Commiphora myrrha stimulates insulin secretion from β-cells through activation of atypical protein kinase C and mitogen-activated protein kinase

Insulin secretion is a process that is highly regulated and controlled by various effectors. Increasing cytosolic calcium (Ca2+) and protein kinase activation play important roles in insulin-stimulus secretion coupling. Glucose and other nutrients stimulate insulin secretion primarily through an ATP-sensitive potassium (KATP) channel-dependent pathway. When glucose enters β-cells, it is metabolized rapidly, generating adenosine triphosphate (ATP), which closes KATP channels, resulting in depolarization of β-cells and opening of voltage gated Ca2+ channels (VGCC). Opening of VGCC results in Ca2+ influx, elevation of intracellular Ca2+ ([Ca2+]i) and insulin exocytosis (Howell, 1984; Rutter et al., 2015; Yang and Berggren, 2006).

Non-nutrients can also potentiate insulin secretion through receptor-mediated generation of second messengers and activation of protein kinases (Howell, S. et al., 1994; Jones and Persaud, 1998). Protein kinase C (PKC) is an important signaling pathway involved in the stimulation and augmentation of insulin secretion. There are three different classifications and multiple isoforms of PKC: typical PKCs (PKCα, β1, β2, γ), novel PKCs (δ, ε, η, θ) and atypical PKCs (ι, ζ) (Fleming and Storz, 2017; Knutson and Hoenig, 1994). These PKCs also differ in their upstream activators. Typical PKC isoforms require Ca2+ and diacylglycerol (DAG) for activation. The release of Ca2+ and generation of DAG is mainly mediated by phospholipase C (PLCβ), which hydrolyses phosphatidylinositol bisphosphate (PIP2) to generate inositol trisphosphate (IP3), which increases Ca2+ release from intracellular stores, and DAG. Novel PKCs require DAG but not Ca2+ for activation. On the other hand, atypical PKC isoforms such as PKC iota (PKCι) and PKC zeta (PKCζ) require neither Ca2+ nor DAG for activation. Instead, they are activated by phosphatidylserine (Howell et al., 1990; Jones and Persaud, 1998).

Phosphorylation of Akt (protein kinase B), via activation of phosphoinositide 3-kinase (PI3K), can stimulate insulin secretion from β-cells (Huang et al., 2018).

Another well-known signaling pathway in β-cells is protein kinase A (PKA). Adenylate cyclase (AC) generates cyclic adenosine monophosphate (cAMP) from ATP, which in turn, amplifies the stimulus signal through PKA-dependent pathways (Furman et al., 2010; Seino and Shibasaki, 2005). Calcium-calmodulin dependent protein kinase II (CaMKII) has also been reported to stimulate insulin secretion (Jones and Persaud, 1998). Mitogen-activated protein kinases (MAPK), specifically extracellular signal-regulated kinases (ERK1/2), have also been implicated in the stimulation of insulin synthesis and secretion (Ikushima et al., 2021; Khoo et al., 2004; Lawrence et al., 2005, 2008).

The use of plant extracts in the management of type 2 diabetes mellitus (T2DM) is on the rise. We have recently been working on a promising plant named Commiphora myrrha (CM). The resin of CM, which is a reddish-brown material that is produced upon injury of the stem of the plant, is considered a very important herbal remedy in northeastern Africa, Asia and the Middle East for the treatment of DM (Al-Rowais, 2002; Ali-Shtayeh et al., 2012; Alsanad et al., 2018; Ashur et al., 2017; Bakhotmah and Alzahrani, 2010; Garrow and Egede, 2006). In vivo animal studies showed that administration of aqueous CM resin extract raised plasma insulin levels and reduced blood glucose concentrations in streptozotocin (STZ)-treated rats, a lean animal model of diabetes (Helal et al., 2005; Moustafa et al., 2009; Salama et al., 2014) and in db/db mice, an obese animal model of diabetes (Ubillas et al., 1999). In addition, oral intake of CM (in combination with other herbs) improved symptoms of DM in diabetic women in a placebo-controlled clinical trial (Shokoohi et al., 2017).

We have previously reported that CM resin directly stimulated insulin secretion in vitro from MIN6 cells and isolated mouse and human islets without compromising plasma membrane integrity or cell viability (Al-Romaiyan et al., 2020). However, the underlying mechanism(s) or signaling pathway(s) by which CM extract induced insulin secretion remain unknown. CM could stimulate insulin secretion by opening VGCC or activating kinases or both. Therefore, in this study, we investigated and elucidated the possible intracellular key effectors involved in CM-induced insulin secretion in β-cell lines and primary islets.

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