Metabolic Paradox: 'Starvation Amidst Plenty'
At the biochemical level, diabetes mellitus largely mimics a state of ordinary starvation because in both cases the insulin/glucagon ratio is critically decreased. The key difference lies in the blood sugar level: diabetes presents with severe hyperglycemia, yet cells of insulin-dependent tissues (primarily muscle and adipose tissue) cannot uptake it.
Due to the lack of insulin signaling, GLUT-4 receptors are not translocated to the cell membranes, and glucose remains in the bloodstream. An intracellular energy deficit ensues. Trying to escape 'starvation', the body triggers massive catabolism of its own structures:
- Protein breakdown (proteolysis) is enhanced, leading to loss of muscle mass and azotemia.
- Glycogenolysis is activated.
- The rate of fat breakdown (lipolysis) sharply increases.
The liver uses the released amino acids to synthesize new glucose (gluconeogenesis), which only exacerbates the already high hyperglycemia. This excess sugar begins to be excreted in the urine, drawing massive volumes of water along with it and causing osmotic diuresis (polyuria).
Pathogenesis of Diabetic Ketoacidosis
Removing the inhibitory effect of insulin on hormone-sensitive lipase leads to a massive release of free fatty acids into the blood. They travel to the liver, where they undergo intensive $\beta$-oxidation. As a result of this process, an excess of acetyl-CoA is formed.
Normally, acetyl-CoA should be oxidized in the tricarboxylic acid (TCA/Krebs) cycle by combining with oxaloacetate. However, in diabetes, oxaloacetate is massively consumed for gluconeogenesis. A metabolic block occurs: unutilized acetyl-CoA accumulates and is redirected toward the synthesis of ketone bodies (acetone, acetoacetate, and $\beta$-hydroxybutyrate).
When the rate of ketone body production exceeds the capacity of tissues to utilize them, they accumulate in the blood. Because these substances are acids, their excess shifts blood pH toward the acidic side, causing severe metabolic acidosis and toxic damage to the nervous system.
Mechanisms of Late Vascular Complications
Chronically high blood sugar triggers non-enzymatic glycation reactions. Unlike normal enzymatic carbohydrate attachment to proteins, this process occurs randomly: glucose molecules 'stick' to the free amino groups of proteins, irreversibly altering their structure.
The rate of damage accumulation directly depends on the half-life of the specific protein. Slowly turning over protein structures are affected first:
- Macroangiopathies. Glycation of collagen and elastin in the walls of large arteries leads to a loss of elasticity and contributes to the development of atherosclerosis, coronary artery disease, and lower extremity peripheral artery disease.
- Microangiopathies. Capillaries of the renal glomeruli (nephropathy) and retinal vessels (retinopathy) are damaged. The main pathological marker is the thickening of basement membranes of small vessels, which impairs microcirculation and filtration.
An early indicator of glycation is erythrocyte hemoglobin. A glucose molecule binds to the $\beta$-chains of hemoglobin, forming the $HbA_{1c}$ fraction, the level of which can increase 2-to-3-fold in diabetes.
Polyol Pathway and Nerve Tissue Damage
Another pathway of hyperglycemia-induced toxicity is the activation of glucose conversion into the polyhydric alcohol sorbitol. This process actively occurs in target tissues: Schwann cells of nerve fibers, the eye lens, and vascular endothelium.
The problem is that sorbitol is practically not used in other biochemical reactions, and the rate of its efflux from cells is extremely low. Accumulating intracellularly, sorbitol sharply increases the internal osmotic pressure of the cell. It draws in water, swells, and becomes damaged.
In Schwann cells, osmotic edema leads to demyelination of nerve fibers and the development of severe diabetic neuropathy. In the eye lens, this same process, supplemented by the glycation of structural proteins (crystallins), causes opacity and the formation of diabetic cataracts.