Comparison on cognitive outcomes of antidiabetic agents for type 2 diabetes: A systematic review and network meta-analysis.

We aimed to summarise current evidence on different antidiabetic drugs to delay cognitive impairment, including mild cognitive impairment, dementia, Alzheimer's disease (AD) and vascular dementia, among subjects with type 2 diabetes mellitus (T2DM). Medline, Cochrane and Embase databases were searched from inception to 31 July 2022. Two investigators independently reviewed and screened trials comparing antidiabetic drugs with no antidiabetic drugs, placebo, or other active antidiabetic drugs on cognitive outcomes in T2DM. Data were analysed using meta-analysis and network meta-analysis. Twenty-seven studies met the inclusion criteria, including 3 randomised controlled trials, 19 cohort studies and 5 case-control studies. Compared with non-user, SGLT-2i (OR 0.41 [95% CI 0.22-0.76]), GLP-1RA (OR 0.34 [95% CI 0.14-0.85]), thiazolidinedione (OR 0.60 [95% CI 0.51-0.69]), and DPP-4i (OR 0.78 [95% CI 0.61-0.99]) users had a decreased risk of dementia, whereas sulfonylurea (OR 1.43 [95% CI 1.11-1.82]) increased dementia risk. Network meta-analysis showed that SGLT-2i was most likely to rank best (SUCRA = 94.4%), GLP-1 RA second best (SUCRA = 92.7%), thiazolidinedione third best (SUCRA = 74.7%) and DPP-4i fourth best (SUCRA = 54.9%), while sulfonylurea second worst (SUCRA = 20.0%) for decreasing dementia outcomes, by synthesising evidence from direct and indirect comparisons of multiple intervention. Evidence suggests the effects of SGLT-2i ≈ GLP-1 RAs > thiazolidinedione > DPP-4i for delaying cognitive impairment, dementia and AD outcomes, whereas sulfonylurea was associated with the highest risk. These findings provide evidence for evaluating the optional treatment for clinical practice. PROSPERO REGISTRATION: Registration no. CRD42022347280.

Lower serum PRL is associated with the development of non-alcoholic fatty liver disease: a retrospective cohort study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has become an epidemic worldwide and has been linked to a series of metabolic co-morbidities. Prolactin (PRL) has recently been found to have a negative effect on NAFLD, but a causal relationship is not well-understood. Here we investigated the causative relationship between PRL and NAFLD occurrence. METHODS: In this retrospective cohort study, we enrolled patients without NAFLD who were diagnosed by abdominal ultrasonography undergone serum PRL testing at 8.00 a.m. at baseline, and followed up for a median of 32 (19, 46) months. RESULTS: This study enrolled 355 persons [215 men and 140 women; media age 56 (49, 64) years], in which 72 (20.28%) patients who eventually developed NAFLD. Compared with those in the non-NAFLD group, basal serum PRL levels of patients were lower in the NAFLD group [male: 7.35 (5.48, 10.60) vs. 9.13 (6.92, 12.50) ug/L, P = 0.002; female: 5.66 (4.67, 9.03) vs. 9.01 (6.31, 11.60) ug/L, P = 0.009]. The prevalence of NAFLD was significantly decreased along with the increased quartile of basal serum PRL levels in both genders (P < 0.05). Serum PRL concentration was independently associated with NAFLD development [male: OR, 0.881 (0.777, 0.998), P = 0.047; female: OR, 0.725 (0.554, 0.949), P = 0.019]. CONCLUSION: Our study is the first to find that basal serum PRL level can predict the occurrence of NAFLD and it may be a potential biomarker to prevent and treat NAFLD.

Effect of probiotics combined with metformin on improvement of menstrual and metabolic patterns in women with polycystic ovary syndrome: a randomized clinical trial.

