Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice

Abstract

The small intestine is the major site for nutrient absorption, which is critical in maintenance of euglycemia. Leptin, a key hormone involved in energy homeostasis, directly affects nutrient transport across the intestinal epithelium. Catestatin (CST), a 21-amino acid peptide derived from proprotein chromogranin A, has been shown to modulate leptin signaling. Therefore, we reasoned that leptin and CST could modulate intestinal Na+-glucose transporter 1 (SGLT1) expression in the context of obesity and diabetes. We found that hyperleptinemic db/db mice exhibit increased mucosal mass, associated with an enhanced proliferative response and decreased apoptosis in intestinal crypts, a finding absent in leptin deficient ob/ob mice. Intestinal SGLT1 abundance was significantly decreased in hyperleptinemic, but not leptin-deficient mice, indicating leptin regulation of SGLT1 expression. Phlorizin, a SGLT1/2 inhibitor, was without effect in an oral glucose tolerance test in db/db mice. The alterations in architecture and SGLT1 abundance were not accompanied by changes in the localization of intestinal alkaline phosphatase, indicating intact differentiation. Treatment of db/db mice with CST restored intestinal SGLT1 abundance and intestinal turnover, suggesting a cross-talk between leptin and CST, without affecting plasma leptin levels. Consistent with this hypothesis, we identified structural homology between CST and the AB-loop of leptin and protein-protein docking revealed binding of CST and leptin with the Ig-like binding site III of the leptin receptor. In summary, downregulation of SGLT1 in an obese type 2 diabetic mouse model with hyperleptinemia is presumably mediated via the short form of the leptin receptor and reduces overt hyperglycemia.

Chronic Hyperinsulinaemic Hypoglycaemia in Rats Is Accompanied by Increased Body Weight, Hyperleptinaemia, and Decreased Neuronal Glucose Transporter Levels in the Brain

“…However, in the present study, there was a tendency for a decline in SGLT1 levels (6-7% in HI-F and 17–32% in HI-M versus the respective controls), which approached statistical significance after 8 weeks of HI-infusion (2-way ANOVA, p = 0.0703) and was significantly decreased in HI-M after 8 weeks, when performing a post hoc unpaired t -test on group HI-M versus CTRL-M ( p = 0.0436). SGLT1 levels have been shown to be decreased by leptin in vitro in rat jejunal mucosa [51], as well as in vivo in the small intestine of an obese type 2 diabetic mouse model with hyperleptinaemia [52]. This suggests that, similar to GLUT3, SGLT1 in the brain may be prone to regulation by leptin with hyperleptinaemia inducing a downregulation.…”

Alterations of voltage‐dependent K+ channels in the mesenteric artery during the early and chronic phases of diabetes

“…Several type 1 diabetic disease models including diabetes‐prone (DP) BB rats and streptozotocin (STZ)‐induced diabetic models have been used to study type 1 diabetes . Type 2 diabetes is characterized by insulin resistance, for which db/db mice, OLETF rats, and ZFDM rats serve as experimental animal models . Among these, the OLETF rat is a useful animal model for type II diabetes .…”

“…21,22 Type 2 diabetes is characterized by insulin resistance, for which db/db mice, OLETF rats, and ZFDM rats serve as experimental animal models. [23][24][25][26][27][28][29] Among these, the OLETF rat is a useful animal model for type II diabetes. [24][25][26][27] OLETF rats have a disease similar to human diabetes because the onset of diabetes is relatively slow (after 18 weeks of age), blood sugar levels increase gradually, disease occurs more frequently in males, and diabetes is accompanied by mild obesity.…”

Sodium-glucose cotransport

“…Intestinal SGLT1 expression does not require leptin because leptin-deficient mice have normal SGLT1 expression; however, hyperleptinemic mice [50] or leptin administration to rats [51] severely reduced SGLT1. Thus, leptin may play a role in regulating SGLT1 expression.…”

“…In addition, intestine-specific deletion of the leptin receptor isoform b resulted in downregulation of SGLT1 and a delayed onset of obesity [52]. Our own studies identified that intestinal SGLT1 expression and membrane abundance are severely reduced in hyperleptinemic db/db mice [50]. The signaling pathways for leptin-induced SGLT1 regulation remain elusive but might include leptin-induced activation of both PKA and PKC as described in rat enterocytes [51,53].…”