{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T12:59:32Z","timestamp":1777899572054,"version":"3.51.4"},"reference-count":54,"publisher":"American Physiological Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"published-print":{"date-parts":[[2012,9,15]]},"abstract":"<jats:p>Insulin therapy using insulin detemir (d-INS) has demonstrated weight-sparing effects compared with other insulin formulations. Mechanisms underlying these effects, however, remain largely unknown. Here we postulate that the intestinal tissues' selective preference allows d-INS to exert enhanced action on proglucagon (Gcg) expression and the production of glucagon-like peptide (GLP)-1, an incretin hormone possessing both glycemia-lowering and weight loss effects. To test this hypothesis, we used obese type 2 diabetic db\/ db mice and conducted a 14-day intervention with daily injection of a therapeutic dose of d-INS or human insulin (h-INS) in these mice. The body weight of the mice after 14-day daily injection of d-INS (5 IU\/kg) was decreased significantly compared with those injected with the same dose of h-INS or saline. The weight-sparing effect of d-INS was associated with significantly elevated circulating levels of total GLP-1 and reduced food intake. Histochemistry analysis demonstrated that d-INS induced rapid phosphorylation of protein kinase B (Akt) in the gut L cells of normal mice. Western blotting showed that d-INS stimulated Akt activation in a more rapid and enhanced fashion in the mouse distal ileum compared with those by h-INS. In vitro investigation in primary fetal rat intestinal cell (FRIC) cultures showed that d-INS increased Gcg mRNA expression as determined by Northern blotting and real-time RT-PCR. Consistent with these in vivo investigations, d-INS significantly increased GLP-1 secretion in FRIC cultures. Consistently, d-INS was also shown to induce rapid phosphorylation of Akt in the clonal gut cell line GLUTag. Furthermore, d-INS increased \u03b2-catenin phosphorylation, its nuclear translocation, and enhanced cAMP response element-binding protein (CREB) phosphorylation in a phosphatidylinositol 3-kinase and\/or mitogen-activated protein kinase kinase\/extracellular signal-regulated kinase-sensitive manner. We suggest that the weight-sparing benefit of d-INS in mice is related to its intestinal tissues preference that leads to profound stimulation of Gcg expression and enhanced GLP-1 secretion in intestinal L cells, potentially involving the activation of insulin\/\u03b2-catenin\/CREB signaling pathways.<\/jats:p>","DOI":"10.1152\/ajpendo.00328.2011","type":"journal-article","created":{"date-parts":[[2012,7,19]],"date-time":"2012-07-19T08:10:50Z","timestamp":1342685450000},"page":"E740-E751","source":"Crossref","is-referenced-by-count":10,"title":["Insulin detemir enhances proglucagon gene expression in the intestinal L cells via stimulating \u03b2-catenin and CREB activities"],"prefix":"10.1152","volume":"303","author":[{"given":"Shenghao","family":"Liu","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, 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