Type 2 diabetes affects more than 500 million people worldwide. In a new study, researchers from Weill Cornell Medical College in the United States found a new pathway that stimulates insulin production in the preclinical diabetes model for healthy pancreas β cell growth. This discovery brings hope for future treatment, which will improve the life of patients with type 2 diabetes. The relevant research results have recently been published in the Journal of Clinical Investigation, titled “Noncanonical CDK4 signaling rescues diabetes in a mouse model by promoting β cell differentiation”.
Dr. Laura Alonso, Director of the Center for Metabolic Health at Will Cornell Medical School, said, “This is reassuring because the field has long believed that cell proliferation leads to ‘dedifferentiation’ and loss of cell function. Our research findings go against this dogma, indicating that if we can find a way to trigger the replication of β cells in vivo, it will not impair their ability to produce and secrete insulin.”
When β cells fail
Type 2 diabetes is usually associated with obesity, and body tissues will be resistant to insulin, which means that they cannot absorb and use blood sugar. At the same time, insulin is produced in the pancreas β cells also fail – their numbers decrease and their function is lost.
Dr. Alonso and her colleagues reproduced these situations in a diabetes mouse model lacking IRS2, a protein that allows insulin to transmit signals to cells to absorb blood sugar. These mice showed insulin resistance, which is an important feature of human type 2 diabetes. Dr. Alonso said, “In addition, the IRS2 protein impacts β cellular function and the number of β cells”.
The primary task of rescuing these mice is to improve the number of β cells. But how to do it? She and her team carefully studied the molecular mechanisms that control cell proliferation. They observed that in IRS-deficient diabetes mice, β cells failed to increase the production of cyclin D2. After pairing with a protein called CDK4, this protein can drive cell division. Previous studies have shown that mice lacking CDK4 also develop diabetes. Based on this, testing whether increasing the activity of CDK4 helps to increase the number of β cells seems logical.
β Cell proliferation – quantity and quality
When Dr. Alonso and her research team introduced an active form of CDK4 (which is more easily attached to cyclin D2) to these diabetes mice through genetic means, the first thing they noticed was that their blood sugar returned to normal. Compared to untreated IRS2 mutant mice, their number of the β cells has increased.
Dr. Alonso said, “But even better, the β cells of these treated mice look very healthy, while the β cells of the original diabetes mice look very bad. Improving the activity of CDK4 can make β cells filled with insulin. This supports the concept that expanding the β cell quantity without affecting functionality.”
Although CDK4 itself is not a feasible therapeutic target as its ability to stimulate cell proliferation may increase the risk of cancer, Dr. Alonso believes that exploring the molecular pathways involved in β cell division and function may one day lead to clinical breakthroughs.
She mentioned Ozempic, one of the most concerned new anti-diabetes drugs. Dr. Alonso said, “This drug was discovered by a scientist when he studied the toxin in the saliva of the Gila monster. Therefore, it is clear that understanding the working principle of basic biology can bring real progress in the treatment and even prevention of diabetes.”
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Reference
Rachel E. Stamateris et al. Noncanonical CDK4 signaling rescues diabetes in a mouse model by promoting β cell differentiation. Journal of Clinical Investigation, 2023, doi:10.1172/JCI166490.