The prevalence of type 2 diabetes in people with psychiatric disorders: an umbrella review protocol.

BACKGROUND: Many epidemiological studies have investigated the prevalence of type 2 diabetes in individuals with a psychiatric disorder. In an umbrella review, we aim to systematically summarize existing systematic reviews examining the prevalence of type 2 diabetes in people with a psychiatric disorder. When information is available in the identified systematic reviews, comparisons with control groups without a psychiatric disorder will be made. Furthermore, we aim to assess the quality of the included systematic reviews. METHODS: The umbrella review will be based on a comprehensive systematic search of systematic reviews of observational (cross-sectional or longitudinal) studies investigating the prevalence of type 2 diabetes in people with a psychiatric disorder. Four electronic databases (Embase, PsycINFO, PubMed, and the Cochrane Database of Systematic Reviews) will be searched. Retrieved papers will be screened for eligibility by two independent reviewers. Furthermore, the reference lists of all included publications will be screened. Data will be extracted by using an a priori developed data extraction form and two independent reviewers will assess the risk of bias in the included systematic reviews using with the Risk of Bias in Systematic Reviews (ROBIS) tool. A narrative data-synthesis and a subsequent meta-analysis based on the primary studies will be made. DISCUSSION: For each psychiatric disorder, the data regarding the prevalence of type 2 diabetes will be summarized and discussed. When possible, comparisons with control groups will be reported and discussed. Finally, future implications and recommendations for clinical care will be presented. SYSTEMATIC REVIEW REGISTRATION: This protocol was submitted for registration with the International Prospective Register of Systematic Reviews (PROSPERO) on December 9, 2019 (registration number: pending).

Glucose effectiveness is a critical pathogenic factor leading to glucose intolerance and type 2 diabetes: An ignored hypothesis.

BACKGROUND: Although the ability of glucose to mediate its own in vivo metabolism is long documented, the quantitative measurement of whole body glucose-mediated glucose disposal at basal insulin levels (glucose effectiveness [GE]), followed the introduction of the Minimal Model intravenous glucose tolerance test technique. METHODS: A literature review, combined with our own studies, of the role of GE in glucose metabolism in normal and "at risk" individuals, was undertaken to determine GE's contribution to glucose homeostasis. RESULTS: GE accounts for ~45% to 65% of glucose disposal in man. A negative association between GE and insulin meditated glucose disposal (Si), is present in normal subjects without a family history of type 2 diabetes mellitus but is absent in normoglycaemic "at risk" relatives with a positive family history of diabetes mellitus. Intracellular GE disposal is mediated by mass action of glucose through the skeletal muscle membrane via facilitated Glut 4 transporters. However, GE is frequently forgotten as a significant contributor to the development of glucose intolerance in "at risk" individuals. Only limited studies have examined the role of a lower GE in such normoglycemic subjects with preexisting mild insulin resistance and ß-cell dysfunction. These studies demonstrate that in "at risk" individuals, an initial low GE is a key contributor and predictor of future glucose intolerance, whereas an initial raised GE is protective against future glucose intolerance. CONCLUSION: In "at risk" individuals, a low GE and genetically determined vulnerable ß-cell function are more critical determinants of future glucose intolerance than their preexisting insulin-resistant state.

Low-dose spironolactone reduces plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension.

Diabetic patients with hypertension are at particularly high risk of vascular damage and consequently cardiovascular and renal disease. Fibulin-1, an extracellular matrix glycoprotein, is increased in arterial tissue and plasma from individuals with type 2 diabetes. This study aimed to evaluate whether antihypertensive treatment with spironolactone changes plasma fibulin-1 levels. In a multicenter, double-blind, randomized, placebo-controlled study, 119 patients with type 2 diabetes and resistant hypertension were included. A dose of spironolactone 25 mg or matching placebo was added to previous treatment at randomization. Blood pressure (BP) and plasma fibulin-1 were measured at baseline and at 16 weeks follow-up. Overall, 112 patients completed the study. All measures of BP were reduced in the spironolactone group at follow-up. Plasma fibulin-1 was significantly reduced after spironolactone treatment (P=0.009), but increased after placebo (P=0.017). Baseline plasma fibulin-1 correlated with BP and estimated glomerular filtration rate. Increased levels of plasma fibulin-1 (P=0.004) were observed in diabetic participants reporting erectile dysfunction as compared with participants who did not. Treatment with low-dose spironolactone reduced plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension. This supports the hypothesis that the antihypertensive effect of the mineralocorticoid receptor blocker in part may be due to regression of vascular remodeling.

