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

1
Translational Physiology Research Group, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK
2
Research Collaborator, Aerospace Medicine and Vestibular Research Laboratory, Mayo Clinic, Scottsdale, AZ 85259, USA
3
Faculty of Health and Environmental Sciences, School of Public Health and Interdisciplinary Studies, Auckland University of Technology, Auckland 0627, New Zealand
*
Author to whom correspondence should be addressed.
Academic Editor: Susan J. Burke
Biomedicines 2021, 9(7), 800; https://doi.org/10.3390/biomedicines9070800
Received: 21 May 2021 / Revised: 2 July 2021 / Accepted: 5 July 2021 / Published: 9 July 2021
(This article belongs to the Special Issue Emerging Paradigms in Insulin Resistance)
Unlike 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. View Full-Text
Keywords: hyperinsulinaemia; insulin resistance; osteocalcin; beta-hydroxybutyrate; phenotype; stages; serotonin; glucagon-like peptide-1; glucagon; type 2 diabetes; hyperglycaemia hyperinsulinaemia; insulin resistance; osteocalcin; beta-hydroxybutyrate; phenotype; stages; serotonin; glucagon-like peptide-1; glucagon; type 2 diabetes; hyperglycaemia
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MDPI and ACS Style

Cooper, I.D.; Brookler, K.H.; Kyriakidou, Y.; Elliott, B.T.; Crofts, C.A.P. Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm. Biomedicines 2021, 9, 800. https://doi.org/10.3390/biomedicines9070800

AMA Style

Cooper ID, Brookler KH, Kyriakidou Y, Elliott BT, Crofts CAP. Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm. Biomedicines. 2021; 9(7):800. https://doi.org/10.3390/biomedicines9070800

Chicago/Turabian Style

Cooper, Isabella D., Kenneth H. Brookler, Yvoni Kyriakidou, Bradley T. Elliott, and Catherine A.P. Crofts. 2021. "Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm" Biomedicines 9, no. 7: 800. https://doi.org/10.3390/biomedicines9070800

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