Effect of TNF-α on the expression of ABCA1 in pancreatic β-cells

ATP-binding cassette transporter A1 (ABCA1), a 254-kD membrane protein, is a key regulator of lipid efflux from cells to apolipoproteins. ABCA1 in pancreatic β-cells influences insulin secretion and cholesterol homeostasis. Tumor necrosis factor (TNF)-α is a pleiotropic cytokine that elicits a wide spectrum of physiological events, including cell proliferation, differentiation and apoptosis and is also known to decrease glucose-dependent insulin secretion in pancreatic islets. In the present study, we examined the role of TNF-α on ABCA1 expression in rat pancreatic islets and INS-1 cells. ABCA1 protein levels decreased in response to rising concentrations of TNF-α in pancreatic islets. Real-time polymerase chain reaction analysis showed a significant decrease in ABCA1 mRNA expression. In parallel with its effect on endogenous ABCA1 mRNA levels, TNF-α suppressed the activity of a reporter construct containing the ABCA1 promoter. This effect was abrogated by BIRB796, but not by SB203580 or LY-294002. The constitutively active form of p38 mitogen-activated protein kinase (MAPK) γ suppressed ABCA1 promoter activity but not p38-MAPK (α, β), while a dominant-negative mutant of p38-MAPK γ blocked the effect of TNF-α on ABCA1 promoter activity. BIRB796 inhibited the increased cholesterol ester content induced by TNF-α. However, BIRB796 had no effect on either the decreased insulin content or the ABCA1 suppression caused by TNF-α in INS-1 cells. We checked the influence of TNF-α of insulin secretion and glucose-stimulated insulin secretion in rat pancreatic islet and INS-1 cell. TNF-α suppressed the insulin secretion and glucose-stimulated insulin secretion in both rat pancreatic islet and INS-1 cell. In summary, TNF-α suppressed the expression of endogenous ABCA1 and suppress the insulin secretion in pancreatic islets and INS-1 cells. These findings raise the possibility that TNF-α may affect insulin secretion by controlling ABCA1 expression.

PHYTOCHEMISTRY, MODE OF ACTION AND PHARMACOLOGICAL APPLICATIONS OF 4-HYDROXYISOLEUCINE FROM TRIGONELLA FOENUM GRAECUM

Herbal products are emerging as promising anti-diabetic drugs due to lower cost, lesser side effects and renewable natural sources. 4-hydroxyisoleucine is reported as the bioactive compound, which is responsible for anti-diabetic activity of fenugreek. This review illustrates the overall properties, synthesis, mode of action and pharmacological profile of 4-hydroxyisoleucine. From the seeds of Trigonella foenum graecum an unusual amino acid, 4-hydroxyisoleucine has been isolated which significantly improved lipid profile and it increased glucose-induced insulin release in human and rat pancreatic islet cells. No adverse effect or toxic effect of 4-hydroxyisoleucine has been found. Marketed preparations are also available.

Acute Exposure to a Precursor of Advanced Glycation End Products Induces a Dual Effect on the Rat Pancreatic Islet Function

Aim.Chronic diseases are the leading cause of death worldwide. Advanced glycation end products, known as AGEs, are a major risk factor for diabetes onset and maintenance. Methylglyoxal (MG), a highly reactive metabolite of glucose, is a precursor for the generation of endogenous AGEs.Methods.In this current study we incubatedin vitropancreatic islets from adult rats in absence or presence of MG (10 μmol/l) with different concentrations of glucose and different metabolic components (acetylcholine, epinephrine, potassium, forskolin, and leucine).Results.Different effects of MG on insulin secretion were evidenced. In basal glucose stimulation (5.6 mM), MG induced a significant (P<0.05) increase of insulin secretion. By contrast, in higher glucose concentrations (8.3 mM and 16.7 mM), MG significantly inhibited insulin secretion (P<0.05). In the presence of potassium, forskolin, and epinephrine, MG enhanced insulin secretion (P<0.05), while when it was incubated with acetylcholine and leucine, MG resulted in a decrease of insulin secretion (P<0.05).Conclusion.We suggest that MG modulates the secretion activity of beta-cell depending on its level of stimulation by other metabolic factors. These results provide insights on a dual acute effect of MG on the pancreatic cells.