Molecular pathology of pancreatic diseases

By Anders Molven, Gade Laboratory for Pathology, University of Bergen, Norway

The pancreas serves both exocrine and endocrine functions in the body. Most of the organ’s mass consists of acinar and ductal cells, the exocrine tissue that produces digestive enzymes and delivers them to the alimentary tract. The endocrine cells are found in the islets of Langerhans, which are dispersed as small, bead-like structures throughout the pancreas. The islets secrete the glucose-regulating peptides insulin and glucagon and other hormones.

The pancreas is central in the pathogenesis of diabetes, a very common disorder with increasing prevalence worldwide and where chronically high blood sugar is the hallmark. Acute and chronic inflammations constitute another group of pancreatic disorders. The third main group is pancreatic cancer which is a very serious disease as it can be cured only in few patients. Hence, pancreatic cancer is now the fourth leading cause of cancer deaths in the Western world although tumors occur much more frequently in many other organs of the body.

We study both endocrine and exocrine diseases of the pancreas at the molecular level. The research is divided into four main projects:

1) Molecular mechanisms in pancreatic adenocarcinoma
2) Carboxyl ester lipase in chronic pancreatitis and MODY8
3) Genetics of congenital hyperinsulinism of infancy
4) Causes of monogenic diabetes

Potential master, PhD and exchange students are welcome to contact our group at any time.

Our research group in Bergen, Norway hosted the 51st Annual Meeting of the European Pancreatic Club in June 2019. There were 670 participants from over 40 different countries. The program booklet can be downloaded here: EPC2019

We have published a review in Pancreatology on the CEL gene in pancreatic diseases. It can be accessed here. To see all publications by A. Molven, click here:               

Our research is or has been supported by

• Research Council of Norway
• Novo Nordisk Fonden
• Norwegian Cancer Society
• Western Norway Regional Health Authority
  
• Stiftelsen Kristian Gerhard Jebsen
  

The most common – but unfortunately also most serious – type of cancer in the pancreas is denoted pancreatic ductal adenoarcinoma. In this project, we aim at identifying and examining new molecular markers for this tumor type. The goal is to obtain a better understanding of how pancreatic ductal adenoarcinomas arise and grow. We have previously isolated the tumor cells by laser microdissection and analyzed them for mutations in the genes KRAS, BRAF and EGFR. Moreover, we studied the expression pattern of the postulated stem cell markers CD133 and CD44 in normal and cancerous pancreatic tissue. More recent projects have focused on how the gene ABO (determining blood type) may be implicated in pancreatic cancer and on the implications of those genetic alterations that are detected in pancreatic juice sampled directly from patients. Currently, we are aiming to develop a novel mouse model for pancreatic cancer based on mutations in the CEL gene, which encodes the digestive enzyme carboxyl ester lipase.

CD133 expression (brown) in normal pancreatic tissue.
The protein is expressed in acini centers and on the internal
surface of small ducts. The red area is an islet of Langerhans.

CD133 expression (brown) in pancreatic cancer. The
protein is strongly expressed on the internal surface
of duct-like structures formed by the cancer cells.

Current participants / major collaborators

Researcher Karianne Fjeld, Gade Laboratory for Pathology, UoBergen
PhD student Renate V. Seierstad, Gade Laboratory for Pathology, UoBergen
Master student Silje H. Johansen, Gade Laboratory for Pathology, UoBergen
Senior technician Solrun Steine, Gade Laboratory for Pathology, UoBergen
Dr. Marjolein Liedenbaum, Department of Radiology, Haukeland Univ. Hospital
Professor Ingfrid S. Haldorsen, Department of Clinical Medicine, UoBergen
Researcher Ivonne Regel, Dept. of Medicine, University Hospital LMU Munich, Germany
Professor Nils Halberg, Department of Biomedicine, UoBergen
Professor Oddmund Nordgård, Stavanger University Hospital/University of Stavanger
Professor Caroline S. Verbeke, Department of Pathology, University of Oslo

From 2020, we are part of the National Group of Expertise for Research on Pancreatic Cancer, funded by the Norwegian Cancer Society and led by Professor Caroline S. Verbeke, University of Oslo.

Publications

Brekke RS, Gravdal A, El Jellas K, Curry GE, Lin J, Wilhelm SJ, Steine SJ, Mas E, Johansson S, Lowe ME, Johansson BB, Xiao X, Fjeld K & Molven A (2024). Common single-base insertions in the VNTR of the carboxyl ester lipase (CEL) gene are benign and also likely to arise somatically in the exocrine pancreas. Human Molecular Genetics 33: 1001-1014.

