% confidence interval 0.03 to 0.26). This difference corresponds to a benefit of 2.4 (95% confidence interval 0.4 to 4.3) mm on a 0-100 mm visual analogue scale. When analysed over time of follow-up, interventions including arthroscopy showed a small benefit of 3-5 mm for pain at three and six months but not later up to 24 months. No significant benefit on physical function was found (effect size 0.09, -0.05 to 0.24). Nine studies reporting on harms were identified. Harms included symptomatic deep venous thrombosis (4.13 (95% confidence interval 1.78 to 9.60) events per 1000 procedures), pulmonary embolism, infection, and death. CONCLUSIONS: The small inconsequential benefit seen from interventions that include arthroscopy for the degenerative knee is limited in time and absent at one to two years after surgery. Knee arthroscopy is associated with harms. Taken together, these findings do not support the practise of arthroscopic surgery for middle aged or older patients with knee pain with or without signs of osteoarthritis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014009145.

Efficacy and safety of ginger in osteoarthritis patients: a meta-analysis of randomized placebo-controlled trials.

The aim of this study was to assess the clinical efficacy and safety of oral ginger for symptomatic treatment of osteoarthritis (OA) by carrying out a systematic literature search followed by meta-analyses on selected studies. Inclusion criteria were randomized controlled trials (RCTs) comparing oral ginger treatment with placebo in OA patients aged >18 years. Outcomes were reduction in pain and reduction in disability. Harm was assessed as withdrawals due to adverse events. The efficacy effect size was estimated using Hedges' standardized mean difference (SMD), and safety by risk ratio (RR). Standard random-effects meta-analysis was used, and inconsistency was evaluated by the I-squared index (I(2)). Out of 122 retrieved references, 117 were discarded, leaving five trials (593 patients) for meta-analyses. The majority reported relevant randomization procedures and blinding, but an inadequate intention-to-treat (ITT) analysis. Following ginger intake, a statistically significant pain reduction SMD = -0.30 ([95% CI: [(-0.50, -0.09)], P = 0.005]) with a low degree of inconsistency among trials (I(2) = 27%), and a statistically significant reduction in disability SMD = -0.22 ([95% CI: ([-0.39, -0.04)]; P = 0.01; I(2) = 0%]) were seen, both in favor of ginger. Patients given ginger were more than twice as likely to discontinue treatment compared to placebo ([RR = 2.33; 95% CI: (1.04, 5.22)]; P = 0.04; I(2) = 0%]). Ginger was modestly efficacious and reasonably safe for treatment of OA. We judged the evidence to be of moderate quality, based on the small number of participants and inadequate ITT populations. Prospero: CRD42011001777.

Knee extensor muscle weakness is a risk factor for development of knee osteoarthritis. A systematic review and meta-analysis.

The objective of this study was to perform a systematic review and meta-analysis on the association between knee extensor muscle weakness and the risk of developing knee osteoarthritis. A systematic review and meta-analysis was conducted with literature searches in Medline, SPORTDiscus, EMBASE, CINAHL, and AMED. Eligible studies had to include participants with no radiographic or symptomatic knee osteoarthritis at baseline; have a follow-up time of a minimum of 2 years, and include a measure of knee extensor muscle strength. Hierarchies for extracting data on knee osteoarthritis and knee extensor muscle strength were defined prior to data extraction. Meta-analysis was applied on the basis of the odds ratios (ORs) of developing symptomatic knee osteoarthritis or radiographic knee osteoarthritis in subjects with knee extensor muscle weakness. ORs for knee osteoarthritis and 95% confidence intervals (CI) were estimated and combined using a random effects model. Twelve studies were eligible for inclusion in the meta-analysis after the initial searches. Five cohort studies with a follow-up time between 2.5 and 14 years, and a total number of 5707 participants (3553 males and 2154 females), were finally included. The meta-analysis showed an overall increased risk of developing symptomatic knee osteoarthritis in participants with knee extensor muscle weakness (OR 1.65 95% CI 1.23, 2.21; I(2) = 50.5%). This systematic review and meta-analysis showed that knee extensor muscle weakness was associated with an increased risk of developing knee osteoarthritis in both men and women.

