Weight-loss drugs - for whom, how, how long? / Vektreduserende medisiner ­ for hvem, hvordan, hvor lenge?

Drug treatment of obesity is undergoing a scientific revolution, and it can be hard to keep up. Two relatively new drugs that suppress hunger and increase feelings of satiety can now be prescribed by all Norwegian doctors.

m6A Regulators in Human Adipose Tissue - Depot-Specificity and Correlation With Obesity.

Background: N6-methyladenosine (m6A) is one of the most abundant post-transcriptional modifications on mRNA influencing mRNA metabolism. There is emerging evidence for its implication in metabolic disease. No comprehensive analyses on gene expression of m6A regulators in human adipose tissue, especially in paired adipose tissue depots, and its correlation with clinical variables were reported so far. We hypothesized that inter-depot specific gene expression of m6A regulators may differentially correlate with clinical variables related to obesity and fat distribution. Methods: We extracted intra-individually paired gene expression data (omental visceral adipose tissue (OVAT) N=48; subcutaneous adipose tissue (SAT) N=56) of m6A regulators from an existing microarray dataset. We also measured gene expression in another sample set of paired OVAT and SAT (N=46) using RT-qPCR. Finally, we extracted existing gene expression data from peripheral mononuclear blood cells (PBMCs) and single nucleotide polymorphisms (SNPs) in METTL3 and YTHDF3 from genome wide data from the Sorbs population (N=1049). The data were analysed for differential gene expression between OVAT and SAT; and for association with obesity and clinical variables. We further tested for association of SNP markers with gene expression and clinical traits. Results: In adipose tissue we observed that several m6A regulators (WTAP, VIRMA, YTHDC1 and ALKBH5) correlate with obesity and clinical variables. Moreover, we found adipose tissue depot specific gene expression for METTL3, WTAP, VIRMA, FTO and YTHDC1. In PBMCs, we identified ALKBH5 and YTHDF3 correlated with obesity. Genetic markers in METTL3 associate with BMI whilst SNPs in YTHDF3 are associated with its gene expression. Conclusions: Our data show that expression of m6A regulators correlates with obesity, is adipose tissue depot-specific and related to clinical traits. Genetic variation in m6A regulators adds an additional layer of variability to the functional consequences.

Glucose tolerance before and after renal transplantation.

BACKGROUND: Renal insufficiency predisposes to insulin resistance, hyperparathyroidism and derangements in calcium phosphate and nitrogenous compound balance, leading to pre-transplant hyperglycaemia. These metabolic risk factors are not fully corrected after renal transplantation. The present study aimed to assess the role of pre-transplant glycaemia and the named metabolic risk factors in post-transplant hyperglycaemia [PHYG; impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes mellitus (DM)]. METHODS: This is a retrospective cohort study involving 301 patients without pre-transplant DM. Measurements included a pre- and post-transplant oral glucose tolerance test (OGTT) as well as glomerular filtration rate (GFR), parathyroid hormone (PTH), phosphate, calcium and urea measured 10 weeks post-transplant. The risk of PHYG at 10 weeks post-transplant was analysed using multiple logistic regression. RESULTS: Ninety-three patients (31%) had PHYG (two IFG, 52 IGT, 39 DM). Variables associated with PHYG included pre-transplant 2-h glycaemia [OR 1.26, 95% CI (1.09, 1.46)] and post-transplant urea levels [OR 1.14, 95% CI (1.02, 1.27)]. Older age, non-Caucasian ethnicity, previous transplants, >or=3 HLA class 1 mismatches and high prednisolone doses were likewise associated with an increased PHYG risk (all P < 0.05). CONCLUSIONS: Pre-transplant glycaemia and high post-transplant levels of urea were associated with a greater risk of PHYG. This seemed to be independent of GFR, PTH, phosphate, calcium and traditional risk factors such as age and glucocorticoid load.

Impaired glucose homeostasis in renal transplant recipients receiving basiliximab.

