Small Molecules for Treatment of Diabetes by Induction of Cellular Senescence

Ben-Porath Ittai, HUJI, School of Medicine - IMRIC, Developmental Biology and Cancer Research
Dor Yuval , HUJI, School of Medicine - IMRIC, Developmental Biology and Cancer Research


  • Enhancement of glucose-stimulated insulin secretion by pancreatic beta cells is a major therapeutic goal in diabetes.
  • Glucose tolerance deteriorates with age, reflecting reduced responsiveness of beta cells to glucose stimulation and reduced responsiveness of peripheral tissues to insulin. Beta cell proliferation declines dramatically at an early age, potentially contributing to a reduced beta cell mass and an increased risk of diabetes with age.
  • Cellular senescence is thought to contribute to age-associated deterioration of tissue hysiology. The senescence effector p16Ink4a is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized.

Our Innovation

A novel paradigm that enhanced glucose stimulated insulin secretion (GSIS) by forcing the senescence of pancreatic beta cells via the activation of the master regulator of senescence p16Ink4a.

  • The underlying mechanisms leads to increased cell size and increased mitochondrial activity which promotes increased insulin secretion.
  • Regulating normal functional tissue maturation with age.
  • Enable the generation of cells with the capacity to secrete high levels of insulin.


  • It was demonstrated that beta cell-specific activation of p16Ink4a in transgenic mice induce beta cells senescence and enhance glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis.
  • Furthermore, it was found that islets from human adults contain p16Ink4a -expressing senescent beta cells and that senescence induced by p16Ink4a in a human beta cell line increases GSIS in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins.


Fig. 1: p16Ink4a expression enhances insulin secretion, (a) Insulin levels secreted by islets isolated from indicated tet-treated mice and incubated in medium with low (2.8 mM) or high (16.7 mM) glucose concentrations for 1h. (b) Mean insulin levels secreted by islets from the indicated mice and assayed as in a. Secreted insulin levels were normalized to beta cell number in each sample and are shown relative to the value observed for control islets in medium with high glucose (defined as 1). (c) Insulin content in equal numbers of beta cells, sorted on the basis of GFP expression, from control (Ins2-rtTA;tet-GFP) or p16-expressing (Ins2-rtTA;tet-GFP;tet-p16) mice (n = 2 per group). Values are presented relative to those of the control (d) Glucose tolerance test of wild-type (WT, n = 2), Pdx1-tTA (n = 2) and Pdx1-tTA; tet-p16 (n = 4) mice following p16 activation for 2 weeks.


  • Various clinical approaches, including transplantation in diabetic patients, enhancement of insulin secretion by endogenous beta-cells and more.
  • Drugs for enhancement of insulin secretion       
  • Protocols for directed differentiation of stem cells to beta cells.



Contact for more information:

Mel Larrosa
VP Business Development Healthcare
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