Gastrointestinal symptom burden in diabetic autonomic and peripheral neuropathy - A Danes cohort study.

OBJECTIVE: We investigated associations between gastrointestinal symptoms - evaluated as a combined weighted symptom score (CWSS) - Diabetic autonomic neuropathy (DAN), and distal symmetrical polyneuropathy (DSPN) in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Cross-sectional study in a tertiary outpatient clinic. CWSS was calculated based on questionnaires: gastroparesis composite symptom index (GCSI) and gastrointestinal symptom rating score (GSRS). DAN and DSPN were addressed using the composite autonomic symptom score 31 (COMPASS-31) questionnaire, cardiac autonomic reflex tests (CARTs), electrochemical skin conductance (ESC), vibration perception threshold (VPT), Michigan Neuropathy Screening Instrument (MNSI), pain- and thermal sensation. Analyses were adjusted for age, sex, diabetes duration, smoking, LDL-cholesterol, HbA1C and systolic blood pressure. Type 1 and type 2 diabetes were evaluated separately. RESULTS: We included 566 with type 1 diabetes and 377 with type 2 diabetes. Mean ± SD age was 58 ± 15 years and 565 (59.9 %) were women. A high CWSS was present in 143 (25 %) with type 1 and 142 (38 %) with type 2 diabetes. The odds of DAN by COMPASS-31 (p < 0.001) were higher in the high score group. For type 1 diabetes, odds of cardiac autonomic neuropathy were higher in the high CWSS group. The odds of DSPN by VPT and MNSI in type 1 diabetes, and by ESC, VPT and pain sensation in type 2 diabetes were higher in the high CWSS group. CONCLUSIONS: A high symptom score was associated with neuropathy by COMPASS-31 and vibration perception. Gastrointestinal symptom burden associated inconsistently with other neuropathy tests between diabetes types.

Systemic Cytokine Expression in Diabetes Is Associated with Prolonged Gastrointestinal Transit Times and Cardinal Gastroparesis Symptoms.

Gastroenteropathy is a common complication in diabetes associated with damages to the enteric nervous system. Systemic low-grade inflammation facilitates neurotoxicity, and associations with peripheral and autonomic neuropathy have been reported. However, less is known of associations with gastroenteropathy. To explore the area cross-sectionally, we included individuals with diabetes (type 1: 56, type 2: 100) and 21 healthy controls. Serum levels of interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, and interferon (IFN)-γ were measured by multiplex technology. Segmental gastrointestinal transit times were assessed by wireless motility capsule investigations. Symptoms of gastroparesis were rated on Gastroparesis Cardinal Symptom Index questionnaires. Compared to healthy, levels of TNF-α were decreased in type 1 diabetes and increased in type 2 diabetes, while colonic transit time was increased (all p < 0.05). In diabetes, associations between IL-8 and prolonged gastric emptying (odds ratio (OR) 1.07, p = 0.027) and between IL-10 and prolonged colonic transit (OR 29.99, p = 0.013) were seen. Inverse correlations between IL-6 and nausea/vomiting (rho = -0.19, p = 0.026) and bloating (rho = -0.29; p < 0.001) were found. These findings indicate a plausible interaction between inflammation and the enteric nervous system in diabetes, which raises the question of whether anti-inflammatory strategies could be applied in management of diabetic gastroenteropathy.

Low-grade inflammation in type 2 diabetes: a cross-sectional study from a Danish diabetes outpatient clinic.

OBJECTIVES: To investigate low-grade inflammation in type 2 diabetes and explore associations to clinical aspects as well as microvascular and macrovascular complications. DESIGN: Cross-sectional analysis. SETTING: The outpatient diabetes clinic at the Department of Endocrinology at Aalborg University Hospital, Denmark. PARTICIPANTS: 100 participants with type 2 diabetes confirmed by a haemoglobin A1c (HbA1c)≥6.5% for a minimum of 1 year and 21 healthy controls. OUTCOME MEASURES: Serum levels of 27 inflammation-related biomarkers measured by immunoassay. Associations with microvascular and macrovascular complications, body weight, glycaemic control, medication and sex were investigated in the diabetes cohort. RESULTS: Serum levels of tumour necrosis factor (TNF)-α and eotaxin were elevated in type 2 diabetes (p<0.05), while interleukin (IL)-7 was decreased (p<0.001). IL-12/IL-23p40, IL-15, macrophage-derived chemokine (MDC) and C reactive protein (CRP) levels were increased with body weight (p<0.05), while eotaxin and TNF-α were increased with elevated HbA1c levels (p<0.04). Dipeptidyl peptidase-4 inhibitor therapy was associated with lower levels of induced protein-10, MDC and thymus and activation regulated chemokine (p<0.02), while females had higher levels of MDC (p=0.027). Individuals with ≥3 diabetic complications had elevated levels of IL-6, IL-10, IL-12/IL-23p40, IL-15 and CRP compared with those with ≤3 (p<0.05). CONCLUSION: The level of low-grade inflammation in type 2 diabetes is associated with obesity, glycaemic regulation, therapeutical management, sex and complications. Our results underline the importance of addressing inflammatory issues in type 2 diabetes, as these may predispose for crippling comorbidities.

Cardiac vagal tone as a novel screening tool to recognize asymptomatic cardiovascular autonomic neuropathy: Aspects of utility in type 1 diabetes.

AIMS: To test the performance of the cardiac vagal tone (CVT) derived from a 5-minute ECG recording compared with the standardized cardiovascular autonomic reflex tests (CARTs). METHODS: Cross-sectional study included 56 well-phenotyped adults with type 1 diabetes (19-71 years, 2-54 years disease-duration). Autonomic testing included: standardized CARTs obtained with the VAGUS™, CVT, and indices of heart rate variability (HRV) obtained at 24- and 120-hour, and electrochemical skin conductance assessed with SUDOSCAN®. ROC AUC and cut-off values were calculated for CVT to recognize CAN based on ≥ 2 (established CAN, n = 7) or 1 (borderline CAN, n = 9) abnormal CARTs and compared to HRV indices and electrochemical skin conductance. RESULTS: Established CAN: The cut-off CVT value of 3.2LVS showed 67% sensitivity and 87% specificity (p = 0.01). Indices of HRV at either 24-hour (AUC > 0.90) and 120-hour (AUC > 0.88) performed better than CVT. Borderline CAN: The cut-off CVT value of 5.2LVS indicated 88% sensitivity and 63% specificity (p = 0.07). CVT performed better than HRV indices (AUC < 0.72). Electrochemical skin conductance (AUC:0.63-0.72) had lower sensitivity and specificity compared with CVT. CONCLUSIONS: Implementation of CVT with a clinically applicable cut-off value may be considered a quicker and accessible screening tool which could ultimately decrease the number of unrecognized CAN and initiate earlier prevention initiatives.

Circulating Inflammatory Markers Are Inversely Associated with Heart Rate Variability Measures in Type 1 Diabetes.

INTRODUCTION: A neuroimmune communication exists, and compelling evidence suggests that diabetic neuropathy and systemic inflammation are linked. Our aims were (1) to investigate biomarkers of the ongoing inflammation processes including cytokines, adhesion molecules, and chemokines and (2) to associate the findings with cardiovascular autonomic neuropathy in type 1 diabetes by measuring heart rate variability and cardiac vagal tone. MATERIALS AND METHODS: We included 104 adults with type 1 diabetes. Heart rate variability, time domain, and frequency domains were calculated from a 24-hour Holter electrocardiogram, while cardiac vagal tone was determined from a 5-minute electrocardiogram. Cytokines (interleukin- (IL-) 1α, IL-4, IL-12p70, IL-13, IL-17, and tumor necrosis factor- (TNF-) α), adhesion molecules (E-selectin, P-selectin, and intercellular adhesion molecule- (ICAM-) 1), and chemokines (chemokine (C-C motif) ligand (CCL)2, CCL3, CCL4, and C-X-C motif chemokine (CXCL)10) were assessed using a Luminex multiplexing technology. Associations between concentrations of inflammatory biomarkers and continuous variables of heart rate variability and cardiac vagal tone were estimated using multivariable linear regression adjusting for age, sex, disease duration, and smoking. RESULTS: Participants with the presence of cardiovascular autonomic neuropathy had higher systemic levels of IL-1α, IL-4, CCL2, and E-selectin than those without cardiovascular autonomic neuropathy. IL-1α, IL-4, IL-12, TNF-α, and E-selectin were inversely associated with both sympathetic and parasympathetic heart rate variability measures (p > 0.01). Discussion. Our results show that several pro- and anti-inflammatory factors, believed to be involved in the progression of diabetic polyneuropathy, are associated with cardiovascular autonomic neuropathy, suggesting that these factors may also contribute to the pathogenesis of cardiovascular autonomic neuropathy. Our findings emphasize the importance of the neuroimmune regulatory system in the pathogenesis of neuropathy in type 1 diabetes.

