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.

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.

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.

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.

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.

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.

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.

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.

Glucocorticoid induced insulin resistance impairs basal but not glucose entrained high-frequency insulin pulsatility in humans.

AIMS/HYPOTHESIS: Type II (non-insulin-dependent) diabetes mellitus is characterized by abnormal insulin secretion, which involves a disrupted basal and glucose-entrained insulin pulsatility, and by insulin resistance. The aim of this study was to examine the influence of glucocorticoid-mediated insulin resistance on the regularity of high frequency insulin pulsatility. METHODS: Eight healthy men (means +/- SD; age 24.4 +/- 0.5 years, BMI 23.2 +/- 0.7 kg/m2) were examined after prednisolone treatment (30 mg/day) or placebo for 6 days in a double-blind, placebo controlled, cross-over study with a 6-week washout period. Blood was collected every minute for 60 min during baseline and glucose-entrainment. Time-series were assessed by spectral and autocorrelation analyses and a first-phase insulin secretion test was carried out. RESULTS: Prednisolone treatment led to insulin resistance as expected (HOMA-S; prednisolone vs placebo; 1.85 +/- 0.26 vs 1.02 +/- 0.10; p < 0.01) with exaggerated first-phase insulin secretion (3016 +/- 468 pmol/l vs 1688 +/- 207 pmol/l; p < 0.01), suggesting a stable disposition index. During baseline, normalized spectral power of serum insulin concentration time-series was reduced during prednisolone exposure compared with placebo (8.40 +/- 0.95 vs 11.79 +/- 1.66; p < 0.05) indicating a disturbed high-frequency oscillatory insulin release. A similar trend was observed using autocorrelation analysis (0.23 +/- 0.04 vs 0.32 +/- 0.07; p = 0.12). During glucose entrainment no difference in normalized spectral power or in the autocorrelation coefficient between prednisolone and placebo (p > 0.1) was observed. CONCLUSION/INTERPRETATION: Six days of prednisolone treatment resulted in a pertubed high-frequency insulin release in the fasting state whereas the ability of glucose to entrain insulin secretion was preserved. This indicates a mechanism of pertubed glucose-insulin feedback mechanism which causes irregular oscillatory insulin release.

High-frequency insulin pulsatility and type 2 diabetes: from physiology and pathophysiology to clinical pharmacology.

Like many other hormones insulin is released in a pulsatile manner, which results in oscillatory concentrations in peripheral blood. The oscillatory pattern is believed to improve release control and to enhance the hormonal action. Insulin oscillates with a slow ultradian periodicity (approximately 140 min) and a high-frequency periodicity (approximately 6-10 min). Only the latter will be discussed in this review, which focusses almost exclusively on human data. Probably at least 75% of insulin secretion is released in a very regular pulsatile fashion in healthy people. In contrast, type 2 diabetic subjects exhibit in general irregular oscillations of basal plasma insulin. Furthermore, disturbed pulsatile insulin release is also a common feature in people prone to develop diabetes e.g. first-degree relatives of patients with type 2 diabetes. Tiny glucose oscillations (approximately 0.3mM) are capable of easily governing or entraining insulin oscillations in healthy people. This differs from type 2 diabetic individuals underlining a profound disruption of the beta-cells in type 2 diabetes to sense or respond to physiological glucose excursions. A pivotal question is how approximately 1,000,000 islets each containing from a few to several thousand beta-cells can be coordinated to secrete insulin in a pulsatile manner. Coordination is extremely complex involving the intrapancreatic neural network, the intraislet communication and metabolic oscillations in the individual beta-cell itself, but our understanding is still rather rudimentary. It is important to realize how antidiabetic treatment influences high-frequency insulin pulsatility. Only a few studies have been performed, but very recently it has been demonstrated that acute as well as long-term administration of the sulfonylurea compound gliclazide results in a substantial amplification (approximately 50%) of the pulsatile insulin secretion in type 2 diabetes. The fraction between pulsatile vs nonpulsatile insulin secretion is stable, which may be essential for controlling glucose and lipid homeostasis in type 2 diabetes. The influence of repaglinide, thiazolidinediones and a potential future antidiabetic compound (GLP-1) on pulsatile insulin secretion is also discussed briefly. Evaluation of high-frequency insulin pulsatility may be an important player in future tailoring of antidiabetic drugs and may turn out to be relevant as a predictor of type 2 diabetes in people at high risk for developing the disease.

