Type 2 diabetes mellitus (mechanism of disease)

This is a mechanism of disease map for type 2 diabetes, covering the etiologies, pathophysiology, and manifestations of T2DM.

ADDITIONAL TAGS:
Chronic inflammation
Signs / symptoms
Labs / tests / imaging results
Type 2 diabetes mellitus
Etiologies
Core concepts
Social determinants of
health / Risk factors
Genetics / hereditary
Microbial pathogenesis
Osmolarity regulation
Intercellular communication
Glucose homeostasis
Energy balance
Manifestations
Pathophysiology
Genetic factors:
-child with diabetic parent has 40% risk of T2DM
-monozygotic twin concordance 75%
Visceral adiposity (obesity)
+
Low grade chronic inflammation

Oxidative and metabolic stress
Risk factors:
-Family history (1st degree relative)
-Race/ethnicity
-Physical inactivity
-Hx cardiovascular disease
-Polycystic ovary syndrome
-Conditions associated with insulin resistance: (severe obesity, high-calorie diet)
-Hypertension
-Dyslipidemia
-Hx gestational diabetes
Initially, there is compensation (↑ insulin secretion). Over time, ↓ insulin secretion capacity
Adipose catabolism (lipolysis → release of glycerol + fatty acids)
Muscle catabolism (protein breakdown + release of amino acids)
Amino acids and glycerol carbons are used for gluconeogenesis
Polyphagia
Weight loss
↑ hepatic glucose output, ↓ peripheral tissue glucose uptake
Hyperglycemia
↑ glucose filtering
at nephron
Kidney unable to reabsorb filtered glucose
Glycosuria
Osmotic diuresis
Polyuria
Dehydration, volume depletion
↓ circulating volume → ↓ renal blood flow →
↓ glucose to nephron
Polydipsia
Hyperosmolarity in blood and tissues
Stimulation of osmoreceptors in hypothalamus
Blurred vision
Dysfunction of blood-retinal barrier: retinal vessel microangiopathy → macular edema
Central obesity → increased plasma levels of free fatty acids → impaired insulin-dependent glucose uptake into hepatocytes, myocytes, and adipocytes
Dysfunction of
pancreatic beta cells:
accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas → decreased endogenous insulin production
Increased serine kinase activity in fat and skeletal muscle cells → phosphorylation of insulin receptor substrate (IRS)-1 → decreased affinity of IRS-1 for PI3K → decreased expression of GLUT4 channels → decreased cellular glucose uptake
Peripheral insulin resistance
↑ demand for glucose lowering hormones → ↑ production of pro-insulin and pro-amylin → enzymes can't keep up → accumulation of pro-amylin