Effects of Exogenous GIP and GLP-2 on Bone Turnover in Individuals With Type 2 Diabetes.

CONTEXT: Individuals with type 2 diabetes (T2D) have an increased risk of bone fractures despite normal or increased bone mineral density. The underlying causes are not well understood but may include disturbances in the gut-bone axis, in which both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are regulators of bone turnover. Thus, in healthy fasting participants, both exogenous GIP and GLP-2 acutely reduce bone resorption. OBJECTIVE: The objective of this study was to investigate the acute effects of subcutaneously administered GIP and GLP-2 on bone turnover in individuals with T2D. METHODS: We included 10 men with T2D. Participants met fasting in the morning on 3 separate test days and were injected subcutaneously with GIP, GLP-2, or placebo in a randomized crossover design. Blood samples were drawn at baseline and regularly after injections. Bone turnover was estimated by circulating levels of collagen type 1 C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), sclerostin, and PTH. RESULTS: GIP and GLP-2 significantly reduced CTX to (mean ± SEM) 66 ± 7.8% and 74 ± 5.9% of baseline, respectively, compared with after placebo (P = .001). In addition, P1NP and sclerostin increased acutely after GIP whereas a decrease in P1NP was seen after GLP-2. PTH levels decreased to 67 ± 2.5% of baseline after GLP-2 and to only 86 ± 3.4% after GIP. CONCLUSION: Subcutaneous GIP and GLP-2 affect CTX and P1NP in individuals with T2D to the same extent as previously demonstrated in healthy individuals.

The Importance of Endogenously Secreted GLP-1 and GIP for Postprandial Glucose Tolerance and ß-Cell Function After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy Surgery.

Enhanced secretion of glucagon-like peptide 1 (GLP-1) seems to be essential for improved postprandial ß-cell function after Roux-en-Y gastric bypass (RYGB) but is less studied after sleeve gastrectomy (SG). Moreover, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. We studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed-meal tests in unoperated (CON), SG-operated, and RYGB-operated people with no history of diabetes. Postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. The effect of GLP-1R versus GIPR blockade differed between groups. GLP-1R blockade reduced ß-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the surgical groups but had no effect in CON. GIPR blockade reduced ß-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. Our results support that GIP is the most important incretin hormone in unoperated people, whereas GLP-1 and GIP are equally important after SG, and GLP-1 is the most important incretin hormone after RYGB.

Effect of Meal Texture on Postprandial Glucose Excursions and Gut Hormones After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy.

Background and aims: The metabolic consequences after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are often studied using a liquid mixed meal. However, liquid meals may not be representative of the patients' everyday diet. We therefore examined postprandial glucose and gut hormone responses using mixed meals differing only with respect to meal texture. Methods: Twelve RYGB-operated, 12 SG-operated, and 12 unoperated individuals (controls) were enrolled in the study. Participants were matched on age, sex, and body mass index. In randomized order, each participant underwent a liquid and a solid 4-h mixed meal test on separate days. The meals were isocaloric (309 kcal), and with identical macronutrient composition (47 E% carbohydrate, 18 E% protein, 32 E% fat, and 3 E% dietary fibers). The liquid meal was blended to create a smooth liquid texture while the other meal retained its solid components. Results: Postprandial glucose concentrations (peak and incremental area under curve, iAUC) did not differ between the two meal textures in any group. In the control group, peak C-peptide was higher after the liquid meal compared with the solid meal (p = 0.04), whereas iAUCs of C-peptide were similar between the two meals in all groups. Peak of glucagon-like peptide-1 (GLP-1) was higher after the liquid meal compared with the solid meal in RYGB- and SG-operated individuals (RYGB p = 0.02; SG p < 0.01), but iAUC of GLP-1 did not differ between meal textures within any group. Peak of glucose-dependent insulin tropic polypeptide (GIP) was higher after the liquid meal in the SG and control groups (SG p = 0.02; controls p < 0.01), but iAUCs of GIP were equal between meals. There were no differences in total AUC of ghrelin between the liquid and solid meals within any of the groups. Conclusion: A liquid and a solid meal with identical macronutrient composition result in similar postprandial glucose responses, both in operated and unoperated individuals. Small differences were observed for the postprandial peaks of C-peptide, GLP-1, and GIP concentrations. Overall, a liquid meal is suitable for evaluating glucose tolerance, ß-cell function, and gut hormones responses, both after RYGB and SG and in unoperated individuals. Clinical Trial Registration: [www.clinicaltrials.gov], identifier [NCT04082923].

The role of GLP-1 in postprandial glucose metabolism after bariatric surgery: a narrative review of human GLP-1 receptor antagonist studies.

The Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) bariatric procedures lead to remission or improvement of type 2 diabetes. A weight loss-independent augmentation of postprandial insulin secretion contributes to the improvement in glycemic control after RYGB and is associated with a ∼10-fold increase in plasma concentrations of the incretin hormone glucagon-like peptide-1 (GLP-1). However, the physiologic importance of the markedly increased postprandial GLP-1 secretion after RYGB has been much debated. The effect of GLP-1 receptor blockade after RYGB has been investigated in 12 studies. The studies indicate a shift toward a more prominent role for GLP-1 in postprandial ß-cell function after RYGB. The effect of GLP-1 receptor antagonism on glucose tolerance after RYGB is more complex and is associated with important methodological challenges. The postprandial GLP-1 response is less enhanced after SG compared with RYGB. However, the effect of GLP-1 receptor blockade after SG has been examined in 1 study only and needs further investigation.

Effect and safety of endoscopic sleeve gastroplasty for treating obesity - a systematic review.

INTRODUCTION: Endoscopic sleeve gastroplasty (ESG) represents a novel endoscopic bariatric procedure. It is performed with an endoscope equipped with a suturing device; sutures are placed so that they create a tube-shaped stomach, thereby facilitating weight loss. The aim of this study was to conduct a systematic review evaluating the effectiveness and safety of ESG for treatment of obesity. METHODS: This review was conducted in accordance with the PRISMA guidelines; a protocol was registered with PROSPERO before the start of the study. MEDLINE, Embase and Clinicaltrials.gov were searched through 20 February 2020. RESULTS: A total of 1,088 articles were assessed. In all, 23 studies met the inclusion criteria. The average total weight loss at 12 months was 16.3%. ESG was associated with a significantly greater weight loss than both intragastric balloon insertion (21.3 ± 6.6 versus 13.9 ± 9.0% total weight loss (TWL) at 12 months, p less than 0.05) and "high-intensity diet and lifestyle therapy" (20.6 ± 8.3 versus 14.3 ± 10.2% TWL at 12 months, p less than 0.05). In contrast, ESG was associated with a significantly lower weight loss than laparoscopic sleeve gastrectomy (17.1 ± 6.5 versus 23.6 ± 7.6% TWL at six months, p less than 0.05). ESG had a significantly lower rate of adverse events than both laparoscopic sleeve gastrectomy (5.2 versus 16.9%, p less than 0.05) and intragastric balloon placement (5.2 versus 17%, p less than 0.05). CONCLUSIONS: ESG is a safe method for treatment of obesity and facilitates a significant weight loss.

Survival of selected patients with ovarian cancer treated with fertility-sparing surgery.

RESEARCH QUESTION: How many patients in Denmark were treated with fertility-sparing surgery (FSS) for epithelial ovarian cancer (EOC) and what was their prognosis compared with patients treated with radical surgery (RS)? DESIGN: This study was a retrospective Danish nationwide study, evaluating the effect of FSS compared with RS in patients with EOC, age ≤45 years and International Federation of Gynecology and Obstetrics (FIGO) stage ≤IC3 from 2005 to 2016. RESULTS: A total of 106 patients were included. Of these, 13 were treated with FSS and 93 were treated with RS. Median age was 27 versus 42 years (P < 0.0001). Overall survival did not differ significantly between the two groups. Overall survival rate in the FSS group was 100%, while the overall survival in the RS group was 87%. Disease-specific survival was 100% in the FSS group and 91% in the RS group. CONCLUSIONS: This study shows that patients treated with FSS for FIGO stage I EOC do not have an impaired survival compared with patients treated with RS. Nevertheless, the conclusion must be interpreted with caution due to the limited number of patients and the retrospective nature of the study. Larger studies are needed before conclusions can be drawn.

Staging of early lymph node metastases with the sentinel lymph node technique and predictive factors in T1/T2 oral cavity cancer: A retrospective single-center study.

BACKGROUND: The purpose of this study was to examine the diagnostic accuracy of detecting lymph node metastases and to identify predictive and prognostic clinicopathological factors in patients with oral squamous cell carcinoma (OSCC) undergoing sentinel lymph node biopsy (SLNB). METHODS: All patients diagnosed with cT1 to T2N0 OSCC who underwent a diagnostic SLNB between 2007 and 2013 were included. RESULTS: We identified 253 patients, of whom 27% had a positive sentinel lymph node (SLB). The false-negative rate, sensitivity, and negative predictive value (NPV) were 5%, 88%, and 95%, respectively. Patients with micrometastases as well as macrometastases had a separately, significantly shorter disease-specific survival than patients with pN0 disease. In a logistic regression model, the maximum tumor thickness, perineural invasion, and differentiation grade were independent predictive factors for the presence of metastases. CONCLUSION: These data support the use of the SLNB technique as an accurate and safe staging tool in patients with OSCC with a cN0 neck. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1033-E1040, 2016.

