SGLT2
Ghrelin facilitates GLUT2-, SGLT1-and SGLT2-mediated intestinal glucose transport in goldfish (Carassius auratus), 2017
Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion, 2019
δ-Cells: The Neighborhood Watch in the Islet Community, 2019
Simple Summary
Pancreatic islets are micro-organs composed of several endocrine cell types, including α-cells (secreting glucose-elevating glucagon), β-cells (releasing glucose-lowering insulin) and δ-cells (producing somatostatin, a potent inhibitor of insulin and glucagon secretion). Despite their low percentage within the islets (~5%), δ-cells play an important role in maintaining a balanced hormone output. This is facilitated by their complex morphology projections enabling interaction with other endocrine cells. δ-cells are electrically excitable and, like in β-cells, KATP channels mediate the metabolic signals by modulating δ-cell membrane potential. However, Ca2+ signals amplified by mobilization of intracellular Ca2+ stores play a fundamental part in the process of glucose-induced somatostatin secretion and this can be independent of δ-cell electrical activity. Apart from their intrinsic regulatory mechanisms, δ-cells’ somatostatin secretion is tightly modulated by neighboring “non-δ-cells”, fulfilling its reciprocal feedback paracrine function. In this review, we summarize the structural features of δ-cells; the intracellular signaling of δ-cells in response to nutritional stimuli; and the molecular signals mediating the paracrine crosstalk between δ- and non-δ-cells. Finally, the function of δ-cells and their intercellular interactions are impaired in diabetes. Thus, restoring δ-cell function/signaling in diabetes would be a promising approach for developing novel treatment for diabetes.
Somatostatin secretion by Na+-dependent Ca2+-induced Ca2+ release in pancreatic delta cells, 2020
Abstract
Pancreatic islets are complex micro-organs consisting of at least three different cell types: glucagon-secreting alpha, insulin-producing beta and somatostatin-releasing delta cells1. Somatostatin is a powerful paracrine inhibitor of insulin and glucagon secretion2. In diabetes, increased somatostatinergic signalling leads to defective counter-regulatory glucagon secretion3. This increases the risk of severe hypoglycaemia, a dangerous complication of insulin therapy4. The regulation of somatostatin secretion involves both intrinsic and paracrine mechanisms5 but their relative contributions and whether they interact remain unclear. Here we show that dapagliflozin-sensitive glucose- and insulin-dependent sodium uptake stimulates somatostatin secretion by elevating the cytoplasmic Na+ concentration (intracellular [Na+]; [Na+]i) and promoting intracellular Ca2+-induced Ca2+ release. This mechanism also becomes activated when [Na+]i is elevated following the inhibition of the plasmalemmal Na+-K+ pump by reductions of the extracellular K+ concentration emulating those produced by exogenous insulin in vivo6. Islets from some donors with type-2 diabetes hypersecrete somatostatin, leading to suppression of glucagon secretion that can be alleviated by a somatostatin receptor antagonist. Our data highlight the role of Na+ as an intracellular second messenger, illustrate the significance of the intra-islet paracrine network and provide a mechanistic framework for pharmacological correction of the hormone secretion defects associated with diabetes that selectively target the delta cells.
Versatile Functions of Somatostatin and Somatostatin Receptors in the Gastrointestinal System, 2021
Somatostatin (SST) and somatostatin receptors (SSTRs) play an important role in the brain and gastrointestinal (GI) system. SST is produced in various organs and cells, and the inhibitory function of somatostatin-containing cells is involved in a range of physiological functions and pathological modifications. The GI system is the largest endocrine organ for digestion and absorption, SST-endocrine cells and neurons in the GI system are a critical effecter to maintain homeostasis via SSTRs 1-5 and co-receptors, while SST-SSTRs are involved in chemo-sensory, mucus, and hormone secretion, motility, inflammation response, itch, and pain via the autocrine, paracrine, endocrine, and exoendocrine pathways. It is also a power inhibitor for tumor cell proliferation, severe inflammation, and post-operation complications, and is a first-line anti-cancer drug in clinical practice. This mini review focuses on the current function of producing SST endocrine cells and local neurons SST-SSTRs in the GI system, discusses new development prognostic markers, phosphate-specific antibodies, and molecular imaging emerging in diagnostics and therapy, and summarizes the mechanism of the SST family in basic research and clinical practice. Understanding of endocrines and neuroendocrines in SST-SSTRs in GI will provide an insight into advanced medicine in basic and clinical research.
Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2, 2017
Background:
The sympathetic nervous system (SNS) regulates glucose metabolism in various organs including the kidneys. The sodium glucose cotransporter 2 (SGLT2) mediates glucose reabsorption in renal proximal tubules and its inhibition has been shown to improve glucose control, cardiovascular and renal outcomes. We hypothesized that SNS-induced alterations of glucose metabolism may be mediated via regulation of SGLT2.
