Limits...
Inhibition of insulin fibrillation by osmolytes: Mechanistic insights.

Choudhary S, Kishore N, Hosur RV - Sci Rep (2015)

Bottom Line: We have studied here using a number of biophysical tools the effects of osmolytes, betaine, citrulline, proline and sorbitol which differ significantly in terms of their physical characteristics such as, charge distribution, polarity, H-bonding abilities etc, on the fibrillation of insulin.Among these, betaine, citrulline, and proline are very effective in decreasing the extent of fibrillation.Proline also causes a substantial delay in the onset of fibrillation in the concentration range (50-250 mM) whereas such an effect is seen for citrulline only at 250 mM, and in case of betaine this effect is not seen at all in the whole concentration range.

View Article: PubMed Central - PubMed

Affiliation: UM-DAE Centre for Excellence in Basic Sciences, Mumbai University Campus, Mumbai 400098, India.

ABSTRACT
We have studied here using a number of biophysical tools the effects of osmolytes, betaine, citrulline, proline and sorbitol which differ significantly in terms of their physical characteristics such as, charge distribution, polarity, H-bonding abilities etc, on the fibrillation of insulin. Among these, betaine, citrulline, and proline are very effective in decreasing the extent of fibrillation. Proline also causes a substantial delay in the onset of fibrillation in the concentration range (50-250 mM) whereas such an effect is seen for citrulline only at 250 mM, and in case of betaine this effect is not seen at all in the whole concentration range. The enthalpies of interaction at various stages of fibrillation process have suggested that the preferential exclusion of the osmolyte and its polar interaction with the protein are important in inhibition. The results indicate that the osmolytes are most effective when added prior to the elongation stage of fibrillation. These observations have significant biological implications, since insulin fibrillation is known to cause injection amyloidosis and our data may help in designing lead drug molecules and development of potential therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus

Limiting enthalpies of interaction of insulin with (A) betaine, (B) citrulline, (C) proline, and (D) sorbitol at different stages of fibrillation.
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f6: Limiting enthalpies of interaction of insulin with (A) betaine, (B) citrulline, (C) proline, and (D) sorbitol at different stages of fibrillation.

Mentions: A typical ITC experiment provides a set of values of the heat liberated or absorbed at different concentrations of insulin in the solution. The limiting standard enthalpy of interaction (ΔH°) is indicative of the nature of solute-solvent interactions without contributions from solute-solute and solvent-solvent interactions. In the cases where the heat of interaction was observed to be concentration dependent, the value of ΔH° was obtained from a linear fit to the experimental data points. If the heat of interaction did not show any concentration dependence, an average of the experimental data points was taken as a limiting standard enthalpy of interaction (The raw ITC data has been included in the supplementary information). Figure 6 shows the value of limiting standard enthalpy of interactions (ΔH°) of insulin with the osmolytes betaine, citrulline, proline and sorbitol at different concentrations and at different stages of fibrillation of insulin.


Inhibition of insulin fibrillation by osmolytes: Mechanistic insights.

Choudhary S, Kishore N, Hosur RV - Sci Rep (2015)

Limiting enthalpies of interaction of insulin with (A) betaine, (B) citrulline, (C) proline, and (D) sorbitol at different stages of fibrillation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663473&req=5

f6: Limiting enthalpies of interaction of insulin with (A) betaine, (B) citrulline, (C) proline, and (D) sorbitol at different stages of fibrillation.
Mentions: A typical ITC experiment provides a set of values of the heat liberated or absorbed at different concentrations of insulin in the solution. The limiting standard enthalpy of interaction (ΔH°) is indicative of the nature of solute-solvent interactions without contributions from solute-solute and solvent-solvent interactions. In the cases where the heat of interaction was observed to be concentration dependent, the value of ΔH° was obtained from a linear fit to the experimental data points. If the heat of interaction did not show any concentration dependence, an average of the experimental data points was taken as a limiting standard enthalpy of interaction (The raw ITC data has been included in the supplementary information). Figure 6 shows the value of limiting standard enthalpy of interactions (ΔH°) of insulin with the osmolytes betaine, citrulline, proline and sorbitol at different concentrations and at different stages of fibrillation of insulin.

Bottom Line: We have studied here using a number of biophysical tools the effects of osmolytes, betaine, citrulline, proline and sorbitol which differ significantly in terms of their physical characteristics such as, charge distribution, polarity, H-bonding abilities etc, on the fibrillation of insulin.Among these, betaine, citrulline, and proline are very effective in decreasing the extent of fibrillation.Proline also causes a substantial delay in the onset of fibrillation in the concentration range (50-250 mM) whereas such an effect is seen for citrulline only at 250 mM, and in case of betaine this effect is not seen at all in the whole concentration range.

View Article: PubMed Central - PubMed

Affiliation: UM-DAE Centre for Excellence in Basic Sciences, Mumbai University Campus, Mumbai 400098, India.

ABSTRACT
We have studied here using a number of biophysical tools the effects of osmolytes, betaine, citrulline, proline and sorbitol which differ significantly in terms of their physical characteristics such as, charge distribution, polarity, H-bonding abilities etc, on the fibrillation of insulin. Among these, betaine, citrulline, and proline are very effective in decreasing the extent of fibrillation. Proline also causes a substantial delay in the onset of fibrillation in the concentration range (50-250 mM) whereas such an effect is seen for citrulline only at 250 mM, and in case of betaine this effect is not seen at all in the whole concentration range. The enthalpies of interaction at various stages of fibrillation process have suggested that the preferential exclusion of the osmolyte and its polar interaction with the protein are important in inhibition. The results indicate that the osmolytes are most effective when added prior to the elongation stage of fibrillation. These observations have significant biological implications, since insulin fibrillation is known to cause injection amyloidosis and our data may help in designing lead drug molecules and development of potential therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus