Daily Endocrinology Research Analysis

BACKGROUND: For individuals with obesity and type 2 diabetes, weight loss improves insulin sensitivity and β-cell function and can induce remission of diabetes. However, the long-term comparative effectiveness of standard gastric bypass and sleeve gastrectomy on remission of type 2 diabetes remains unclear. We aimed to compare the effects of gastric bypass and sleeve gastrectomy on type 2 diabetes remission, weight loss, and cardiovascular risk factors 5 years after surgery. METHODS: We present a secondary analysis of a two-armed, single-centre, triple-blind, randomised controlled trial conducted at a public tertiary obesity centre in Norway. Adults (ie, age ≥18 years) with type 2 diabetes and obesity were randomly assigned (1:1) by a computerised random number generator to laparoscopic gastric bypass or sleeve gastrectomy, with balanced block sizes of ten. Study personnel, participants, and the primary-outcome assessor were all masked to the allocation until 1 year after surgery, after which further follow-up was open label. Changes in key secondary outcomes, including type 2 diabetes remission, weight loss, and cardiovascular risk factors, were assessed 5 years after surgery. The trial procedure estimand assessed treatment effects in all randomised participants, with data collected after conversional surgery removed from analyses. The trial was registered with ClinicalTrials.gov (NCT01778738) and was completed in December, 2022. FINDINGS: Between Oct 15, 2012, and Sept 1, 2017, 319 patients were assessed for eligibility, resulting in 109 participants who were randomly assigned to gastric bypass (n=54) or sleeve gastrectomy (n=55). The baseline mean age was 47·7 years (SD 9·6), mean BMI 42·3 kg/m INTERPRETATION: Gastric bypass was superior to sleeve gastrectomy regarding long-term remission of type 2 diabetes, weight loss, and LDL cholesterol concentrations, at the expense of a higher frequency of symptomatic postprandial hypoglycaemia. These findings could inform clinical practice and future guidelines regarding the preferred surgical procedure in patients with type 2 diabetes. FUNDING: Vestfold Hospital Trust. TRANSLATION: For the Norwegian translation of the abstract see Supplementary Materials section.

β-hydroxybutyrate (β-HB; 3-hydroxybutyric acid) may serve as a signaling metabolite in many physiological processes beyond a fuel source for tissues. However, whether and how it is involved in ketone body metabolism is still unknown. The present study aims to investigate the role of lysine β-hydroxybutyrylation (Kbhb) modification mediated by β-HB in regulating ketone body metabolic homeostasis both in vivo and in vitro. The starvation ketosis and type 1 diabetes mouse models were introduced to evaluate the influence of β-HB on Kbhb modification in mice. The Kbhb modifications of 3-oxoacid CoA-transferase 1 (OXCT1) and HMG-CoA synthase 2, two rate-limiting enzymes involved in ketogenesis and utilization, showed a positive correlation with the level of β-HB both in vitro and in vivo. The modification levels of the enzymes increased during fasting but decreased after refeeding. However, the Kbhb modification level in all detected tissues showed minor change since the blood ketone body increased nonsignificantly in the type 1 diabetes mouse model. The in vitro experiments further indicated that mutation at the Kbhb modification site significantly inhibited the enzymatic activity of OXCT1 but not HMG-CoA synthase 2. Sirtuin 1 (SIRT1) and CREB-binding protein (CBP) were identified both in vitro and in vivo as potential Kbhb dehydrogenase and transferase for OXCT1, respectively. Kbhb modification at lysine 421 of OXCT1 increases its enzyme activity during β-HB accumulation, accelerating the utilization of the ketone body and finally maintaining metabolism homeostasis. Our present study proposes a new ketone body metabolic regulatory mode primarily mediated by Kbhb modifications of OXCT1 during β-HB accumulation.

Obesity-associated inflammation is characterized by macrophage infiltration into peripheral tissues, contributing to the progression of prediabetes and type 2 diabetes. 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids and promotes the migration of macrophages, yet its role in obesity-associated inflammation remains incompletely understood. Furthermore, differences between mouse and human orthologs of 12-LOX have limited efforts to study existing pharmacologic inhibitors of 12-LOX. In this study, we used a human gene replacement mouse model in which the gene encoding mouse 12-LOX (Alox15) is replaced by the human ALOX12 gene. As a model of obesity and dysglycemia, we administered male mice a high-fat diet. We subsequently investigated the effects of VLX-1005, a potent and selective small molecule inhibitor of human 12-LOX. Oral administration of VLX-1005 resulted in improved glucose homeostasis, decreased β-cell dedifferentiation, and reduced macrophage infiltration in islets and adipose tissue. Analysis of the stromal vascular fraction from adipose tissue showed a reduction in myeloid cells and cytokine expression with VLX-1005 treatment, indicating decreased adipose tissue inflammation. In a distinct mouse model in which Alox15 was selectively deleted in myeloid cells, we observed decreased β-cell dedifferentiation and reduced macrophage infiltration in both islets and adipose tissue, suggesting that the effects of VLX-1005 may relate to the inhibition of 12-LOX in macrophages. These findings highlight 12-LOX as a key factor in obesity-associated inflammation and suggest that 12-LOX inhibition could serve as a therapeutic strategy to improve glucose homeostasis and peripheral inflammation in the setting of obesity and type 2 diabetes.