Method:
We used human renal proximal tubule cells to investigate the effects of noradrenaline on SGLT2 regulation. Mice fed a high-fat diet were oral gavaged with dapagliflozin and the expression of noradrenaline and tyrosine hydroxylase was measured in the kidney and heart.Results:
Noradrenaline treatment resulted in a pronounced increase in SGLT2 and interleukin (IL)-6 expression in HK2 cells and promoted translocation of SGLT2 to the cell surface. In vivo, dapagliflozin treatment resulted in marked glucosuria in high-fat diet-fed mice. SGLT2 inhibition significantly reduced high-fat diet-induced elevations of tyrosine hydroxylase and noradrenaline in the kidney and heart. We also aimed to assess the levels of hypertension-related cytokines in the kidneys of our mice treated with and without dapagliflozin. Excitingly, we demonstrate that SGLT2 inhibition with dapagliflozin promoted a trend towards reduced tumour necrosis factor-alpha and elevated IL-1β protein levels in the kidney.Conclusion:
Our in-vitro and in-vivo studies provide first evidence for an important cross-talk between the SNS and SGLT2 regulation that may not only account for SNS-induced alterations of glucose metabolism but potentially contribute to cardiovascular and renal protection observed with SGLT2 inhibitors.
The effect of acute dual SGLT1/SGLT2 inhibition on incretin release and glucose metabolism after gastric bypass surgery, 2020
… The insulinotropic and anorexigenic gut hormone … expression and postprandial glucose
absorption are enhanced in the proximal intestine of morbidly obese humans (33). Expression of
Vertical sleeve gastrectomy lowers kidney SGLT2 expression in the mouse, 2019
Abstract
Background Bariatric surgery has been established to improve insulin sensitivity and glucose clearance, but also increases insulin and glucagon secretion. Each of the above effects have also been observed following treatment with sodium glucose co-transporter 2 (SGLT2) inhibitors.
Aim To determine whether there is an effect of bariatric surgery (Vertical Sleeve Gastrectomy; VSG) on renal SGLT2 expression in mice.
Methods Eighteen lean mice underwent VSG (n=8) or sham (n=9) surgery. Glucose tolerance tests with or without treatment with the SGLT2 inhibitor dapagliflozin were performed four weeks post operatively, in order to assess if pharmacological SGLT2 inhibition has the same euglycemic effects after bariatric surgery. Kidneys were harvested from fed mice and SGLT2 expression was analysed using Quantitative reverse-transcription PCR and immunofluorescence.
Results VSG mice displayed significantly improved glucose tolerance (AUC=103±6.8; AUC=66.6±2.9 in control and VSG mice, respectively; p<0.001), despite an absence of significant weight loss when compared to sham operated mice (p=0.37, Mann-Whitney test). Treatment of sham-operated mice with dapagliflozin (10 mg/kg) improved glucose tolerance. In contrast, dapagliflozin did not further improve glucose tolerance in VSG-operated mice. Moreover, qRT-PCR and immunofluorescence analysis on mouse kidneys demonstrated a significant lowering of SGLT2 expression at both the mRNA (n=7, p<0.0001) and protein (n=5, p=0.0007) levels four weeks after VSG.
Conclusions Vertical sleeve gastrectomy in lean animals causes a significant inhibition of SGLT2 expression in the kidney cortex. These findings are in line with our previous results on the effects of Duodenal Jejunal Bypass in lean rats, and point towards a physiologically-relevant gut-kidney axis. SGLT2 inhibition may thus be an important mechanism through which bariatric surgery improves glucose tolerance in man.
Sleeve Gastrectomy Surgery Improves Glucose Metabolism by Downregulating the Intestinal Expression of Sodium–Glucose Cotransporter-3, 2022
The Effects of SGLT2 Inhibitors on Lipid Metabolism, 2020
Abstract
Sodium glucose co-transporter 2 (SGLT2) inhibitors are effective antihyperglycemic agents by inhibiting glucose reabsorption in the proximal tubule of the kidney. Besides improving glycemic control in patients with type 2 diabetes, they also have additional favorable effects, such as lowering body weight and body fat. Several clinical studies have demonstrated their positive effect in reducing cardiovascular morbidity and mortality. Furthermore, the use of SGLT2 inhibitors were associated with fewer adverse renal outcomes comparing to other diabetic agents, substantiating their renoprotective effect in diabetic patients. SGLT2 inhibitors have also remarkable effect on lipid metabolism acting at different cellular levels. By decreasing the lipid accumulation, visceral and subcutaneous fat, they do not only decrease the body weight but also change body composition. They also regulate key molecules in lipid synthesis and transportation, and they affect the oxidation of fatty acids. Notably, they shift substrate utilization from carbohydrates to lipids and ketone bodies. In this review we intended to summarize the role of SGLT2 inhibitors in lipid metabolism especially on lipoprotein levels, lipid regulation, fat storage and substrate utilization.
Perspective of SGLT2 inhibition in treatment of conditions connected to neuronal loss: focus on Alzheimer's disease and ischemia-related brain injury, 2020
… alterations in SGLT2 expression [48]. HNF-1α appears to directly control SGLT2 expression
in mice and humans [49]. Researchers demonstrated that elevated HNF-1α expression and …
SGLT2+upregulation+by+estrogens