Musiime M, Erusappan PM, Cukierman E, Chang J, Molven A, Hansen U, Zeltz C & Gullberg D (2024). Fibroblast integrin α11β1 is a collagen assembly receptor in mechanoregulated fibrillar adhesions. Matrix Biology 134: 144-161.

Tjensvoll K, Lapin M, Gilje B, Garresori H, Oltedal S, Forthun RB, Molven A, Rozenholc Y & Nordgård O (2022). Novel hybridization- and tag-based error-corrected method for sensitive ctDNA mutation detection using ion semiconductor sequencing. Scientific Reports 12: 5816.

Liu XZ, Rulina A, Choi MH, Pedersen L, Lepland J, Takle ST, Madeleine N, Peters SD, Wogsland CE, Grøndal SM, Lorens JB, Goodarzi H, Lønning PE, Knappskog S, Molven A & Halberg N (2022). C/EBPB-dependent adaptation to palmitic acid promotes stemness in hormone receptor negative breast cancer. Nature Communications 13: 69.

Choi MH, Tjora E, Forthun RB, Engjom T, Ræder H, Hovland R & Molven A (2021). KRAS mutation analysis by droplet digital PCR of duodenal juice from patients with MODY8 and other pancreatic diseases. Pancreatology 21: 1460-1465.

Shafiee S, Gelebart P, Popa M, Hellesøy M, Hovland R, Forthun RB, Lee J, Tohyama K, Molven A, Parekkadan B, Gjertsen BT, Kittang AO & McCormack E (2021). Preclinical characterisation and development of a novel myelodysplastic syndrome-derived cell line. British Journal of Haematology 193: 415-419.

Pedersen L, Panahandeh P, Siraji M, Knappskog S, Lønning PE, Zhu Q, Gordillo R, Scherer P, Molven A, Teigen K & Halberg N (2020). Golgi-localized PAQR4 mediates anti-apoptotic ceramidase activity in breast cancer. Cancer Research 80: 2163-2174.

Choi MH, Mejlænder-Andersen E, Manueldas S, El Jellas K, Steine SJ, Tjensvoll K, Sætran HA, Knappskog S, Hoem D, Nordgård O, Hovland R & Molven A (2019). Mutation analysis by deep sequencing of pancreatic juice from patients with pancreatic ductal adenocarcinoma. BMC Cancer 19: 11.

Zeltz C, Alam J, Liu H, Erusappan PM, Hoschuetzky H, Molven A, Parajuli H, Cukierman E, Costea DE, Lu N & Gullberg D (2019). α11β1 integrin is induced in a subset of cancer-associated fibroblasts in desmoplastic tumor stroma and mediates in vitro cell migration. Cancers (Basel) 11: 6.

El Jellas K, Johansson BB, Fjeld K, Antonopoulos A, Immervoll H, Choi MH, Hoem D, Lowe ME, Lombardo D, Njølstad PR, Dell A, Mas E, Haslam SM & Molven A (2018). The mucinous domain of pancreatic carboxyl-ester lipase (CEL) contains core 1/core 2 O-glycans that can be modified by ABO blood group determinants. Journal of Biological Chemistry 293:19476-19491.

El Jellas K, Hoem D, Hagen KG, Kalvenes MB, Aziz S, Steine SJ, Immervoll H, Johansson S, Molven A (2017). Associations between ABO blood groups and pancreatic ductal adenocarcinoma: influence on resection status and survival. Cancer Medicine 6: 1531-1540.

Dalva M, El Jellas K, Steine SJ, Ringdal M, Torsvik J, Immervoll H, Lerch MM, Johansson BB, Hoem D, Johansson S, Njølstad PR, Weiss U, Fjeld K & Molven A (2017). Copy number variants and VNTR length polymorphisms of the carboxyl-ester lipase (CEL) gene as risk factors in pancreatic cancer. Pancreatology 17: 83-88.

Calatayud D, Dehlendorff C, Boisen MK, Hasselby JP, Schultz NA, Werner J, Immervoll H, Molven A, Hansen CP & Johansen JS (2017). Tissue microRNA profiles as diagnostic and prognostic biomarkers in patients with resectable pancreatic ductal adenocarcinoma and periampullary cancers. Biomarker Research 5: 8.

Pettersen K, Andersen S, Degen S, Tadini V, Grosjean J, Hatakeyama S, Tesfahun AN, Moestue S, Kim J, Nonstad U, Romundstad PR, Skorpen F, Sørhaug S, Amundsen T, Grønberg BH, Strasser F, Stephens N, Hoem D, Molven A, Kaasa S, Fearon K, Jacobi C & Bjørkøy G (2017). Cancer cachexia associates with a systemic autophagy-inducing activity mimicked by cancer cell-derived IL-6 trans-signaling. Scientific Reports 7: 2046.

