Hepatic fatty acid and glucose handling in metabolic disease: Potential impact on cardiovascular disease risk.

The prevalence of metabolic diseases, including type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing. Although invariably associated with obesity, the importance of fat deposition in non-adipose tissue organs has yet to be fully explored. Pathological ectopic fat deposition within the liver (known as (MASLD)) has been suggested to underlie the development of T2DM and is now emerging as an independent risk factor for cardiovascular disease (CVD). The process of hepatic de novo lipogenesis (DNL), that is the synthesis of fatty acids from non-lipid precursors (e.g. glucose), has received much attention as it sits at the intersect of hepatic glucose and fatty acid handling. An upregulation of the DNL pathway has been suggested to be central in the development of metabolic diseases (including MASLD, insulin resistance, and T2DM). Here we review the evidence to determine if hepatic DNL may play a role in the development of MASLD and T2DM and therefore underlie an increased risk of CVD.

Metformin maintains intrahepatic triglyceride content through increased hepatic de novo lipogenesis.

OBJECTIVE: Metformin is a first-line pharmacotherapy in the treatment of type 2 diabetes, a condition closely associated with non-alcoholic fatty liver disease (NAFLD). Although metformin promotes weight loss and improves insulin sensitivity, its effect on intrahepatic triglyceride (IHTG) remains unclear. We investigated the effect of metformin on IHTG, hepatic de novo lipogenesis (DNL), and fatty acid (FA) oxidation in vivo in humans. DESIGN AND METHODS: Metabolic investigations, using stable-isotope tracers, were performed in ten insulin-resistant, overweight/obese human participants with NAFLD who were treatment naïve before and after 12 weeks of metformin treatment. The effect of metformin on markers of s.c. adipose tissue FA metabolism and function, along with the plasma metabolome, was investigated. RESULTS: Twelve weeks of treatment with metformin resulted in a significant reduction in body weight and improved insulin sensitivity, but IHTG content and FA oxidation remained unchanged. Metformin treatment was associated with a significant decrease in VLDL-triglyceride (TG) concentrations and a significant increase in the relative contribution of DNL-derived FAs to VLDL-TG. There were subtle and relatively few changes in s.c. adipose tissue FA metabolism and the plasma metabolome with metformin treatment. CONCLUSIONS: We demonstrate the mechanisms of action of metformin whereby it improves insulin sensitivity and promotes weight loss, without improvement in IHTG; these observations are partly explained through increased hepatic DNL and a lack of change in FA oxidation.

Risk factors associated with post-operative uveitis after cataract surgery: a retrospective case-control study.

BACKGROUND/AIM: Post-operative uveitis is the most common complication after cataract surgery in the UK. The study aims to evaluate the risk of post-operative uveitis in cataract surgery patients of different ethnicity in the presence and absence of co-morbidities as well as operative complications using multivariate analysis. METHODS: A retrospective case-control study of patients undergoing phacoemulsification cataract surgery between January 2018 to December 2019 at two hospital sites. Differences in demographic and clinical characteristics were compared between two groups defined by the development of post-operative uveitis. Statistically significant factors in univariate analysis were further analysed using multivariate analysis to account for confounders. RESULTS: One thousand and five hundred eighty seven eyes had undergone phacoemulsification cataract operations with 104 (6.6%) developing post-operative uveitis. Compared to eyes of White/Mixed/Other ethnicity, Asian and Afro-Caribbean eyes were associated with a twofold (OR 2.02, 95% CI 1.16-3.52, P = 0.013) and fivefold (OR 5.15, 95% CI 2.85-9.29, P < 0.001) risk of post-operative uveitis, respectively. Complicated surgery involving eyes with small pupil/iris hooks/Malyugin ring (OR 2.70, 95% CI 1.16-6.30, P = 0.022) and posterior capsular rupture (OR 6.00, 95% CI 2.55-14.12, P < 0.001) were associated with an increased risk of post-operative uveitis. CONCLUSIONS: The factors significantly associated with a post-operative uveitis outcome were patients of Asian and Afro-Caribbean ethnicity, small intra-operative pupil size, use of iris hooks or Malyugin ring and PCR. The post-operative management plan should be tailored in these group of patients with a view of early assessment and prompt management of symptoms.