Decrease of EEG Coherence during hypoglycemia in type 1 diabetic subjects.

Hypoglycemic events have been proven to be associated with measurable EEG changes. Several works in the literature have evaluated these changes by considering approaches at the single EEG channel level, but multivariate analyses have been scarcely investigated in Type 1 diabetes (T1D) subjects. The aim of the present work is to assess if and how hypoglycemia affects EEG coherence in a subset of EEG channels acquired in a hospital setting where eye- and muscle activation-induced artifacts are virtually absent. In particular, EEG multichannel data, acquired in 19 T1D hospitalized subjects undertaken to an insulin-induced hypoglycemia experiment, are considered. Computation of Partial Directed Coherence (PDC) through multivariate autoregressive models of P3-A1A2, P4-A1A2, C3-A1A2 and C4-A1A2 EEG channels shows that a decrease in the value of coherence, most likely related to the progressive loss of cognitive function and altered cerebral activity, occurs when passing from eu- to hypoglycemia, in both theta ([4, 8] Hz) and alpha ([8, 13] Hz) bands.

Similar weight-adjusted insulin secretion and insulin sensitivity in short-duration late autoimmune diabetes of adulthood (LADA) and type 2 diabetes: Action LADA 9 [corrected].

AIMS: To explore insulin sensitivity and insulin secretion in people with latent autoimmune diabetes in adulthood (LADA) compared with that in people with type 2 diabetes. METHODS: A total of 12 people with LADA, defined as glutamic acid decarboxylase (GAD) antibody positivity and > 1 year of insulin independency (group A) were age-matched pairwise to people with type 2 diabetes (group B) and to six people with type 2 diabetes of similar age and BMI (group C). ß-Cell function (first-phase insulin secretion and assessment of insulin pulsatility), insulin sensitivity (hyperinsulinemic-euglycemic clamp) and metabolic response during a mixed meal were studied. RESULTS: Both first-phase insulin secretion and insulin release during the meal were greater (P = 0.05 and P = 0.009, respectively) in type 2 diabetes as compared with LADA; these differences were lost on adjustment for BMI (group C) and could be explained by BMI alone in a multivariate analysis. Neither insulin pulsatility, incretin secretion nor insulin sensitivity differed among the groups. CONCLUSIONS: We found no evidence that LADA and type 2 diabetes were distinct disease entities beyond the differences explained by BMI.

Impact of exercise type and dose on pain and disability in knee osteoarthritis: a systematic review and meta-regression analysis of randomized controlled trials.

OBJECTIVE: To identify the optimal exercise program, characterized by type and intensity of exercise, length of program, duration of individual supervised sessions, and number of sessions per week, for reducing pain and patient-reported disability in knee osteoarthritis (OA). METHODS: A systematic review and meta-analysis of randomized controlled trials were performed. Standardized mean differences (SMDs) were combined using a random-effects model. Study-level covariates were applied in meta-regression analyses in order to reduce between-study heterogeneity. RESULTS: Forty-eight trials were included. Similar effects in reducing pain were found for aerobic, resistance, and performance exercise (SMD 0.67, 0.62, and 0.48, respectively; P = 0.733). These single-type exercise programs were more efficacious than programs that included different exercise types (SMD 0.61 versus 0.16; P < 0.001). The effect of aerobic exercise on pain relief increased with an increased number of supervised sessions (slope 0.022 [95% confidence interval 0.002, 0.043]). More pain reduction occurred with quadriceps-specific exercise than with lower limb exercise (SMD 0.85 versus 0.39; P = 0.005) and when supervised exercise was performed at least 3 times a week (SMD 0.68 versus 0.41; P = 0.017). No impact of intensity, duration of individual sessions, or patient characteristics was found. Similar results were found for the effect on patient-reported disability. CONCLUSION: Optimal exercise programs for knee OA should have one aim and focus on improving aerobic capacity, quadriceps muscle strength, or lower extremity performance. For best results, the program should be supervised and carried out 3 times a week. Such programs have a similar effect regardless of patient characteristics, including radiographic severity and baseline pain.

