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The intestinal epithelium is continuously regenerated through proliferation and differentiation of stem cells located in the intestinal crypts. Obesity affects this process and results in greater stem cell proliferation and altered tissue growth and function. Obesity-induced high levels of insulin and insulin-like growth factor-1 in the stem cell niche are found to impact proliferation in rodents indicating that insulin and insulin-like growth factor-1 receptors may play a role in modulating intestinal epithelial stem cell proliferation. To determine whether insulin or insulin-like growth factor-1 can induce proliferation in human intestinal epithelial stem cells, and if two downstream insulin and insulin-like growth factor-1 receptor signaling pathways, PI3K/Akt and ERK, are involved, we used primary small intestinal epithelial crypts isolated from obese humans and investigated (1) the effect of insulin or insulin-like growth factor-1 on crypt proliferation, and (2) the effect of insulin and insulin-like growth factor-1 signaling inhibitors on insulin or insulin-like growth factor-1-induced proliferation. We found that insulin and insulin-like growth factor-1 enhanced the proliferation of crypt cells, including intestinal epithelial stem cells. Inhibition of the PI3K/Akt pathway attenuated insulin and insulin-like growth factor-1-induced proliferation, but inhibition of the ERK pathway had no effect. These results suggest that the classical metabolic PI3K pathway and not the canonical proliferation ERK pathway is involved in the insulin/insulin-like growth factor-1-induced increase in crypt proliferation in obese humans, which may contribute to abnormal tissue renewal and function. Impact statement This study investigates if insulin or insulin-like growth factor-1 (IGF-1) induces intestinal epithelial proliferation in humans, and if insulin and IGF-1 receptor signaling is involved in this process in obesity. Although obesity-induced high levels of insulin and IGF-1 in the stem cell niche are found to impact the proliferation of intestinal epithelial stem cells in rodents, we are the first to investigate this effect in humans. We found that insulin and IGF-1 enhanced the proliferation of intestinal crypts (including stem cells and other crypt cells) isolated from obese humans, and PI3K/Akt, and not ERK signaling was involved in insulin or IGF-1-induced proliferation. The imbalance in signaling between PI3K/Akt and ERK pathways may point to a pathway-specific impairment in insulin/IGF-1 receptor signaling. We propose that this may contribute to reciprocal relationships between insulin/IGF-1 receptor resistance and intestinal epithelial proliferation that leads to abnormal tissue renewal and function.

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This cross-sectional study compares alcohol pharmacokinetics in patients who underwent sleeve gastrectomy with control participants who did not undergo surgery.

Background: Understanding how blood alcohol concentrations (BAC) achieved after drinking are determined is critical to predicting alcohol exposure to the brain and other organs and alcohol's effects. However, predicting end-organ exposures is challenging, as there is wide variation in BAC achieved after drinking a specified volume of alcohol. This variation is partly due to differences in body composition and alcohol elimination rates (AER), but there are limited data on how obesity affects AER. Here, we assess associations between obesity, fat-free mass (FFM), and AER in women and examine whether bariatric surgeries, which are linked to an increased risk of alcohol misuse, affect these associations.Methods: We analyzed data from three studies that used similar intravenous alcohol clamping procedures to estimate AER in 143 women (21 to 64 years old) with a wide range of body mass index (BMI; 18.5 to 48.4 kg/m 2 ). Body composition was measured in a subgroup using dual-energy X-ray absorptiometry (n = 42) or Bioimpedance (n = 60), and 19 of the women underwent bariatric surgery 2.1 ± 0.3 years before participation. We analyzed data using multiple linear regression analyses.Results: Obesity and older age were associated with a faster AER (BMI: r s = 0.70 and age: r s = 0.61, both p < 0.001). Compared to women with normal weight, AER was 52% faster (95% Confidence Interval: 42% to 61%) in women with obesity. However, BMI lost predictive value when adding fat-free mass (FFM) to the regression model. Age, FFM, and its interaction explained 72% of individual variance in AER (F (4, 97) = 64.3, p < 0.001). AER was faster in women with higher FFM, particularly women in the top tertile of age. After controlling for FFM and age, bariatric surgery was not associated with differences in AER (p = 0.74). Conclusions:Obesity is associated with a faster AER, but this association is mediated by an obesity-related increase in FFM, particularly in older women. Previous findings of a reduced alcohol clearance following bariatric surgery compared with prior to surgery are likely explained by a reduction in FFM post-surgery.

Background Shortly after bariatric surgery, insulin sensitivity improves and circulating Fetuin-A (FetA) declines. Elevated FetA may decrease insulin sensitivity by inhibiting insulin receptor autophosphorylation. FetA also mediates inflammation through toll-like receptor 4 and influences monocyte migration and macrophage polarization in the adipocyte. The role of dietary changes on FetA is unclear. It is also unknown whether changes in FetA are associated with adipocyte size, an indicator of insulin sensitivity. Methods Sleeve gastrectomy patients ( n = 39) were evaluated prior to the preoperative diet, on the day of surgery (DOS) and six-weeks postoperatively. At each visit, diet records, anthropometrics and fasting blood were collected. Adipocyte diameter was measured in omental adipose collected during surgery. Results Although significant weight loss did not occur during the preoperative diet, HOMA-IR improved ( p < 0.0001) and FetA decreased by 12% ( p = 0.01). Six-weeks postoperatively, patients lost 9% of body weight ( p = 0.02) and FetA decreased an additional 26% ( p < 0.0001). HOMA-IR was unchanged during this time. Omental adipocyte size on DOS was not associated with preoperative changes in dietary intake, body composition or HOMA-IR. However, adipocyte size was strongly associated with both pre- ( r = 0.41, p = 0.03) and postoperative ( r = − 0.44, p = 0.02) change in FetA. Conclusion FetA began to decrease during the preoperative diet. Greater FetA reduction during this time was associated with smaller adipocytes on DOS. Therefore, immediate, post-bariatric improvements in glucose homeostasis may be partly explained by dietary changes. The preoperative diet protocol significantly reduced insulin resistance, a modifiable risk factor for other non-bariatric procedures. Therefore, this dietary protocol may also be used preoperatively for procedures beyond bariatric surgery.

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