Dimcevski G, Kotopoulis S, Bjånes T, Hoem D, Schjøtt J, Gjertsen BT, Biermann M, Molven A, Sørbye H, McCormack E, Postema M & Gilja OH (2016). A human clinical trial using ultrasound and microbubbles to enhance treatment of inoperable pancreatic cancer. Journal of Controlled Release 243: 172-181.

Hoem D, Straume O, Immervoll H, Akslen LA & Molven A (2013). Vascular proliferation is associated with survival in pancreatic ductal adenocarcinoma. APMIS 121: 1037-1046.

Immervoll H, Hoem D, Steffensen OJ, Miletic H & Molven A (2011). Visualization of CD44 and CD133 in normal pancreas and pancreatic ductal adenocarcinomas: Non-overlapping membrane expression in cell populations positive for both markers. Journal of Histochemistry & Cytochemistry 59: 441-455.

Hoem D, Jensen D, Steine S, Thorsen TE, Viste A & Molven A (2008). Clinicopathological characteristics and non-adhesive organ culture of insulinomas. Scandinavian Journal of Surgery 97: 42-49.

Immervoll H, Hoem D, Sakariassen PØ, Steffensen OJ & Molven A (2008). Expression of the “stem cell marker” CD133 in pancreas and pancreatic ductal adenocarcinomas. BMC Cancer 8: 48.

Wang J, Sakariassen PØ, Tsinkalovsky O, Immervoll H, Bøe SO, Svendsen A, Prestegarden L, Røsland G, Thorsen F, Stuhr L, Molven A, Bjerkvig R & Enger PØ (2008). CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells. International Journal of Cancer 122: 761-768.

Søreide K, Immervoll H & Molven A (2006). Pancreatic intraepithelial neoplasia – precursors to pancreatic cancer. Tidsskrift for Den Norske Lægeforening 126: 905-908. [in Norwegian]

Immervoll H, Hoem D, Kugarajh K, Steine S & Molven A (2006). Molecular analysis of the EGFR-RAS-RAF pathway in pancreatic ductal adenocarcinomas: Lack of mutations in the BRAF and EGFR genes. Virchows Archiv  448: 788-796.

• American Pancreatic Association

• Animated Pancreas Patient

• Beta Cell Biology Consortium

• Catalogue of Somatic Mutations in Cancer (COSMIC)

• European Pancreas Center, Heidelberg

• European Pancreatic Club

• Human Islet Research Network

• Hungarian Pancreatic Study Group

• International Association of Pancreatology

• PancreasFest (annual pancreatology conference in Pittsburgh)

• Pancreapedia

• Pancreas Academy (highly recommended)

• Pancreas (Official journal of the American Pancreatic Association)

• Pancreatology (Official journal of the Int. Assoc. of Pancreatology)

• Pancreatic Cancer Action (UK)

• Pancreatic Cancer Action Network (USA)

• Pancreatic Cancer Europe

• Pancreatic Cancer Network Norway (in Norwegian)

• Pancreatic Cancer Pages at the National Cancer Institute, USA

• Pancreatic Cancer / Pancreas Basics (Johns Hopkins, USA)

• Pancreatic Cell News 

Diabetes can be divided into several subtypes. The two most common are type 1 and type 2 diabetes. In some cases, the disease is inherited as a monogenic disorder denoted “maturity-onset diabetes of the young” (MODY), of which there are at least ten variants. We are studying Norwegian MODY families with the aim to identify their mutations and to understand the biological effects of the affected proteins by performing functional analyses. Examples of our research results are our discoveries that mutations in the insulin gene (INS) can cause MODY and that disturbed insulin signaling may lead to a syndrome of lipodystrophy, short stature and insulin resistance. We have a special interest in MODY8, the MODY type caused by mutations in the carboxyl ester lipase (CEL) gene.

Cells with normal (left) and mutant (right) HNF1-alpha protein, which causes MODY3 or

HNF1A-MODY. Normally, the protein is present in the nucleus only. The mutant form

accumulates in the cytoplasm.

Participants / collaborators

About 30 persons at the University of Bergen and Haukeland University Hospital participate in this research effort, which is lead by profs. Pål R. Njølstad and Stefan Johansson at the Section for Pediatrics, Department of Clinical Science. The projects involve extensive international collaboration and were performed under the auspices of the KG Jebsen Center for Diabetes Research (2012-2018), which now is continued as the Bergen Center for Diabetes Research.

Publications

Gravdal A, Wilhelm SJ; CEL-MODY Mouse Project; Lowe ME, Molven A, Xiao XK & Fjeld K. (2025). The MODY-causing mutation of the human carboxyl ester lipase gene (CEL) triggers chronic pancreatitis but not diabetes in mice. Gastroenterology (in press).

