Stellan Sandler

Mechanisms of destruction and repair/regeneration of insulin-producing cells in type 1 diabetes.

The prevailing view is that an autoimmune reaction selectively destroys the insulin-producing ß-cells in the pancreas in type 1 diabetes (T1DM). The aim of this project is to investigate cellular and molecular mechanisms involved in pancreatic ß-cell damage and repair in this disease. We postulate that after certain types of damage ß-cell function can be restored (Fig. 1). Furthermore, we believe that the ß-cell is not a passive victim during a situation of potentially harmful exposure, but depending on gene expression and functional activity of the ß-cell, the outcome can be affected. The aims of the present research projects are to investigate cellular and molecular mechanisms involved in pancreatic ß-cell damage and repair in T1DM

Fig. 1. Schematic view of the ß-cell outcome following different immunologic or toxic assaults. In fetal and neonatal life, ß-cell replication is increased, but later it becomes restricted. After birth ß-cells acquire the full capacity to synthesise and release insulin (speckled symbols) upon appropriate stimuli. At one or several occasions in life, ß-cells in some individuals are subject to damage (irregular arrows) which will lead to suppressed ß-cell function and a reduction in insulin secretion. Depending on the genetic predisposition an autoimmune reaction will be launched which in certain individuals will cause extensive cell death leading to type 1 diabetes. In other individuals ß-cells will survive, but their secretory function is impaired, which may have consequences for the glucose homeostasis. In some other individuals the ß-cells may completely recover and the glucose tolerance will only be transiently disturbed. The latter outcome is most likely also dependent on genes regulating ß-cell resistance to damage and ß-cell repair.

Topics we are currently investigating:

  • Evaluation of cytokine traps in experimental T1DM.
  • Mitochondrial targeted preconditioning, using KATP-channel openers (KCO), to rescue ß-cells against acute destruction
  • Kinetics of the regulatory T cell response in T1DM in mice
  • Studies of bank voles developing diabetes.
  • Mechanisms of statin protection against murine T1DM.

Example of findings and hypopthesis

Mechanism of mitochondrial KATP channel opening and ß-cell protection, cf topic B,

Fig. 2. NNC 55-0321 acutely down-regulates mitochondrial function. A lowered respiratory chain activity is accompanied by increased ROS production, PKCe activation and phosphorylation of the survival promoting kinase Akt. Inhibition of mitochondrial function by NNC 55-0321 may be caused by opening of a mitochondrial potassium channel (mKATP), which promotes K+ entry from the intermembrane space (IMS) into the mitochondrial matrix (M), thereby increasing pH and inhibiting the respiratory chain (I). Alternatively, NNC 55-0321 can directly inhibit mitochondrial respiration independently of the presence of and conductance in an mKATP (II). NNC 55-0462 primarily acts on the plasma membrane bound KATP channel and causes inhibition of insulin secretion by preventing depolarization of the plasma membrane, but this does not provide protection against ß-cell damage. From Sandler et al. Biochem Pharmacol 76:1748-1756 (2008)


The aims of the present research projects are to investigate cellular and molecular mechanisms related to pancreatic ß-cell damage and repair in T1DM, and in some cases probably also in T2DM. It is anticipated that a deeper knowledge of these issues will lead to new strategies for intervention in the autoimmune ß-cell destructive processes, as well as novel methods to enhance ß-cell resistance against direct cytotoxic damage. We hope that by studying cell signaling and the mechanisms leading to ß-cell death, it will be able possible to elucidate which factors that are crucial for ß-cell survival and possibly indentify candidate genes/proteins conferring ß-cell susceptibility or resistance to destruction in T1DM.


For further information about this research group please contact
Professor Stellan Sandler: