Aims/hypothesis: Roux-en-Y gastric bypass surgery (RYGB) frequently results in remission of type 2 diabetes as well as exaggerated secretion of glucagon-like peptide-1 (GLP-1). Here, we assessed RYGB-induced transcriptomic alterations in the small intestine and investigated how they were related to the regulation of GLP-1 production and secretion in vitro and in vivo. Methods: Human jejunal samples taken perisurgically and 1 year post RYGB (n=13) were analysed by RNA-seq. Guided by bioinformatics analysis we targeted four genes involved in cholesterol biosynthesis, which we confirmed to be expressed in human L cells, for potential involvement in GLP-1 regulation using siRNAs in GLUTag and STC-1 cells. Gene expression analyses, GLP-1 secretion measurements, intracellular calcium imaging and RNA-seq were performed in vitro. OGTTs were performed in C57BL/6j and iScd1^−/− mice and immunohistochemistry and gene expression analyses were performed ex vivo. Results: Gene Ontology (GO) analysis identified cholesterol biosynthesis as being most affected by RYGB. Silencing or chemical inhibition of stearoyl-CoA desaturase 1 (SCD1), a key enzyme in the synthesis of monounsaturated fatty acids, was found to reduce Gcg expression and secretion of GLP-1 by GLUTag and STC-1 cells. Scd1 knockdown also reduced intracellular Ca²⁺ signalling and membrane depolarisation. Furthermore, Scd1 mRNA expression was found to be regulated by NEFAs but not glucose. RNA-seq of SCD1 inhibitor-treated GLUTag cells identified altered expression of genes implicated in ATP generation and glycolysis. Finally, gene expression and immunohistochemical analysis of the jejunum of the intestine-specific Scd1 knockout mouse model, iScd1^−/−, revealed a twofold higher L cell density and a twofold increase in Gcg mRNA expression. Conclusions/interpretation: RYGB caused robust alterations in the jejunal transcriptome, with genes involved in cholesterol biosynthesis being most affected. Our data highlight SCD as an RYGB-regulated L cell constituent that regulates the production and secretion of GLP-1. Graphical

The increasing prevalence of obesity has led to a rise in bariatric surgery as an effective intervention for weight loss and associated co-morbidities. However, concerns persist regarding increased alcohol consumption after surgery. To objectively assess long-term changes in alcohol use after bariatric surgery, we used the highly specific alcohol biomarker phosphatidylethanol (PEth). Kalmar County Hospital, Sweden. This longitudinal cohort study included 1238 patients who underwent Roux-en-Y gastric bypass or sleeve gastrectomy at Kalmar County Hospital from 2010 to 2020. Patients were divided into 2 cohorts based on preoperative PEth sampling (n = 327 with, n = 911 without). PEth levels were measured before surgery and at intervals up to 10 years postoperatively, using .30 μmol/L (approximately 210 ng/mL) as the threshold for heavy alcohol use. Mean PEth concentrations increased from .07 to .38 μmol/L (P < .001) in men and from .06 to .11 μmol/L nonsignificantly in women. The proportion of patients that postoperatively exceeded the heavy drinking threshold rose significantly over time. At 5 years, 37.5% of men and 4.8% of women had PEth values above .30 μmol/L (both P < .001). Men were at significantly higher risk (odds ratio: 7.89, 95% confidence interval: 3.76-16.57; P < .001). This pattern remained consistent at the 10-year follow-up. Alcohol consumption, as measured by PEth, increased significantly after bariatric surgery, particularly in men. These findings support routine postoperative alcohol screening and suggest incorporating PEth testing into long-term follow-up protocols.

Context: Statin use is associated with increased risk of type 2 diabetes (T2D) and mild hyperglycemia. The underlying mechanisms are not well studied, and the effect of statin treatment on glucagon-like peptide 1 (GLP-1) secretion or production is unknown. Objective: This work aimed to assess the effects of rosuvastatin on GLP-1 secretion and production. Methods: We performed association studies in the Malmö Diet and Cancer study cardiovascular cohort (MDCS-CC) reexamination cohort, in vitro investigations using GLUTag cells and acute and chronic studies in female, normoglycemic C57Bl/6j mice. Results: Studies in the MDCS-CC reexamination cohort (n = 3734) revealed that in individuals without T2D, statin usage was associated with higher fasting glucose-dependent insulinotropic peptide (GIP), insulin, glucose, glucagon, and homeostatic model assessment of insulin resistance, but not GLP-1. However, in patients with T2D, statin usage was associated with higher fasting GLP-1 levels. Rosuvastatin treatment or 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (Hmgcr) knockdown (KD) reduced GLP-1 secretion and increased Gcg messenger RNA in GLUTag cells. Rosuvastatin acutely reduced postprandial GLP-1 secretion, whereas chronic rosuvastatin treatment in mice caused hyperglycemia and increased postprandial GLP-1 levels. The acute effect of Hmgcr KD on GLP-1 secretion could be mimicked by targeting intracellular cholesterol using a PCSK9 inhibitor. Finally, transcriptomic alterations induced by rosuvastatin were limited to genes involved in cholesterol biosynthesis. Conclusion: We have established HMGCR as a regulator of GLP-1 secretion and provide a plausible explanation for the clinically observed mild hyperglycemia associated with statin use. Given the negative acute effect on GLP-1 secretion, monitoring of blood glucose levels is recommended after prescribing rosuvastatin.