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.

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.

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.

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.

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.

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.

Failure of physiological plasma glucose excursions to entrain high-frequency pulsatile insulin secretion in type 2 diabetes.

Insulin is released in high-frequency pulsatile bursts at intervals of 6-13 min. Intrapancreatic mechanisms are assumed to coordinate pulsatile insulin release, but small oscillations in plasma glucose concentrations may contribute further. To gain additional insight into beta-cell (patho)physiology, we explored the ability of repetitive small glucose infusions (6 mg/kg over 1 min every 10 min) to modify rapid pulsatile insulin secretion in 10 type 2 diabetic individuals (plasma glucose 9.3 +/- 1.0 mmol/l, HbA1c 7.9 +/- 0.5%, mean +/- SE) and 10 healthy subjects. All subjects were investigated twice in randomly assigned order: during saline and during glucose exposure. Blood was collected every minute for 90 min to create a plasma insulin concentration time-series for analysis using 3 complementary algorithms: namely, spectral analysis, autocorrelation analysis, and approximate entropy (ApEn). During saline infusion, none of the algorithms were able to discriminate between diabetic and control subjects (P > 0.20). During glucose entrainment, spectral density peaks (SP) and autocorrelation coefficients (AC) increased significantly (P < 0.001), and ApEn decreased (P < 0.01), indicating more regular insulin time-series in the healthy volunteers. However, no differences were observed in the diabetic individuals between the glucose and saline conditions. Furthermore, in spite of identical absolute glucose excursions (approximately 0.3 mmol/l) glucose pulse entrainment led to a complete (SP: 4.76 +/- 0.62 [range 2.08-7.60] vs. 17.24 +/- 0.93 [11.70-20.58], P < 0.001; AC: 0.01 +/- 0.05 [0.33-0.24] vs. 0.64 +/- 0.05 [0.35-0.83], P < 0.001) or almost complete (ApEn: 1.59 +/- 0.02 [1.48-1.67] vs. 1.42 +/- 0.05 [1.26-1.74], P < 0.005) separation of the insulin time-series in diabetic and control subjects. Even elevating the glucose infusion rate in the diabetic subjects to achieve comparable relative (and hence higher absolute) glucose excursions (approximately 4.9%) failed to entrain pulsatile insulin secretion in this group. In conclusion, the present study demonstrates that failure to respond adequately with regular oscillatory insulin secretion to recurrent high-frequency and (near)-physiological glucose excursion is a manifest feature of beta-cell malfunction in type 2 diabetes. Whether the model will be useful in unmasking subtle (possible prediabetic) defects in beta-cell sensitivity to glucose drive remains to be determined.

Repaglinide acutely amplifies pulsatile insulin secretion by augmentation of burst mass with no effect on burst frequency.

OBJECTIVE: Repaglinide is a new oral hypoglycemic agent that acts as a prandial glucose regulator proposed for the treatment of type 2 diabetes by stimulating insulin secretion. The aim of this study was to explore actions of repaglinide on the rapid pulsatile insulin release by high-frequency insulin sampling and analysis of insulin-concentration time series. RESEARCH DESIGN AND METHODS: We examined 8 healthy lean male subjects in a single-dose double-blind placebo-controlled crossover design. After the subjects underwent an overnight fast, blood sampling was initiated and continued every minute for 120 min. After 40 min, a single dose (0.5 mg) of repaglinide or placebo was given. Serum insulin-concentration time series were assessed by deconvolution analyses and the regularity statistic by approximate entropy (ApEn). RESULTS: Average insulin concentration was increased after repaglinide administration (basal vs. stimulated period, P values are placebo vs. repaglinide) (25.1 +/- 3.6 vs. 33.5 +/- 4.1 pmol/l, P < 0.001). Insulin secretory burst mass (15.8 +/- 2.2 vs. 19.6 +/- 2.8 pmol x l(-1) x pulse(-1), P = 0.02) and amplitude (6.1 +/- 0.9 vs. 7.7 +/- 1.2 pmol x l(-1) x min(-1), P = 0.008) were augmented after repaglinide administration. A concomitant trend toward an increase in basal insulin secretion was observed (2.5 +/- 0.3 vs. 3.2 +/- 0.4 pmol x l(-1) x min(-1), p = 0.06), while the interpulse interval was unaltered (6.8 +/- 1.0 vs. 5.4 +/- 0.4 min/pulse, P = 0.38). ApEn increased significantly after repaglinide administration (0.623 +/- 0.045 vs. 0.670 +/- 0.034, P = 0.04), suggesting less orderly oscillatory patterns of insulin release. CONCLUSIONS: In conclusion, a single dose of repaglinide amplifies insulin secretory burst mass (and basal secretion) with no change in burst frequency. The possible importance of these mechanisms in the treatment of type 2 diabetes characterized by disrupted pulsatile insulin secretion remains to be clarified.