Acute pain induces insulin resistance in humans.

BACKGROUND: Painful trauma results in a disturbed metabolic state with impaired insulin sensitivity, which is related to the magnitude of the trauma. The authors explored whether pain per se influences hepatic and extrahepatic actions of insulin. METHODS: Ten healthy male volunteers underwent two randomly sequenced hyperinsulinemic-euglycemic (insulin infusion rate, 0.6 mU x kg(-1) x min(-1) for 180 min) clamp studies 4 weeks apart. Self-controlled painful electrical stimulation was applied to the abdominal skin for 30 min, to a pain intensity of 8 on a visual analog scale of 0-10, just before the clamp procedure (study P). In the other study, no pain was inflicted (study C). RESULTS: Pain reduced whole-body insulin-stimulated glucose uptake from 6.37+/-1.87 mg x kg(-1) x min(-1) (mean +/- SD) in study C to 4.97+/-1.38 mg x kg(-1) x min(-1) in study P (P < 0.01) because of a decrease in nonoxidative glucose disposal, as determined by indirect calorimetry (2.47+/-0.88 mg x kg(-1) x min(-1) in study P vs. 3.41+/-1.03 mg x kg(-1) x min(-1) in study C; P < 0.05). Differences in glucose oxidation rates were not statistically significant. The suppression of isotopically determined endogenous glucose output during hyperinsulinemia tended to be decreased after pain (1.67+/-0.48 mg x kg(-1) x min(-1) in study P vs. 2.04+/-0.45 mg x kg(-1) x min(-1) in study C; P = 0.06). Pain elicited a twofold to threefold increase in serum cortisol (P < 0.01), plasma epinephrine (P < 0.05), and serum free fatty acids (P < 0.05). Similarly, circulating concentrations of glucagon and growth hormone tended to increase during pain. CONCLUSIONS: Acute severe pain decreases insulin sensitivity, primarily by affecting nonoxidative glucose metabolism. It is conceivable that the counterregulatory hormonal response plays an important role. This may indicate that pain relief in stress states is important for maintenance of normal glucose metabolism.

Acute and short-term administration of a sulfonylurea (gliclazide) increases pulsatile insulin secretion in type 2 diabetes.

