Intracellular calcium channels: Potential targets for type 2 diabetes mellitus?

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder. Despite the availability of numerous pharmacotherapies, a range of adverse reactions, including hypoglycemia, gastrointestinal discomfort, and lactic acidosis, limits their patient applicability and long-term application. Therefore, it is necessary to screen novel therapeutic drugs for T2DM treatment that have high efficacy but few adverse effects. AMP-activated protein kinase (AMPK) stands out as one of the most powerful targets for T2DM treatment. It can be activated through energy-sensing or calcium signaling. Medications that activate AMPK through the energy-sensing mechanism exhibit remarkable potency, but they are accompanied by lactic acidosis, carrying an alarmingly high mortality rate. Interestingly, medications that activate AMPK through calcium signaling, such as gliclazide, seldom induce lactic acidosis. However, the efficacy of gliclazide is much lower than metformin. Therefore, it is necessary to explore targets that activate AMPK calcium signaling to avoid lactic acidosis while maintaining high potency. Ion channels are the main controller of intracellular calcium flow. Specific agonists and inhibitors targeting ion channels have been reported to activate AMPK. In this review, we will summarize the structure and function of calcium-permeable ion channels and discuss the potential of targeting these calcium channels for T2DM treatment.