Abstract
BackgroundDiabetes mellitus is characterized jointly by hyperglycemia and hyperinsulinemia that make insulin more prone to be glycated and evolve insulin advanced glycation end products (Insulin- AGE). Here, we report the effect of beta-hydroxy butyrate (BHB) (the predominant ketone body) on the formation of insulin-AGE, insulin glycation derived liposomal lipid peroxidation and insulin-AGE toxicity in microglial cells.MethodsThe inhibitory effect of BHB was monitored as a result of insulin incubation in the presence of glucose or fructose using AGE-dependent fluorescence, Tyr fluorescence as well as anilinonaphthalenesulfonate (ANS) andthioflavin T (ThT) binding, and circular dichroism (CD) investigations. To study lipid peroxidation induced by insulin glycation, thiobarbituric acid (TBA) assay and thiobarbituric acid reactive substance (TBARS) monitoring were used. The effect of insulin–AGE on microglial viability was investigated by 3-(4, 5 dimethylthiazol-2-yl)—2, 5-diphenyltetrazoliumbromide (MTT) cell assay and Annexin V/propidium iodide (PI) staining.ResultsHere we are reporting the inhibitory effect of BHB on insulin glycation and generation of insulin-AGE as a possible explanation for insulin resistance. Moreover, the protective effect of BHB on consequential glycation derived liposomal lipid peroxidation as a causative event in microglial apoptosis is reported.ConclusionThe reduced insulin fibril formation, structural inertia to glycation involved conformational changes, anti-lipid peroxidation effect, and increasing microglia viability indicated the protective effect of BHB that disclose insight on the possible preventive effect of BHB on Alzheimer’s disease.
Highlights
Type 1 Diabetes is generally characterized by raised level of blood sugar due to imperfection in insulin secretion, type 2 diabetes is characterized by insulin resistance that results in both of hyperglycemia and hyperinsulinemia and type 3 diabetes is characterized with neurodegeneration linked with insulin resistance
We are reporting the inhibitory effect of beta-hydroxy butyrate (BHB) on insulin glycation and generation of insulin advance glycation end product as a possible explanation for insulin resistance
When insulin was incubated in the presence of glucose or fructose, insulin was glycated and advanced glycation end products (AGE)-dependent fluorescence was increased by the time, followed by a protein conformational change monitored by decreasing ThT binding analysis. Protein intrinsic (Tyr) or increasing ANS fluorescence intensities; while BHB inhibited all three mentioned cases
Summary
Type 1 Diabetes is generally characterized by raised level of blood sugar (hyperglycemia) due to imperfection in insulin secretion, type 2 diabetes is characterized by insulin resistance that results in both of hyperglycemia and hyperinsulinemia and type 3 diabetes is characterized with neurodegeneration linked with insulin resistance. It is established that protein glycation, oxidative stress, and lipid peroxidation are key processes in diabetes and related complications [3, 4]. Due to the glucose autooxidation and protein glycation, hyperglycemia result in increased production of reactive oxygen species (ROS) that originates oxidative stress as an imbalance between radical- generating and radical-scavenging systems [5]. Diabetes mellitus is characterized jointly by hyperglycemia and hyperinsulinemia that make insulin more prone to be glycated and evolve insulin advanced glycation end products (Insulin- AGE). We report the effect of beta-hydroxy butyrate (BHB) (the predominant ketone body) on the formation of insulin-AGE, insulin glycation derived liposomal lipid peroxidation and insulin-AGE toxicity in microglial cells
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