Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm

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aut.relation.endpage800
aut.relation.issue7en_NZ
aut.relation.journalBiomedicinesen_NZ
aut.relation.startpage800
aut.relation.volume9en_NZ
aut.researcherCrofts, Catherine
dc.contributor.authorCooper, IDen_NZ
dc.contributor.authorBrookler, KHen_NZ
dc.contributor.authorKyriakidou, Yen_NZ
dc.contributor.authorElliott, BTen_NZ
dc.contributor.authorCrofts, CAPen_NZ
dc.date.accessioned2021-07-14T03:13:53Z
dc.date.available2021-07-14T03:13:53Z
dc.description.abstractUnlike bolus insulin secretion mechanisms, basal insulin secretion is poorly understood. It is essential to elucidate these mechanisms in non-hyperinsulinaemia healthy persons. This establishes a baseline for investigation into pathologies where these processes are dysregulated, such as in type 2 diabetes (T2DM), cardiovascular disease (CVD), certain cancers and dementias. Chronic hyperinsulinaemia enforces glucose fueling, depleting the NAD+ dependent antioxidant activity that increases mitochondrial reactive oxygen species (mtROS). Consequently, beta-cell mitochondria increase uncoupling protein expression, which decreases the mitochondrial ATP surge generation capacity, impairing bolus mediated insulin exocytosis. Excessive ROS increases the Drp1:Mfn2 ratio, increasing mitochondrial fission, which increases mtROS; endoplasmic reticulum-stress and impaired calcium homeostasis ensues. Healthy individuals in habitual ketosis have significantly lower glucagon and insulin levels than T2DM individuals. As beta-hydroxybutyrate rises, hepatic gluconeogenesis and glycogenolysis supply extra-hepatic glucose needs, and osteocalcin synthesis/release increases. We propose insulin’s primary role is regulating beta-hydroxybutyrate synthesis, while the role of bone regulates glucose uptake sensitivity via osteocalcin. Osteocalcin regulates the alpha-cell glucagon secretory profile via glucagon-like peptide-1 and serotonin, and beta-hydroxybutyrate synthesis via regulating basal insulin levels. Establishing metabolic phenotypes aids in resolving basal insulin secretion regulation, enabling elucidation of the pathological changes that occur and progress into chronic diseases associated with ageing.en_NZ
dc.identifier.citationBiomedicines, 9(7), 800. doi:10.3390/biomedicines9070800
dc.identifier.doi10.3390/biomedicines9070800en_NZ
dc.identifier.issn2227-9059en_NZ
dc.identifier.urihttps://hdl.handle.net/10292/14366
dc.languageenen_NZ
dc.publisherMDPI AGen_NZ
dc.relation.urihttps://www.mdpi.com/2227-9059/9/7/800
dc.rights© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
dc.rights.accessrightsOpenAccessen_NZ
dc.subjectHyperinsulinaemia; Insulin resistance; Osteocalcin; Beta-hydroxybutyrate; Phenotype; Stages; Serotonin; Glucagon-like peptide-1; Glucagon; Type 2 diabetes; Hyperglycaemia
dc.titleMetabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigmen_NZ
dc.typeJournal Article
pubs.elements-id434032
pubs.organisational-data/AUT
pubs.organisational-data/AUT/Faculty of Design & Creative Technologies
pubs.organisational-data/AUT/Faculty of Design & Creative Technologies/School of Engineering, Computer & Mathematical Sciences
pubs.organisational-data/AUT/Faculty of Design & Creative Technologies/School of Engineering, Computer & Mathematical Sciences/BioDesign Lab
pubs.organisational-data/AUT/Faculty of Health & Environmental Science
pubs.organisational-data/AUT/Faculty of Health & Environmental Science/School of Public Health & Interdisciplinary Studies
pubs.organisational-data/AUT/PBRF
pubs.organisational-data/AUT/PBRF/PBRF Health and Environmental Sciences
pubs.organisational-data/AUT/PBRF/PBRF Health and Environmental Sciences/HI Interprofessional 2018 PBRF
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