Table 8 Courtesy [8, 9, 53] The five stages of T2DM: the natural progressive history of T2DM

LATENT STAGE: [EARLY]

Insulin Resistance:

• Genetic Component

• Environmental component. Modifiable: obesity/sedentary life style. Nonmodifiable: aging.

Beta Cell Defect: (Dysfunction)

• Genetic ....... Abnormal processing, storage or secretion.

• Intracellular/extracellular amylin fibril toxicity. Abnormal processing, storage or secretion.

Intra-Islet Endothelial Absorptive Defect:

• Heparan sulfate proteoglycan (HSPG) PERLECAN of the capillary endothelial cells avidly attracts amylin (IAPP) and the islet amyloid forms an envelope around the capillary. This is in addition to the increase in the basement membrane associated with the pseudohypoxia (associated with glucotoxicity) and the redox stress within the capillary.

TRANSITION STAGE: [MIDDLE]

Persistent Hyperinsulinemia

Persistent Hyperamylanemia

• Continued remodeling of the endocrine pancreas (amyloid).

• Beta cell displacement, dysfunction, mass reduction and diffusion barrier.

IGT STAGE (Impaired Glucose Tolerance): [LATE] "Pre-diabetes" Human Health Services (HHS) and American Diabetes Association (ADA) term.

[Start treatment at this time]

[Diagnose earlier: rejuvenation of the 2 hour glucose tolerance blood sugar 140–199 mg/dL]

• Increased insulin resistance [Feeds forward] > Glucotoxicity [Feeds forward] > Insulin resistance [Feeds forward] > Glucotoxicity: creating a vicious cycle.

• Islet amyloid. Increasing beta cell defect. Loss of beta cell mass with displacement. (Remodeling of islet architecture including extracellular matrix). Beta cell loss centrally.

IFG STAGE (Impaired Fasting Glucose): [LATER] "Pre-diabetes" Human Health Services (HHS) and American Diabetes Association (ADA) term.

[Blood sugar ranging 110–126 mg/dL]

[Impaired hepatic glucose production]

• Increasing global insulin resistance (hepatic) with subsequent gluconeogenesis. Feeding forward in the vicious cycle to accelerate insulin resistance globally.

OVERT STAGE: [TO LATE]

[50% loss of beta cell function]

Va, Vb, Vc. Phases I, II, III: mild, moderate/severe, complete. Use medications that do not increase insulin or amylin. Use combination therapy. Start treatment at stage III-IV (IGT-IFG).

• Paradigm Shift. Start treatment at the earlier stage of IGT.