Metabolic control of insulin secretion
Principal investigator; Mulder, Hindrik, Associate Professor, MD/PhD
Clinical speciality: Endocrinology and diabetology
Diabetes Mellitus is caused by deficient insulin secretion from pancreatic beta-cells. Thorough knowledge of how insulin secretion is controlled is a pre-requisite to prevent the disease or to devise therapies restoring insulin secretion. It is widely embraced that fuel metabolism in pancreatic beta-cells controls secretion of the hormone. We examine regulation of metabolic processes and pathways in beta-cells that exert this control over insulin secretion, and whether they are perturbed in Type 2 Diabetes.
We analyze and manipulate fuel metabolism in clonal insulin-producing cells and animal models. Findings from large-scale genetic analyses guide us in choosing targets for our analysis. Mitochondrial function is of particular interest. It plays a key role in beta-cells to regulate insulin secretion and beta-cell mass. Specifically, we have examined the role of TFB1M. It was originally identified as a transcription factor in mitochondria. Now, it is thought to act as an adenosine dimethyl-transferase, controlling translation of proteins in mitochondria. We have shown that a variant of TFB1M is associated with Type 2 Diabetes. The pathogenetic process appears to be perturbation of oxidative phosphorylation due to deficient mitochondrial protein synthesis in beta-cells. Consequently, insulin secretion is impaired. To investigate metabolism in a global and unbiased fashion, we have developed a metabolomics approach. Metabolites are extracted from clonal beta-cells, islets or plasma, separated by gas chromatography and identified/quantified by mass spectrometry. Many glycolytic and TCA cycle intermediates have been quantified in extracts from beta-cells cultured under different conditions. This approach recently revealed an unexpected regulatory role of the pentose phosphate pathway in control of insulin secretion. Currently, we are building a database of metabolite responses in human islets exposed to low and high glucose. The data will be included in a comprehensive systems biology analysis of pathogenic processes leading to Type 2 Diabetes, including data on genetic variants (GWAS) and mRNA sequence and abundance (microarray and RNA sequencing).
Link to project homepage: http://www.ludc.med.lu.se/research-units/molecular-metabolism/
5 recent original publications
Koeck Thomas, Olsson Anders H, Dekker Nitert Marloes, Sharoyko Vladimir, Ladenvall Claes, Kotova Olga, Reiling Erwin, Rönn Tina, Parikh Hemang, Taneera Jalal, Eriksson Johan, Metodiev Metodi D, Larsson Nils-Göran, Balhuizen Alexander, Luthman Holger, Stančáková Alena, Kuusisto Johanna, Laakso Markku, Poulsen Pernille, Vaag Allan, Groop Leif, Lyssenko Valeriya, Mulder Hindrik, Ling Charlotte
A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.
Cell metabolism. 2011; 13: 80 - 91
Spégel Peter, Malmgren Siri, Sharoyko Vladimir, Newsholme Philip, Köck Thomas, Mulder Hindrik
Metabolomic analyses reveal profound differences in glycolytic and tricarboxylic acid cycle metabolism in glucose-responsive and -unresponsive clonal beta-cell lines
Biochemical Journal. 2011; 435: 277 - 284
Krus Ulrika, Kotova Olga, Spégel Peter, Hallgard Elna, Sharoyko Vladimir, Vedin Anna, Moritz Thomas, Sugden Mary C., Köck Thomas, Mulder Hindrik
Pyruvate dehydrogenase kinase 1 controls mitochondrial metabolism and insulin secretion in INS-1 832/13 clonal beta-cells
Biochemical Journal. 2010; 429: 205 - 213
Malmgren Siri, Nicholls David G, Tanera Jalaal, Bacos Karl, Tamaddon Ashkan, Wibom Rolf, Groop Leif, Ling Charlotte, Mulder Hindrik, Sharoyko Vladimir V
Tight coupling between glucose and mitochondrial metabolism is required for robust insulin secretion in clonal -cells
Journal of Biological Chemistry. 2009; 284: 32395-404
Fex Malin, Haemmerle G, Wierup Nils, Dekker Nitert Marloes, Rehn M, Ristow M, Zechner R, Sundler Frank, Holm Cecilia, Eliasson L, Mulder Hindrik
A beta cell-specific knockout of hormone-sensitive lipase in mice results in hyperglycaemia and disruption of exocytosis.
Diabetologia. 2009; 52: 271-80
Further publications here (new window)
|Total financing:||5.5 MSEK||Gov grant for clinical research ("ALF"):||2.0 MSEK|
|Total external financing:||2.5 MSEK||Natl and intl prioritized grants:||1.0 MSEK|