Osteoarthritis 2012 year in review: rehabilitation and outcomes.

UNLABELLED: Recent scientific advances in the treatment of hip and knee osteoarthritis (OA) relating to education, exercise, weight control and passive non-pharmacological and non-surgical treatments such as manual therapy, orthoses/orthotics and other aids are described. METHODS: A systematic literature search was performed in Medline from July 2011 to 10 April 2012 using the terms 'osteoarthritis, knee', 'osteoarthritis, hip' rehabilitation, physical therapy, exercise therapy and preoperative intervention; both as text words and as MeSH terms where possible. Trials evaluating rehabilitation interventions were included if they were randomized controlled trials (RCTs) or systematic reviews. Outcome papers were identified by combining the initial search with the terms 'outcome', 'measure*', 'valid*', 'reliabil*' or 'responsiveness'. Outcome studies were included if they contributed methodologically to advancing outcome measurement. RESULTS: The literature search identified 550 potentially relevant papers. Seventeen RCTs on rehabilitation were selected and the results from these were supported by six systematic reviews. Sixteen outcomes papers were considered relevant, but did not add significantly to current knowledge about outcome measures in OA and so, were not included. CONCLUSION: The current research focus on non-pharmacological and non-surgical treatments for hip and/or knee OA, when combined in systematic reviews, is improving the available evidence to identify best practice treatment. Education, exercise and weight loss are effective in the long term and supported as cost-effective first-line treatments.

The impact of calcineurin inhibitors on insulin sensitivity and insulin secretion: a randomized crossover trial in uraemic patients.

AIMS: The calcineurin inhibitors cyclosporine and tacrolimus are implicated in post-transplant complications such as new-onset diabetes after transplantation. The relative contribution of each calcineurin inhibitor to new-onset diabetes after transplantation remains unclear. We sought to compare the impact of cyclosporine and tacrolimus on glucose metabolism in humans. METHODS: Eight haemodialysis patients received 8-10 days of oral treatment followed by 5-h infusions with cyclosporine, tacrolimus and saline in a randomized, investigator-blind, crossover study. Glucose metabolism and ß-cell function was investigated through: a hyperinsulinaemic-euglycaemic clamp, an intravenous glucose tolerance test and insulin concentration time series. RESULTS: Cyclosporine and tacrolimus decreased insulin sensitivity by 22% (P = 0.02) and 13% (P = 0.048), respectively. The acute insulin response and pulsatile insulin secretion were not significantly affected by the drugs. CONCLUSION: In conclusion, 8-10 days of treatment with cyclosporine and tacrolimus impairs insulin sensitivity to a similar degree in haemodialysis patients, while acute insulin responses and pulsatile insulin secretion remain unaffected.

Repaglinide treatment amplifies first-phase insulin secretion and high-frequency pulsatile insulin release in Type 2 diabetes.

AIMS/HYPOTHESIS: First-phase insulin release and coordinated insulin pulsatility are disturbed in Type 2 diabetes. The present study was undertaken to explore a possible influence of the oral prandial glucose regulator, repaglinide, on first-phase insulin secretion and high-frequency insulin pulsatility in Type 2 diabetes. METHODS: We examined 10 patients with Type 2 diabetes in a double-blind placebo-controlled, cross-over design. The participants were treated for 6 weeks with either repaglinide [2-9 mg/day (average 5.9 mg)] or placebo in random order. At the end of each treatment period, first-phase insulin secretion was measured. Entrainment of insulin secretion was assessed utilizing 1-min glucose bolus exposure (6 mg/kg body weight every 10 min) for 60 min during (A) baseline conditions, i.e. 12 h after the last repaglinide/placebo administration, and (B) 30 min after an oral dose of 0.5 mg repaglinide/placebo with subsequent application of time-series analyses. RESULTS: Postprandial (2-h) blood glucose was significantly reduced by repaglinide after 5 weeks of treatment (P < 0.001). The fall in HbA(1c) did not reach statistical significance (P = 0.07). AUC(ins,0-12 min) during the first-phase insulin secretion test was enhanced (P < 0.05). In addition, glucose entrained insulin secretory burst mass and amplitude increased markedly (burst mass: repaglinide, 44.4 +/- 6.0 pmol/l/pulse vs. placebo, 31.4 +/- 3.3 pmol/l/pulse, P < 0.05; burst amplitude: repaglinide, 17.7 +/- 2.4 pmol/l/min vs. placebo, 12.6 +/- 1.3 pmol/l/min, P < 0.05) while basal insulin (non-pulsatile) secretion was unaltered. After acute repaglinide exposure (0.5 mg) basal insulin secretion increased significantly (P < 0.05). Neither acute nor chronic repaglinide administration influenced frequency or regularity of insulin pulses during entrainment. CONCLUSION/INTERPRETATION: Repaglinide augments first-phase insulin secretion as well as high-frequency insulin secretory burst mass and amplitude during glucose entrainment in patients with Type 2 diabetes, while regularity of the insulin release process was unaltered.

