TRPM2 Ca²⁺ channel regulates energy balance and glucose metabolism

Abstract

TRPM2 Ca(2+)-permeable cation channel is widely expressed and activated by markers of cellular stress. Since inflammation and stress play a major role in insulin resistance, we examined the role of TRPM2 Ca(2+) channel in glucose metabolism. A 2-h hyperinsulinemic euglycemic clamp was performed in TRPM2-deficient (KO) and wild-type mice to assess insulin sensitivity. To examine the effects of diet-induced obesity, mice were fed a high-fat diet for 4-10 mo, and metabolic cage and clamp studies were conducted in conscious mice. TRPM2-KO mice were more insulin sensitive partly because of increased glucose metabolism in peripheral organs. After 4 mo of high-fat feeding, TRPM2-KO mice were resistant to diet-induced obesity, and this was associated with increased energy expenditure and elevated expressions of PGC-1α, PGC-1β, PPARα, ERRα, TFAM, and MCAD in white adipose tissue. Hyperinsulinemic euglycemic clamps showed that TRPM2-KO mice were more insulin sensitive, with increased Akt and GSK-3β phosphorylation in heart. Obesity-mediated inflammation in adipose tissue and liver was attenuated in TRPM2-KO mice. Overall, TRPM2 deletion protected mice from developing diet-induced obesity and insulin resistance. Our findings identify a novel role of TRPM2 Ca(2+) channel in the regulation of energy expenditure, inflammation, and insulin resistance.

Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance

“…These results suggest that IL-10 effects may be mediated by intracellular IL-10 signaling in skeletal muscle. To that end, we have previously found that the obesity-induced signal to activate local inflammation may involve oxidative stress and altered Ca 2ϩ homeostasis in skeletal muscle (42). Muscle IL-10 levels also tended to be lower in M-IL10R Ϫ/Ϫ mice, which might be the result of a feedback mechanism.…”

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

“…Uchida et al [15] reported that TRPM2 knockout mice exhibit slightly elevated basal insulin, impaired glucose tolerance, but normal fasting blood glucose levels. Zhang et al [17], by contrast, reported that TRPM2 knockout improves glucose tolerance (due to improved insulin sensitivity), but has no effect on basal glucose or insulin levels. The reason for the discrepancy between the two reports is unclear, but the finding that TRPM2 knockout improves insulin sensitivity suggests that TRPM2 channels could also be a potential target for T2D.…”

“…This model is thought to closely resemble human T1D because MLDS causes β-cell death by promoting DNA breakdown, PARP activation, T-cell-dependent immune reaction and cytokine-induced oxidative stress [34]. We injected wild-type and TRPM2-deficient mice (TRPM2 − / − ) [17,22] with MLDS or vehicle and followed changes in blood glucose levels as a marker of β-cell death. The results ( Figure 4A) show that, unlike the wild-type mice, TRPM2-deficient mice are markedly resistant to MLDS-induced hyperglycaemia.…”

“…Its activation thus can raise cytosolic Ca 2 + through extracellular entry and lysosomal release. The TRPM2 channel is proposed to play a dual role in β-cell physiology with modest TRPM2-mediated Ca 2 + elevation being implicated in glucose-stimulated insulin secretion [15,16], although the in vivo evidence in TRPM2-knockout mice is somewhat controversial [15,17]. However, strong activation of the channel causes excessive Ca 2 + elevation resulting in β-cell death [9,11,12,14,18].…”

Glucagon‑like peptide‑1 potentiates glucose‑stimulated insulin secretion via the transient receptor potential melastatin 2 channel

“…There are ~30 types of TRP channels that have been reported to be expressed on β-cells, including TRP vanilloid, TRP ankyrin, TRP canonical and TRP melastatin (TRPM) (6). Among these channels, TRPM2, a Ca 2+ -permeable channel, was demonstrated to be associated with glucose metabolism and insulin secretion, yet little is known about the underlying mechanisms of these associations (7).…”