The high-frequency oscillatory pattern of insulin release is disturbed in type 2 diabetes. Although sulfonylurea drugs are widely used for the treatment of this disease, their effect on insulin release patterns is not well established. The aim of the present study was to assess the impact of acute treatment and 5 weeks of sulfonylurea (gliclazide) treatment on insulin secretory dynamics in type 2 diabetic patients. To this end, 10 patients with type 2 diabetes (age 53 +/- 2 years, BMI 27.5 +/- 1.1 kg/m(2), fasting plasma glucose 9.8 +/- 0.8 mmol/l, HbA(1c) 7.5 +/- 0.3%) were studied in a double-blind placebo-controlled prospective crossover design. Patients received 40-80 mg gliclazide/placebo twice daily for 5 weeks with a 6-week washout period intervening. Insulin pulsatility was assessed by 1-min interval blood sampling for 75 min 1) under baseline conditions (baseline), 2) 3 h after the first dose (80 mg) of gliclazide (acute) with the plasma glucose concentration clamped at the baseline value, 3) after 5 weeks of treatment (5 weeks), and 4) after 5 weeks of treatment with the plasma glucose concentration clamped during the sampling at the value of the baseline assessment (5 weeks-elevated). Serum insulin concentration time series were analyzed by deconvolution, approximate entropy (ApEn), and spectral and autocorrelation methods to quantitate pulsatility and regularity. The P values given are gliclazide versus placebo; results are means +/- SE. Fasting plasma glucose was reduced after gliclazide treatment (baseline vs. 5 weeks: gliclazide, 10.0 +/- 0.9 vs. 7.8 +/- 0.6 mmol/l; placebo, 10.0 +/- 0.8 vs. 11.0 +/- 0.9 mmol/l, P = 0.001). Insulin secretory burst mass was increased (baseline vs. acute: gliclazide, 43.0 +/- 12.0 vs. 61.0 +/- 17.0 pmol. l(-1). pulse(-1); placebo, 36.1 +/- 8.4 vs. 30.3 +/- 7.4 pmol. l(-1). pulse(-1), P = 0.047; 5 weeks-elevated: gliclazide vs. placebo, 49.7 +/- 13.3 vs. 37.1 +/- 9.5 pmol. l(-1). pulse(-1), P < 0.05) with a similar rise in burst amplitude. Basal (i.e., nonoscillatory) insulin secretion also increased (baseline vs. acute: gliclazide, 8.5 +/- 2.2 vs. 16.7 +/- 4.3 pmol. l(-1). pulse(-1); placebo, 5.9 +/- 0.9 vs. 7.2 +/- 0.9 pmol. l(-1). pulse(-1), P = 0.03; 5 weeks-elevated: gliclazide vs. placebo, 12.2 +/- 2.5 vs. 9.4 +/- 2.1 pmol. l(-1). pulse(-1), P = 0.016). The frequency and regularity of insulin pulses were not modified significantly by the antidiabetic therapy. There was, however, a correlation between individual values for the acute improvement of regularity, as measured by ApEn, and the decrease in fasting plasma glucose during short-term (5-week) gliclazide treatment (r = 0.74, P = 0.014, and r = 0.77, P = 0.009, for fine and coarse ApEn, respectively). In conclusion, the sulfonylurea agent gliclazide augments insulin secretion by concurrently increasing pulse mass and basal insulin secretion without changing secretory burst frequency or regularity. The data suggest a possible relationship between the improvement in short-term glycemic control and the acute improvement of regularity of the in vivo insulin release process.

Irregular circulating insulin concentrations in type 2 diabetes mellitus: an inverse relationship between circulating free fatty acid and the disorderliness of an insulin time series in diabetic and healthy individuals.

Insulin is released in a high-frequency pulsatile secretory pattern, which is reflected as quantifiable oscillations in peripheral circulating insulin concentrations. Type 2 diabetes mellitus is characterized by a broad spectrum of abnormalities in beta-cell function, including disturbed pulsatile insulin secretion as assessed by autocorrelation analysis. To achieve further insight into beta-cell pathophysiology in type 2 diabetes, we examined the orderliness of the baseline serum insulin time series (blood collection every minute for 75 minutes) in 16 type 2 diabetics (fasting plasma glucose, 170 +/- 10 mg/dL [mean +/- SE]; serum free fatty acid [FFA], 0.794 +/- 0.083 mmol/L; and known diabetes duration, 6 +/- 2 years) and 15 healthy controls (serum FFA, 0.523 +/- 0.055 mmol/L). We used approximate entropy (ApEn), a recently introduced scale- and model-independent measure of serial irregularity. ApEn was significantly increased in the type 2 diabetics compared with the controls (0.671 +/- 0.016 v 0.653 +/- 0.008, P = .04), indicating more irregular serum insulin time series in diabetics. Autocorrelation also discriminated between groups, although only when the data were pooled. Interestingly, an inverse relationship between ApEn and serum FFA was observed in the controls (r = -.63, P = .01) and diabetics (r = -.65, P < .01), whereas no relationships were found between ApEn and the age, body mass index (BMI), or plasma glucose. In conclusion, type 2 diabetes is characterized by an increased disorderliness of the fasting serum insulin time series, strongly suggesting perturbed rapid oscillatory insulin release. An inverse relationship between ApEn and fasting serum FFA among both groups might suggest a hitherto unknown stabilizing action of FFA on the high-frequency pulsatile insulin release process. This hypothesis needs to be tested in experimental designs that more specifically focus on this issue, eg, during changes in serum FFA.