Glucose effectiveness in nondiabetic relatives: dysglycemia and ß-cell function at 10 years.

AIMS: Reduced glucose effectiveness is a predictor of future glucose tolerance in individuals with a family history of type 2 diabetes. We examined retrospectively at 10 years in normoglycemic relatives of diabetic subjects (RELs) the pathophysiological role of glucose effectiveness in the development of isolated impaired fasting glucose, glucose intolerance, and acute insulin release. METHODS: At 0 years, 19 RELs and 18 matched control subjects had glucose effectiveness (GE), insulin sensitivity, acute insulin release (AIR)IVGTT, and disposition index measured during an iv glucose tolerance test (IVGTT), using the minimal model analysis. At 0 and 10 years, oral glucose tolerance (OGTT) and AIROGTT were determined. RESULTS: At 0 years, fasting glucose (FG) and GE were raised in RELs, but insulin sensitivity and AIROGTT were reduced (P ≤ .05) compared with controls. At 10 years, RELs developed raised fasting and 2-hour OGTT glucose. FG10y correlated significantly with FG0y and body mass index0y and negatively with √GE and 2-hour OGTT glucose10y with FG0y and negatively with AIRIVGTT0y and AIROGTT0y. Log AIROGTT10y correlated with √GE, log AIRIVGTT0y and log AIROGTT0y. Multiple regression analyses demonstrated the following: REL FG10y was predicted by combined FG0y, √GE and body mass index0y (radj(2) = 56%; P ≤ .001) and 2-hour OGTT glucose10y weakly related by FG0y,and √GE (r(adj)(2) = 25%; P = .06). Log AIROGTT10y was predicted by AIRIVGTT0y and √GE (r(adj)(2) = 46%; P ≤ .004). CONCLUSION: In normoglycemic RELs, a relative reduction of glucose effectiveness is an important contributor over 10 years to the development of isolated impaired fasting glucose and reduced acute insulin secretion.

Oral salmon calcitonin attenuates hyperglycaemia and preserves pancreatic beta-cell area and function in Zucker diabetic fatty rats.

BACKGROUND AND PURPOSE: Oral salmon calcitonin (sCT), a dual-action amylin and calcitonin receptor agonist, improved glucose homeostasis in diet-induced obese rats. Here, we have evaluated the anti-diabetic efficacy of oral sCT using parameters of glycaemic control and beta-cell morphology in male Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. EXPERIMENTAL APPROACH: Male ZDF rats were treated with oral sCT (0.5, 1.0 or 2 mg·kg(-1) ) or oral vehicle twice daily from age 8 to 18 weeks. Zucker lean rats served as control group. Fasting and non-fasted blood glucose, glycosylated haemoglobin (HbA1c) and levels of pancreas and incretin hormones were determined. Oral glucose tolerance test and i.p. glucose tolerance test were compared, and beta-cell area and function were evaluated. KEY RESULTS: Oral sCT treatment dose-dependently attenuated fasting and non-fasted hyperglycaemia during the intervention period. At the end of the study period, oral sCT treatment by dose decreased diabetic hyperglycaemia by ∼9 mM and reduced HbA1c levels by 1.7%. Furthermore, a pronounced reduction in glucose excursions was dose-dependently observed for oral sCT treatment during oral glucose tolerance test. In addition, oral sCT treatment sustained hyperinsulinaemia and attenuated hyperglucagonaemia and hypersecretion of total glucagon-like peptide-1 predominantly in the basal state. Lastly, oral sCT treatment dose-dependently improved pancreatic beta-cell function and beta-cell area at study end. CONCLUSIONS AND IMPLICATIONS: Oral sCT attenuated diabetic hyperglycaemia in male ZDF rats by improving postprandial glycaemic control, exerting an insulinotropic and glucagonostatic action in the basal state and by preserving pancreatic beta-cell function and beta-cell area.

Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the separate impact of insulin resistance and impaired glucose tolerance (IGT) on the incretin effect. METHODS: Twenty-one healthy glucose-tolerant first-degree relatives of patients with type 2 diabetes underwent a 75 g OGTT, an isoglycaemic i.v. glucose test and a mixed meal to evaluate the incretin effect before and after treatment with dexamethasone to increase insulin resistance. Beta cell glucose sensitivity, beta cell index and fasting proinsulin were measured as indices of beta cell function. RESULTS: After dexamethasone, ten individuals had increased insulin resistance but normal glucose tolerance (NGT), while 11 individuals with an equal increase in insulin resistance developed IGT. In the NGT and IGT groups, the incretin effects were 71 ± 3.2% and 67 ± 4.6% (p = 0.4) before treatment, but decreased significantly in both groups to 58 ± 5.2% and 32 ± 8.8% (p < 0.05 between groups) after treatment. Dexamethasone increased total glucagon-like peptide-1 and glucose-dependent insulinotropic peptide responses to the OGTT. The impaired incretin effect in NGT was observed in the absence of reductions in beta cell glucose sensitivity and beta cell index during i.v. glucose, corrected for insulin resistance, but in parallel with increased proinsulin/C-peptide ratio. CONCLUSION/INTERPRETATION: Insulin resistance and IGT, representing two stages in the path towards diabetes, are associated with differential reductions in the incretin effect seen before the development of IGT and overt type 2 diabetes. The reduction is unrelated to secretion of incretin hormones, but is related to insulin resistance and subtle beta cell defects, and is further aggravated on development of IGT. TRIAL REGISTRATION: ClinicalTrials.gov NCT00784745. FUNDING: This study was supported by a grant from the Novo Nordisk Foundation.

Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes.

AIMS/HYPOTHESIS: There is substantial evidence that mitochondrial dysfunction is linked to insulin resistance and is present in several tissues relevant to the pathogenesis of type 2 diabetes. Here, we examined whether common variation in genes involved in oxidative phosphorylation (OxPhos) contributes to type 2 diabetes susceptibility or influences diabetes-related metabolic traits. METHODS: OxPhos gene variants (n = 10) that had been nominally associated (p < 0.01) with type 2 diabetes in a recent genome-wide meta-analysis (n = 10,108) were selected for follow-up in 3,599 type 2 diabetic and 4,956 glucose-tolerant Danish individuals. A meta-analysis of these variants was performed in 11,729 type 2 diabetic patients and 43,943 non-diabetic individuals. The impact on OGTT-derived metabolic traits was evaluated in 5,869 treatment-naive individuals from the Danish Inter99 study. RESULTS: The minor alleles of COX10 rs9915302 (p = 0.02) and COX5B rs1466100 (p = 0.005) showed nominal association with type 2 diabetes in our Danish cohort. However, in the meta-analysis, none of the investigated variants showed a robust association with type 2 diabetes after correction for multiple testing. Among the alleles potentially associated with type 2 diabetes, none negatively influenced surrogate markers of insulin sensitivity in non-diabetic participants, while the minor alleles of UQCRC1 rs2228561 and COX10 rs10521253 showed a weak (p < 0.01 to p < 0.05) negative influence on indices of glucose-stimulated insulin secretion. CONCLUSIONS/INTERPRETATION: We cannot rule out the possibility that common variants in or near OxPhos genes may influence beta cell function in non-diabetic individuals. However, our quantitative trait studies and a sufficiently large meta-analysis indicate that common variation in proximity to the examined OxPhos genes is not a major cause of insulin resistance or type 2 diabetes.

Effects of mealtime insulin aspart and bedtime neutral protamine Hagedorn insulin on postprandial coagulation and fibrinolysis in patients with type 2 diabetes.

