Type 2 Diabetes: Has the Role of Sphingolipids been Deciphered?

Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis. Nature Cell Biology 2023

Model illustrating the role of very-long-chain sphingolipids (VLSLs) in insulin secretion. The processing of proinsulin to insulin is dependent on the enzyme PCSK1, which binds to the transport protein Tmed2. Tmed2 itself binds to VLSLs. During the development of beta cell dysfunction, the ratio of specific VLSLs to long-chain sphingolipids (LSLs) is altered, leading to insufficient availability of active PCSK1 in secretory granules and hence impaired insulin processing, which results in impaired glucose-stimulated insulin secretion (GSIS). © Bengt Belgardt, DDZ

The conversion of proinsulin to insulin in the beta cells of people with diabetes is impaired. In the journal Nature Cell Biology, researchers reported on possible causes: Among others, a loss of function of the CerS2 enzyme, which is responsible for the production of very-long-chain sphingolipids.

Sphingolipid metabolism disorder has previously been linked to obesity. These lipids are essential for almost all types of cells and membranes; however, their role in the beta cells (β cells) has, until now, been unclear.

Under the direction of Dr. Bengt-Frederik Belgardt of the Institute for Vascular and Islet Cell Biology at the German Diabetes Center, researchers in Dusseldorf, Cologne, and Munich, along with researchers from the German Centre for Diabetes Research (DZD), in collaboration with colleagues in Switzerland and Germany, among others, have produced new findings showing that sphingolipids play a crucial role in the processing of proinsulin.

In a type 2 diabetes mouse model, the researchers observed an imbalance affecting certain types of long-chain and very-long-chain sphingolipids in the pancreatic beta cells.

CerS2 Knockout Reduces Insulin Secretion
A potential cause of the observed imbalance is a reduction in ceramide synthase 2 (CerS2) activity. This enzyme is the most common ceramide synthase in human beta cells without diabetes and is necessary for the generation of very-long-chain sphingolipids (also known as VLSLs). If the enzyme stops being produced, this process ceases to function.

CerS2 knockout in the pancreatic beta cells of mice caused reduced insulin content in the beta cells, insulin secretion dysfunction, and glucose tolerance impairment. Furthermore, the reduction of the insulin-to-proinsulin ratio points to limited proinsulin processing.

Proinsulin Processing Depends on Sphingolipids
To gain in-depth insights into the mechanisms, the researchers investigated the various protein interactions. They identified the transport protein Tmed2 as being crucial during proinsulin conversion. Their hypothesis: The binding of sphingolipids with Tmed2 promotes the transport of the Pcsk1 enzyme to the insulin-secreting vesicles.

When the CerS2 enzyme is missing, this affects the binding of sphingolipids to Tmed2, among others, as well as the functioning of the enzyme Pcsk1, which is essential for proinsulin processing. These findings may partially explain the impaired proinsulin to insulin conversion observed in those with type 2 diabetes.


Original publication:
Kerstin Griess, Michael Rieck, Nadine Müller, Gergely Karsai, Sonja Hartwig, Angela Pelligra, Robert Hardt, Caroline Schlegel, Jennifer Kuboth, Celina Uhlemeyer, Sandra Trenkamp, Kay Jeruschke, Jürgen Weiss, Leon Peifer-Weiss, Weiwei Xu, Sandra Cames, Xiaoyan Yi, Miriam Cnop, Mathias Beller, Holger Stark, Arun Kumar Kondadi, Andreas S. Reichert, Daniel Markgraf, Marianne Wammers, Dieter Häussinger, Oliver Kuss, Stefan Lehr, Decio Eizirik, Heiko Lickert, Eckhard Lammert, Michael Roden, Dominic Winter, Hadi Al-Hasani, Doris Höglinger, Thorsten Hornemann, Jens C. Brüning & Bengt-Frederik Belgardt: Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis. Nature Cell Biology, 2023. DOI: 10.1038/s41556-022-01027-2