BACKGROUND: The pathogenesis of new onset diabetes after transplantation (NODAT) is multifactorial. Suppression of regulatory T lymphocytes may have a negative impact on pancreatic beta-cells. Induction with basiliximab affects regulatory T-cell function and may therefore, theoretically, also affect glucose homeostasis in renal transplant recipients. METHODS: All kidney recipients > or =50 years of age without diabetes mellitus transplanted from 1 January 2005 to 31 December 2007 were included in a single-centre retrospective study. Immunosuppression consisted of steroids, mycophenolate mofetil and cyclosporine. Basiliximab was introduced as induction therapy 1 January 2007. An oral glucose tolerance test (OGTT) was performed in all patients 10 weeks post-transplant. RESULTS: A total of 264 patients were recruited. One hundred and thirty-four patients received basiliximab. In the basiliximab group, 51.5% developed NODAT, impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) versus 36.9% in the group without induction therapy (P = 0.017). In recipients with normal OGTT, the mean fasting glucose at 10 weeks was 5.18 mmol/l (SD: 0.54) in the basiliximab group (n = 65) and 4.84 mmol/l (SD: 0.64) in the no induction group (n = 82) (P = 0.001). CONCLUSION: Use of basiliximab as induction therapy may be associated with impaired glucose homeostasis after kidney transplantation.

Associations between Lifetime Adversity and Obesity Treatment in Patients with Morbid Obesity.

BACKGROUND: Bariatric surgery is associated with greater and more sustainable weight loss compared with lifestyle intervention programs. On the other hand, bariatric surgery may also be associated with physical and psychosocial complications. The influence of psychological evaluation on treatment choice, however, is not known. We aimed to examine variables associated with treatment choice and, specifically, if self-reported lifetime adversity influenced obesity treatment, i.e. bariatric surgery, high-intensive lifestyle treatment or low-intensive lifestyle treatment in primary care. METHODS: We consecutively included 924 patients from the registry study of patients with morbid obesity at Akershus University Hospital, Lørenskog, Norway. Treatment selection was made through a shared decision-making process. Self-reported lifetime adversity was registered by trained personnel. Logistic regression models were used to assess the associations between obesity treatment and possible predictors. RESULTS: Patients who chose bariatric surgery were more likely to have type 2 diabetes (DM2) compared with patients who chose lifestyle treatment (bariatric surgery: 35%, high-intensive lifestyle treatment: 26%, and low-intensive lifestyle treatment: 26%; p = 0.035). Patients who chose bariatric surgery were less likely than patients who chose lifestyle intervention to report lifetime adversity (bariatric surgery: 39%, high-intensive lifestyle treatment: 47%, and low-intensive lifestyle treatment: 51%; p = 0.004). After multivariable adjustments, increasing BMI, having DM2, and joint pain were associated with choosing bariatric surgery over non-surgical obesity treatment (odds ratio [95% CI]: BMI 1.03 [1.01-1.06], DM2 1.47 [1.09-1.99], and joint pain 1.46 [1.08-1.96]). Self-reported lifetime adversity was furthermore associated with lower odds of choosing bariatric surgery in patients with morbid obesity (0.67 [0.51-0.89]). CONCLUSION: This study shows that increasing BMI, DM2, and joint pain were all associated with treatment choice for obesity. In addition, self-reported lifetime adversity was associated with the patients' treatment choice for morbid obesity. Consequently, we suggest that decisions concerning obesity treatment should include dialogue-based assessments of the patients' lifetime adversity.

Single-centre, triple-blinded, randomised, 1-year, parallel-group, superiority study to compare the effects of Roux-en-Y gastric bypass and sleeve gastrectomy on remission of type 2 diabetes and ß-cell function in subjects with morbid obesity: a protocol for the Obesity surgery in Tønsberg (Oseberg) study.

INTRODUCTION: Bariatric surgery is increasingly recognised as an effective treatment option for subjects with type 2 diabetes and obesity; however, there is no conclusive evidence on the superiority of Roux-en-Y gastric bypass or sleeve gastrectomy. The Oseberg study was designed to compare the effects of gastric bypass and sleeve gastrectomy on remission of type 2 diabetes and ß-cell function. METHODS AND ANALYSIS: Single-centre, randomised, triple-blinded, two-armed superiority trial carried out at the Morbid Obesity Centre at Vestfold Hospital Trust in Norway. Eligible patients with type 2 diabetes and obesity were randomly allocated in a 1:1 ratio to either gastric bypass or sleeve gastrectomy. The primary outcome measures are (1) the proportion of participants with complete remission of type 2 diabetes (HbA1c≤6.0% in the absence of blood glucose-lowering pharmacologic therapy) and (2) ß-cell function expressed by the disposition index (calculated using the frequently sampled intravenous glucose tolerance test with minimal model analysis) 1 year after surgery. ETHICS AND DISSEMINATION: The protocol of the current study was reviewed and approved by the regional ethics committee on 12 September 2012 (ref: 2012/1427/REK sør-øst B). The results will be disseminated to academic and health professional audiences and the public via publications in international peer-reviewed journals and conferences. Participants will receive a summary of the main findings. TRIAL REGISTRATION NUMBER: NCT01778738;Pre-results.

