This study showed that the REE increased significantly after LC in patients with T2DM, and the utilization of carbohydrate elevated while that of fat decreased. And the glucose and lipid metabolism improved with the increased TBA level.
BAs played an important role in the elimination of cholesterol and the absorption of vitamins and fats [20]. It was synthesized from cholesterol in the liver, accounting for catabolism of approximately 50% of the daily cholesterol output. BAs are stored in gallbladder and secreted into the intestine when a meal is ingested, yet 95% of BAs are reabsorbed and transported back to the liver via the portal vein, escaped BAs were converted to secondary BAs by intestinal microbiota and excreted in the feces. This system is known as enterohepatic circulation [21]. The rhythmic filling and emptying of gallbladder control the flow of bile into the intestine and thereby the enterohepatic circulation. Normally, the pool and circulation of BAs maintains a dynamic balance, while it would be disrupted by biliary intervention or in pathological condition.
Gallbladder was considered merely to concentrate and store bile by absorbing water and ions previously, while recent studies showed that cholecystectomy would affect the metabolism of BAs. Several studies have demonstrated that TBA levels increase markedly after cholecystectomy [8, 22], while other studies showed BAs remained unchanged [9] or decreased [12]. In our study TBA level increased significantly after LC, the underlying mechanism was still not elucidated. Removal of gallbladder leads BAs to continuously secret into duodenum, theoretically faster circulated BAs would inhibit the cholesterol 7α-hydroxylase in the liver, the rate-limiting enzyme for bile formation, thereby reduce the bile synthesis. However, increased TBA level were observed in most studies or at least unchanged. Increased bile loss in feces due to the enhanced enterohepatic circling after cholecystectomy have been demonstrated [13], thereby the bile synthesis compensatory increased. We suspected massive loss of bile lead to an excessive bile synthesis, it may play a predominant role for the bile synthesis, but further studies were still need to be performed.
In recent years, increasing attention has been paid to the role of BAs as a signaling molecular, that regulate various hormones and receptors and modulate whole-body metabolic homeostasis [23]. The most widely studied receptors are the farnesoid X receptor (FXR) and the membrane G protein-coupled BA receptors (GPBAR1/TGR5) [24]. FXR stimulates the secretion of fibroblast growth factor 19 into the portal circulation and activates its fibroblast growth factor 4 liver receptor, leading to decreased gluconeogenesis glycemia and improved insulin sensitivity and glucose and lipid metabolism in diabetes [25, 26]. BAs activate TGR5, which is expressed in enteroendocrine L cells and stimulates the secretion of glucagon-like peptide-1, thereby improving liver and pancreatic function, stimulating insulin secretion from β-cells, increasing insulin sensitivity and glucose tolerance [27].
Moreover, BAs are also involved in the energy expenditure, in line with previous studies, we found REE increased after cholecystectomy [7, 10]. The activation of TGR5 by BAs induces thyroid hormone deiodinase type 2, which converts the inactive thyroid hormone thyroxine to active triiodothyronine thereby increased energy expenditure [28]. Moreover, plasm BAs can directly promote heat production in brown adipose tissue and skeletal muscle, which were two of important organs for thermogenesis [29, 30]. Energy expenditure is also influenced by an interplay of BAs and intestinal microbiota. The level and composition of TBA affect the gut microbial community abundance and composition [31]. The gut microbiota can digest complex food components and produce signaling molecules, including short-chain fatty acids, lipopolysaccharides, and peptidoglycan etc. Such signaling molecules promoted energy intake, use, and expenditure [32].
Although studies reported glucose deteriorated in normal patients after LC [6, 33], this may not be applied to the patients with T2DM due to the damaged metabolic regulation. Our study showed that glucose improved in patients with T2DM after LC,the total effective rate was 45%, the level of FPG and A1C decreased compared to baseline. While there were no significant changes in food intake and body weight. Therefore, these improvements were unrelated to food intake and weight loss. Increased BAs may be responsible for the glucose improvement, according to abovementioned mechanism, BAs can directly or indirectly activate several gut hormones, thereby improved insulin resistant which was also confirmed by the estimation of HOMA-IR in present study. Moreover, the proportion of carbohydrates in the REE increased after LC while that of fat decreased. Carbohydrates are the most important source of energy, and approximately 50–70% of energy used in the body comes from the breakdown of blood glucose. Therefore, decrease in glucose level also related to the increased REE level.
With the improvement in glucose metabolism, dyslipidemia was also alleviated, HDL-C levels were elevated after surgery, TC and LDL-C concentrations were significantly decreased. Dyslipidemia is an important component of diabetes and has received much attention in recent years, but the underlying pathophysiology is complex and still not well understood [34]. Insulin resistance is believed to be the main trigger for diabetic dyslipidemia. Insulin is involved in the synthesis and secretion of lipoprotein, suppresses lipolysis in adipose tissues, regulates the amount of circulating free fatty acids, and inhibits the transcription of microsomal triglyceride transfer protein in the liver, which mediates the transfer of triglycerides to nascent apolipoprotein B, the predominant surface protein of very-low-density lipoprotein. A reduction in insulin resistance positively regulates this process, helping lower the lipoprotein. Therefore, the reduction in insulin resistance may lead to the improvement of dyslipidemia which was confirmed in our study. Additionally, beneficial changes of lipids metabolism were more likely occurred in dyslipidemic patient after biliary interventions, this had also been proved in several previous studies [13, 35], but this effects were not found in patients with normal lipids metabolism. Nevertheless, the underlying mechanism of this difference between dyslipidemic and non-dyslipidemic patients was still unclear.
There are a few limitations of this study. A randomized study needed to be performed to confirm our results, and the effects on gut hormones also need to be investigated. Nevertheless, the results of our study show that the level of TBA and REE increased after cholecystectomy in patients with T2DM, and indicate the possible role of the BAs and REE in remission of T2DM which may be a potential possibility for treatment of metabolic diseases.