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Background: The development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes are still missing., Methods: Liver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice., Results: Here, we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182-5 p was the most associated with whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene LRP6 was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182-5 p overexpression. Weight loss in obese mice decreased hepatic miR-182-5 p and restored Lrp6 expression and other miR-182-5 p target genes. Hepatic overexpression of miR-182-5 p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days., Conclusions: By mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression of LRP6 by miR-182-5 p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182-5 p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis., Funding: This work was supported by research funding from the Deutsche Forschungsgemeinschaft (KI 1887/2-1, KI 1887/2-2, KI 1887/3-1 and CRC-TR296), the European Research Council (ERC, CoG Yoyo LepReSens no. 101002247; PTP), the Helmholtz Association (Initiative and Networking Fund International Helmholtz Research School for Diabetes; MB) and the German Center for Diabetes Research (DZD Next Grant 82DZD09D1G)., Competing Interests: CK, JB, MB, AM, NT, NL, CG, MK, KI, AJ, JW, SW, OM, PP, IC, HL, KS, SS, HK No competing interests declared, (© 2023, Krause et al.)

Aims/hypothesis: IRS2 is an important molecular switch that mediates insulin signalling in the liver. IRS2 dysregulation is responsible for the phenomenon of selective insulin resistance that is observed in type 2 diabetes. We hypothesise that epigenetic mechanisms are involved in the regulation of IRS2 in the liver of obese and type 2 diabetic individuals., Methods: DNA methylation of seven CpG sites was studied by bisulphite pyrosequencing and mRNA and microRNA (miRNA) expression was assessed by quantitative real-time PCR in liver biopsies of 50 obese non-diabetic and 31 obese type 2 diabetic participants, in a cross-sectional setting. Methylation-sensitive luciferase assays and electrophoretic mobility shift assays were performed. Furthermore, HepG2 cells were treated with insulin and high glucose concentrations to induce miRNA expression and IRS2 downregulation., Results: We found a significant downregulation of IRS2 expression in the liver of obese individuals with type 2 diabetes (0.84 ± 0.08-fold change; p = 0.0833; adjusted p value [p a ] = 0.0417; n = 31) in comparison with non-diabetic obese participants (n = 50). This downregulation correlated with hepatic IRS2 DNA methylation at CpG5. Additionally, CpG6, which is located in intron 1 of IRS2, was hypomethylated in type 2 diabetes; this site spans the sterol regulatory element binding transcription factor 1 (SREBF1) recognition motif, which likely acts as transcriptional repressor. The adjacent polymorphism rs4547213 (G>A) was significantly associated with DNA methylation at a specificity-protein-1 (SP1) binding site (CpG3). Moreover, DNA methylation of cg25924746, a CpG site located in the shore region of the IRS2 promoter-associated CpG island, was increased in the liver of individuals with type 2 diabetes, as compared with those without diabetes. A second epigenetic mechanism, upregulation of hepatic miRNA hsa-let-7e-5p (let-7e-5p) in obese individuals with type 2 diabetes (n = 29) vs non-diabetic obese individuals (n = 49) (1.2 ± 0.08-fold change; p = 0.0332; p a  = 0.0450), is likely to act synergistically with altered IRS2 DNA methylation to decrease IRS2 expression. Mechanistic in vitro experiments demonstrated an acute upregulation of let-7e-5p expression and simultaneous IRS2 downregulation in a liver (HepG2) cell line upon hyperinsulinaemic and hyperglycaemic conditions., Conclusions/interpretation: Our study highlights a new multi-layered epigenetic network that could be involved in subtle dysregulation of IRS2 in the liver of individuals with type 2 diabetes. This might lead to fine-tuning of IRS2 expression and is likely to be supplementary to the already known factors regulating IRS2 expression. Thereby, our findings could support the discovery of new diagnostic and therapeutic strategies for type 2 diabetes. Graphical abstract.

