Glucose Induces Mouse β-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor

Abstract

An important goal in diabetes research is to understand the processes that trigger endogenous β-cell proliferation. Hyperglycemia induces β-cell replication, but the mechanism remains debated. A prime candidate is insulin, which acts locally through the insulin receptor. Having previously developed an in vivo mouse hyperglycemia model, we tested whether glucose induces β-cell proliferation through insulin signaling. By using mice lacking insulin signaling intermediate insulin receptor substrate 2 (IRS2), we confirmed that hyperglycemia-induced β-cell proliferation requires IRS2 both in vivo and ex vivo. Of note, insulin receptor activation was not required for glucose-induced proliferation, and insulin itself was not sufficient to drive replication. Glucose and insulin caused similar acute signaling in mouse islets, but chronic signaling differed markedly, with mammalian target of rapamycin (MTOR) and extracellular signal–related kinase (ERK) activation by glucose and AKT activation by insulin. MTOR but not ERK activation was required for glucose-induced proliferation. Cyclin D2 was necessary for glucose-induced β-cell proliferation. Cyclin D2 expression was reduced when either IRS2 or MTOR signaling was lost, and restoring cyclin D2 expression rescued the proliferation defect. Human islets shared many of these regulatory pathways. Taken together, these results support a model in which IRS2, MTOR, and cyclin D2, but not the insulin receptor, mediate glucose-induced proliferation.

Pancreas regeneration

“…Some of these changes seem to improve β-cell function 90 , but they may broadly suppress the ability of β-cells to respond to proliferative stimuli. There is longstanding evidence that insulin and glucose, both of which are elevated in obesity or insulin resistance, may directly stimulate β-cell proliferation 91–93 . But it remains unclear whether these are the key signals that drive islet hyperplasia.…”

Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity

“…Activation of mTORC1 and S6K1 can inhibit insulin signaling in tissue culture or peripheral tissues (27,49,50), although the molecular mechanisms remain controversial (51). Degradation of IRS-2 proteins can be a key component (26), since IRS-2 is critical for β cell compensation to insulin resistance (52)(53)(54)(55)(56)(57). For the first time, to our knowledge, our results link the axis of glucose/Ca 2+ /Erk/mTORC1/S6K1/IRS-2/Akt in β cells in vivo and demonstrate it as one of the mechanisms underlying the failed β cell compensation in type 2 diabetes.…”

Nutrient regulation of pancreatic β-cell proliferation

“…However, this view has been challenged on a number of grounds [20]. Stamateris et al showed that exposure to insulin does not increase β-cell proliferation in either low or high glucose conditions in mouse islets ex vivo [21]. The authors also showed that mTOR signaling, a pivotal pathway controlling β-cell proliferation (see below), is strongly activated by glucose but not insulin.…”

“…The effects of LKB1 on β-cell proliferation are mediated, in part, by its phosphorylation/activation of AMPK, which in turn inhibits mTOR signaling. Glucose metabolism promotes mTOR signaling and rapamycin exposure abrogates the β-cell proliferative response [21]. mTOR complexes (mTORC) include the rapamycin sensitive, mTORC1, and insensitive, mTORC2.…”