Table 7 The Five Stages of T2DM:

I.

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 oligomers of Islet Amyloid toxicity to the Beta Cell. Abnormal processing, storage or secretion

Islet Amyloid: Diffusion Barrier: Secretory Defect: Intra Islet Absorptive Defect:

II.

TRANSITION STAGE: [MIDDLE]

Persistent Hyperinsulinemia, Hyperproinsulinemia. → Ang II Accelerated Atherosclerosis

Persistent Hyperamylanemia. → AngII Accelerated Atherosclerosis

Continued remodeling of the endocrine pancreas (amyloid).

Beta cell displacement, dysfunction, mass reduction due to the toxic effect of IAPP oligomers and the progressive developing diffusion barrier.

III.

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

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.

IV.

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

   Blood sugar ranging [110–125 mg/dL]

   *ADA new cut point IFG Nov 2003: [100–125 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.

V.

OVERT STAGE: [TOO LATE] FBG 126 or greater: Random or 2 hour OGTT 200 or >

[50% loss of beta cell function at the time of clinical diagnosis]

Use medications that do not increase endogenous insulin or amylin. Use combination therapy. Start treatment at stage III-IV (IGT-IFG).

.

Paradigm Shift. → Diagnose Early → Start treatment Early → Stage III: IGT.