April 14, 2016 - Pathogenesis of DM2 Flashcards
Natural History of DM2
As insulin resistance increases, more insulin will need to be secreted by the pancreatic beta cells. Eventually, you will hit a point where you max out insulin secretion, however the cells are becoming more resistant (or same resistance but insulin levels drop) and the gap will be the excess glucose levels.
Over time, pancreatic beta cells will wear down and stop secreting insulin, leading to higher levels of the gap.
We can change the natural history of diabetes, however.
Clinical Precursors to Overt DM2
Abdominal obesity
Hypertension
Hyperlipidemia
Impaired glucose tolerance
Gestational diabetes
Polycystic ovarian syndrome
Monogenic Forms of Diabetes
Type A IR
Leprechaunism
Rabson-Mendelhall Syndrome
Lipoatrophic diabetes
PPAR - gamma mutations
Actions of Insulin
GO - glucose uptake in muscle and adipose tissue
GO - glycolysis
GO - glycogen synthesis
GO - protein synthesis
GO - uptake of ions (especially K and PO4)
STOP - gluconeogenesis
STOP - glucogenolysis
STOP - ketogenesis
STOP - lipolysis
STOP - proteolysis
Insulin Resistance
At the same level of insulin in the plasma, less glucose is disposed of.
A patient with Type 2 DM will be able to store less glucose at the same concentration of insulin than a patient who is healthy.
Obesity and Insulin Resistance
Obese patients are more resistant to insulin than their non-obese counterparts.
They follow the same daily curve as normal individuals, however they have higher baselines of insulin to keep their blood sugar under control.
Fatty Acids and IR
Fatty acids are preferentially used by the body, and the glucose is not utilized which can lead to an increase in insulin and resistance.
Factors Leading to Insulin Resistance
Free fatty acids
Adipokines
Inflammation
Factors Leading to Beta-Cell Failure
Genetics
Insulin resistance
Age
Amylin
Hexosamines
TNF-a
Lipotoxicity (increase in FFA)
Glucose toxicity
