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The postprandial glucose response is an independent risk factor for type 2 diabetes. Observationally, early glucose response after an oral glucose challenge has been linked to intestinal glucose absorption, largely influenced by the expression of sodium-glucose cotransporter 1 (SGLT1). This study uses Mendelian randomization (MR) to estimate the causal effect of intestinal SGLT1 expression on early glucose response. Involving 1,547 subjects with class II/III obesity from the Atlas Biologique de l'Obésité Sévère cohort, the study uses SGLT1 genotyping, oral glucose tolerance tests, and jejunal biopsies to measure SGLT1 expression. A loss-of-function SGLT1 haplotype serves as the instrumental variable, with intestinal SGLT1 expression as the exposure and the change in 30-min postload glycemia from fasting glycemia (Δ30 glucose) as the outcome. Results show that 12.8% of the 1,342 genotyped patients carried the SGLT1 loss-of-function haplotype, associated with a mean Δ30 glucose reduction of -0.41 mmol/L and a significant decrease in intestinal SGLT1 expression. The observational study links a 1-SD decrease in SGLT1 expression to a Δ30 glucose reduction of -0.097 mmol/L. MR analysis parallels these findings, associating a statistically significant reduction in genetically instrumented intestinal SGLT1 expression with a Δ30 glucose decrease of -0.353. In conclusion, the MR analysis provides genetic evidence that reducing intestinal SGLT1 expression causally lowers early postload glucose response. This finding has a potential translational impact on managing early glucose response to prevent or treat type 2 diabetes., (© 2024 by the American Diabetes Association.)

Metformin (MET) is the most prescribed antidiabetic drug, but its mechanisms of action remain elusive. Recent data point to the gut as MET's primary target. Here, we explored the effect of MET on the gut glucose transport machinery. Using human enterocytes (Caco-2/TC7 cells) in vitro , we showed that MET transiently reduced the apical density of sodium-glucose transporter 1 (SGLT1) and decreased the absorption of glucose, without changes in the mRNA levels of the transporter. Administered 1 h before a glucose challenge in rats (Wistar, GK), C57BL6 mice and mice pigs, oral MET reduced the post-prandial glucose response (PGR). This effect was abrogated in SGLT1-KO mice. MET also reduced the luminal clearance of 2-( 18 F)-fluoro-2-deoxy-D-glucose after oral administration in rats. In conclusion, oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of SGLT1 in enterocytes, which may contribute to the clinical effects of the drug., Competing Interests: The authors declare no competing interests., (© 2023.)

Type 2 diabetes (T2D) and Non-Alcoholic Fatty Liver Disease (NAFLD) are pathologies whose prevalence continues to increase worldwide. Both diseases are precipitated by an excessive caloric intake, which promotes insulin resistance and fatty liver. The role of the intestine and its crosstalk with the liver in the development of these metabolic diseases is receiving increasing attention. Alterations in diet-intestinal microbiota interactions lead to the dysregulation of intestinal functions, resulting in altered metabolite and energy substrate production and increased intestinal permeability. Connected through the portal circulation, these changes in intestinal functions impact the liver and other metabolic organs, such as visceral adipose tissue, hence participating in the development of insulin resistance, and worsening T2D and NAFLD. Thus, targeting the intestine may be an efficient therapeutic approach to cure T2D and NAFLD. In this review, we will first introduce the signaling pathways linking T2D and NAFLD. Next, we will address the role of the gut-liver crosstalk in the development of T2D and NAFLD, with a particular focus on the gut microbiota and the molecular pathways behind the increased intestinal permeability and inflammation. Finally, we will summarize the therapeutic strategies which target the gut and its functions and are currently used or under development to treat T2D and NAFLD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear Farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knock-out (KO) mice, in vitro in GLUTag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in WT and FXR KO mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes.

Background: Pulmonary hypertension is an uncommon feature of Whipple's disease and the underlying pathophysiological mechanism remains a subject of debate., Case Report: A 57-year-old woman was hospitalized for exploration of migrating joint pain that had developed for 5 years. Histologically proven Whipple's disease was diagnosed on duodenal biopsies. The lung angiogram performed to explore signs of right heart failure demonstrated pulmonary hypertension and ruled out pulmonary embolism. Abundant pericardial effusion developed progressively. Antibiotic therapy using sulfamethoxazole-trimethoprime led to a systemic Jarisch Herxheilmer reaction. The pulmonary hypertension resolved rapidly, the pericardial effusion more slowly., Discussion: The pulmonary hypertension in this patient appeared to be directly related to Whipple's disease, probably via vascular infiltration by Tropheryma whippeli.

We report the case of a 52-year-old woman who presented hypoparathyroidism and sarcoidosis. The hypoparathyroidism developed 8 years after the diagnosis of sarcoidosis. No element in favor of an autoimmune disease of the parathyroid could be evidenced. Pathology and immunology blood tests were equally noncontributive. Another pathophysiological mechanism, possibly sarcoidic granulomatous infiltration of the parathyroid glands, was suspected. The patient also presented apparently coincidental vitiligo.

Background: Vitamin B1 deficiency (beriberi) is very uncommon in France. It leads to high output cardiac failure totally different from the situation observed in alcoholic patients. We report a typical case of cardiac beriberi., Case Report: The patient was referred for dyspnea with high output cardiac failure. Echocardiography evidenced severe pulmonary hypertension and high cardiac output. The more common causes of heart failure were ruled out. The dietary habits of the patient (suggested beriberi which was confirmed by the low serum thiamin and therapeutic test with vitamin B1., Discussion: High output cardiac failure should suggest possible Shoshin beriberi, particularly in subjects with imported dietary habits living in a precarious socioeconomic situation.

Objectives: To determine the risk and predictive factors for colonic extension in patients with ileal Crohn's disease., Methods: One hundred and fifty patients with ileal Crohn's disease and no specific colonic lesions on initial colonoscopy were studied retrospectively (median follow-up: 51 months)., Results: Twelve patients (8%) developed colonic lesions. Ten-year cumulated risks (95% confidence interval) for colonic extension were 17.2% (range: 5.8-28.6) in the whole group, and 22.4% (range: 8.7-36.1) in the group of 86 patients with repeated colonoscopy. Young age at diagnosis was the only factor predicting colonic extension. Seven patients with colonic extension required immunosuppressive therapy but none underwent surgery., Conclusion: Ileal Crohn's disease has a low tendency for colonic extension. Colonic extension has no major prognostic implications.