Purpose: The purpose of this study is to study a heterogeneous group of obese patients undergoing Bariatric surgery(BS) and its impact on glycemic control. Secondary endpoints include changes in lipid profile and albuminuria. BS has shown to effectively reduce body-weight. However, the impact on obesity-related comorbidities varies strongly between individuals. Especially postoperative short- and long-term improvement of Diabetes is an active area of investigation., Methods: We conducted a retrospective analysis from baseline to 24 months post bariatric surgery in our interdisciplinary obesity outpatient-clinic. Follow-up data was collected from 215 patients who had undergone either Roux-en-Y gastric bypass or Sleeve Gastrectomy. The prevalence of and changes in the major obesity-related comorbidities and concurrent medication were assessed., Results: Standard parameters of diabetic control showed a U-shaped curve with initial improvement after six months, but with a gradual worsening after the first year of follow-up. Weight loss resulted in dose reduction of oral antidiabetic medication and insulin in 85% and 100% of patients, respectively. With weight loss, a significant improvement in lipid profile one year after surgery was seen. Subgroup analysis demonstrated gender- and age-dependent differences in overall benefit., Conclusions: Current data on diabetes remission might be too optimistic and close follow-up should be provided to prevent gradual worsening of glucose metabolism after BS., Competing Interests: The authors declare no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The objective was to evaluate cost-utility of bariatric surgery in Germany for a lifetime and 10-year horizon from a health care payer perspective., Methods: State-transition Markov model provided absolute and incremental clinical and monetary results. In the model, obese patients could undergo surgery, develop post-surgery complications, experience diabetes type II, cardiovascular diseases or die. German Quality Assurance in Bariatric Surgery Registry and literature sources provided data on clinical effectiveness and safety. The model considered three types of surgeries: gastric bypass, sleeve gastrectomy, and adjustable gastric banding. The model was extensively validated, and deterministic and probabilistic sensitivity analyses were performed to evaluate uncertainty. Cost data were obtained from German sources and presented in 2012 euros (€)., Results: Over 10 years, bariatric surgery led to the incremental cost of €2909, generated additional 0.03 years of life and 1.2 quality-adjusted life years (QALYs). Bariatric surgery was cost-effective at 10 years with an incremental cost-effectiveness ratio of €2457 per QALY. Over a lifetime, surgery led to savings of €8522 and generated an increment of 0.7 years of life or 3.2 QALYs. The analysis also depicted an association between surgery and a reduction of obesity-related adverse events (diabetes, cardiovascular disorders). Delaying surgery for up to 3 years, resulted in a reduction of life years and QALYs gained, in addition to a moderate reduction in associated healthcare costs., Conclusions: Bariatric surgery is cost-effective at 10 years post-surgery and may result in a substantial reduction in the financial burden on the healthcare system over the lifetime of the treated individuals. It is also observed that delays in the provision of surgery may lead to a significant loss of clinical benefits.

Background: The aim of this study was to demonstrate feasibility and safety of a new electric duodenal stimulation system (EDS, BALANCE) in humans. Secondary objectives were to evaluate the effect on glycemic control and weight loss in patients with obesity and type 2 diabetes mellitus (T2DM)., Methods: In an open-labeled, prospective, single-arm, non-randomized multicenter study, 12 obese T2DM patients with a mean HbA1c of 8.0% received laparoscopic implantation of the BALANCE duodenal stimulating device. Adverse events, changes in glycemic control, cardiovascular parameters, and weight were collected. The follow-up period after implantation was 12 months., Results: Device related severe adverse events did not occur. Mean HbA1c decreased by 0.8% (p = 0.02) and mean fasting blood glucose level (FBG) was reduced by 19% (p = 0.038) after the 12 months. Mean HDL level increased from 44 to 48 mg/dl (p = 0.033)., Conclusions: EDS is a feasible and safe procedure. Positive effects on T2DM and some cardiovascular parameters (HDL, weight) were seen. However, further prospective randomized blinded studies are needed in order to evaluate the potential of this new minimally invasive method.

Background: The endoluminal mechanical device SatiSphere is a new endoscopically implantable device designed to delay transit time of nutrients through the duodenum. It consists of a 1-mm nitinol wire with pigtail ends and several mesh spheres mounted along its course, released in the duodenum and gastric antrum to conform to the duodenal C loop configuration and thereby self-anchor., Methods: The objective is to test the safety, efficacy, and effect on body weight in a 2:1 randomized study, as well as incretin secretion in a subgroup., Results: Of 31 included cases (11 men, mean age 42.9 years, mean BMI 41.3 kg/m2), 21 patients treated with endoscopic device insertion with scheduled device removal after 3 months were compared with 10 controls. In 10 of 21 patients, device migration occurred, in two cases necessitating emergency surgery, which led to termination of the trial. Weight loss after 3 months was 6.7, 4.6, and 2.2 kg in the groups completing therapy, all treatment cases using intention to treat (ITT) analysis and controls. Excess weight loss was significantly increased by endoluminal mechanical device insertion (18.4, 12.2, and 4.4% in completers, ITT analysis group and controls; p = 0.02 for completers vs. controls). Measuring glucose, insulin, and glucagon-like peptide 1 (GLP-1) following a mixed-meal test with the device in place and after removal (n = 7), the device delayed glucose absorption and insulin secretion and altered kinetics in GLP-1 levels., Conclusions: The device might be short-term effective in reducing body weight, which might be mediated through alterations in incretin metabolism. However, frequent device migration necessitates device modifications.