AIM: Acute hyperglycaemia induces coagulation activation in diabetes patients. We hypothesized that rapid-acting insulin has a beneficial postprandial effect on coagulation and fibrinolysis compared with intermediate-acting insulin because of its ability to lower postprandial hyperglycaemia. METHODS: This was tested in a parallel controlled study in well-controlled patients with type 2 diabetes assigned to bedtime neutral protamine Hagedorn (NPH) insulin (n = 41) or mealtime insulin aspart (n = 37). They were served standard diabetic meals for breakfast (8:00 hours) and lunch (12:00 hours). Blood samples were collected at 7:40 hours (fasting), 9:30, 11:30, 13:30 and 15:30 hours and analysed for glucose, activated factor VII (FVIIa), D-dimer, prothrombin fragment 1+2 (F1+2), tissue plasminogen activator antigen (t-PA) and plasminogen activator inhibitor activity (PAI). RESULTS: The postprandial glucose response differed significantly between insulin regimens with a postprandial increase on NPH insulin and a decrease on insulin aspart. There was a significant postprandial decrease in F1+2, PAI and t-PA, and no changes in FVIIa and D-dimer, on both insulin regimens, but with no differences between insulin treatment groups. CONCLUSIONS: The rapid-acting insulin analogue aspart and the intermediate-acting insulin NPH had similar postprandial effects on markers of coagulation activation and fibrinolysis despite different effects on postprandial glucose response.

A novel oral form of salmon calcitonin improves glucose homeostasis and reduces body weight in diet-induced obese rats.

AIM: To investigate the effects of acute and chronic administration of a novel oral formulation of salmon calcitonin (sCT) on glycaemic control, glucose homeostasis and body weight regulation in diet-induced obese (DIO) rats-an animal model of obesity-related insulin resistance and type 2 diabetes. METHODS: DIO rats were acutely given a single dose of oral sCT (0.5 and 2 mg/kg), its oral vehicle N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC) or injectable sCT (5 and 10 µg/kg) (n = 8), followed by oral glucose tolerance test (OGTT). Other DIO rats were chronic treated twice daily with oral vehicle 5-CNAC (n = 6), oral sCT (0.5 and 2 mg/kg) or injectable sCT (10 µg/kg) (n = 8). Fasting and postprandial glucose and pancreatic hormones, body weight and insulin sensitivity were assessed. RESULTS: A single dose of oral sCT acutely reduced glucose and insulin area under the curve during OGTT by approximately 65 and 85%, respectively, compared with vehicle (p < 0.001). Chronic treatment with oral sCT significantly reduced both fasting and postprandial glucose and insulin levels by approximately 1.5 mM and 65%, respectively, compared with vehicle. Oral sCT concomitantly improved insulin sensitivity (homeostatic model assessment, HOMA). In contrast, injectable sCT resembling higher systemic exposure did not improve glycaemic control, either acutely or during chronic treatment. Furthermore, both oral and injectable sCT reduced body weight by 15% compared with vehicle (p < 0.05). CONCLUSION: A novel oral form of sCT showed antidiabetic effects in DIO rats by improving glycaemic control, glucose homeostasis, insulin sensitivity and body weight.

The effect of motivational interviewing on glycaemic control and perceived competence of diabetes self-management in patients with type 1 and type 2 diabetes mellitus after attending a group education programme: a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to measure the efficacy of motivational interviewing (MI) compared with usual care on changes in glycaemic control and competence of diabetes self-management in patients with diabetes mellitus. METHODS: Patients were eligible if they had type 1 or 2 diabetes mellitus, were over 18 years of age and had participated in a 4 day group education programme offered at a diabetes clinic at a university hospital in Denmark. Exclusion criteria included pregnancy, severe debilitating disease and cognitive deficit. Out of 469 patients who attended the group education programme, 349 patients were randomised to either a usual care control group or an intervention group, which received up to five individual counselling sessions in 1 year based on MI, in addition to usual care. A randomised parallel design was used and open-label allocation was done by random permuted blocks, with allocation concealment by sequentially numbered, sealed, opaque envelopes. The primary outcome was glycated haemoglobin (HbA(1c)). Analysis regarding measurements of glycated haemoglobin (HbA(1c)) and competence of self-management (using the Problem Areas in Diabetes Scale [PAID] and Perceived Competence for Diabetes Scale [PCDS]) was based on 298 participants followed for a 24 month period. Data were collected at the Department of Endocrinology at Odense University Hospital. Our hypotheses were that MI could: (1) reduce HbA(1c) levels; (2) increase self-efficacy; and (3) increase diabetes self-care, compared with usual care. RESULTS: Out of the 176 included in the control group and 173 in the intervention group, 153 and 145 were analysed in the groups, respectively. When using the baseline value as covariate there were no significant differences in change score between the two study groups with regard to mean level of HbA(1c) (0.131, p = 0.221), PAID scores (-1.793, p = 0.191) or PCDS scores (0.017, p = 0.903) at the 24 month follow-up, using a mixed effects regression model. The patients in the intervention group showed significantly higher levels of perceived competence in dealing with diabetes compared with the control group (mean change score = -0.387, p = 0.002) following 1 year of intervention. CONCLUSION/INTERPRETATION: We were unable to demonstrate any benefit, over or above usual care, of MI in patients with diabetes who have just completed a diabetes education programme, and who have well-regulated diabetes. TRIAL REGISTRATION: Clinical Trials NCT00555854.

