Isosteviol Has Beneficial Effects on Palmitate-Induced α-Cell Dysfunction and Gene Expression

Abstract

BackgroundLong-term exposure to high levels of fatty acids impairs insulin secretion and exaggerates glucagon secretion. The aim of this study was to explore if the antihyperglycemic agent, Isosteviol (ISV), is able to counteract palmitate-induced α-cell dysfunction and to influence α-cell gene expression.Methodology/Principal FindingsLong-term incubation studies with clonal α-TC1–6 cells were performed in the presence of 0.5 mM palmitate with or without ISV. We investigated effects on glucagon secretion, glucagon content, cellular triglyceride (TG) content, cell proliferation, and expression of genes involved in controlling glucagon synthesis, fatty acid metabolism, and insulin signal transduction. Furthermore, we studied effects of ISV on palmitate-induced glucagon secretion from isolated mouse islets. Culturing α-cells for 72-h with 0.5 mM palmitate in the presence of 18 mM glucose resulted in a 56% (p<0.01) increase in glucagon secretion. Concomitantly, the TG content of α-cells increased by 78% (p<0.01) and cell proliferation decreased by 19% (p<0.05). At 18 mM glucose, ISV (10−8 and 10−6 M) reduced palmitate-stimulated glucagon release by 27% (p<0.05) and 27% (p<0.05), respectively. ISV (10−6 M) also counteracted the palmitate-induced hypersecretion of glucagon in mouse islets. ISV (10−6 M) reduced α-TC1–6 cell proliferation rate by 25% (p<0.05), but ISV (10−8 and 10−6 M) had no effect on TG content in the presence of palmitate. Palmitate (0.5 mM) increased Pcsk2 (p<0.001), Irs2 (p<0.001), Fasn (p<0.001), Srebf2 (p<0.001), Acaca (p<0.01), Pax6 (p<0.05) and Gcg mRNA expression (p<0.05). ISV significantly (p<0.05) up-regulated Insr, Irs1, Irs2, Pik3r1 and Akt1 gene expression in the presence of palmitate.Conclusions/SignificanceISV counteracts α-cell hypersecretion and apparently contributes to changes in expression of key genes resulting from long-term exposure to palmitate. ISV apparently acts as a glucagonostatic drug with potential as a new anti-diabetic drug for the treatment of type 2 diabetes.

The Dynamic Effects of Isosteviol on Insulin Secretion and Its Inability to Counteract the Impaired β-Cell Function during Gluco-, Lipo-, and Aminoacidotoxicity: Studies In Vitro

“…We have shown that ISV improves glucose and insulin sensitivity, lowers plasma triglycerides, lowers weight in diabetic KKAy mice, and markedly changes the gene expression profile of key insulin regulatory genes [ 33 , 34 ]. Additionally, we found evidence that ISV counteracts α-cell hypersecretion and contributes to changes in the expression of key genes after long-term exposure to palmitate [ 35 ].…”

Impact of glucagon‐like peptide‐1 (7‐36) amide, isosteviol and 5‐aminoimidazole‐4‐carboxamide 1‐β‐d‐ribofuranoside on leucine‐mediated α‐cell dysfunction

“…Although AICAR increased MafB gene expression, it did not change glucagon hypersecretion to 5 mM leucine. Most recently we found that ISV decreased palmitateinduced hyperglucagonaemia in both the mouse islets and α-TC1-6 cells [53]. ISV 10 −6 M did not significantly decrease glucagon hypersecretion or change CHO content, TG content or α-cell proliferation to long-term leucine exposure.…”

Glucagon: The renewal of an old hormone in the pathophysiology of diabetes (胰升糖素：一种老激素在糖尿病病理生理中的新作用)

“…Similarly, expression of Pdx1 , Nk6.1 , NeuroD1/B2 , HFN1α , HFN4α , and Foxa2 mRNA was decreased by 40–60%; these changes were reversible when hyperglycemia was corrected after 4 weeks but only partially after 14 weeks . In the db / db mouse model of T2D, chronic hyperglycemia also led to decreases in Nkx6.1 , NeuroD1/B2 , Pdx1 and Pax6 mRNA expression at 16 weeks, whereas HFN1α mRNA expression was unaffected . Furthermore, 24‐h exposure of human islets to a long‐chain fatty acid mixture resulted in marked reduction of Pdx1 and Pax6 expression …”