Svalastoga P, Kaci A, Molnes J, Solheim MH, Johansson BB, Krogvold L, Skrivarhaug T, Valen E, Johansson S, Molven A, Sagen JV, Søfteland E, Bjørkhaug L, Tjora E, Aukrust I & Njølstad PR (2023). Characterization of HNF1A variants in paediatric diabetes in Norway using functional and clinical investigations to unmask phenotype and monogenic diabetes. Diabetologia 66: 2226-2237.

El Jellas K, Dušátková P, Haldorsen IS, Molnes J, Tjora E, Johansson BB, Fjeld K, Johansson S, Průhová Š, Groop L, Löhr J-M, Pål R. Njølstad PR & Molven A (2022). Two new mutations in the CEL gene causing diabetes and hereditary pancreatitis: How to correctly identify MODY8 cases. Journal of Clinical Endocrinology & Metabolism 107: e1455-1466.

Althari A, Najmi LA, Bennett AJ, Aukrust I, Rundle JK, Colclough K, Molnes J, Kaci A, Nawaz S, van der Lugt T, Hassanali N, Mahajan A, Molven A, Ellard S, McCarthy MI, Bjørkhaug L, Njølstad PR & Gloyn AL (2020). Unsupervised clustering of missense variants in HNF1A using multidimensional functional data aids clinical interpretation. American Journal of Human Genetics 107: 670-682.

Helgeland Ø, Vaudel M, Júlíusson PB, Holmen OL, Juodakis J, Bacelis J, Jacobsson B, Lindekleiv H, Hveem K, Lie RT, Knudsen GP, Stoltenberg C, Magnus P, Sagen JV, Molven A, Johansson S & Njølstad PR (2019). Genome-wide association study reveals dynamic role of genetic variation in infant and early childhood growth. Nature Communications 10: 4448.

Solheim MH, Winnay JN, Batista TM, Molven A, Njølstad PR & Kahn CR (2018). Mice carrying a dominant-negative human PI3K mutation are protected from obesity and hepatic steatosis but not diabetes. Diabetes 67: 1297-1309.

Sagen JV, Bjørkhaug L, Haukanes BI, Grevle L, Molnes J, Nedrebø BG, Søvik O, Njølstad PR, Johansson S & Molven A (2017). The HNF1A mutant Ala180Val: Clinical challenges in determining causality of a rare HNF1A variant in familial diabetes. Diabetes Research and Clinical Practice 133: 142-149.

Solheim MH, Clermont AC, Winnay JN, Hallstensen E, Molven A, Njølstad PR, Rødahl E & Kahn CR (2017). Iris malformation and anterior segment dysgenesis in mice and humans with a mutation in PI 3-kinase. Investigative Ophthalmology & Visual Science 58: 3100-3106.

Johansson BB, Irgens HU, Molnes J, Sztromwasser P, Aukrust I, Juliusson PB, Søvik O, Levy S, Skrivarhaug T, Joner G, Molven A, Johansson S & Njølstad PR (2017). Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry. Diabetologia 60: 625-635.

Najmi LA, Aukrust I, Flannick J, Molnes J, Burtt N, Molven A, Groop L, Altshuler D, Johansson S, Bjørkhaug L & Njølstad PR (2017). Functional investigations of HNF1A identify rare variants as risk factors for type 2 diabetes in the general population. Diabetes 66: 335-346.

Winnay JN, Solheim MH, Dirice E, Sakaguchi M, Noh HL, Kang HJ, Takahashi H, Chudasama KK, Kim JK, Molven A, Kahn CR & Njølstad PR (2016). PI3-kinase mutation linked to insulin and growth factor resistance in vivo. Journal of Clinical Investigation 126: 1401-1412

Irgens HU, Fjeld K, Johansson BB, Ringdal M, Immervoll H, Leh S, Søvik O, Johansson S, Molven A & Njølstad PR (2015). Glycogenin-2 is dispensable for liver glycogen synthesis and glucagon-stimulated glucose release. Journal of Clinical Endocrinology & Metabolism 100: E767-775.

Helgeland Ø, Hertel JK, Molven A, Ræder H, Platou CG, Midthjell K, Hveem K, Nygård O, Njølstad PR & Johansson S (2015). The chromosome 9p21 CVD- and T2D-associated regions in a Norwegian population (the HUNT2 Survey). International Journal of Endocrinology 2015: 164652.

Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, Mahajan A, Fuchsberger C, Atzmon G, Benediktsson R, Blangero J, Bowden DW, Brandslund I, Brosnan J, Burslem F, Chambers J, Cho YS, Christensen C, Douglas DA, Duggirala R, Dymek Z, Farjoun Y, Fennell T, Fontanillas P, Forsén T, Gabriel S, Glaser B, Gudbjartsson DF, Hanis C, Hansen T, Hreidarsson AB, Hveem K, Ingelsson E, Isomaa B, Johansson S, Jørgensen T, Jørgensen ME, Kathiresan S, Kong A, Kooner J, Kravic J, Laakso M, Lee JY, Lind L, Lindgren CM, Linneberg A, Masson G, Meitinger T, Mohlke KL, Molven A, Morris AP, Potluri S, Rauramaa R, Ribel-Madsen R, Richard AM, Rolph T, Salomaa V, Segrè AV, Skärstrand H, Steinthorsdottir V, Stringham HM, Sulem P, Tai ES, Teo YY, Teslovich T, Thorsteinsdottir U, Trimmer JK, Tuomi T, Tuomilehto J, Vaziri-Sani F, Voight BF, Wilson JG, Boehnke M, McCarthy MI, Njølstad PR, Pedersen O, Groop L, Cox DR, Stefansson K & Altshuler D (2014). Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nature Genetics 45: 1380-1385.

Chudasama KK, Winnay J, Johansson S, Claudi T, König R, Haldorsen I, Johansson B, Woo JR, Aarskog D, Sagen JV, Kahn CR, Molven A & Njølstad PR (2013). SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. American Journal of Human Genetics 93: 150-157.

Flannick J, Beer NL, Bick AG, Agarwala V, Molnes J, Gupta N, Burtt NP, Florez JC, Meigs JB, Taylor H, Lyssenko V, Irgens H, Fox E, Burslem F, Johansson S, Brosnan MJ, Trimmer JK, Newton-Cheh C, Tuomi T, Molven A, Wilson JG, O’Donnell CJ, Kathiresan S, Hirschhorn JN, Njølstad PR, Rolph T, Seidman JG, Gabriel S, Cox DR, Seidman CE, Groop L & Altshuler D (2013). Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of type 2 diabetes. Nature Genetics 45: 1380-1385.

Irgens HU, Molnes J, Johansson BB, Ringdal M, Skrivarhaug T, Undlien DE, Søvik O, Joner G, Molven A & Njølstad PR (2013). Prevalence of monogenic diabetes in the population-based Norwegian Childhood Diabetes Registry. Diabetologia 56: 1512-1519.

Johansson S, Irgens H, Chudasama KK, Molnes J, Aerts J, Roque FS, Jonassen I, Levy S, Lima K, Knappskog PM, Bell GI, Molven A & Njølstad PR (2012). Exome sequencing and genetic testing for MODY. PLoS ONE 7 (5): e38050.

Negahdar M, Johansson BB, Aukrust I, Molnes J, Molven A, Matschinsky FM, Søvik O, Kulkarni RN, Flatmark T, Njølstad PR & Bjørkhaug L (2012). GCK-MODY diabetes associated with protein misfolding, cellular self-association and degradation. BBA Molecular Basis of Disease 1822: 1705-1715.

Njølstad PR & Molven A (2012). To test, or not to test: time for a MODY calculator? Diabetologia 55: 1231-1234.

Haldorsen IS, Ræder H, Vesterhus M, Molven A & Njølstad PR (2012). The role of pancreatic imaging in monogenic diabetes mellitus. Nature Reviews Endocrinology 8: 148-159.

Søvik O, Aagenæs Ø, Eide SÅ, Mackay D, Temple IK, Molven A & Njølstad PR (2012). Familial occurrence of neonatal diabetes with duplications in chromosome 6q24: treatment with sulfonylurea and 40-yr follow-up. Pediatric Diabetes 13: 155-162.

Gonc EN, Ozturk BB, Haldorsen IS, Molnes J, Immervoll H, Ræder H, Molven A, Søvik O, & Njølstad PR (2012). HNF1B mutation in a Turkish child with renal and exocrine pancreas insufficiency, diabetes and liver disease. Pediatric Diabetes 13: e1-e5.

Molven A & Njølstad PR (2011). Role of molecular genetics in transforming diagnosis of diabetes mellitus. Expert Review of Molecular Diagnostics 11: 313-320.

Hertel JK, Johansson S, Ræder H, Platou CGP, Midthjell K, Hveem K, Molven A & Njølstad PR (2011). Evaluation of four novel genetic variants affecting hemoglobin A1c levels in a population-based type 2 cohort (the HUNT2 study). BMC Medical Genetics 12: 20 (1-6).