Counter-regulatory hormone responses to spontaneous hypoglycaemia during treatment with insulin Aspart or human soluble insulin: a double-blinded randomized cross-over study.

AIMS: To compare insulin Aspart and human insulin with respect to glycaemic control, hypoglycaemic frequency and counter-regulatory responses to spontaneous hypoglycaemia. METHODS: Glycaemic control, hypoglycaemic frequency, p-insulin concentrations, insulin dosages and patients' satisfaction were examined in a randomized, double-blinded cross-over study for two periods of 8 weeks. Sixteen patients with type 1 diabetes were subjected to three daily injections of human soluble insulin or Aspart in addition to Neutral Protamine Hagedorn (NPH) insulin twice daily. Each intervention period was followed by hospitalization where episodes of spontaneous hypoglycaemia and counter-regulatory hormone responses were evaluated from frequently obtained blood samples. RESULTS: No difference between soluble insulin and insulin Aspart was found regarding HbA1c (7.0 ± 0.2 vs. 7.0 ± 0.2%, ns), hypoglycaemic frequency (1.1 ± 0.2 vs. 0.9 ± 0.1 events per patient per week, ns), nocturnal hypoglycaemia, severe hypoglycaemic events, dosages of bolus insulin (31.8 ± 0.4 vs. 30.0 ± 0.6 IU day(-1), ns), or NPH insulin (26.7 ± 1.8 vs. 26.0 ± 1.7 IU day(-1) , ns) or in patients satisfaction (ns). Modest differences existed in the counter-regulatory responses regarding growth hormone, glucagon and ghrelin whereas no differences were found in relation to free fatty acid, cortisol, insulin-like growth factor (IGF)-I, IGF-II and IGF-binding proteins 1 and 2. Treatment with insulin Aspart resulted in well-defined peaks in serum insulin concentrations as compared with more blunted insulin peaks using human soluble insulin. CONCLUSION: Although insulin Aspart treatment was associated with clear postprandial insulin peaks, no improvement in glycaemic control was obtained and no difference in the hypoglycaemic frequency was observed. However, insulin Aspart elicited a slightly different physiological response to spontaneous hypoglycaemia compared with human insulin.

Cost-effectiveness analyses of elective orthopaedic surgical procedures in patients with inflammatory arthropathies.

OBJECTIVE: To examine the costs per quality-adjusted life year (QALY) gained for surgical interventions in patients with inflammatory arthropathies, and to compare the costs per QALY gained for replacement versus non-replacement surgical interventions. METHODS: In total, 248 patients [mean age 57 (SD 13) years, 77% female] with inflammatory arthropathies underwent orthopaedic surgical treatment and responded to mail surveys at baseline and during follow-up (3, 6, 9, and 12 months). Questionnaires included the quality-of-life EuroQol-5D (EQ-5D) and Short Form-6D (SF-6D) utility scores. The health benefit from surgery was subsequently translated into QALYs. The direct treatment costs in the first year were, for each patient, derived from the hospital's cost per patient accounting system (KOSPA). The costs per QALY were estimated and future costs and benefits were discounted at 4%. RESULTS: Improvement in utility at 1-year follow-up was 0.10 with EQ-5D and 0.03 with SF-6D (p < 0.05). The estimated 10-year cost per QALY gained was EUR 5000 for hip replacement surgery (EUR18 600 using SF-6D) and EUR 10 500 (EUR 48 500 using SF-6D) for all replacement procedures. The 5-year cost per QALY was EUR 17 800 for non-replacement surgical procedures measured by EQ-5D (SF-6D: EUR 67 500). CONCLUSIONS: Elective orthopaedic surgery in patients with inflammatory arthropathies was cost-effective when measured with EQ-5D, and some procedures were also cost-effective when SF-6D was used in the economic evaluations. Hip replacement surgery was most cost-effective, irrespective of the method of analysis.