Liraglutide treatment reduced interleukin-6 in adults with type 1 diabetes but did not improve established autonomic or polyneuropathy.

AIMS: Type 1 diabetes can be complicated with neuropathy that involves immune-mediated and inflammatory pathways. Glucagon-like peptide-1 receptor agonists such as liraglutide, have shown anti-inflammatory properties, and thus we hypothesized that long-term treatment with liraglutide induced diminished inflammation and thus improved neuronal function. METHODS: The study was a randomized, double-blinded, placebo-controlled trial of adults with type 1 diabetes and confirmed symmetrical polyneuropathy. They were randomly assigned (1:1) to receive either liraglutide or placebo. Titration was 6 weeks to 1.2-1.8 mg/d, continuing for 26 weeks. The primary endpoint was change in latency of early brain evoked potentials. Secondary endpoints were changes in proinflammatory cytokines, cortical evoked potential, autonomic function and peripheral neurophysiological testing. RESULTS: Thirty-nine patients completed the study, of whom 19 received liraglutide. In comparison to placebo, liraglutide reduced interleukin-6 (-22.6%; 95% confidence interval [CI]: -38.1, -3.2; P = .025) with concomitant numerical reductions in other proinflammatory cytokines. However neuronal function was unaltered at the central, autonomic or peripheral level. Treatment was associated with -3.38 kg (95% CI: -5.29, -1.48; P < .001] weight loss and a decrease in urine albumin/creatinine ratio (-40.2%; 95% CI: -60.6, -9.5; P = .02). CONCLUSION: Hitherto, diabetic neuropathy has no cure. Speculations can be raised whether mechanism targeted treatment, e.g. lowering the systemic level of proinflammatory cytokines may lead to prevention or treatment of the neuroinflammatory component in early stages of diabetic neuropathy. If ever successful, this would serve as an example of how fundamental mechanistic principles are translated into clinical practice similar to those applied in the cardiovascular and nephrological clinic.

Population pharmacokinetics of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen.

BACKGROUND: The ß-lactam antibiotic piperacillin (in combination with tazobactam) is commonly chosen for empirical treatment of suspected bacterial infections. However, pharmacokinetic variability among patient populations and across ages leads to uncertainty when selecting a dosing regimen to achieve an appropriate pharmacodynamic target. OBJECTIVES: To guide dosing by establishing a population pharmacokinetic model for unbound piperacillin in febrile children receiving cancer chemotherapy, and to assess pharmacokinetic/pharmacodynamic target attainment (100% fT > 1×MIC and 50% fT > 4×MIC) and resultant exposure, across body weights. METHODS: Forty-three children admitted for 89 febrile episodes contributed 482 samples to the pharmacokinetic analysis. The typical doses required for target attainment were compared for various dosing regimens, in particular prolonged infusions, across MICs and body weights. RESULTS: A two-compartment model with inter-fever-episode variability in CL, and body weight included through allometry, described the data. A high CL of 15.4 L/h (70 kg) combined with high glomerular filtration rate (GFR) values indicated rapid elimination and hyperfiltration. The target of 50% fT > 4×MIC was achieved for an MIC of 4.0 mg/L in a typical patient with extended infusions of 2-3 (q6h) or 3-4 (q8h) h, at or below the standard adult dose (75 and 100 mg/kg/dose for q6h and q8h, respectively). Higher doses or continuous infusion were needed to achieve 100% fT > 1×MIC due to the rapid piperacillin elimination. CONCLUSIONS: The licensed dose for children with febrile neutropenia (80 mg/kg q6h as a 30 min infusion) performs poorly for attainment of fT>MIC pharmacokinetic/pharmacodynamic targets. Given the population pharmacokinetic profile, feasible dosing regimens with reasonable exposure are continuous infusion (100% fT > 1×MIC) or prolonged infusions (50% fT > 4×MIC).

Piperacillin pharmacokinetics and target attainment in children with cancer and fever: Can we optimize our dosing strategy?

