In vivo bicarbonate deficiency and insulin dissolution

Area of Science:

• Biochemistry
• Endocrinology
• Physiology

Background:

• Exogenous insulin formulations, like U100 regular insulin, stabilize as hexamers due to zinc and peptide concentrations.
• Following administration, insulin disassociates into monomers, the biologically active form, in human plasma.
• The dissolution rate of insulin crystals in plasma is influenced by its chemical environment.

Purpose of the Study:

• To investigate the effect of plasma pH and bicarbonate levels on the dissolution rate of insulin crystals.
• To determine if reduced bicarbonate and pH in diabetic ketoacidosis impact insulin monomer availability.

Main Methods:

• Normal human plasma was used to assess the dissolution time of hexagonal insulin crystals.
• Acid titration was employed to lower pH and simulate conditions of bicarbonate depletion.
• Plasma from Type I diabetics in severe acidosis was studied, followed by bicarbonate repletion and pH normalization.

Main Results:

• Normal plasma demonstrated rapid dissolution of insulin crystals (3-8 minutes).
• Acid titration to pH 6.30 inhibited dissolution, which was restored by bicarbonate repletion.
• Plasma from diabetic ketoacidosis patients showed significantly inhibited insulin crystal dissolution (>25 minutes).
• Bicarbonate replenishment and pH normalization in diabetic plasma restored insulin dissolution rates.

Conclusions:

• Plasma bicarbonate concentration and pH are critical factors influencing insulin dissolution.
• Reduced bicarbonate and pH in diabetic ketoacidosis may limit the availability of active insulin monomers.
• These findings suggest a potential mechanism for the insulin insensitivity observed in severe diabetic ketoacidosis.