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In this issue of Journal of Endocrinology, Schuyler et al. show that intimal lesions in atherosclerosis-prone diabetic apoE −/− mice are reduced by insulin treatment. An increase of metalloproteinase-9 expression was observed in untreated diabetic apoE −/− mice; this was absent in insulin-treated mice. The study suggests that hindering of tissue-remodeling metalloproteinases may account for the beneficial effects of proper metabolic control in patients with diabetes. This clinically relevant finding prompts further exploration.
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In this issue of Journal of Endocrinology, Dr Han and colleagues report a protective effect of the glutamate dehydrogenase activator 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) under diabetes-like conditions that impair β-cell function in both a pancreatic β-cell line and db/db mice. Based on these observations, the authors suggest that BCH could serve as a novel treatment modality in type 2 diabetes. The present commentary discusses the importance of the findings. Some additional questions are raised, which may be addressed in future investigations, as there is some concern regarding the BCH treatment of β-cell failure.
Department of Clinical Science, Unit for Diabetes and Celiac Disease, Clinical Research Centre, Malmö University Hospital, SE-20502 Malmö, Sweden
Institute of Nutrition, University of Jena, D-07743 Jena, Germany
Lund University Diabetes Centre, SE-22184 Lund, Sweden
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Department of Clinical Science, Unit for Diabetes and Celiac Disease, Clinical Research Centre, Malmö University Hospital, SE-20502 Malmö, Sweden
Institute of Nutrition, University of Jena, D-07743 Jena, Germany
Lund University Diabetes Centre, SE-22184 Lund, Sweden
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Department of Clinical Science, Unit for Diabetes and Celiac Disease, Clinical Research Centre, Malmö University Hospital, SE-20502 Malmö, Sweden
Institute of Nutrition, University of Jena, D-07743 Jena, Germany
Lund University Diabetes Centre, SE-22184 Lund, Sweden
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Department of Clinical Science, Unit for Diabetes and Celiac Disease, Clinical Research Centre, Malmö University Hospital, SE-20502 Malmö, Sweden
Institute of Nutrition, University of Jena, D-07743 Jena, Germany
Lund University Diabetes Centre, SE-22184 Lund, Sweden
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Department of Clinical Science, Unit for Diabetes and Celiac Disease, Clinical Research Centre, Malmö University Hospital, SE-20502 Malmö, Sweden
Institute of Nutrition, University of Jena, D-07743 Jena, Germany
Lund University Diabetes Centre, SE-22184 Lund, Sweden
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β-Cell-specific gene targeting is a widely used tool when studying genes involved in β-cell function. For this purpose, several conditional β-cell knockouts have been generated using the rat insulin promoter 2-Cre recombinase (RIP2-Cre) mouse. However, it was recently observed that expression of Cre alone in β-cells may affect whole body glucose homeostasis. Therefore, we investigated glucose homeostasis, insulin secretion, and β-cell mass in our line of RIP2-Cre mice bred onto the C57BL/6J genetic background. We used 12- and 28-week-old female RIP2-Cre mice for analyses of insulin secretion in vitro, glucose homeostasis in vivo and β-cell mass. Our mouse line has been backcrossedfor14generationstoyieldanear100%pureC57BL/6J background. Wefound thatfastingplasmaglucoseand insulinlevels were similar in both genotypes. An i.v. glucose tolerance test revealed no differences in glucose clearance and insulin secretion between 12-week-old RIP2-Cre and WT mice. Moreover, insulin secretion in vitro in islets isolated from 28-week-old RIP2-Cre mice and controls was similar. In addition, β-cell mass was not different between the two genotypes at 28 weeks of age. In our experiments, we observed no differences in glucose tolerance, insulin secretion in vivo and in vitro, or in β-cell mass between the genotypes. As our RIP2-Cre mice are on a near 100% pure genetic background (C57BL/6J), we suggest that the perturbations in glucose homeostasis previously reported in RIP2-Cre mouse lines can be accounted for by differences in genetic background.
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Department of Chemistry, Center for Analysis and Synthesis, Lund University, Sweden
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Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.
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Mitochondrial network functionality is vital for glucose-stimulated insulin secretion in pancreatic beta cells. Altered mitochondrial dynamics in pancreatic beta cells are thought to trigger the development of type 2 diabetes mellitus. Fission protein 1 (Fis1) might be a key player in this process. Thus, the aim of this study was to investigate mitochondrial morphology in dependence of beta cell function, after knockdown and overexpression of Fis1. We demonstrate that glucose-unresponsive cells with impaired glucose-stimulated insulin secretion (INS1-832/2) showed decreased mitochondrial dynamics compared with glucose-responsive cells (INS1-832/13). Accordingly, mitochondrial morphology visualised using MitoTracker staining differed between the two cell lines. INS1-832/2 cells formed elongated and clustered mitochondria, whereas INS1-832/13 cells showed a homogenous mitochondrial network. Fis1 overexpression using lentiviral transduction significantly improved glucose-stimulated insulin secretion and mitochondrial network homogeneity in glucose-unresponsive cells. Conversely, Fis1 downregulation by shRNA, both in primary mouse beta cells and glucose-responsive INS1-832/13 cells, caused unresponsiveness and significantly greater numbers of elongated mitochondria. Overexpression of FIS1 in primary mouse beta cells indicated an upper limit at which higher FIS1 expression reduced glucose-stimulated insulin secretion. Thus, FIS1 was overexpressed stepwise up to a high concentration in RINm5F cells using the RheoSwitch system. Moderate FIS1 expression improved glucose-stimulated insulin secretion, whereas high expression resulted in loss of glucose responsiveness and in mitochondrial artificial loop structures and clustering. Our data confirm that FIS1 is a key regulator in pancreatic beta cells, because both glucose-stimulated insulin secretion and mitochondrial dynamics were clearly adapted to precise expression levels of this fission protein.