BACKGROUND: Data on piperacillin-tazobactam pharmacokinetics and optimal dosing in children with cancer and fever are limited. Our objective was to investigate piperacillin pharmacokinetics and the probability of target attainment (PTA) with standard intermittent administration (IA), and to simulate PTA in other dosing regimens. PROCEDURE: This prospective pharmacokinetic study was conducted from April 2016 to January 2018. Children with cancer receiving empiric piperacillin-tazobactam to treat infections were included. Piperacillin-tazobactam 100 mg/kg was infused over 5 min every 8 hours (IA). An optimized sample schedule provided six blood samples per subject for piperacillin concentration determination. The evaluated targets included: (1) 100% time of free piperacillin concentration above the minimum inhibitory concentration (fT > MIC) and (2) 50% fT > 4× MIC. MIC50 and MIC90 were defined based on an intrainstitutional MIC range. RESULTS: A total of 482 piperacillin concentrations were obtained from 43 children (aged 1-18 years) during 89 fever episodes. Standard IA resulted in insufficient target attainment, with significant differences in piperacillin pharmacokinetics for different body weights. Median fT > MIC was 61.2%, 53.5%, and 36.3% for MIC50 (2.0 mg/L), MIC90 (4.0 mg/L), and breakpoint for Pseudomonas aeruginosa (16.0 mg/L), respectively. Correspondingly, the median fT > 4× MIC was 43%, 36.3%, and 20.1%. Simulations showed that only continuous infusion reached a PTA of 95% for MIC = 16.0 mg/L, while extended infusion lasting half of the dosing interval reached a PTA of 95% for MIC ≤ 8 mg/L. CONCLUSIONS: Our data revealed insufficient PTA with standard IA of piperacillin-tazobactam in children with cancer and fever. Alternative dosing strategies, preferably continuous infusion, are required to ensure adequate PTA.

Situational but Not Dispositional Pain Catastrophizing Correlates With Early Postoperative Pain in Pain-Free Patients Before Surgery.

UNLABELLED: Pain catastrophizing may be assessed as a dispositional measure using a previous painful experience as a reference or as a situational measure using an actual ongoing pain as a reference. The latter has shown more robust correlations with pain-related outcomes; the relative influence of dispositional and situational pain catastrophizing remains unknown in relation to populations with no pain before surgery. Forty-two consecutive patients who underwent corrective surgery for funnel chest were asked to complete the Pain Catastrophizing Scale with reference to 1) a previous painful experience (dispositional pain catastrophizing), 2) experimental pain during a 2-minute cold pressor test (situational experimental pain catastrophizing), and 3) clinical pain 3 days after surgery (situational clinical pain catastrophizing) to investigate whether these measures predicted immediate pain intensity and unpleasantness in the early postoperative period. Thirty-four patients were available for analyses. Dispositional pain catastrophizing was unrelated to situational experimental and situational clinical pain catastrophizing and to postoperative pain and unpleasantness (P > .05). In contrast, the 2 situation-specific pain catastrophizing measures were strongly associated (ρ = .59, P = .0002). In analyses adjusted for preoperative anxiety, depression, and cold pressor pain sensitivity, situational experimental and situational clinical pain catastrophizing correlated with postoperative movement-evoked pain (ß = 1.36, P = .01 and ß = 1.24, P = .02, respectively) and unpleasantness (ß = 1.32, P = .01 and ß = 1.36, P = .01, respectively). PERSPECTIVE: Pain catastrophizing should be captured in relation to specific painful events in otherwise healthy patients. Future studies might benefit from assessing situational pain catastrophizing to identify patients at risk for increased postoperative pain to optimize stratified pain treatment.

Number of drugs most frequently found to be independent risk factors for serious adverse reactions: a systematic literature review.

In order to reduce the numbers of medication errors (MEs) that cause adverse reactions (ARs) many authors have tried to identify patient-related risk factors. However, the evidence remains controversial. The aim was to review systematically the evidence on the relationship between patient-related risk factors and the risk of serious ARs. A systematic search in Pubmed, Embase, Cochrane Systematic Reviews, Psychinfo and SweMed+ was performed. Included full text articles were hand searched for further references. Peer reviewed papers including adults from primary and secondary healthcare were included if they clearly defined seriousness of the ARs and described correlations to risk factors by statistical analysis. A total of 28 studies were identified including 85,212 patients with 3385 serious ARs, resulting in an overall frequency of serious ARs in 4% of patients. Age, gender and number of drugs were by far the most frequently investigated risk factors. The total number of drugs was the most consistent correlated risk factor found in both univariate and multivariate analyses. The number of drugs is the most frequently documented independent patient-related risk factor for serious ARs in both the general adult population as well as in the elderly. The existing evidence is however conflicting due to heterogeneity of populations and study methods. The knowledge of patient-related risk factors for experiencing ARs could be used for electronic risk stratification of patients and thereby allocation of healthcare resources to high risk patients.