Hertel JK, Johansson S, Sonestedt E, Jonsson A, Lie RT, Platou CGP, Nilsson PM, Rukh G, Midthjell K, Hveem K, Melander O, Groop L, Lyssenko V, Molven A, Orho-Melander M & Njølstad PR (2011). FTO, type 2 diabetes and weight gain throughout adult life. A meta-analysis of 41,504 subjects from the Scandinavian HUNT, MDC, and MPP studies. Diabetes 60: 1637-1644.

Lango Allen H, Johansson S, Ellard S, Shields B, Hertel JK, Ræder H, Colclough K, Molven A, Frayling TM, Njølstad PR, Hattersley AT & Weedon MN (2010). Polygenic risk variants for type 2 diabetes susceptibility modify age at diagnosis in monogenic HNF1A diabetes. Diabetes 59: 266-271.

Ragvin A, Moro E, Fredman D, Navratilova P, Drivenes Ø, Engström PG, Alonso ME, Mustienes EC, Skarmeta JLG, Tavares MJ, Casares F, Manzanares M, van Heyningen V, Molven A, Njølstad PR Argenton F, Lenhard B & Becker TS (2010). Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4 and IRX3. Proceedings of the National Academy of Sciences USA107: 775-780.

Laborie LB, Mackay DJG, Temple IK, Molven A, Søvik O & Njølstad PR (2010). DNA hypomethylation, transient neonatal diabetes and prune belly sequence in one of two identical twins. European Journal of Pediatrics 169: 207-213.

Hertel JK, Johansson S, Ræder H, Midthjell K, Lyssenko V, Groop L, Molven A & Njølstad PR (2008). Genetic analysis of recently identified type 2 diabetes loci in 1,638 unselected patients with type 2 diabetes and 1,858 control participants from a Norwegian population-based cohort (the HUNT study). Diabetologia 51: 971-977.

Sagen JV, Bjørkhaug L, Molnes J, Ræder H, Grevle L, Søvik O, Molven A & Njølstad PR (2008). Diagnostic screening of MODY2/GCK mutations in the Norwegian MODY Registry. Pediatric Diabetes 9: 442-449.

Søvik O, Njølstad PR, Jellum E & Molven A (2008). Wolcott-Rallison syndrome with 3-hydroxydicarboxylic aciduria and lethal outcome. Journal of Inherited Metabolic Disease 31: 547 (#106, 1-5).

Vesterhus M, Haldorsen IS, Ræder H, Molven A & Njølstad PR (2008). Reduced pancreatic volume in hepatocyte nuclear factor 1A-maturity-onset diabetes of the young. Journal of Clinical Endocrinology & Metabolism 93: 3505-3509.

Eide SÅ, Ræder H, Johansson S, Midthjell K, Søvik O, Njølstad PR & Molven A (2008). Prevalence of HNF1A (MODY3) mutations in a Norwegian population (the HUNT2 Study). Diabetic Medicine 25: 775-781.

Haldorsen IS, Vesterhus M, Ræder H, Jensen DK, Søvik O, Molven A & Njølstad PR (2008). Lack of pancreatic body and tail in HNF1B mutation carriers. Diabetic Medicine 25: 782-787.

Molven A, Ringdal M, Nordbø AM, Ræder H, Støy J, Lipkind GM, Steiner DF, Philipson LH, Bergmann I, Aarskog D, Undlien DE, Joner G, Søvik O, the Norwegian Childhood Diabetes Study Group, Bell GI & Njølstad PR (2008). Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes 57: 1131-1135.

Vesterhus M, Ræder H, Johansson S, Molven A & Njølstad PR (2008). Pancreatic exocrine dysfunction in maturity-onset diabetes of the young type 3. Diabetes Care 31: 306-310.

Johansson S, Ræder H, Eide SÅ, Midthjell K, Hveem K, Søvik O, Molven A & Njølstad PR (2007). Studies in 3,523 Norwegians and meta-analysis in 11,571 subjects indicate that variants in the hepatocyte nuclear factor 4α (HNF4A) P2 region are associated with type 2 diabetes in Scandinavians. Diabetes 56: 3112-3117.

Sagen JV, Odili S, Bjørkhaug L, Zelent D, Buettger C, Kwagh J, Stanley C, Dahl-Jørgensen K,de Beaufort C, Bell GI, Han Y, Grimsby J, Taub R, Molven A, Søvik O, Njølstad PR & Matschinsky FM (2006). From clinicogenetic studies of maturity-onset diabetes of the young to unravelling complex mechanisms of glucokinase regulation. Diabetes 55: 1713-1722.

Ræder H, Bjørkhaug L, Johansson S, Mangseth K, Sagen JV, Hunting A, Følling I, Johansen O, Bjørgaas M, Paus PN, Søvik O,  Molven A & Njølstad PR (2006). A hepatocyte nuclear factor-4alpha gene (HNF4A) P2 promoter haplotype linked with late-onset diabetes: Studies of HNF4A variants in the Norwegian MODY registry. Diabetes 55: 1899-1903.

