Decreased levels of metabolic enzymes in pancreatic islets of patients with type 2 diabetes
Open accessAbstract
Aims/hypothesis Glucose-stimulated insulin secretion is defective in patients with type 2 diabetes. We sought to acquire new information about enzymes of glucose metabolism, with an emphasis on mitochondrial enzymes, by comparing pancreatic islets of type 2 diabetes patients with those of non-diabetic controls.Methods Expression of genes encoding 13 metabolic enzymes was estimated with microarrays and activities of up to nine metabolic enzymes were measured.Results The activities of the mitochondrial enzymes, glycerol phosphate dehydrogenase, pyruvate carboxylase (PC) and succinyl-CoA:3-ketoacid-CoA transferase (SCOT) were decreased by 73%, 65% and 92%, respectively, in the diabetic compared with the non-diabetic islets. ATP citrate lyase, a cytosolic enzyme of the mitochondrial citrate pyruvate shuttle, was decreased 57%. Activities of propionyl-CoA carboxylase, NADP-isocitrate dehydrogenase, cytosolic malic enzyme, aspartate aminotransferase and malate dehydrogenase were not significantly different from those of the control. The low activities of PC and SCOT were confirmed with western blots, which showed that their protein levels were low. The correlation of relative mRNA signals with enzyme activities was good in four instances, moderate in four instances and poor in one instance. In diabetic islets, the mRNA signal of the islet cell-enriched transcription factor musculoaponeurotic fibrosarcoma oncogene homologue A, which regulates expression of islet genes, including the PC gene, was decreased to 54% of the control level. PC activity and protein levels in the non-diabetic islets were significantly lower than in islets from non-diabetic rodents.Conclusions/interpretation Low levels of certain islet metabolic enzymes, especially mitochondrial enzymes, are associated with human type 2 diabetes.
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Chronic hyperglycemia is associated with marked changes in expression of metabolic genes in mouse β-cells, and similar changes are observed in islets from individuals with T2DM.
“Chronic hyperglycemia is also associated with marked changes in expression of metabolic genes in mouse β-cells (97) and similar changes are observed in islets from individuals with T2DM (409, 430, 606).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [409]
Insulin-secreting pancreatic β-cells and islets from people with type 2 diabetes show mitochondrial physiology alterations, including membrane hyperpolarization and decreased activities of glycerol phosphate dehydrogenase, pyruvate carboxylase, and succinyl-CoA-3-ketoacid-CoA transferase.
“Additionally, analysis of insulin-secreting pancreatic β-cells and islets from patients with T2DM showed alterations in mitochondrial physiology, such as hyperpolarization of the mitochondrial membrane and decreased activities of the enzymes glycerol phosphate dehydrogenase, pyruvate carboxylase and succinyl-CoA–3-ketoacid-CoA transferase147,148.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [148]
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- Authors
- MacDonald, M. J., Longacre, M. J., Langberg, E.-C., Tibell, A., Kendrick, M. A., Fukao, T., & Ostenson, C.-G.
- Affiliations
- University of Wisconsin–Madison (US)
- Karolinska Institutet (SE)
- Gifu University (JP)
- Corresponding author
- MacDonald, M. J.
- Venue
- Diabetologia
- Published
- 2009-03-19
- Volume
- 52
- Issue
- 6
- Pages
- 1087-1091
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC2903059
- OpenAlex
- W2083850806
- Cited by
- 115
- References
- 10
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 2 · 2023: 1 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 6 · 2018: 7 · 2017: 10 · 2016: 5 · 2015: 8 · 2014: 8 · 2013: 11 · 2012: 7
- FWCI
- 10.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Vetenskapsrådet
- National Institutes of Health (DK28348)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 28348, R01DK028348)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- type 2 diabetes, pancreatic islets, glucose metabolism enzymes, mitochondrial enzymes, pyruvate carboxylase, glycerol-3-phosphate dehydrogenase, ATP citrate lyase, Maf transcription factors, glucose-stimulated insulin secretion, islet gene expression
- MeSH terms
- Adult, Aged, Aspartate Aminotransferases, ATP Citrate (pro-S)-Lyase, Diabetes Mellitus, Type 2, Female, Glycerolphosphate Dehydrogenase, Humans, Isocitrate Dehydrogenase, Malate Dehydrogenase, Male, Middle Aged, Pyruvate Carboxylase, Blotting, Western, Coenzyme A-Transferases, Polymerase Chain Reaction, Methylmalonyl-CoA Decarboxylase
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