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.

Human trophoblast interferons enhance major histocompatibility complex class I antigen expression on human term trophoblast cells in culture.

The expression and regulation of major histocompatibility complex class I (MHC class I) antigens by virus-induced human trophoblast interferons (tro-IFNs) were examined in term trophoblast cultures. Flow cytometry studies using fluorescence monoclonal antibodies against MHC class I antigens revealed that isolated cytotrophoblasts can express MHC class I antigens. The expression of these antigens increased with stimulation of trophoblast cultures with tro-IFN-alpha and -beta. One hundred IU tro-IFN-alpha and -beta/ml induced no significant higher levels of MHC class I antigens as compared with the control, whereas 1000 IU tro-IFN-alpha and -beta/ml did. The tro-IFN-enhanced expression of MHC class I antigens may be important as it increases the efficiency of local and viral antigen presentation, cytotoxicity by T cell response and local inflammatory processes, thereby preventing virus spread from mother to fetus.

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.

Assessment of insulin secretion in relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus: evidence of early beta-cell dysfunction.

To examine beta-cell function in glucose-tolerant offspring of type 2 diabetic families, 41 insulin-resistant (hyperinsulinemic-euglycemic clamp, P < .001) first-degree relatives and 32 controls underwent oral (OGTT) and intravenous (IVGTT) glucose tolerance tests and a constant intravenous glucose infusion (4.0 or 4.5 mg/kg/min) with blood sampling every minute for insulin determinations. Insulin concentration time-series were analyzed with complementary mathematical models (deconvolution and autocorrelation analysis, approximate entropy [ApEn], and coefficient of variation [CV] for a 6-point moving average, together with a combined index for regularity and stationarity [RaS] based on the last 2 measures). During the OGTT, the area under the curve (AUC) for plasma glucose was moderately (11%) but significantly (P < .01) elevated in the relatives despite a trend for increased serum insulin (AUC, P = .14). The acute-phase serum insulin response (IVGTT) did not differ between groups (2,055 +/- 330 v 1,766 +/- 229 pmol/L x 10 min, P = .84) but was inappropriately low (individually, P < .05 v control group) for the degree of insulin resistance in 16 relatives. Deconvolution analysis of the insulin time-series did not uncover differences in either the intersecretory pulse interval (5.8 +/- 0.2 v5.7 +/- 0.2 min/pulse) or the fractional secretory burst amplitude (133% +/- 10% v 116% +/- 7% over basal) between the 2 groups. Similarly, significant autocorrelation coefficients were observed in a comparable number of relatives and control subjects (P = .74). In contrast, the RaS index was significantly higher (ie, insulin time-series was more irregular and nonstationary) in the relatives (0.221 +/- 0.194) than in the controls (-0.318 +/- 0.176, P < .05), primarily attributed to the pattern of insulin secretion in relatives with a strong genetic burden. In conclusion, nonstationary and disorderly insulin secretion patterns during glucose stimulation and a low acute-phase serum insulin response associated with significant insulin resistance suggest early beta-cell regulatory dysfunction in individuals genetically predisposed to type 2 diabetes mellitus prior to any evident alterations in insulin secretory burst frequency or mass.

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.