Capsaicin‐sensitive sensory fibers in the islets of Langerhans contribute to defective insulin secretion in Zucker diabetic rat, an animal model for some aspects of human type 2 diabetes

Abstract

The system that regulates insulin secretion from beta-cells in the islet of Langerhans has a capsaicin-sensitive inhibitory component. As calcitonin gene-related peptide (CGRP)-expressing primary sensory fibers innervate the islets, and a major proportion of the CGRP-containing primary sensory neurons is sensitive to capsaicin, the islet-innervating sensory fibers may represent the capsaicin-sensitive inhibitory component. Here, we examined the expression of the capsaicin receptor, vanilloid type 1 transient receptor potential receptor (TRPV1) in CGRP-expressing fibers in the pancreatic islets, and the effect of selective elimination of capsaicin-sensitive primary afferents on the decline of glucose homeostasis and insulin secretion in Zucker diabetic fatty (ZDF) rats, which are used to study various aspects of human type 2 diabetes mellitus. We found that CGRP-expressing fibers in the pancreatic islets also express TRPV1. Furthermore, we also found that systemic capsaicin application before the development of hyperglycemia prevents the increase of fasting, non-fasting, and mean 24-h plasma glucose levels, and the deterioration of glucose tolerance assessed on the fifth week following the injection. These effects were accompanied by enhanced insulin secretion and a virtually complete loss of CGRP- and TRPV1-coexpressing islet-innervating fibers. These data indicate that CGRP-containing fibers in the islets are capsaicin sensitive, and that elimination of these fibers contributes to the prevention of the deterioration of glucose homeostasis through increased insulin secretion in ZDF rats. Based on these data we propose that the activity of islet-innervating capsaicin-sensitive fibers may have a role in the development of reduced insulin secretion in human type 2 diabetes mellitus.

Role of TRPV channels in regulating various pancreatic β-cell functions: Lessons from <i>in vitro</i> studies

“…Another experiments showed that the hIAPPinduced intracellular Ca 2+ rise in min6 cells can be also suppressed by ruthenium red, which is a noncompetitive pan inhibitor of TRPs, in particularly TRPV channels including TRPV4 (and also TRPV1) (56,57 (47). Consistent with the incapability of capsaicin to affect calcium levels in rat primary β-cells, others reported that rat pancreatic islets lack TRPV1 (49). Similar data were obtained by Diaz-Garcia et al who studied whether TRPV1 is expressed in rat pancreatic β-cells (50).…”

Monoacylglycerol as a Metabolic Coupling Factor in Glucose-Stimulated Insulin Secretion

“…(Suri and Szallasi, 2008;Venkatachalam and Montell, 2007;Vriens et al, 2009). The presence of TRPV1-receptor in pancreatic -cells has been investigated by different groups and while its presence and functionality has been shown in normal rat islet -cells (Akiba et al, 2004;Barbasa and Fleig, 2008), studies done on ZDF rats (Gram et al, 2007) and in the Type-1 diabetes model, NOD mice (8 week old with insulinitis) (Razavi et al, 2006) were unable to show the TRPV1-R presence in the islets. It has been demonstrated that TRPV1-R has its ligand/ agonist binding site intracellularly and its activation by capsaicin or other agonists leads to Ca 2+ influx (Vriens et al, 2009), which is a pre-requisite for insulin granule fusion with plasma membrane for exocytosis.…”

“…Our results demonstrated the expression of TRPV1-R at both mRNA as well as protein level (Fig 19A) in islets and in INS cells. Activation of TRPV1-R by capsaicin both in vitro (Akiba et al, 2004;Barbasa and Fleig, 2008) and also in vivo has been shown to elevate insulin secretion and Ca 2+ influx (Alevizos et al, 2007;Gram et al, 2007;Moesgaard et al, 2005). Both 1-and 2-MAG have recently been shown to activate TRPV1-R in vitro leading to Ca 2+ influx and also in vivo (Iwasaki et al, 2008).…”

“…TRPV1 is a plasma membrane localized non-selective cation channel, which preferentially functions in the influx of Ca 2+ ions, when stimulated (Venkatachalam and Montell, 2007). Besides, it is also known that capsaicin, which activates TRPV1, stimulates insulin secretion both in vitro in beta cells (Akiba et al, 2004) and in vivo in ZDF rats (Gram et al, 2007). The ligand-binding site of TRPV1 is known to be on the inner side of the plasma membrane.…”

“…Systemic use of capsaicin could increase glucose tolerance in the Zucker fatty rat (Gram et al, 2007). TRPV-1 deficient mice have been generated and proved to be resistant to obesity after high fat feeding (Motter and Ahern, 2008).…”