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

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.

Keywords: beta-hydroxybutyrate; glucagon; glucagon-like peptide-1; hyperglycaemia; hyperinsulinaemia; insulin resistance; osteocalcin; phenotype; serotonin; stages; type 2 diabetes.

Figure 1

Schematic representation of beta-cell intracellular mechanisms involved in insulin secretion. Adenosine diphosphate (ADP), adenosine triphosphate (ATP), calcium (Ca²⁺), glucagon-like peptide-1 (GLP-1), glucose transporter 1 (GLUT1), G-protein coupled receptor 6A (GPRC6A), inositol-1,4,5-trisphosphate (IP3), plasma membrane (PM), osteocalcin (OCN), oxidative phosphorylation (OxPhos), phospholipase C (PLC), potassium (K⁺).

Figure 2

Schematic representations of basal and bolus insulin secretory patterns (A) and secretion regulation (B). (A) The red line conceptually models glucose bolus mediated insulin secretory response pattern (Kraft I) [36], and the blue line conceptually models basal insulin pulsatile secretory pattern, in metabolically healthy individuals [34]. (B) Schematic representation of the regulatory cycles of basal and bolus insulin secretion in metabolically healthy, habitually fasted individuals. Beta-hydroxybutyrate (BHB), blood glucose (BG), glucagon-like peptide-1 (GLP-1), osteocalcin (OCN).

Figure 3

Classification of metabolic phenotypes. Beta-Hydroxybutyrate (BHB), haemoglobin A1c (HbA1c), oral glucose tolerance test (OGTT), osteocalcin (OCN), type 2 diabetes mellitus (T2DM).

Figure 4

Proposed basal insulin, beta-hydroxybutyrate, osteocalcin feedback cycle in phenotype-1 individuals. Beta-hydroxybutyrate (BHB), central nervous system (CNS), glucagon-like peptide-1 (GLP-1), insulin resistance (IR), glucose-insulin resistance (IR-G), osteocalcin (OCN), red blood cells (RBC), tryptophan hydroxylase (Tph).