Objectives: The aim of this study was to access the efficacy of probiotics combined with metformin on improvement of menstrual and metabolic patterns in women with polycystic ovary syndrome (PCOS). Methods: In this single-centre, controlled, randomized clinical trial (NCT03336840), 60 non-obese women with PCOS were randomly assigned (1:1:1) to receive probiotics (4 g daily), metformin (1.5 g daily) or their combination for 12 weeks. The primary outcome was the improvement of menstrual patterns. The secondary outcomes included changes in anthropometric, metabolic profiles and hormonal levels. Results: After 12-week treatment, the recovery rate of menstrual cycle was 40% in probiotics group, 55% in metformin group and 80% in combination group (p = 0.035). Meanwhile, the ovulation rate was 30% in probiotics group, 55% in metformin group and 75% in combination group (p = 0.017). Serum anti-Müllerian hormone, testosterone, free androgen index, BMI, fasting blood glucose, HOMA-IR, lipid profiles were decreased after probiotics or metformin treatment in non-obese women with PCOS. Conclusion: In the present trial, probiotics combined with metformin was superior to probiotics or metformin alone to improve menstrual patterns in women with PCOS. Metabolic and hormonal profiles were also improved after probiotics or metformin treatment.

Excessive free fatty acid sensing in pituitary lactotrophs elicits steatotic liver disease by decreasing prolactin levels.

The pituitary is the central endocrine gland with effects on metabolic dysfunction-associated steatotic liver disease (MASLD). However, it is not clear whether the pituitary responds to free fatty acid (FFA) toxicity, thus dysregulating hepatic lipid metabolism. Here, we demonstrate that decreased prolactin (PRL) levels are involved in the association between FFA and MASLD based on a liver biospecimen-based cohort. Moreover, overloaded FFAs decrease serum PRL levels, thus promoting liver steatosis in mice with both dynamic diet intervention and stereotactic pituitary FFA injection. Mechanistic studies show that excessive FFA sensing in pituitary lactotrophs inhibits the synthesis and secretion of PRL in a cell-autonomous manner. Notably, inhibiting excessive lipid uptake using pituitary stereotaxic virus injection or a specific drug delivery system effectively ameliorates hepatic lipid accumulation by improving PRL levels. Targeted inhibition of pituitary FFA sensing may be a potential therapeutic target for liver steatosis.

Low levels of osteocalcin, but not CTX or P1NP, are associated with nonalcoholic hepatic steatosis and steatohepatitis.

AIM: The association of bone turnover with the incidence and progression of nonalcoholic fatty liver disease (NAFLD) is unclear. We aimed to evaluate serum levels of bone turnover markers in relation to NAFLD and nonalcoholic hepatic steatohepatitis (NASH). METHODS: Two cohorts were involved in our study. For the first cohort, 370 participants without NAFLD were retrospectively recruited and followed up for incident NAFLD according to ultrasound. For the second cohort, 562 subjects who underwent liver biopsy were included and grouped into non-NAFLD, non-NASH or NASH according to the NASH Clinical Research Network system. The bone turnover markers osteocalcin, C-terminal telopeptide (CTX) and N-terminal propeptide of type-1 procollagen (P1NP) were measured. RESULTS: Baseline osteocalcin was significantly lower in subjects who developed NAFLD (13.93 [11.03;16.39] versus 18.24 [15.45;22.47] ng/ml, P < 0.001), with a median of 26.4 months of follow-up. Low levels of osteocalcin, but not CTX or P1NP, was an independent predictor of incident NAFLD (OR 0.755 [95%CI 0.668; 0.855] P < 0.001). Moreover, the osteocalcin level was negatively associated with the degree of liver steatosis. Furthermore, subjects with NASH had significantly lower osteocalcin than non-NASH and non-NAFLD group (13.28 [10.49;16.59] versus 14.91 [12.45;18.09] versus 18.21 [15.04;22.05] ng/ml, all P < 0.001). A low osteocalcin level was an independent risk factor for NASH (OR for highest versus lowest quartile: 0.282 [0.147;0.543] P < 0.001). CONCLUSION: Low level of osteocalcin, but not CTX or P1NP, was associated with NAFLD and NASH, indicating its potential role as an important endocrine regulator of hepatic energy metabolism.