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Rui Ma,1 Xiao-long Deng,2 Qi-qi-ge Aleteng,1 Lei Li,1 Jun Zhu3 1Department of Endocrinology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People’s Republic of China; 2Department of Endocrinology, Shunde Hospital of Southern Medical University, Foshan, Guangdong, 528300, People’s Republic of China; 3Department of Endocrinology, People’s Hospital of Shenzhen Baoan District, Shenzhen, Guangdong, 518101, People’s Republic of ChinaCorrespondence: Jun Zhu, Department of Endocrinology, People’s Hospital of Shenzhen Baoan District, Shenzhen, 518101, Guangdong, People’s Republic of China, Tel +86 13899981212, Email zhujun_dr@outlook.comObjective: In this study, transcriptome sequencing was performed on patients with type 2 diabetes mellitus treated with different prognosis to explore the differential level genes of different hypoglycemic effects of sitagliptin.Methods: Patients with newly diagnosed T2DM (within six months of diagnosis) were selected as the study subjects. Patients were given sitagliptin 100 mg once a day orally. After 12 weeks of regular drug therapy, the reduction in glycated hemoglobin was compared before and after drug administration. The patients were then divided into two groups: the significantly effective group (M) and the less effective group (N). High-throughput sequencing of the transcriptome was conducted to detect the differential expression levels of genes in peripheral blood mononuclear cells. Expanded sample size validation of the candidate differential genes was conducted using reverse transcription-polymerase chain reaction (RT-PCR).Results: After 12 weeks of treatment with sitagliptin, high-throughput sequencing of the transcriptome found that expression of the following genes was different when comparing the significantly effective group (M) and the less effective group (N): ghrelin (GHRL), insulin-like growth factor-1 receptor (IGF1R), mitogen-activated protein kinase-3 (MAPK3), phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit delta (PIK3CD), and the suppressor of cytokine signaling-3 (SOCS3). The validation results of RT-PCR showed that, in the significantly effective group (M), the expression of IGF1R was significantly increased (P = 0.034), the expression of MAPK3 was significantly reduced (P = 0.002), and the expression of SOCS3 was also significantly reduced (P < 0.001).Conclusion: There was a significant difference in gene level between patients with significant hypoglycemic effect and patients with poor hypoglycemic effect, and the expression of IGF1R increased and the expression of MAPK3 and SOCS3 decreased.Keywords: sitagliptin, hypoglycemic effects, transcriptome sequencing, RT-PCR, SOCS3

Patients with type 2 diabetes respond differently to sitagliptin, an oral anti-hyperglycemic medication. Patients whose blood sugar levels were effectively managed while using sitagliptin had significantly lower levels of a protein called suppressor of cytokine signaling 3 (SOCS3), according to our earlier research. In this study, we established an in vitro insulin resistance cell model for human HepG2 cells to investigate the possible mechanism of the effect of sitagliptin on glucose metabolism via the SOCS3/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. Since insulin resistance first develops in the liver, palmitic acid was used to generate an insulin resistance cell model in human HepG2 cells, after which small interfering ribonucleic acid (siRNA)-SOCS3 and sitagliptin were used to intervene. We then examined the changes in cell viability and biochemical indices in the insulin resistance cell model. SOCS3, Akt, and glycogen synthase kinase 3beta (GSK-3b) gene expression levels were quantified using reverse transcription-polymerase chain reaction, and the protein expression levels of SOCS3, Akt, phosphorylated Akt (p-Akt), GSK-3b, and phosphorylated GSK-3b (p-GSK-3b) were quantified using Western blot. In results: the expression of the SOCS3 gene was considerably raised in both the insulin resistance model group and the insulin resistance model + siRNA-negative control group, but decreased following treatment with sitagliptin. After sitagliptin intervention, the protein expression of Akt, p-Akt, and p-GSK-3b were dramatically decreased in the model group, while SOCS3 was significantly decreased. We conclude that sitagliptin can reduce insulin resistance by downregulating SOCS3 and regulating glucose metabolism in a hypoglycemic manner. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia, the age-related loss of muscle mass and function, is closely associated and frequently concomitant with non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the clinical features of the sarcopenic NAFLD patients from middle-aged and older people., Methods: A total of 1305 patients with NAFLD from the Shanghai Changfeng Study were included for analysis. Sarcopenia was diagnosed based on the height-adjusted appendicular skeletal muscle mass (ASM/height 2 ). We comprehensively analyzed the metabolic phenotype, carotid artery condition, liver fibrosis score, and serum metabolomic profile of each participant., Results: Among the middle-aged and older population, 68.1% of patients with sarcopenia and NAFLD were lean. Sarcopenia was independently associated with increased risk of carotid plaque (OR, 2.22; 95%CI 1.23-4.02) and liver fibrosis (OR, 2.07; 95%CI 1.24-3.44), and the sarcopenic lean NAFLD patients were characterized by a higher risk of carotid plaque (p = 0.008) and liver fibrosis (p = 0.001) than the non-sarcopenic lean NAFLD patients, despite their lower BMI and similar prevalence of metabolic syndrome and diabetes. Further serum metabolomic examination indicated that the sarcopenic lean NAFLD patients presented a distinct metabolomic profile prone to carotid plaque and liver fibrosis, with upregulated serum valine, N-acetylneuraminyl-glycoproteins, lactic acid, small LDL triglycerides and VLDL5 components, and reduced components of HDL4. A sarcopenic characterization score based on above metabolites was established and could also predict increased risk of carotid plaque and liver fibrosis., Conclusion: The presence of sarcopenia identifies a special subgroup of lean NAFLD with increased risk of cardiovascular disease and liver fibrosis clinically., (© 2022. Asian Pacific Association for the Study of the Liver.)

Background: The PNPLA3 and TM6SF2 gene variants have been found to cause NAFLD with a favourable cardiovascular risk profile., Aims: To investigate the effects of the NAFLD risk alleles on the all-cause and cause-specific mortality in 5581 Chinese adults., Methods: The genome-wide genotypes were detected using a genotyping array and serum lipoprotein profiles were examined using 1H NMR platform. Liver fat content (LFC) was measured using a quantitative ultrasound method. The vital status was determined using official registration data., Results: Genome-wide association analysis showed that a series of variants in PNPLA3 were associated with LFC, including rs738409 C>G variant (P = 8.6 × 10 -7 ). Further analyses validated the associations of TM6SF2 rs58542926 C>T and MBOAT7 rs641738 C>T variants with NAFLD. During 29 425.1 person-years of follow-up, the overall mortality was 816 per 100 000 person-years, where 299 deaths were attributable to cardiovascular disease and 85 to liver disease. The PNPLA3 rs738409 C>G variant was independently associated with increased liver-specific mortality (P for trend = 0.034) but reduced cardiovascular mortality (P for trend = 0.047). A composite genetic-predisposition score of PNPLA3, TM6SF2, and MBOAT7 risk alleles presented similar opposite effects on liver-specific and cardiovascular mortality. Moreover, interactions of the NAFLD risk alleles with adiposity for liver-specific mortality were found (P interaction  < 0.05). The reduced serum VLDL1 concentration was responsible for the increased liver-specific mortality related to NAFLD risk alleles., Conclusion: The PNPLA3 rs738409 C>G variant and its combination with TM6SF2 rs58542926 C>T and MBOAT7 rs641738 C>T variants increase liver-specific mortality but reduce cardiovascular mortality in overweight/obese Chinese., (© 2022 John Wiley & Sons Ltd.)