Figure 15.

T2DM may be considered a spectrum disease. The development of overt or clinical T2DM could be considered a spectrum disease, in that, end-organ tissue remodeling in response to multiple metabolic toxicities begin long before the clinical diagnosis of T2DM is made; see Figure 1, Figure 3 and Figure 5. Note that there are multiple variables (black boxed-in numbers 1–3) that contribute to the development of T2DM and its associated multiple end-organ complications (including the pancreatic islet—isletopathy) even prior to the clinical diagnosis of overt T2DM (black boxed-in number 4). Importantly, there are multiple variables within metabolic syndrome (MetS) (black boxed-in number 1), which consist of having three of the following five ATP guideline variables consisting of: central obesity (≥94 cm (for males), 80 cm (females)); triglycerides concentration ≥ 150 mg/dL; HDL cholesterol concentration < 40 mg/dL (males), <50 mg/dL (females); values of blood pressure ≥130/85 mmHg and fasting glycemia ≥ 100 mg/dL or HbA1c ≥ 6.5 that contribute to its summation equation [8,9]. Lipotoxicity was not assigned a boxed-in number because HDL cholesterol and triglycerides variables are included in MetS (black boxed-in number 1) as one of the five criteria for diagnosing MetS. Hypertension may be one of the most common health problems associated with obesity and is included in MetS (black boxed-in number1) variables and is not within the scope of this paper to discuss in greater depth. The importance of insulin and leptin resistance (black boxed-in number 3) is central and may be critical to islet and even brain remodeling and therefore is not to be underestimated. Note the novel simple mathematical summation equations that are introduced with black boxed-in variables 1–4 and that the author has assigned various weighted numbers (based on their relative importance) in parentheses for summation equation totals, which points to the importance of each variable and their summation. The author is aware that that the weighted values of each of the variables utilized in these summation equations are debatable. ATP III = adult treatment panel III (ATP III) report of the National Cholesterol Education Program; HbA1c = hemoglobin A1C; HDL = high-density lipoprotein; MetS = metabolic syndrome; T2DM = type 2 diabetes mellitus.