Abstract
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.
Highlights
The hormone insulin is synthesized and secreted by pancreatic beta cells [1,2]
The commonly accepted principle is that insulin is secreted in a basal/bolus pattern, with the latter predominately released upon rising blood glucose stimulus [3,4]
Once we understand the processes by which insulin is secreted in both the basal and bolus states in a healthy person, we can begin to unravel the pathologies whereby these processes are dysregulated, such as in type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), certain cancers and dementias [6]
Summary
The hormone insulin is synthesized and secreted by pancreatic beta cells [1,2]. The commonly accepted principle is that insulin is secreted in a basal/bolus pattern, with the latter predominately released upon rising blood glucose (most likely from a meal) stimulus [3,4]. The mechanism by which bolus insulin is secreted from the pancreas is well established [5]; little is known about the mechanisms by which basal insulin is secreted. Once we understand the processes by which insulin is secreted in both the basal and bolus states in a healthy person, we can begin to unravel the pathologies whereby these processes are dysregulated, such as in type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), certain cancers and dementias [6].
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