Insulin detemir enhances proglucagon gene expression in the intestinal L cells via stimulating β-catenin and CREB activities

Abstract

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- insulin; protein kinase B; glycogen synthase kinase-3; extracellular signal-regulated kinase; ␤-catenin; adenosine 3=,5=-cyclic monophosphate response element-binding protein; Wnt; proglucagon; gut; L cells INSULIN THERAPY IS A CRITICAL treatment for type 1 diabetes patients, and it is also becoming increasingly accepted for type 2 diabetes for the reduction of diabetic complications (48). Weight gain is a primary adverse effect in both type 1 and type 2 diabetic patients on insulin therapy (7, 50). However, patients using long-acting insulin analogs, particularly insulin detemir (d-INS), often show decreased weight gain (16,39).Insulin exerts a variety of biological effects through activation of its cell surface receptor (43). Activation of phosphatidylinositol 3-kinase (PI3-K) and protein kinase B (Akt) is a critical event that triggers diverse downstream signaling cascades and effector responses (23). In the periphery, activation of this pathway conveys insulin actions such as glucose transport, gene transcription, and protein synthesis (23, 53). In the brain, integral insulin signaling via the PI3-K/Akt pathway is related to nutrient homeostasis and appetite regulation (36).d-INS has a fatty acid chain addition at LysB29 that permits reversible albumin binding (15). Diabetic patients with d-INS therapy usually show both improved glycemic control and weight stability (16, 18) compared with other basal insulin therapies. The molecular mechanisms underlying the weightsparing benefit of d-INS remain largely unknown. It has been proposed that d-INS could cross the blood-brain barrier faster and in higher quantities than other types of insulin to induce stronger effect in the brain (17). As a result, reduced appetite may contribute to its weight-sparing benefit (4).We have demonstrated recently that insulin stimulates proglucagon (Gcg) expression in the intestinal endocrine L cells but not in the pancreatic ␣-cells (53). In colon cancer cells, insulin stimulates ␤-catenin (␤-cat) Ser 675 phosphorylation, which was associated with enhanced nuclear localization of ␤-cat and the binding of ␤-cat/TCF7L2 to Wnt target promoters (41). The bipartite transcription factor ␤-cat/TCF is the key downstream effector in the Wnt signaling pathway while the phosphorylation of ␤-cat at Ser 675 increases its nuclear translocation (44). Interestingly, insulin appears to use the same cisand trans-elements that are used by the ...

Short‐chain fatty acids increase intracellular calcium levels and enhance gut hormone release from STC‐1 cells via transient receptor potential Ankyrin1

“…Expression of the genes of calcineurin pathway (but not CRTC-pathway) was downregulated in the presence of HC-030031. These pathways regulate the gene expression of pre-proglucagon (GCG), the precursor involved in synthesis of proglucagon-derived gut hormones and proconvertase1/3 (PCSK-1), the enzyme required for breakdown of pre-proglucagon to its derived gut hormones and their release [55][56][57]. SCFA-induced increase in expression of these genes was prevented by HC-030031.…”

GLP-1(28–36) improves β-cell mass and glucose disposal in streptozotocin-induced diabetic mice and activates cAMP/PKA/β-catenin signaling in β-cells in vitro

“…Although PKA is the canonical stimulator of CREB and ATF-1 phosphorylation, insulin has been shown to stimulate CREB phosphorylation in pancreatic ␤-cells and in other cell lineages (18,20). This, along with the lack of the activation of CRE element-fused luciferase reporter gene expression by GLP-1(28 -36)amide, reported recently by Liu et al (22), drove us to further investigate whether GLP-1(28 -36)amide indeed stimulates cytoplasmic cAMP levels and PKA activity.…”

Low Molecular Weight Chitosan Accelerates Glucagon-like Peptide-1 Secretion in Human Intestinal Endocrine Cells via a p38-Dependent Pathway

“…The cAMP-related signaling pathway has been found to be involved in the proglucagon gene transcription and GLP-1 production . Liu et al have also shown that insulin stimulates the phosphorylations of β-catenin and cAMP response element-binding protein (CREB) in intestinal L cells in a phosphatidylinositol 3-kinase (PI3K)- and/or ERK MAPK-sensitive manner and then enhances proglucagon gene expression . Cell division cycle 42 (Cdc42) has been demonstrated to regulate actin remodeling, activation of ERK MAPK and Cdc42-dependent p21-activated kinase-1 (PAK1), and GLP-1 secretion in response to insulin in intestinal endocrine L cells .…”