Neuroendocrine Cell biology
Frank Sundler, MD, PhD, Professor emeritus
Jan Hedenbro, MD, Associate Professor
Using gastric bypass surgery (GBP) to identify new T2D treatments
It is now generally accepted that GBP provokes remission of T2D in most (80%) cases. Therefore T2D patients undergoing GBP can be examined to identify preventive and curative processes in the disease. Glycemia is normalized prior to substantial weight loss. Hence, weight loss cannot account for remission of T2D. Using GBP patients with a gastrostomy catheter to the bypassed stomach and a porcine model of GBP, we showed that GBP has beneficial effects on metabolism independent of both weight loss and meal size. Furthermore, we have recently shown that meal size alone cannot account for exaggerated insulin and incretin responses after GBP. Interestingly, in pigs we showed that GBP led to improved glycemia, improved beta cell function and increased beta cell mass, despite identical body weight and food intake as in the control group.
Thus, the explanation of the anti-diabetic effect of GBP must be found in how the GI-tract interacts with the pancreatic islets, and the target tissues of insulin (liver, skeletal muscle, adipose tissue). Hitherto, the field has focused on changes in single hormones as mechanistic explanation for the remission of T2D after GBP, e.g. increased secretion of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) or reduced levels of the insulinostatic hormone ghrelin after GBP.
Although, we have provided anatomical explanation for these effects of GBP in humans and pigs, we believe that these single hormone-based theories are insufficient to explain the effects of GBP. Instead, an array of events acting in concert underlies the beneficial effects observed. If the mechanisms behind the remission were to be resolved new treatment regimens for T2D could be developed.
Specific aims: 1) Assess whether GBP-induced T2D remission is under genetic influence. 2) Compare immediate effects of GBP with that of food restriction. 3) Assess how GBP-induced microbiota alterations affect T2D remission and epigenetic regulation and gene expression in the gut. 4) Assess whether altered splanchnic blood flow is key to GBP-induced remission of T2D using PET-MRI.
Antidiabetic actions of CART
We have shown that CART is an important islet regulatory peptide and a constituent of human alpha- and beta cells. CART KO mice exhibit perturbed insulin secretion and glucose tolerance and CART augments glucose-stimulated insulin secretion (GSIS) and remarkably, CART further potentiates the insulinotropic effect of GLP-1. Furthermore, CART is a powerful inhibitor of glucagon secretion. Thus, CART is able to lower blood glucose both by enhancing insulin secretion and by reducing glucagon secretion. Furthermore, CART protects beta cells against glucotoxicity-induced cell death and CART is upregulated in islets of T2D patients and rodent models of T2D, as a response to hyperglycemia. Altogether these are properties that make CART-based agents highly interesting for treatment of T2D.
The yet unidentified CART receptor is a potential drug target for T2D therapy. Its identification would be an important step towards development of CART-based therapies. Our goal is to identify the CART-receptor and evaluate the potential for CART-based substances as a future treatment against T2D.
Single cell RNA sequencing of human islets
The islets are vital regulators of metabolism, but unbiased analysis of their cellular composition and gene regulatory networks at cell type specific level is lacking.
As a part of our larger effort to understand gene-regulation in normal and T2D islets we are mapping gene expression in transcriptionally defined cell types in human islets using single cell RNAseq. Cell-type specific gene expression will allow us to proceed with extraordinary precision and will lead to a major leap forward for understanding of islet biology and what fails in T2D. We have established a pipeline for single cell RNAseq of human islet cells and successfully sequenced >2000 cells from human donors. This resulted in a model comprising >10 distinct cell types, including cells expressing the major islet hormones. This model will be confirmed using multiple single molecule in situ hybridization and immunohistochemistry. In addition to sequencing more cells to resolve the rare populations and subpopulations, we address how our model is affected by T2D in terms of cell composition and gene-regulatory networks.
The project is a collaboration between the Wierup group and a laboratory at the fore front of single cell sequencing technology (http://www.hjerling-leffler-lab.org/) and has the potential to shift our understanding of the cellular basis for T2D.