Bjørkhaug L, Bratland A, Njølstad PR & Molven A (2005). Functional dissection of the HNF-1-alpha transcription factor: A study on nuclear localization and transcriptional activation. DNA and Cell Biology 24: 661-669.

Bjørkhaug L, Johansson S, Ræder H, Thorsby PM, Undlien DE, Søvik O, Molven A, Sagen JV & Njølstad PR (2005). Molecular diagnostics in diabetes mellitus. Tidsskrift for Den Norske Lægeforening 125: 2968-2972. [in Norwegian]

Njølstad PR, Molven A & Søvik O (2005). Diagnosis and management of MODY in a pediatric setting. Pp. 84-93 in Diabetes in Childhood and Adolescence (Eds. Chiarelli F, Dahl-Jørgensen K & Kiess W). Karger, Basel, Switzerland 2005. ISBN 3-8055-7766-4.

Sagen JV, Baumann ME, Salvesen HB, Molven A, Søvik O & Njølstad PR (2005). Diagnostic screening of NEUROD1 (MODY6) in subjects with MODY or gestational diabetes. Diabetic Medicine 22: 1012-1015.

Sagen JV, Ræder H, Hathout E, Shehadeh N, Gudmundsson K, Bævre H, Abuelo D, Phornphutkul C, Molnes J, Bell GI, Gloyn AL, Hattersley AT, Molven A, Søvik O & Njølstad PR (2004). Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: Patient characteristics and initial response to sulfonylurea therapy. Diabetes 53: 2713-2718.

Njølstad PR, Sagen JV, Bjørkhaug L, Odili S, Shehadeh N, Bakry D, Sarici SU, Alpay F, Molnes J, Molven A, Søvik O & Matschinsky FM (2003). Permanent neonatal diabetes mellitus caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes 52: 2854-2860.

Bjørkhaug L, Sagen JV, Thorsby P, Søvik O, Molven A & Njølstad PR (2003). Hepatocyte nuclear factor-1alpha gene mutations and diabetes in Norway. Journal of Clinical Endocrinology & Metabolism 88: 920-931

Njølstad PR, Søvik O, Cuesta-Muñoz A, Bjørkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM & Bell GI (2001). Neonatal diabetes mellitus due to complete glucokinase deficiency. New England Journal of Medicine 344: 1588-1592.

Bjørkhaug L, Ye H, Horikawa Y, Søvik O, Molven A & Njølstad PR (2000). MODY associated with two novel hepatocyte nuclear factor-1alpha loss-of-function mutations (P112L and Q466X). Biochemical and Biophysical Research Communications 279: 792-798.

Bjørkhaug L, Søvik O, Bell GI, Njølstad PR & Molven A (2000). A simple test for the high-frequency mutation in the HNF-1alpha/MODY3 gene. Diabetologia 43: 818-819.

Congenital  hyperinsulinism of infancy is a disease of newborn children where life-threatening hypoglycemia (low blood glucose) arises because insulin secretion from the pancreas is inappropriately elevated. We are studying families with this condition. By genome-wide genetic screening in one such family, we discovered that mutations in the HADH gene can cause the disease. These mutations lead to deficiency of short-chain hydroxy-acyl-dehydrogenase (SCHAD), an enzyme which participates in mitochondrial fatty acid oxidation. We have investigated genetic HADH variants and are studying the disease mechanism both in cellular and mouse models.

We have also characterized the mutation spectrum of the sulfonylurea receptor-1 gene (ABCC8), which is the most commonly mutated gene causing congenital hyperinsulinism in Norway. Diagnostic screening is offered for mutations in the ABCC8 gene as well as in other genetic causes of congenital hyperinsulinism (KCNJ11, GLUD1, GCK, HADH, HNF4A, HK1 and others). We have recently characterized and summarized all congenital hyperinsulinism cases referred to Haukeland University Hospital during the last two decades.

Example of a family with congenital hyperinsulinism of infancy. Family trees

like this are an important tool when determining which genes to examine.

Current participants / main collaborators

Medical student Christoffer Drabløs Velde, Gade Laboratory for Pathology, UoBergen
Molecular biologist Janniche Torsvik, Gade Laboratory for Pathology, UoBergen
Researcher Kelly Velasco, Department of Biomedicine, UoBergen
Ass. prof. Diana Toivola, Åbo Akademi University, Turku, Finland
Professor Rohit N. Kulkarni, Joslin Diabetes Center, Harvard Medical School, Boston, USA
Professor Pål R. Njølstad, Section for Pediatrics, Dept. of Clinical Science, UoBergen

Publications

Velde CD, Molnes J, Berland S, Njølstad PR & Molven A (2025). Clinical and genetic characteristics of congenital hyperinsulinism in Norway: A nationwide cohort study. The Journal of Clinical Endocrinology and Metabolism  110: 554-563.

