Free Fatty Acid-Induced Inhibition of Glucose and Insulin-Like Growth Factor I-induced Deoxyribonucleic Acid Synthesis in the Pancreatic Beta-Cell Line INS-1

Endocrinology. 2001 Jan;142(1):229-40. doi: 10.1210/endo.142.1.7863.

Abstract

Pancreatic beta-cell mitogenesis is increased by insulin-like growth factor I (IGF-I) in a glucose-dependent manner. In this study it was found that alternative beta-cell nutrient fuels to glucose, pyruvate, and glutamine/leucine independently induced and provided a platform for IGF-I to induce INS-1 cell DNA synthesis in the absence of serum. In contrast, long chain FFA (>/=C(12)) inhibited 15 mM glucose-induced [(3)H]thymidine incorporation (+/-10 nM IGF-I) by 95% or more within 24 h above 0.2 mM FFA complexed to 1% BSA (K(0.5) for palmitate/1% BSA = 65-85 microM for 24 h; t(0.5) for 0.2 mM palmitate/1% BSA = approximately 6 h). FFA-mediated inhibition of glucose/IGF-I-induced ss-cell DNA synthesis was reversible, and FFA oxidation did not appear to be required, nor did FFA interfere with glucose metabolism in INS-1 cells. An examination of mitogenic signal transduction pathways in INS-1 cells revealed that glucose/IGF-I induction of early signaling elements in SH2-containing protein (Shc)- and insulin receptor substrate-1/2-mediated pathways leading to downstream mitogen-activated protein kinase and phosphoinositol 3'-kinase activation, were unaffected by FFA. However, glucose-/IGF-I-induced activation of protein kinase B (PKB) was significantly inhibited, and protein kinase Czeta was chronically activated by FFA. It is possible that FFA-mediated inhibition of ss-cell mitogenesis contributes to the reduction of beta-cell mass and the subsequent failure to compensate for peripheral insulin resistance in vivo that is key to the pathogenesis of obesity-linked diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Cell Division / drug effects*
  • Cell Line
  • DNA / biosynthesis*
  • DNA / drug effects
  • Enzyme Activation
  • Fatty Acids, Nonesterified / pharmacology*
  • GRB2 Adaptor Protein
  • Glucose / pharmacology*
  • Insulin-Like Growth Factor I / pharmacology*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Kinetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Palmitic Acid / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase C / metabolism
  • Protein-Serine-Threonine Kinases*
  • Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • Fatty Acids, Nonesterified
  • GRB2 Adaptor Protein
  • Proteins
  • Proto-Oncogene Proteins
  • Palmitic Acid
  • Insulin-Like Growth Factor I
  • DNA
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • protein kinase C zeta
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • Glucose