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

Cooper, I., Brookler, Kenneth H, Kyriakidou, Yvoni, Elliott, B. and Crofts, C. 2021. Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm. Biomedicines. 9 (7) 800. https://doi.org/10.3390/biomedicines9070800

TitleMetabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm.
TypeJournal article
AuthorsCooper, I., Brookler, Kenneth H, Kyriakidou, Yvoni, Elliott, B. and Crofts, C.
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.
Keywordsbeta-hydroxybutyrate
insulin resistance
glucagon
serotonin
phenotype
type 2 diabetes
glucagon-like peptide-1
stages
hyperglycaemia
hyperinsulinaemia
osteocalcin
Article number800
JournalBiomedicines
Journal citation9 (7)
ISSN2227-9059
Year2021
PublisherMDPI
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.3390/biomedicines9070800
PubMed ID34356863
Publication dates
Published online09 Jul 2021

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