A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota–host cross-talk. We developed an enzyme activity–screening platform to investigate how gut microbiota–derived enzymes might influence host physiology. We discovered that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 was able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Furthermore, the current drugs targeting human DPP4, including sitagliptin, had little effect on microbial DPP4. Using high-throughput screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.

Insulin resistance and impaired insulin secretion lead to disorders of glucose metabolism, which contributes to the development of diabetes. Hydrogen sulfide (H2S), a novel gasotransmitter, is found to play important roles in regulation of glucose metabolism homeostasis. This study aimed to summarize and discuss current data about the function of H2S in insulin secretion and insulin resistance regulation as well as the underlying mechanisms. H2S could be endogenously produced in islet β cells, liver, adipose, skeletal muscles, and the hypothalamus, and regulates local and systemic glucose metabolism. It is reported that H2S suppresses insulin secretion, promotes or reduces the apoptosis of islet β cells. It plays important roles in the regulation of insulin sensitivity in insulin responsive tissues. H2S inhibits glucose uptake and glycogen storage, and promotes or inhibits gluconeogenesis, mitochondrial biogenesis and mitochondrial bioenergetics in the liver. In adipose tissue, several investigators indicated that H2S promoted glucose uptake in adipocytes, while other studies reported that H2S inhibits this process. H2S has also been shown to promote adipogenesis, inhibit lipolysis, and regulate adiponectin and MCP-1 secretion from adipocytes. In skeletal muscle, H2S increases glucose uptake and improves insulin sensitivity. It is also observed that H2S modulates circadian-clock genes in muscle. Hypothalamic CBS/H2S pathway reduces obesity and improves insulin sensitivity via the brain-adipose interaction. Most studies indicated plasma H2S levels decreased in diabetic patients. However, the mechanisms by which H2S regulates systemic glucose metabolism remain unclear. Whether H2S acts as a new promising target for diabetes mellitus treatment merits further studies.

Context It remains unclear whether the thyroid system could regulate the atherogenic remnant cholesterol (RC) levels in euthyroid status. Objective We aimed to investigate the relationship between sensitivity to thyroid hormones and RC levels in Chinese euthyroid population. Methods This study included 18 766 euthyroid adults. High RC levels were defined as the upper quartile of RC levels. The thyroid hormone sensitivity indices, including thyroid feedback quantile-based index (TFQI), thyroid-stimulating hormone index (TSHI), thyrotrophic thyroxine resistance index (TT4RI), and free triiodothyronine to free thyroxine (FT3/FT4) ratio were calculated. Linear and binary logistic regression analysis were applied to determine the associations between those composite indices with RC levels by genders. Results Both females and males with high RC levels exhibited co-existing higher TSH and FT4 levels. Linear regression analysis revealed that TFQI, TSHI, and TT4RI were positively, while FT3/FT4 ratio levels were negatively associated with serum RC levels. The odds ratios (ORs) (95% CI) for high RC levels were increased with rising TFQI quartiles (Q) [females: Q3 1.41 (1.22-1.63), Q4 1.61 (1.39-1.86); males: Q3 1.25 (1.09-1.45), Q4 1.38 (1.19-1.59), all P for trend < 0.001] after full adjustment, with Q1 as the reference. TSHI and TT4RI yielded similar results. By contrast, the ORs (95% CI) for high RC levels were decreased with increasing FT3/FT4 ratio quartiles in both genders (P for trend < 0.001). Conclusion In euthyroid adults, reduced sensitivity to thyroid hormones was associated with high RC levels. Our results suggested an additive cardiometabolic risk of euthyroid population with thyroid hormones insensitivity.