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Glucagon-like peptide 1 (GLP-1) is produced by the L subtype of enteroendocrine cells (EECs). Patients with type 2 diabetes (T2D) exhibit reduced incretin effect, but the pathophysiology and functional change of the L-cells remain unclear. Deciphering the mechanisms of the biological changes in L-cells under T2D conditions may assist in the research of gut-based strategies for T2D therapy. We investigated the fasting serum GLP-1 levels and the distribution of colonic L-cells in young and aged participants with and without T2D. Additionally, we established an aged male T2D Wistar rat model subjected to a long-term high-fat and high-fructose (HFHF) diet. Histological investigations and single-cell RNA sequencing (scRNA-seq) analyses were performed to explore the mechanisms underlying functional changes in the colonic EECs. We observed a decline in circulating GLP-1 levels and a reduced number of colonic L-cells in elderly patients with T2D. The mechanisms underlying impaired L-cell formation and disturbed GLP-1 production were revealed using aged T2D rats induced by a long-term HFHF diet. The scRNA-seq results showed that the transcription factors that regulate L-cell commitment, such as Foxa1 , were downregulated, and the expression of genes that participate in encoding GLP-1, GLP-1 posttranslational processing, hormone secretion, and nutrient sensing was disturbed. Taken together, the reduced L-cell lineage commitment and disturbed L-cell functions might be the major cause of the reduced GLP-1 production in aged populations with T2D. Our study provides new insights for identifying novel targets in colonic L-cells for improving endogenous GLP-1 production. • Aged patients with T2D are more susceptible to having diminished GLP-1 production than their age-matched controls. • A shortage of colonic L-cells might lead to the loss of GLP-1 production in aged subjects with T2D. • The disturbed L-cell lineage commitment and L-cell functions might be the main causes of impaired GLP-1 production. [ABSTRACT FROM AUTHOR]

Hormone therapy (HT) has failed to improve learning and memory in postmenopausal women according to recent clinical studies; however, the reason for failure of HT in improving cognitive performance is unknown. In our research, we found cognitive flexibility was improved by 17β-Estradiol (E2) in mice 1 week after ovariectomy (OVX ST), but not in mice 3 months after ovariectomy (OVX LT). Isobaric tags for relative and absolute quantitation (iTRAQ) revealed increased cannabinoid receptor interacting protein 1 (CNRIP1) in E2-treated OVX LT mice compared with E2-treated OVX ST mice. Adeno-associated virus 2/9 (AAV2/9) delivery of Cnrip1 short-hairpin small interfering RNA (Cnrip1 -shRNA) rescued the impaired cognitive flexibility in E2 treated OVX LT mice. This effect is dependent on CB1 function, which could be blocked by AM251—a CB1 antagonist. Our results indicated a new method to increasing cognitive flexibility in women receiving HT by disrupting CNRIP1. • Estrogen fails to rescue cognitive flexibility in long-term estrogen-deprived female mice. • CNRIP1 protein is increased in long-term estrogen-deprived female mice compared with short-term group. • Disrupting CNRIP1 rescues cognitive flexibility long-term estrogen-deprived female mice after estrogen treatment. [ABSTRACT FROM AUTHOR]