Patients with inflammatory arthropathies undergo feet surgery later in the disease course than hand surgery.

OBJECTIVES: Inflammatory arthropathies often results in functional impairment and joint damage and deformity. Hand and foot are frequent locations for surgical interventions. Our objective is to compare disease duration, patient reported health status measures and use of medication in patients with inflammatory arthropathies referred for hand or foot surgery. METHODS: Patients referred for hand or foot surgery at the Diakonhjemmet Hospital responded to mail surveys preoperatively, including AIMS2, HAQ, SF-36, EQ-5, and visual analogue scales addressing patient global assessment of disease activity, fatigue, general pain and pain in the actual joint. Data on disease duration, surgical treatment and medication were collected from the hospital records. RESULTS: 116 patients (mean (SD) age 57 (13) years, 76% female) with inflammatory arthropathies underwent hand (n=52, mean (SD) age 55 (13) years) or foot (n=64, mean (SD) age 58 (13) years) surgery. Disease duration at the time of surgery was significantly longer for patients referred for foot vs. hand surgery (19 (13) vs. 13 (10) years, p=0.04). Patients undergoing foot surgery used more frequently biological or conventional disease-modifying antirheumatic drug at the time of surgery than patients having hand surgery (50% vs. 71%, respectively, p=0.02). Baseline values for the patient-reported health status measures were mainly similar for the two patient groups. CONCLUSIONS: Patients undergoing surgical procedures in the foot had significantly longer disease duration and were more frequently on potent medication at the time of surgery than patients undergoing hand surgery. The observation may indicate that the impact of foot damage in inflammatory arthropathies is underestimated.

Plasma osteoprotegerin concentrations in peripheral sensory neuropathy in Type 1 and Type 2 diabetic patients.

AIMS: Osteoprotegerin (OPG) has been linked to different diabetes complications, including cardiovascular disease, and new findings have indicated a specific role in diabetic peripheral neuropathy, but the exact mechanism is unknown. To investigate a possible association between OPG and diabetic peripheral sensory neuropathy, we therefore analysed plasma OPG in Type 1 and Type 2 diabetic patients with and without peripheral neuropathy. SUBJECTS AND METHODS: Two hundred Type 1 diabetes mellitus (T1DM) patients and 305 Type 2 diabetes mellitus (T2DM) patients participated in the study. Plasma OPG was measured with a sandwich immunoassay. Peripheral neuropathy was assessed by the Semmes-Weinstein monofilament test. RESULTS: In T2DM, plasma OPG concentrations were significantly higher in the peripheral neuropathy group (P < 0.001). Furthermore, there was a significant relationship between the presence of neuropathy in T2DM and plasma OPG levels on logistic regression (P = 0.006). However, when investigated in a full multiple regression model including other long-term diabetes complications, the association became insignificant (P = 0.092). In T1DM, the difference in plasma OPG between groups did not reach significance (P = 0.066). However, plasma OPG significantly correlated to peripheral neuropathy in this group also (P = 0.022), although this correlation was not significant in a multiple linear regression model (P = 0.051). CONCLUSION: Plasma OPG levels are related to peripheral neuropathy in both Type 1 and Type 2 diabetes, although with the strongest relationship in T2DM. Before understanding the significance of this, the pathological mechanism involved and, speculatively, a possible use of plasma OPG as a peripheral sensory neuropathy marker, a larger prospective study is needed.

Identification of asymptomatic type 2 diabetes mellitus patients with a low, intermediate and high risk of ischaemic heart disease: is there an algorithm?

