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Circadian disorder such as light exposure at night are risk factors for NAFLD Prolactin (PRL), a pituitary derived hormone, is recently shown to improve fatty liver. Noteworthy, PRL is secreted in an oscillating pattern. We aimed to explore the role of PRL rhythm in hepatic lipid metabolism. Serum PRL levels in 8:00, 16:00, and 24:00 of subjects without or with NAFLD were evaluated. A cosine model was fitted to the curve of dynamic PRL levels. Luciferase report assay, ChIP and EMSA were used to examine the mechanism of PRL rhythm. Hight fat diet (HFD) C57BL/6 mice were categorized into HFD, HFD+jet-lag group for 16 weeks and serum PRL levels at ZT0, ZT4, ZT8, ZT12, ZT16, ZT20 were determined. Then mice in HFD+jet-lag group were randomly assigned to HFD+ jet lag and HFD+jet-lag+PRL for 14 days. Hepatic lipid content, clock genes and lipid metabolic genes in liver were detected. PRL in 8:00, 16:00 and 24:00 were all significantly lower in NAFLD group than in controls. Cosine curve analysis showed that NAFLD patients had reduced amplitude and delayed phase shift of PRL levels. After adjusted for confounders, light exposure at night is a risk factor for NAFLD, yet this association was dampened after adjusted for PRL rhythm. Luciferase report assay in 293T cell and EMSA assay in human pituitary tissue showed that Prl can be transactivated by core clock gene Rorα via RORα response element RORE. In mice, dynamic PRL attained highest levels at ZT12 in HFD mice but remained low in HFD+jet-lag mice. ChIP analysis showed that binding of Rorα and Prl promoter in HFD mouse pituitary at ZT12 was inhibited under HFD+jet-lag. Furthermore, hepatic lipid content was significantly higher in HFD+jet-lag group than that in HFD, and can be mitigated after 14 days PRL intervention at ZT12. We also found that PRL injection reversed changes of clock and lipid metabolic gene rhythm caused by jet-lag. PRL can serve as an endocrine sensor that transmits rhythmic signals from central nervous system to liver and thus regulating hepatic lipid metabolism. Disclosure: B. Yan: None. P. Zhang: None. D. Zhu: None. Funding: National Natural Science Foundation of China (81900787, 81770819) [ABSTRACT FROM AUTHOR]

Disturbance of innate and adaptive immune systems is responsible for β-cell destruction in type 1 diabetes (T1D). Although increasing evidence indicated a crucial role for B cells in disease pathogenesis, exactly how B-cell subsets contribute to T1D remains unclear. This study aimed to evaluate the potential role of B-cell subset in the development of T1D. We enrolled 56 people with T1D, including 8 people receiving mesenchymal stromal cell (MSC) treatment, 22 people with T2D, and 26 healthy controls. ELISPOT assay was used to assess the role of B-cell subset in activation of diabetogenic T cells. NOD mice and adoptive transfer assays were utilized to study the role of B-cell subset in T1D in vivo. Plasmablasts, but not naïve, unswitched or switched memory B cells, were increased in patients with recent-onset T1D, compared with those with long-term T1D, T2D and healthy controls. In patients with recent-onset T1D, plasmablast number negatively correlated with fasting C-peptide and area under the curve of C-peptide. Plasmablasts decreased in line with an improvement of residual β-cell function 3 months after MSC treatment. Compared with other B-cell subsets, plasmablasts expressed a high level of CD86, which negatively correlated with the residual β-cell function while positively correlated with the number of islet autoantibodies. ELISPOT assay further showed that plasmablasts isolated from participants with T1D induced a dramatic increase of interferon-γ secretion in GAD65 stimulated T cells. Compared with euglycemic NOD mice, the number of plasmablasts was increased in the spleen, pancreatic lymph nodes, and islets of diabetic NOD mice. Moreover, adoptive transfer of plasmablasts mixed with T cells from diabetic NOD mice into NOD/SCID mice accelerated the development of T1D. These data firstly demonstrated that plasmablasts play a vital role in immune disturbance, further expanding the knowledge of T1D pathogenesis. Plasmablasts may serve as a novel therapeutic target in T1D. Disclosure: B. Yan: None. Q. Ling: None. J. Lu: None. D. Zhu: None. [ABSTRACT FROM AUTHOR]

Objective: Large numbers of people with type 2 diabetes are obese. However, changes in cognition and related brain function in obese people with diabetes have not been characterized. Here, we investigated cognition, olfactory function, and odor-induced brain alterations in these patients and therapeutic effects of glucagon-like peptide 1 receptor agonists (GLP-1Ras) on their psychological behavior and olfactory networks.Research Design and Methods: Cognitive, olfactory, and odor-induced brain activation assessments were administered to 35 obese and 35 nonobese people with type 2 diabetes and 35 control subjects matched for age, sex, and education. Among them, 20 obese individuals with diabetes with inadequate glycemic control and metformin monotherapy received GLP-1Ra treatment for 3 months and were reassessed for metabolic, cognitive, olfactory, and neuroimaging changes.Results: Obese subjects with diabetes demonstrated lower general cognition and olfactory threshold scores, decreased left hippocampal activation, and disrupted seed-based functional connectivity with right insula compared with nonobese subjects with diabetes. Negative associations were found between adiposity and episodic memory and between fasting insulin and processing speed test time in diabetes. Mediation analyses showed that olfactory function and left hippocampus activation mediated these correlations. With 3-month GLP-1Ra treatment, obese subjects with diabetes exhibited improved Montreal Cognitive Assessment (MoCA) score, olfactory test total score, and enhanced odor-induced right parahippocampus activation.Conclusions: Obese subjects with type 2 diabetes showed impaired cognition and dysfunctional olfaction and brain networks, the latter of which mediated adiposity in cognitive impairment of diabetes. GLP-1Ras ameliorated cognitive and olfactory abnormalities in obese subjects with diabetes, providing new perspectives for early diagnosis and therapeutic approaches for cognitive decrements in these patients. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is reported to be associated with olfactory dysfunction and cognitive decline. However, whether and how olfactory neural circuit abnormalities involve cognitive impairment in diabetes remains uncovered. This study thus aimed to investigate olfactory network alterations and the associations of odor-induced brain activity with cognitive and metabolic parameters in type 2 diabetes. Participants with normal cognition, including 51 patients with type 2 diabetes and 41 control subjects without diabetes, underwent detailed cognitive assessment, olfactory behavior tests, and odor-induced functional MRI measurements. Olfactory brain regions showing significantly different activation between the two groups were selected for functional connectivity analysis. Compared with the control subjects, patients with diabetes demonstrated significantly lower olfactory threshold score, decreased brain activation, and disrupted functional connectivity in the olfactory network. Positive associations of the disrupted functional connectivity with decreased neuropsychology test scores and reduced pancreatic function were observed in patients with diabetes. Notably, the association between pancreatic function and executive function was mediated by olfactory behavior and olfactory functional connectivity. Our results suggested the alteration of olfactory network is present before clinically measurable cognitive decrements in type 2 diabetes, bridging the gap between the central olfactory system and cognitive decline in diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To examine the effect of intensive glycemic control therapy (IT) on insulin sensitivity and β-cell function in newly diagnosed type 2 diabetic patients compared with subjects with normal glucose tolerance (NGT) and those with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS--Forty-eight newly diagnosed type 2 diabetic patients were randomly assigned to IT for 2 weeks and followed up for 1 year. Intravenous glucose tolerance tests were conducted in NGT, IGT, and diabetic subjects. Blood glucose and insulin were measured before and after IT and at the 1-year follow-up. RESULTS--IT lowered the homeostasis model assessment (HOMA) for insulin resistance (IR) significantly, from 3.12 ± 1.4 (mean ± SD)to 1.72 ± 0.8, a level comparable to the IGT (1.96 ± 1.1) and NGT (1.37 ± 0.6) subjects in the remission group: however, no HOMA-β improvement was observed in nonpermission subjects. HOMA-β in the remission group was improved (mean, interquartile range) from 18.4 (8.3-28.5) to 44.6 (32.1-69.1) and acute insulin response of insulin (AIRins) from 1.50 ± 0.22 to 1.83 ± 0.19 µIU/mL after IT, but was still significantly lower than those in NGT individuals (HOMA-β: 86.4 [56.7-185.2], P < 0.01; AIRins: 2.54 ± 0.39 µIU/mL, P < 0.01). After IT and at 1 year, the hyperbolic relationship between HOMA-β and HOMA sensitivity of remission subjects shifted close to that of IGT subjects. CONCLUSIONS--IT in newly diagnosed type 2 diabetes not only partially restored β-cell function but also greatly restored insulin sensitivity. Compared with IGT and NGT subjects, β-cell function was less restored than insulin sensitivity after IT in the remission subjects. [ABSTRACT FROM AUTHOR]