Hyperglycemia induced complications in diabetes mellitus

A 65-year-old man with a history of type 2 diabetes mellitus is complaining of blurred vision and numbness in his toes. Laboratory results are significant for an increased BUN and creatinine, indicative of renal failure and high HbA1c indicative of chronic persistent hyperglycemia. Out of the several mechanisms proposed, one mechanism responsible for hyperglycemia induced complications in diabetes mellitus is non enzymatic attachment of excess glucose with structural proteins by forming covalent bonds. This reaction should be best described as-

A. Acylation

B. Carboxylation

C. Hydroxylation

D. Esterification

E. Glycation

The correct answer is E- Glycation.

In diabetes mellitus, insulin deficiency promotes hyperglycemia due to non utilization of glucose.

Increased glucose leads to the formation of advanced glycosylation end products (AGEs) via the nonenzymatic glycosylation of intra- and extra cellular proteins. Nonenzymatic glycosylation results from the interaction of glucose with amino groups on proteins (Figure-1). AGEs have been shown to cross-link proteins (e.g., collagen, extracellular matrix proteins), accelerate atherosclerosis, promote glomerular dysfunction, reduce nitric oxide synthesis, induce endothelial dysfunction, and alter extracellular matrix composition and structure. The serum level of AGEs correlates with the level of glycemia, and these products accumulate as glomerular filtration rate declines.

AGE

Figure-1- Formation of advanced glycation end products (AGEs)

Hemoglobin becomes glycated by ketoamine reactions between glucose and other sugars and the free amino groups on the alpha and beta chains (figure-2).Only glycation of the N-terminal valine of the beta chain imparts sufficient negative charge to the hemoglobin molecule to allow separation by charge dependent techniques. These charge separated hemoglobin are collectively referred to as hemoglobin A1 (HbA1).The major form of HbA1 is hemoglobin A1c (HbA1c) where glucose is the carbohydrate. HbA1c comprises 4–6% of total hemoglobin A1. Since glycohemoglobins circulate within red blood cells whose life span lasts up to 120 days, they generally reflect the state of glycemia over the preceding 8–12 weeks, thereby providing an improved method of assessing diabetic control.

Glycated Hb

Figure-2- Formation of glycated hemoglobin

Any condition that shortens erythrocyte survival or decreases mean erythrocyte age (e.g., recovery from acute blood loss, hemolytic anemia) will falsely lower HbA1c irrespective of the assay method used.

As regards other options-

Acylation is attachment of lipid to a structure.

Carboxylation is condensation of a biomolecule with carbon dioxide.

Hydroxylation is attachment of a hydroxyl group to a biomolecule.

Esterification is a condensation of an alcohol with an acid.

Thus in the given problem the correct answer is glycation.

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