AIMS/HYPOTHESIS: The leading cause of death in type 2 diabetes is cardiovascular disease (CVD). We examined the prevalence of myocardial ischaemia in type 2 diabetes patients and tried to establish an algorithm to identify patients with a high risk of ischaemic heart disease. METHODS: Type 2 diabetes patients who had no known or suspected CVD, and had been referred consecutively to a diabetes clinic for the first time (n=305; age 58.6+/-11.3 years; diabetes duration 4.5+/-5.3 years) were screened for myocardial ischaemia using myocardial perfusion scintigraphy (MPS). RESULTS: The univariate predictors of myocardial ischaemia were: atypical or typical angina pectoris, two or more traditional risk factors for CVD, BMI >32 kg/m2, systolic blood pressure >140 mmHg, HbA1c >8.5%, high-sensitivity C-reactive protein >4.0 mg/l, N-terminal pro-brain natriuretic peptide >300 pg/ml, left atrial volume index >32 ml/m2, left ventricular ejection fraction <50%, and carotid and peripheral arterial disease. The algorithm identified low (n=96), intermediate (n=65) and high risk groups (n=115), in which the prevalence of myocardial ischaemia was 15%,23% and 43%, respectively. Overall the algorithm reduced the number of patients referred to MPS from 305 to 144.However, the sensitivity and specificity of the algorithm was just 68% and 62%, respectively. CONCLUSIONS/INTERPRETATION: Our algorithm was able to stratify which patients had a low, intermediate or high risk of myocardial ischaemia based on MPS. However, the algorithm had low sensitivity and specificity, combined with high cost and time requirements. TRIAL REGISTRATION: clinicaltrials.gov NCT00298844 FUNDING: The study was funded by the Danish Cardio vascular Research Academy (DaCRA), The Danish Diabetes Association and The Danish Heart Foundation.

Evidence-based insulin treatment in type 1 diabetes mellitus.

AIM: Evaluation of the evidence base for recommending different insulin treatment regimens in type 1 diabetes. METHODS: A computerised literature survey was conducted using The Cochrane Controlled Trials Register and the Pub Med database for the period of 1982-2007. RESULTS: A meta-analysis on only 49 out of 1295 references showed that CSII compared with conventional or multiple insulin injections therapy demonstrated a significant reduction in mean HbA1c (primary outcome) of 1.2% CI [0.73; 1.59] (P<0.001) without increasing the risk of hypoglycaemia. The evidence for using four versus two daily insulin injections was based on only one publication demonstrating an improved quality of life but no significant reduction in HbA1c or hypoglycaemia. A comparison of rapid-acting insulin analogues and human soluble insulin demonstrated a statistically significant reduction in HbA1c of 0.1% CI: [0.01; 0.16] (P=0.03) using rapid-acting insulin analogues. The mean frequency of hypoglycaemia was reduced with 14+/-3.7% (<0.05). CONCLUSION: The scientific evidence supporting the three common insulin regimens was rather sparse. Only five studies during the past 25 years fulfil the optimal criteria for a clinical trial, and only 5 trials on insulin analogues were performed as double-blinded. Current evidence suggests that CSII treatment results in a significant reduction in HbA1c without inducing more hypoglycaemia. Rapid-acting insulin analogues compared to human soluble insulin provide statistically significant but clinically minor improvement in HbA1c but seem to reduce the risk for hypoglycaemia.

Orthopaedic surgery in 255 patients with inflammatory arthropathies: longitudinal effects on pain, physical function and health-related quality of life.