Reduced incidence of new-onset posttransplantation diabetes mellitus during the last decade.

BACKGROUND: A previous study (1995-1996) of 173 nondiabetic renal transplant recipients (historical cohort; HC) revealed a 20% incidence of new-onset posttransplantation diabetes mellitus (PTDM) and 32% with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). We examined whether glucose tolerance has improved after recent changes in our immunosuppressive protocol and a switch from deferred to preemptive cytomegalovirus (CMV) therapy. METHODS: A total of 321 consecutive, nondiabetic patients (new cohort; NC) were examined 10 weeks after kidney transplantation with an oral glucose tolerance test (n=301) between January 2004 and December 2005. RESULTS: Although recipients in the NC were on average 3 years older [mean (SD): 50.3 (14.6) vs. 47.4 (16.0), P=0.038] and had a higher mean body mass index [24.5 (3.6) vs. 23.5 (3.8) kg/m(2), P=0.003], a significantly lower incidence of both PTDM (13%) and IGT/IFG (18%) was observed in the NC (P<0.001) as compared to the HC. The patients in the NC received a significantly lower mean daily oral prednisolone dose [13.2 (4.7) vs. 15.3 (6.6) mg/day, P<0.001], and had lower frequencies of rejections (36% vs. 57%, P<0.001) and CMV infection (54% vs. 63%, P=0.071). Patients in the NC had significantly lower odds of developing PTDM, even after adjustment for age, prednisolone dose, HLA-B27 status and CMV infection (odds ratio: 0.42, 95% CI: 0.23-0.77, P=0.005). CONCLUSIONS: The odds of developing PTDM are more than halved over the last decade. Possible explanations are changes in immunosuppressive therapy, fewer rejections, and lower doses of steroids.

Undiagnosed diabetes in kidney transplant candidates: a case-finding strategy.

BACKGROUND AND OBJECTIVES: Guidelines recommend that candidates for kidney transplantation (KTx) who do not have diabetes perform a pretransplantation oral glucose tolerance test (OGTT) when fasting plasma glucose (FPG) is <110 mg/dl (<6.1 mmol/L); however, the OGTT is potentially costly and cumbersome. We studied the role of the OGTT for diagnosing diabetes and the accuracy of FPG and glycated hemoglobin (HbA(1c)) for predicting a diabetic OGTT before KTx. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this cross-sectional study, 889 first single-kidney transplant candidates without diabetes, mainly white, performed an OGTT during the transplantation workup. Results were studied using receiver operating characteristic analysis. RESULTS: Of 72 (8.1%) patients with undiagnosed diabetes, only 16 (22%) had a diabetic FPG (> or =126 mg/dl [> or =7.0 mmol/L]). In patients with a nondiabetic FPG, diabetes (2-hour plasma glucose [2h-PG] > or =200 mg/dl [> or =11.1 mmol/L]) was predicted by FPG but not by HbA(1c). Performing the OGTT in patients with FPG 92 to 125 mg/dl (5.1 to 6.9 mmol/L) identified 65 (90%) patients with diabetes (16 by FPG, 49 by 2h-PG) and required seven OGTTs per patient identified. Subjecting all patients with FPG <110 mg/dl (<6.1 mmol/L) to the OGTT identified 60 (83%) patients with diabetes (16 by FPG, 44 by 2h-PG) but required 14 OGTTs per patient. CONCLUSIONS: The OGTT was paramount in finding most cases of undiagnosed diabetes before KTx. FPG but not HbA(1c) predicted a diabetic OGTT. We suggest that white KTx candidates without diabetes perform a pretransplantation OGTT when FPG is 92 to 125 mg/dl (5.1 to 6.9 mmol/L).