Pharmacokinetics of cefuroxime in porcine cortical and cancellous bone determined by microdialysis.

Traditionally, the pharmacokinetics of antimicrobials in bone have been investigated using bone biopsy specimens, but this approach suffers from considerable methodological limitations. Consequently, new methods are needed. The objectives of this study were to assess the feasibility of microdialysis (MD) for measuring cefuroxime in bone and to obtain pharmacokinetic profiles for the same drug in porcine cortical and cancellous bone. The measurements were conducted in bone wax sealed and unsealed drill holes in cortical bone and in drill holes in cancellous bone and in subcutaneous tissue. As a reference, the free and total plasma concentrations were also measured. The animals received a bolus of 1,500 mg cefuroxime over 30 min. No significant differences were found between the key pharmacokinetic parameters for sealed and unsealed drill holes in cortical bone. The mean ± standard error of the mean area under the concentration-time curve (AUC) values from 0 to 5 h were 6,013 ± 1,339, 3,222 ± 1086, 2,232 ± 635, and 952 ± 290 min · µg/ml for free plasma, subcutaneous tissue, cancellous bone, and cortical bone, respectively (P < 0.01, analysis of variance). The AUC for cortical bone was also significantly different from that for cancellous bone (P = 0.04). This heterogeneous tissue distribution was also reflected in other key pharmacokinetic parameters. This study validates MD as a suitable method for measuring cefuroxime in bone. Cefuroxime penetration was impaired for all tissues, and bone may not be considered one distinct compartment.

Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer´s disease - protocol for a controlled, randomized double-blinded trial.

INTRODUCTION: Type 2 diabetes (DM-2) increases the risk of developing Alzheimer´s disease (AD), and patients with AD are more likely to develop DM-2. DM-2 and AD share some pathophysiological features. In AD, amyloid-ß (Aß) is accumulated as extracellular plaques in the gray matter of the brain, while in DM-2 islet amyloid polypeptide (IAPP) is accumulated in the pancreas. Premature cellular degeneration is seen in both diseases. Glucagon-like peptide-1 (GLP-1) reduces the amount of Aß and improves cognition in animal studies. The present study tests the hypothesis that treatment with the long-acting GLP-1 receptor agonist liraglutide affects the accumulation of Aß in patients with AD. MATERIAL AND METHODS: This is a randomized, controlled, double-blinded intervention study with AD patients treated for six months with liraglutide (n = 20) or placebo (n = 20). The primary outcome is change in deposition of Aß in the central nervous system (CNS) by Pittsburgh compound B positron emission tomography (PET). The secondary outcome is evaluation of cognition using a neuro-psychological test battery, and examination of changes in glucose uptake in the CNS by 18F-fluoro-deoxy-glucose PET. Finally, a perfusion-weighted magnetic resonance imaging with contrast will be performed to evaluate blood flow. CONCLUSION: No registered drug affects the deposition of Aß in the brain of AD patients. Our goal is to find a new therapeutic agent that alters the pathophysiology in AD patients by decreasing the formation of Aß plaques and thereby presumably improves the cognitive function. FUNDING: The trial is investigator-initiated and investigator-driven and is supported by Novo Nordisk Scandinavia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01469351.

[Vaginal oestrogen therapy in women with hormone-sensitive breast cancer]. / Vaginal østrogenbehandling ved hormonfølsom brystkræft.

Vaginal atrophy is a common problem in women who have previously been treated for breast cancer. Endocrine therapy plays an essential role in the treatment of breast cancer. Systemic hormonal treatment is contraindicated. Topical oestrogens are an effective treatment for vaginal atrophy, but are poorly studied in this group of patients. Physicians are reluctant to recommend it because of the potential increase in the risk of recurrence. The sparse data available suggest that vaginal oestrogen may be used relatively safely by women who are in tamoxifen treatment, but should not be used by women who receive aromatase inhibitor treatment.