Velde CD, Reigstad H, Tjora E, Guthe HJT, Hansen EV, Molven A & Njølstad PR (2023). Congenital hyperinsulinism. Tidsskrift for den Norske Lægeforening 143: 18.

St-Louis JL, Velasco K, Slipp BA, Hu J, Helgeland G, Steine SJ, De Jesus D, Kulkarni RN & Molven A (2023). Deficiency of the metabolic enzyme SCHAD in pancreatic β-cells promotes amino acid-sensitive hypoglycaemia. Journal of Biological Chemistry 299: 104986.

Velasco K, St-Louis JL, Hovland HN, Thompson N, Ottesen Å, Choi MH, Pedersen L, Njølstad PR, Arnesen T, Fjeld K, Aukrust I, Myklebust LM & Molven A (2021). Functional evaluation of sixteen SCHAD missense variants: Only amino acid substitutions causing congenital hyperinsulinism of infancy lead to loss-of-function phenotypes in vitro. Journal of Inherited Metabolic Disease 44: 240-252.

Helgeland Ø, Vaudel M, Júlíusson PB, Holmen OL, Juodakis J, Bacelis J, Jacobsson B, Lindekleiv H, Hveem K, Lie RT, Knudsen GP, Stoltenberg C, Magnus P, Sagen JV, Molven A, Johansson S & Njølstad PR (2019). Genome-wide association study reveals dynamic role of genetic variation in infant and early childhood growth. Nature Communications 10: 4448.

Patti ME, Goldfine AB, Hu J, Hoem D, Molven A, Goldsmith J, Schwesinger WH, La Rosa S, Folli F & Kulkarni RN (2017). Heterogeneity of proliferative markers in pancreatic β-cells of patients with severe hypoglycemia following Roux-en-Y gastric bypass. Acta Diabetologica 54: 737-747.

Gjelberg HK, Hoem D, Verbeke CS, Eide J, Cooper JC & Molven A (2017). Hypoglycemia and decreased insulin requirement caused by malignant insulinoma in a type 1 diabetic patient: when the hoof beats are from a zebra, not a horse. Clinical Case Reports 5: 761-768.

Molven A, Hollister-Lock J, Hu J, Martinez R, Njølstad PR, Liew CW, Weir G & Kulkarni RN (2016). The hypoglycemic phenotype is islet cell-autonomous in short-chain hydroxyacyl-CoA dehydrogenase-deficient mice. Diabetes 65: 1672-1678.

Molven A, Helgeland G, Sandal T & Njølstad PR (2012). The molecular genetics and pathophysiology of congenital hyperinsulinism caused by short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency. Pp. 137-145 in Monogenic Hyperinsulinemic Hypoglycemia Disorders (Eds. Stanley CA, De Leon DD). Vol. 21 in Frontiers in Diabetes. Karger, Basel, Switzerland 2012. ISBN 978-3-8055-9943-6.

Pörksen S, Laborie LB, Nielsen L, Andersen ML, Sandal T, de Wet H, Schwarz E, Åman J, Swift P, Kocova M, Schönle EJ, de Beaufort C, Hougaard P, Ashcroft F, Molven A, Knip M, Mortensen HB, Hansen L, Njølstad PR & Hvidøre Study Group on Childhood Diabetes (2010). Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 antibodies. BMC Endocrine Disorders 10: 16 (1-10).

Sandal T, Laborie LB, Brusgaard K, Eide SÅ, Christesen HBT, Søvik O, Njølstad PR & Molven A (2009). The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy. Clinical Genetics 75: 440-448.

Christesen HB, Tribble ND, Molven A, Siddiqui J, Sandal T, Brusgaard K, Ellard S, Njølstad PR, Alm J, Jacobsen BB, Hussain K & Gloyn AL (2008). Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation. European Journal of Endocrinology 159: 27-34.

Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njølstad PR, Jellum E & Søvik O (2004). Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes 53: 221-227.

Molven A, Rishaug U, Matre GE, Njølstad PR, Søvik O (2002). Hunting for a hypoglycemia gene: Severe neonatal hypoglycemia in a consanguineous family. American Journal of Medical Genetics 113: 40-46

Anders Molven, PhD

Professor of molecular pathology
Past-President of the European Pancreatic Club

Gade Laboratory for Pathology
Department of Clinical Medicine
University of Bergen
Haukeland University Hospital
N-5021 Bergen, NORWAY

E-mail: anders.molven(a)uib.no