Pathogenesis of Diabetes BMS 200 Week 1

Study Notes

Type 2 Diabetes Mellitus (T2DM) develops from prolonged insulin resistance and is influenced by disrupted lipid and glucose metabolism in various organs: liver, muscle, pancreas, and adipose tissues.
The twin cycle hypothesis illustrates two circular metabolic processes—one in the liver and another in the pancreas—leading to T2DM.

Early insulin resistance starts with caloric excess and an impaired ability to clear glucose through skeletal muscle.
When energy storage depots, primarily in subcutaneous fat and muscle, are saturated, glucose levels rise in circulation.
Elevated free fatty acids (FFAs) in the bloodstream are a result of adipose tissue's reduced ability to convert calories into stored triglycerides.
The liver responds to excess FFAs by:
- Burning energy via beta-oxidation
- Storing energy, leading to hepatic steatosis
- Exporting energy as Very Low-Density Lipoproteins (VLDL) which transport triglycerides to other tissues.

Insulin resistance impacts balance between insulin and glucagon, crucial for liver function.
Fat accumulation (steatosis) exacerbates insulin resistance, leading to increased glucose production and hyperglycemia.
A positive feedback loop develops: insulin resistance increases hepatic steatosis and VLDL levels, further disrupting insulin secretion.

Elevated circulating FFAs from insulin-resistant adipocytes complicate liver metabolism, causing it to repack fats into triglycerides or deposit them as lipid droplets.
High levels of palmitic acid activate TLRs, worsening insulin resistance and hepatic stress.

T2DM shows significant changes in the pancreas, notably in fat accumulation around acinar cells and within islet cells.
Excessive triglycerides from the liver lead to fatty infiltration of the pancreas, contributing to fibrosis and instability in beta-cell function.
Consequences involve potential beta-cell apoptosis, increased ER stress, and de-differentiation, causing beta cells to exhibit glucagon-secreting characteristics like alpha cells.

The interplay between hepatic steatosis, VLDL production, pancreatic fat accumulation, and impaired insulin secretion fosters a continuous cycle worsening T2DM.
This cycle leads to increased hyperglycemia and elevated circulating FFAs.

VLDL synthesis occurs in the liver, primarily composed of triglycerides, phospholipids, and apoproteins like ApoB-100 and ApoC-II.
VLDL transforms into Intermediate-Density Lipoproteins (IDL) and then Low-Density Lipoproteins (LDL) as triglycerides are metabolized in tissues.
LDL clearance depends on the liver's LDL receptor, which binds ApoE and ApoB-100, but if not cleared, LDL can oxidize—linked to atherosclerosis.

Genetic, sex, and age factors limit how much fat can be absorbed by adipose tissue.
Insulin resistance reduces adipose’s ability to store triglycerides, leading to increased FFAs.
Subcutaneous fat can secrete adiponectin, enhancing insulin sensitivity, although its effectiveness decreases under T2DM.

In a UK trial involving 306 recent T2DM patients, participants underwent a weight-loss program, drastically reducing caloric intake (825-853 kcal/day).
At 12 months, 24% of those in the intervention group lost 15 kg or more, showcasing effective lifestyle changes in managing T2DM.