The effect of systematic medication review in elderly patients admitted to an acute ward of internal medicine.

Elderly patients are vulnerable to medication errors and adverse drug events due to increased morbidity, polypharmacy and inappropriate interactions. The objective of this study was to investigate whether systematic medication review and counselling performed by a clinical pharmacist and clinical pharmacologist would reduce length of in-hospital stay in elderly patients admitted to an acute ward of internal medicine. A randomized, controlled study of 100 patients aged 70 years or older was conducted in an acute ward of internal medicine in Denmark. Intervention arm: a clinical pharmacist conducted systematic medication reviews after an experienced medical physician had prescribed the patients' medication. Information was collected from medical charts, interview with the patients and database registrations of drug purchase. Subsequently, medication histories were conferred with a clinical pharmacologist and advisory notes recommending medication changes were completed. Physicians were not obliged to comply with the recommendations. Control arm: medication was reviewed by usual routine in the ward. Primary end-point was length of in-hospital stay. In addition, readmissions, mortality, contact to primary healthcare and quality of life were measured at 3-month follow-up. In the intervention arm, the mean length of in-hospital stay was 239.9 hr (95% CI: 190.2-289.6) and in the control arm: 238.6 hr (95% CI: 137.6-339.6), which was neither a statistical significant nor a clinically relevant difference. Moreover, no differences were observed for any of the secondary end-points. Systematic medication review and medication counselling did not show any effect on in-hospital length of stay in elderly patients when admitted to an acute ward of internal medicine.

SLC30A3 responds to glucose- and zinc variations in beta-cells and is critical for insulin production and in vivo glucose-metabolism during beta-cell stress.

BACKGROUND: Ion transporters of the Slc30A- (ZnT-) family regulate zinc fluxes into sub-cellular compartments. beta-cells depend on zinc for both insulin crystallization and regulation of cell mass. METHODOLOGY/PRINCIPAL FINDINGS: This study examined: the effect of glucose and zinc chelation on ZnT gene and protein levels and apoptosis in beta-cells and pancreatic islets, the effects of ZnT-3 knock-down on insulin secretion in a beta-cell line and ZnT-3 knock-out on glucose metabolism in mice during streptozotocin-induced beta-cell stress. In INS-1E cells 2 mM glucose down-regulated ZnT-3 and up-regulated ZnT-5 expression relative to 5 mM. 16 mM glucose increased ZnT-3 and decreased ZnT-8 expression. Zinc chelation by DEDTC lowered INS-1E insulin content and insulin expression. Furthermore, zinc depletion increased ZnT-3- and decreased ZnT-8 gene expression whereas the amount of ZnT-3 protein in the cells was decreased. Zinc depletion and high glucose induced apoptosis and necrosis in INS-1E cells. The most responsive zinc transporter, ZnT-3, was investigated further; by immunohistochemistry and western blotting ZnT-3 was demonstrated in INS-1E cells. 44% knock-down of ZnT-3 by siRNA transfection in INS-1E cells decreased insulin expression and secretion. Streptozotocin-treated mice had higher glucose levels after ZnT-3 knock-out, particularly in overt diabetic animals. CONCLUSION/SIGNIFICANCE: Zinc transporting proteins in beta-cells respond to variations in glucose and zinc levels. ZnT-3, which is pivotal in the development of cellular changes as also seen in type 2 diabetes (e.g. amyloidosis in Alzheimer's disease) but not previously described in beta-cells, is present in this cell type, up-regulated by glucose in a concentration dependent manner and up-regulated by zinc depletion which by contrast decreased ZnT-3 protein levels. Knock-down of the ZnT-3 gene lowers insulin secretion in vitro and affects in vivo glucose metabolism after streptozotocin treatment.

Is metformin therapy for polycystic ovary syndrome safe during pregnancy?

Polycystic ovary syndrome is characterized among other things by oligo-amenorrhea and may account for more than 75% of cases with anoluvatory infertility. Due to its positive effects on polycystic ovary syndrome-induced infertility metformin has become one of the most common drugs used in this group of patients. The efficacy of the drug as well as the first reports on metformin used in pregnancy has encouraged the continued use of the drug after conception. This MiniReview reviews the current pros and cons of metformin use in pregnancy while awaiting the results of ongoing randomised, controlled clinical trials addressing the subject.