Acute insulin responses to intravenous glucose and GLP-1 are independent of preceding high-frequency insulin pulse-defects induced by glucose entrainment in healthy humans.

The objective of this study was to test the hypothesis that high-frequency oscillations in insulin release is a part of the mechanistic basis of a prompt and adequate insulin response to iv-glucose and GLP-1 exposure. In ten healthy subjects, five different insulin release patterns were induced for 360 min using computer-based glucose infusion (glucose delivered in a constant, a regular pulsatile, an irregular pulse frequency, an irregular pulse amplitude or a regular but very fast-pulsatile manner) in healthy subjects. The amount of glucose infused was identical in all five protocols (24 mg/kg/h). After 360 min, insulin secretion was assessed by means of a first-phase insulin secretion test (25 g glucose) and injection of GLP-1 (9 microg). By frequent blood sampling and analysis of insulin concentration, glucose-induced entrainment was evident in all protocols except in the constant infusion and the very fast-pulse protocol. The first-phase insulin release to glucose and GLP-1-induced insulin release were, however, comparable in the protocols. We therefore conclude from this short-term experimental setting in healthy subjects that beta-cell response to either iv-glucose or GLP-1 is independent of the preceding regularity of oscillations in insulin release.

Beta-cell function and islet morphology in normal, obese, and obese beta-cell mass-reduced Göttingen minipigs.

Herein, we bridge beta-cell function and morphology in minipigs. We hypothesized that different aspects of beta-cell dysfunction are present in obesity and obesity with reduced beta-cell mass by using pulsatile insulin secretion as an early marker. Measures for beta-cell function (glucose and arginine stimulation plus baseline and glucose-entrained pulsatile insulin secretion) and islet morphology were studied in long-term (19-20 mo) obese (n = 5) and obese beta-cell-reduced [nicotinamide + streptozotocin (STZ), n = 5] minipigs and normal controls, representing different stages in the development toward type 2 diabetes. Acute insulin response (AIR) to glucose and arginine were, surprisingly, normal in obese (0.3 g/kg glucose: AIR = 246 +/- 119 vs. 255 +/- 61 pM in control; 67 mg/kg arginine: AIR = 230 +/- 124 vs. 214 +/- 85 pM in control) but reduced in obese-STZ animals (0.3 g/kg glucose: AIR = 22 +/- 36, P < 0.01; arginine: AIR = 87 +/- 92 pM, P < 0.05 vs. control). Baseline pulsatile insulin secretion was reduced in obese (59 +/- 16 vs. 76 +/- 16% in control, P < 0.05) and more so in obese-STZ animals (43 +/- 13%, P < 0.01), whereas regularity during entrainment was increased in obese animals (approximate entropy: 0.85 +/- 0.14 vs. 1.13 +/- 0.13 in control, P < 0.01). Beta-cell mass (mg/kg body wt) was normal in obese and reduced in obese-STZ animals, with pancreatic fat infiltration in both groups. In conclusion, obesity and insulin resistance are not linked with a general reduction of beta-cell function, but dynamics of insulin secretion are perturbed. The data suggest a sequence in the development of beta-cell dysfunction, with the three groups representing stages in the progression from normal physiology to diabetes, and assessment of pulsatility as the single most sensitive marker of beta-cell dysfunction.