Question

In your own words, define muscle weakness and diabetic neuropathy in pathophysiology. (Must cite reference)

Answer 1

Muscle weakness

True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, including muscular dystrophy and inflammatory myopathy. It occurs in neuromuscular junction disorders, such as myasthenia gravis. Muscle weakness can also be caused by low levels of potassium and other electrolytes within muscle cells.

Muscle cells work by detecting a flow of electrical impulses from the brain which signals them to contract through the release of calcium by the sarcoplasmic reticulum. Fatigue may occur due to the nerve, or within the muscle cells themselves.

Substrates within the muscle generally serve to power muscular contractions. They include molecules such as adenosine triphosphate (ATP), glycogen and creatine phosphate. ATP binds to the myosin head and causes the ‘ratchetting’ that results in contraction according to the sliding filament model. Creatine phosphate stores energy so ATP can be rapidly regenerated within the muscle cells from adenosine diphosphate (ADP) and inorganic phosphate ions, allowing for sustained powerful contractions that last between 5–7 seconds. Glycogen is the intramuscular storage form of glucose, used to generate energy quickly once intramuscular creatine stores are exhausted, producing lactic acid as a metabolic byproduct. Contrary to common belief, lactic acid accumulation doesn't actually cause the burning sensation we feel when we exhaust our oxygen and oxidative metabolism, but in actuality, lactic acid in presence of oxygen recycles to produce pyruvate in the liver which is known as the Cori cycle.

Substrates produce metabolic fatigue by being depleted during exercise, resulting in a lack of intracellular energy sources to fuel contractions. In essence, the muscle stops contracting because it lacks the energy to do so.

Diabetic Neuropathy

The deleterious effect of hyperglycemia is confirmed by the occurrence of neuropathy associated with impaired glucose tolerance. In this setting, the neurop deleterious athy is milder than it is in newly diagnosed diabetes, and small-nerve-fiber involvement is the earliest detectable sign of the neuropathy.?

Accumulation of polyols, which is observed in animal model of diabetes, also occurs in humans, but whether the accumulation of polyols in nerves leads to neuropathy is not established, and most aldose-reductase inhibitors tested to treat diabetic polyneuropathy have failed to produce any clinical improvement. In 2006, a study in an adolescent diabetic cohort showed that AKR1B1 polymorphisms might influence the decline of nerve function.

The potential role in diabetic neuropathy of mitochondria of sensory neurons located in dorsal root ganglia has been suggested by several studies. These mitochondria are especially vulnerable, because in the hyperglycemic neuron they are the origin of production of reactive oxygen species, which can damage their DNA and membranes. Deregulation of fission and fusion proteins that control mitochondrial shape and number can impair cell functions and might lead to degeneration.

Advanced glycation end products resulting from hyperglycemia act on specific receptors, inducing monocytes and endothelial cells to increase the production of cytokines and adhesion molecules. Advanced glycation end products have been shown to have an effect on matrix metalloproteinases, which might damage nerve fibers.

An increasing body of data supports a role for oxidative stress in the pathogenesis of diabetic neuropathy in animal models, which has led to clinical trials of antioxidants such as ?-lipoic acid, a powerful antioxidant that scavenges hydroxyl, superoxide and peroxyl radicals and regenerates glutathione. In these trials, ?-lipoic-acid administration improved nerve conduction velocity and had some positive effects on neuropathic symptoms.

In brief, both metabolic and ischemic mechanisms have a role in diabetic neuropathies. Metabolic factors seem to prevail in LDDP, whereas an inflammatory process superimposed on ischemic nerve lesions seems to be responsible for severe forms of focal neuropathies. The thickening and hyalinization of the walls of small blood vessels, which corresponds to reduplication of the basal lamina around endothelial cells, suggest a role for nerve ischemia in diabetic neuropathy.