Metformin is the oral drug of first choice in type 2 diabetes. Therefore a large number of patients undergoing bariatric surgery will be on Metformin treatment. However, use of Metformin has been associated with lactate acidosis. Weight loss following bariatric surgery is most pronounced during the first weeks after the operation and this creates a phase of negative energy balance with ketone body formation. To shed more light on this situation we measured ketone bodies in 90 patients 5 days-18 months after bariatric surgery. Ketone bodies were markedly elevated during the first 3-4 months. Metformin use should therefore be critically reconsidered after bariatric operations., (© J. A. Barth Verlag in George Thieme Verlag KG Stuttgart · New York.)

Background: The young field of obesity surgery (bariatric surgery) in Germany expands as a consequence of the rapid increase of overweight and obesity. New surgical methods, minimal access techniques, and the enormous increase of scientific studies and evidence, all contribute to the success of bariatric surgery, which is the only realistic chance of permanent weight loss and regression of secondary diseases in many cases., Methods: A systematic literature review, classification of evidence, graded recommendations, and interdisciplinary consensus., Results: Obesity surgery is an integral component of the multimodal treatment of obesity, which consists of multidisciplinary evaluation and preparation, conservative and surgical treatment elements, and a life-long follow-up. The guideline confirms the body mass index (BMI)-based spectrum of indications (BMI > 40 kg/m(2) or >35 kg/m(2) with secondary diseases) and extends it through elimination of all age restrictions (>18 years and <60 years) and most of the contraindications. Precondition for surgery is the failure of a structured conservative program of 6-12 months or the expected futility of it. Type II diabetes mellitus becomes an independent indication criterion for BMI < 35 kg/m(2) (metabolic surgery). The standard techniques are gastric balloon, gastric banding, gastric bypass, gastric sleeve, and biliopancreatic diversion. The choice of procedure is based on profound knowledge of results, long-term effects, complications, and patient-specific circumstances. The after-care should be structured and organized long term., Conclusion: The S3-guidelines contain evidence-based recommendations for the indication, selection of procedure, technique, and follow-up. Patient care should improve after implementation of these guidelines in clinical practice. Compliance by decision makers and health insurers is warranted.

Under the hypothesis of obesity as a polygenetic disease numerous genes have been associated with an obese phenotype and metabolic co-morbidities. The cannabinoid receptor 1 (CB 1) is part of an underinvestigated system that participates in appetite control. Previous publications suggest that the endocannabinoid systems interact with the better understood leptin-melanocortin axis. Neuropeptide Y (NPY) is a player in the latter. Finally resistin has been shown to influence NPY expression in the brain. In a cohort of 1721 caucasion men and women with a BMI of 25kg/m(2) or more we therefore investigated three candidate polymorphisms at baseline and following 3 months low fat caloric restriction diet by polymerase chain reaction and restriction digestion: the 1359 G/A variant of the cannabinoid receptor 1 (CB1), the L7P variation in neuropeptide Y (NPY) and the -420C>G polymorphism in resistin. Comparing groups according to genotype for each gene separately revealed significant results at baseline only for the CB1 gene. However, upon dieting significant data was found for all 3 genes. Carriers of at least one A allele in CB1 lost more weight and reduced LDL cholesterol more than wildtype patients. LL homocygotes in NPY had a greater reduction in glucose, triglycerides, and LDL cholesterol whereas in resistin carriers of the G allele had a greater reduction in weight and triglycerides. Creating two groups defined by NPY and resistin genotype, respectively, with similar BMI values resulted in significant differences concerning weight loss and metabolic improvement. In conclusion, genetic polymorphisms associated with obesity may become relevant only under the condition of a low calory diet. The presence of a certain genotype may then be beneficial for obesity treatment.

Metformin is the oral drug of fi rst choice in type 2 diabetes. Therefore a large number of patients undergoing bariatric surgery will be on Metformin treatment. However, use of Metformin has been associated with lactate acidosis. Weight loss following bariatric surgery is most pronounced during the fi rst weeks after the operation and this creates a phase of negative energy balance with ketone body formation. To shed more light on this situation we measured ketone bodies in 90 patients 5 days-18 months after bariatric surgery. Ketone bodies were markedly elevated during the fi rst 3-4 months. Metformin use should therefore be critically reconsidered after bariatric operations. [ABSTRACT FROM AUTHOR]