Table 9 The five stages of T2DM: the natural progressive history of T2DM.

I. LATENT STAGE: [EARLY]

Insulin Resistance:

   *Genetic Component.

   *Environmental Component. [Modifiable] Obesity / Sedentary life style. [Nonmodifiable] Ageing.

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 islet amyloid forms an envelope around the capillary. This is in addition to the increase in basement membrane associated with the pseudohypoxia (associated with glucotoxicity) and the redox stress within the capillary.

II. TRANSITION STAGE: [MIDDLE]

PERSISTENT HYPERINSULINEMIA

PERSISTENT HYPERAMYLINEMIA – Continued remodeling of endocrine pancreas. (AMYLOID) Beta cell displacement, dysfunction, mass reduction, and diffusion barrier.

III. IGT STAGE : *"Pre-diabetes" HHS ADA term (Impaired Glucose Tolerance)

[LATE] *[Start treatment at this time ] [Diagnose earlier: Rejuvenation of the 2 hour glucose tolerance blood sugar 140–199 mg .]

   *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 ECM] Beta cell loss centrally.

IV. IFG STAGE : *"Pre-diabetes" HHS ADA term (Impaired Fasting Glucose)

[LATER] Blood sugar > 110 mg./dl. < 126 mg./dl.

[Impaired Hepatic Glucose Production (HGP)]. Increasing global insulin resistance (HEPATIC) with subsequent gluconeogenesis. Feeding forward in the vicious cycle to accelerate insulin resistance globally

V. OVERT STAGE: [TOO 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)