IPMK modulates hepatic glucose production and insulin signaling

Abstract

Hepatic glucose production (HGP) is crucial for the maintenance of normal glucose homeostasis. Although hepatic insulin resistance contributes to excessive glucose production, its mechanism is not well understood. Here, we show that inositol polyphosphate multikinase (IPMK), a key enzyme in inositol polyphosphate biosynthesis, plays a role in regulating hepatic insulin signaling and gluconeogenesis both in vitro and in vivo. IPMK-deficient hepatocytes exhibit decreased insulininduced activation of Akt-FoxO1 signaling. The expression of messenger RNA levels of phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose 6-phosphatase (G6pc), key enzymes mediating gluconeogenesis, are increased in IPMK-deficient hepatocytes compared to wild type hepatocytes. Importantly, re-expressing IPMK restores insulin sensitivity and alleviates glucose production in IPMK-deficient hepatocytes.Moreover, hepatocyte-specific IPMK deletion exacerbates hyperglycemia and insulin sensitivity in mice fed a high-fat diet, accompanied by an increase in HGP during pyruvate tolerance test and reduction in Akt phosphorylation in IPMK deficient liver. Our results demonstrate that IPMK mediates insulin signaling and gluconeogenesis and may be potentially targeted for treatment of diabetes.

IPMK modulates FFA-induced insulin resistance in primary mouse hepatocytes

“…In this study, we investigated the hypothesis that IPMK plays a role in HFD-induced insulin resistance. IPMK protein levels were decreased in the liver tissues of mice fed HFD (Jung et al, 2022). Moreover, FFA treatment decreased IPMK protein in PMH in a concentration-and timedependent manner.…”

“…It has been shown that IPMK regulates insulin signaling in multiple cell types. We recently reported that the deletion of hepatic IPMK decreased insulin-mediated Akt signaling and aggravated HFD-induced insulin resistance and glucose intolerance (Jung et al, 2022). Moreover, we found a significant decrease in IPMK protein in the liver of insulin-resistant mice subjected to a High-fat diet (HFD) for a long-term period (Jung et al, 2022).…”

“…We recently reported that the deletion of hepatic IPMK decreased insulin-mediated Akt signaling and aggravated HFD-induced insulin resistance and glucose intolerance (Jung et al, 2022). Moreover, we found a significant decrease in IPMK protein in the liver of insulin-resistant mice subjected to a High-fat diet (HFD) for a long-term period (Jung et al, 2022). To examine whether a reduction in hepatic IPMK by HFD contributed to the induction of insulin resistance in mice, we investigated the effect of FFA on IPMK protein in primary mouse hepatocytes (PMH).…”

“…Recently, we have shown that IPMK plays an essential role in hepatic insulin signaling and whole-body glucose metabolism (Jung, Anokye-Danso, Jin, Ahima, & Kim, 2022). Our group reported that the expression of IPMK is decreased in the liver of HFD-fed mice, and loss of hepatic IPMK exacerbates glucose and insulin tolerance in HFD-fed mice compared to WT mice (Jung et al, 2022), indicating that IPMK is involved in the pathogenesis of Insulin resistance. The current work aimed to determine whether a change in IPMK contributes to FFA-induced insulin resistance in the primary hepatocytes.…”

Proinflammatory Polyphosphate Increases in Plasma of Obese Children with Insulin Resistance and Adults with Severe Type 2 Diabetes

“…On the other hand, inositol polyphosphates (InsPs) are another type of phosphate polymers which have recently been found to have strong metabolic connections with polyP [ 38 , 39 , 40 ]. Recently, enzymes of InsPs metabolism have been related to insulin signaling [ 41 ], insulin resistance, and type 2 diabetes [ 42 ]. Therefore, it is to be expected that differences in plasma polyP levels may be connected with InsPs metabolism.…”