ArticleDiabetologia2016
Sequential cleavage of insulin receptor by calpain 2 and γ-secretase impairs insulin signalling.
Article in Diabetologia, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
23 citing papers in PubMed, 31 citations in OpenAlex.
- Calpain inhibition by calpeptin modulates adipocyte lipid metabolism and secretome-mediated inflammatory crosstalk with hepatocytes.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Glycemic variability associated with gamma secretase inhibitor therapy in a type 1 diabetic patient undergoing treatment for desmoid tumor: a case report.Frontiers in endocrinology · 2026Article
- Skeletal muscle disorders as risk factors for type 2 diabetes.Molecular and cellular endocrinology · 2025Review
- Cell Type-Specific Extracellular Vesicles and Their Impact on Health and Disease.International journal of molecular sciences · 2024Review
- Calpain and Cardiometabolic Diseases.International journal of molecular sciences · 2023Review
- Exosomal non coding RNAs as a novel target for diabetes mellitus and its complications.Non-coding RNA research · 2023Review
- Cerebrovascular insulin receptors are defective in Alzheimer's disease.Brain : a journal of neurology · 2023Article
- The emerging roles of extracellular vesicles as intercellular messengers in liver physiology and pathology.Clinical and molecular hepatology · 2022Review
- Insulin infusion decreases medium-sized extracellular vesicles in adults with metabolic syndrome.American journal of physiology. Endocrinology and metabolism · 2022Article
- ADAM17 cleaves the insulin receptor ectodomain on endothelial cells and causes vascular insulin resistance.American journal of physiology. Heart and circulatory physiology · 2022Article
- Research progress of extracellular vesicles in type 2 diabetes and its complications.Diabetic medicine : a journal of the British Diabetic Association · 2022Review
- Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor.Nature communications · 2022Article
- Integrative biology of extracellular vesicles in diabetes mellitus and diabetic complications.Theranostics · 2022Review
- Insulin receptor cleavage induced by estrogen impairs insulin signaling.BMJ open diabetes research & care · 2021Article
- Proteolytic Cleavage of Receptor Tyrosine Kinases.Biomolecules · 2021Review
- Review
- Glucose, insulin, insulin receptor subunits α and β in normal and spontaneously diabetic and obese ob/ob and db/db infertile mouse testis and hypophysis.Reproductive biology and endocrinology : RB&E · 2020Article
- Clinical Potential of Extracellular Vesicles in Type 2 Diabetes.Frontiers in endocrinology · 2020Review
- Circulating Apolipoprotein L1 is associated with insulin resistance-induced abnormal lipid metabolism.Scientific reports · 2019Article
- Calpain-2 promotes MKP-1 expression protecting cardiomyocytes in both in vitro and in vivo mouse models of doxorubicin-induced cardiotoxicity.Archives of toxicology · 2019Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisSoluble insulin receptor (sIR), the ectodomain of the insulin receptor (IR), has been detected in human plasma and its concentration paralleled that of blood glucose. We have previously developed an in vitro model using HepG2 liver-derived cells, which mimics changes in sIR levels in plasma from diabetic patients and shows that calcium-dependent proteases cleave IR extracellularly (a process known as shedding). The present study aimed to reveal the mechanisms of IR cleavage.
methodsUsing the in vitro model, we investigated the molecular mechanisms of IR cleavage, which is accelerated by high-glucose treatment. We also analysed the relationship between IR cleavage and cellular insulin resistance, and the correlation between plasma sIR levels and insulin sensitivity, which was assessed by the euglycaemic-hyperinsulinaemic clamp technique.
resultsHere, we determined that calpain 2, which is secreted into the extracellular space associated with exosomes, directly cleaved the ectodomain of the IRβ subunit (IRβ), which in turn promoted intramembrane cleavage of IRβ by γ-secretase. IR cleavage impaired insulin signalling and the inhibition of IR cleavage (by knockdown of calpain 2 and γ-secretase), restored IR substrate-1 and Akt, independent of IR. Furthermore, the glucose-lowering drug, metformin, prevented IR cleavage accompanied by inhibition of calpain 2 release in exosomes, and re-established insulin signalling. In patients with type 2 diabetes, plasma sIR levels inversely correlated with insulin sensitivity. CONCLUSIONS/
interpretationSequential cleavage of IR by calpain 2 and γ-secretase may contribute to insulin signalling in cells and its inhibition may be partly responsible for the glucose-lowering effects of metformin. Thus, IR cleavage may offer a new mechanism for the aetiology of insulin resistance.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.