Human papillomavirus in head and neck squamous cell carcinoma of unknown primary is a common event and a strong predictor of survival.

BACKGROUND: The purpose of this study was to examine the prevalence of human papillomavirus (HPV) in patients with head and neck squamous cell carcinoma of unknown primary (CUP). METHODS: All patients diagnosed with and treated for CUP between January 1, 2000, and June 1, 2011, at two Danish medical centers were included. All patients received a thorough diagnostic work-up, including FDG-PET, before being diagnosed as CUP. We determined the HPV status in all patients using a combination of HPV DNA PCR and p16 stain. In addition, clinical information on the study patients was retrieved from clinical records. RESULTS: Of the identified 60 patients with CUP, 13 were shown to be positive for HPV DNA, amounting to 22% of the study population. In addition, we were able to show a clear disease-free and overall-survival benefit in the HPV-positive group, with a hazard ratio of 0.16 (95% CI: 0.038-0.67) for over-all survival. This survival benefit was also apparent when adjusted for advanced age in a multivariate Cox regression analysis. CONCLUSION: A fairly large percentage of CUP cases are HPV-related, and because this is related to both the location and prognosis, we recommend HPV testing as part of the diagnostic work-up.

MiR-21 expression in the tumor stroma of oral squamous cell carcinoma: an independent biomarker of disease free survival.

Oral squamous cell carcinoma (OSCC) patients have a high mortality rate; thus, new clinical biomarkers and therapeutic options are needed. MicroRNAs (miRNAs) are short noncoding RNAs that regulate posttranscriptional gene expression and are commonly deregulated in OSCC and other cancers. MicroRNA-21 (miR-21) is the most consistently overexpressed miRNA in several types of cancer, and it might be a useful clinical biomarker and therapeutic target. To better understand the role of miR-21 in OSCC, paraffin-embedded tumor tissue samples from 86 patients with primary OSCC were analyzed by in situ hybridization. We found that miR-21 was primarily expressed in the tumor stroma and in some tumor-associated blood vessels with no expression in the adjacent normal epithelia or stroma. Using image analysis, we quantitatively estimated miR-21 expression levels specifically in the stroma of a cohort of OSCC samples. These miR-21 levels significantly correlated with disease free survival with the highest levels being located in the stroma. Stromal miR-21 expression was independently associated with a poorer prognosis, even after adjusting for clinical parameters (perineural invasion and N-stage) in a multivariate analysis. In summary, we have shown that miR-21 is located in the carcinoma cells, stroma and blood vessels of tumors, and its expression specifically in the stromal compartment has a negative prognostic value in OSCC.

Effect of the EndoBarrier Gastrointestinal Liner on obesity and type 2 diabetes: protocol for systematic review and meta-analysis of clinical studies.

INTRODUCTION: Obese patients with type 2 diabetes undergoing bariatric surgery experience significant and lasting weight loss and improved glycaemic control. However, bariatric surgical procedures such as Roux-en-Y gastric bypass are irreversible and associated with considerable short-term and long-term risks. The EndoBarrier Gastrointestinal Liner or duodenal-jejunal bypass sleeve (DJBS) is a fully reversible procedure that has been developed to treat obesity and type 2 diabetes. We aim to perform a systematic review and meta-analysis of safety and efficacy of DJBS. METHODS AND ANALYSES: A systematic review with meta-analysis (as per the preferred reporting items for systematic reviews and meta-analyses) of randomised controlled trials of the device (vs no intervention, sham and/or low-calorie diet) will be performed. Primary endpoints include change in body weight and glycated haemoglobin and safety. Secondary endpoints constitute changes in other glycaemic parameters and blood lipids and the proportion of patients discontinuing antidiabetic medication. MEDLINE, EMBASE, The Cochrane Library and Science Citation Index will be sought electronically along with manual searches. The primary meta-analysis will use random effects models due to an expected intertrial heterogeneity. Fixed effect meta-analysis will be executed to assess the impact of small trials. Dichotomous data will be analysed using risk difference and continuous data using weighted mean differences, both with 95% CIs. ETHICS AND DISSEMINATION: The study will describe the impact of DJBS on obesity and type 2 diabetes and possibly contribute to clinical decision-making. The results of this study will be disseminated by peer-reviewed publication and scientific presentations. REGISTRATION: PROSPERO CRD42013004819.