OBJECTIVE: To examine the effectiveness of orthopaedic surgery in patients with inflammatory arthropathies with regard to longitudinal changes in pain, physical function and health-related quality of life and explore differences in effectiveness between replacement versus non-replacement surgery and surgery in the upper versus the lower limb. METHODS: 255 patients (mean age 57.5 years (SD 13.1), 76.7% female) with inflammatory arthropathies underwent orthopaedic surgical treatment and responded to mail surveys at baseline and during follow-up (3, 6, 9 and 12 months). The booklet of questionnaires included the arthritis impact measurement scales 2 (AIMS2), health assessment questionnaire (HAQ), short form 36 (SF-36), EQ-5D and visual analogue scales (VAS) addressing patient global, fatigue, general pain and pain in the actual joint. Standardised response means (SRM) were calculated to estimate the magnitude of improvement. RESULTS: Significant improvement was seen for most of the dimensions of health, the largest improvement for pain in the actual joint (SRM 1.17) at one year follow-up. SRM for AIMS-2 physical, SF-36 physical and HAQ were 0.1, 0.48 and 0.05, respectively. The overall numeric improvement (SRM) in utility was 0.10 (0.37) with EQ-5D and 0.03 (0.27) with SF-6D. Improvement overall was similar after surgery in the upper versus the lower limb, but was larger in patients undergoing replacement surgery than in patients undergoing other surgical procedures (SRM 1.54 vs 1.08 for pain in the actual joint). CONCLUSIONS: Surgical procedures have a major positive impact on pain in the actual joint, but improvement is less in other dimensions of health. Health benefits were larger after replacement surgery than after other surgical procedures.

Relationship of glucose concentrations with PAI-1 and t-PA in subjects with normal glucose tolerance.

AIM: To study metabolic risk factors for the development of cardiovascular disease (CVD), including markers of the fibrinolytic system in relation to blood glucose levels in subjects with normal glucose tolerance and fasting blood glucose levels below 5.6 mmol/l. METHODS: Cross-sectional, community-based study from a primary health-care centre of adult subjects with normal glucose tolerance. Analysis of fasting and 2-h post-load blood glucose concentrations were centralized and related to anthropometric characteristics, metabolic variables, inflammatory markers, and coagulation and fibrinolytic variables. RESULTS: Increasing fasting blood glucose concentrations within the normal range in subjects with normal glucose tolerance were associated with increasing age, body mass index, and waist circumference, and with increasing concentrations of metabolic risk factors for development of CVD. After adjustment for gender, age, body mass index (BMI), and fasting insulin, levels of plasmin activator inhibitor (PAI-1) and tissue type plasminogen activator (t-PA) increased significantly with increasing levels of fasting glucose within the normal range (P = 0.012 and P < 0.0001, respectively). CONCLUSIONS: We found risk factors for CVD, specifically key components of the fibrinolytic system, PAI-1 and t-PA, increased with increasing fasting glucose levels even in subjects with normal glucose tolerance. This observation may help to explain the increased risk of CVD with increasing values of fasting glucose in the normal range.

Energy expenditure, body composition and insulin response to glucose in male twins discordant for the Trp64Arg polymorphism of the beta3-adrenergic receptor gene.

AIM: The tryptophan to arginine change in position 64 (Trp64Arg) polymorphism of the beta3-adrenergic receptor (beta3AR) gene has been associated with an increased prevalence of obesity, insulin resistance and type 2 diabetes. In this, decreased rates of energy expenditure and impaired insulin secretion could play a role. METHODS: In 10 male twin pairs discordant for the Trp64Arg polymorphism, we examined insulin response to glucose by an oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT), body composition by the bioimpedance method, dual-energy X-ray absorptiometry scanning and energy expenditure by indirect and direct calorimetry. RESULTS: Twins heterozygous for the Trp64Arg polymorphism showed significantly lower fat mass independent of the method used, and significantly lower fasting insulin and glucose concentrations compared with their homozygous wild-type co-twins. Correspondingly, insulin resistance and insulin secretion determined by homeostasis model assessment were significantly lower in twins carrying the Trp64Arg polymorphism. However, there were no significant differences in adiponectin levels, insulinogenic index assessed by OGTT, or insulin sensitivity, acute insulin response to glucose, glucose effectiveness or insulin disposition index assessed by minimal modelling of the FSIGT. Furthermore, there were no differences in sleeping, resting or post-prandial energy expenditure. CONCLUSIONS: In male twins with a high similarity in genetic and environmental background, the Trp64Arg polymorphism of the beta3AR gene is associated with lower fat mass, fasting insulin levels and an appropriate insulin response to glucose. Thus, heterozygosity for the Trp64Arg variant is unlikely to increase the risk of obesity, insulin resistance or type 2 diabetes.