1. Mechanisms behind impaired insulin secretion and exocytosis in type 2 diabetes – involvement of microRNAs and target proteins
The progression of Type 2 diabetes requires complex beta-cell adaption to meet the increasing demand to produce and secrete more insulin. MicroRNAs (miRNAs) are small non-coding RNAs that have the capacity to take part in such adaptions and expression of several miRNAs is changed prior to the diseased state. Hence, miRNAs can be used as potential biomarkers in prediction and diagnosis of diabetes and its complications and knowledge of the miRNA profile can be utilized for development of novel therapeutic tools. In this project we focus our studies on the following specific aims:
a. Perform detailed cellular analysis of pathways involved in miRNA-controlled regulation of insulin secretion and exocytosis.
b. Rescue of impaired insulin secretion and hyperglycemia using LNA antagomirs
c. Identify blood-based miRNAs that can be used as biomarkers of T2D.
2. CFTR in pancreatic islet cells – role in the development of Cystic fibrosis-related diabetes (CFRD)?
Cystic fibrosis-related diabetes (CFRD) is becoming increasingly common in adults with cystic fibrosis (CF), and is associated with a dramatically heightened morbidity and mortality. Yet the etiopathology of CFRD is large unknown. Observations show that CFRD often correlates with insulin deficiency and/or a significant lower first-phase insulin secretion (See e.g. Moran et al 2010) clearly indicating that other, beta-cell intrinsic factors, may play a causative role in CFRD. We have recently demonstrated that the CF transmembrane conductance regulator (CFTR) is expressed in human and mouse beta-cells and that cAMP-enhanced insulin secretion is reduced after inhibition of CFTR (Edlund et al 2014). We link CFTR to be involved in cAMP-dependent priming of insulin granules a process essential for first phase insulin secretion. We further suggest that CFTR act as a regulator of the calcium- activated chloride channel anoctamin 1 (ANO1). We hypothesize that CFTR is of importance for pancreatic islet alpha- and beta-cell functions, and that alterations in CFTR affect the ability of islets cells to control glucose homeostasis through impaired hormone secretion. In order to test this hypothesis we will use state-of the art techniques to investigate the involvement of CFTR in the control of hormone secretion.
3. Control of glucagon secretion and exocytosis involving alpha- cell enriched microRNAs
The mechanisms around alpha-cell stimulus secretion coupling and exocytosis in human islets and how impairments in this process develops and contributes to the pathogenesis of T2D is not fully understood. Neither is much known about alpha-cell specific microRNAs involved in regulation of glucagon secretion. The objective of this study is therefore to find alpha-cell enriched microRNAs involved in the regulation of glucagon release, to get a better understanding of basic mechanisms controlling alpha-cell physiology and utilize this knowledge to development novel disease therapeutics.
4. Other projects:
Swedish Research Council, ALF-Region Skåne, EFSD/Boehringer Ingelheim Basic Research Programme, Diabetes Foundation, Albert Påhlssons Foundation, Cystic Fibrosis Trust
87 original scientific articles cited >4700 times; H-index 35 and M-index 1.6 (22 years in research).
1. Edlund A, Esguerra JLS, Wendt A, Flodström-Tullberg, M and Eliasson L, CFTR and Anocatamin 1 (ANO1) contribute to cAMP amplified exocytosis and insulin secretion in human and murine pancreatic β-cells, BMC Medicine, 2014, 12:87 http://www.ncbi.nlm.nih.gov/pubmed/24885604
2. Eliasson L and Esguerra JL. Role of non-coding RNAs in pancreatic beta-cell development and physiology. Acta Physiol (Oxf). 2014 Jun;211(2):273-84. (review) http://www.ncbi.nlm.nih.gov/pubmed/24666639
3. Rosengren AH*, Braun M, Mahdi T, Andersson SA, Travers ME, Shigeto M, Zhang E, Almgren P, Ladenvall C, Axelsson A, Edlund A, Pedersen MG, Jonsson A, Ramracheya R, Tanga Y, Walker JN, Johnson PRV, Lyssenko V, McCarthy MI, Groop L, Salehi A, Gloyn A, Renström E, Rorsman P and Eliasson L, Reduced insulin exocytosis in human pancreatic beta-cells with gene variants linked to type-2 diabetes, Diabetes. Jul;61(7):1726-33, 2012 http://www.ncbi.nlm.nih.gov/pubmed/22492527
4. Esguerra JL*, Bolmesson C, Cilio CM and Eliasson L Impaired glucose regulation of microRNAs in the pancreatic islets of the non-obese type 2 diabetes model Goto-Kakizaki rat, PloS ONE, Apr 7;6(4):e18613, 2011 http://www.ncbi.nlm.nih.gov/pubmed/21490936
5. Poy MN, Eliasson L, Krützfeldt J, Kuwajima S, Ma X, MacDonald PE, Pfeffer S, Tuschl T, Rajewsky N, Rorsman P and Stoffel M, A pancreatic islet-specific microRNA regulates insulin secretion, Nature 432:226-230, 2004. http://www.ncbi.nlm.nih.gov/pubmed/15538371
6. Eliasson L, Ämmälä C, Renström E, Berggren P-O, Bertello A-M, Bokvist K, Chibalin A, Deeney J, Flatt PR, Gäbel J, Gromada J, Larsson O, Lindström P, Rhodes CJ and Rorsman P PKC-dependent stimulation of exocytosis by sulfonylureas in pancreatic b-cells, Science 271: 813-815, 1996 http://www.ncbi.nlm.nih.gov/pubmed/862899
Last updated: August 15, 2016
Website contact: LUDC webteam