Elsevier

Metabolism

Volume 53, Issue 11, November 2004, Pages 1443-1448
Metabolism

Stimulatory short-term effects of free fatty acids on glucagon secretion at low to normal glucose concentrations

https://doi.org/10.1016/j.metabol.2004.06.011Get rights and content

Abstract

While free fatty acids (FFA) are well known as insulin secretagogues, their effects on pancreatic α cells have been mostly neglected. In the present study we therefore systematically analyzed the glucagon metabolism of rat pancreatic islets under the influence of FFA. Primary islets were incubated in the presence or absence of 200 μmol/L albumin-complexed palmitate or oleate at 2.8 mmol/L versus 16.7 mmol/L glucose and glucagon secretion was monitored over 8 hours. In addition to these time-course experiments, dose dependency of palmitate-induced effects was tested by a 2-hour incubation with 50 to 300 μmol/L albumin-complexed palmitate at 2.8 mmol/L and 5.6 mmol/L glucose. Apart from glucagon secretion, intracellular immunoreactive glucagon and cellular preproglucagon-mRNA (PPG-mRNA) content were determined from the remaining cell lysates. FFA, especially palmitate, induced a significant and dose-dependent increase of glucagon secretion (in average 2-fold above control) during the first 120 minutes of incubation at low to normal glucose (2.8 and 5.6 mmol/L). There was no significant glucagonotropic effect of FFA at concomitant 16.7 mmol/L glucose. Intracellular glucagon as well as cellular PPG-mRNA content were found to be dose-dependently diminished by palmitate when compared with untreated controls at 5.6 mmol/L glucose. The present analysis therefore points to a new role for FFA as a nutritient secretagogue and a modulator of α-cellular glucagon metabolism.

Section snippets

Materials

Radioimmunoassays for pancreatic glucagon (crossreactivity to oxyntomodulin <0.1%) and for immunoreactive insulin (IRI) were performed with kits from Linco Research (St Louis, MO). Fatty acid ultra-free bovine serum albumin (BSA, Fraction V), protease inhibitor cocktail (Complete), Collagenase P (1.5 U · mg−1), as well as all technical and chemical equipment for semiquantitative Light Cycler Polymerase Chain Reaction (PCR), were from Roche Diagnostics (Mannheim, Germany). Reverse transcription

Time- and glucose-dependent effects of palmitate on glucagon and insulin secretion

At 2.8 mmol/L glucose, palmitate elicited a 1.7- to 2.7-fold (ie, in average a 2.0 [±0.3]-fold) increase in glucagon secretion over 30 minutes (P = .041), 60 minutes (P = .0003), 120 minutes (P = .001), and 240 minutes (P = .0003). The glucagonotropic effect was fading after 480 minutes (Fig 1A). At concomitant 16.7 mmol/L glucose, no relevant glucagonotropic palmitate effect was observed (Fig 1B). Comparing glucagon secretion at 16.7 mmol/L glucose with that at 2.8 mmol/L glucose, we could

Discussion

In the present study, palmitate and oleate induced a relevant increase of glucagon secretion from isolated rat pancreatic islets during short-term exposure (ie, ≤4 hours). This glucagonotropic effect was only observed at low to normal glucose levels (2.8 to 5.6 mmol/L) but not at high glucose (16.7 mmol/L). A decrease of the glucose concentration per se (ie, in the absence of FFA) exerted no relevant glucagonotropic effect, which is in accordance to previous in vitro studies.6, 11, 19 Ishishara

Acknowledgements

The authors acknowledge the excellent technical assistance of Iris Ottinger. They are also indebted to Dr Christa Buechler for helpful discussions.

References (26)

  • G.C. Yaney et al.

    Fatty acid metabolism and insulin secretion in pancreatic beta cells

    Diabetologia

    (2003)
  • A.S. Luyckx et al.

    Arguments for a regulation of pancreatic glucagon secretion by circulating plasma free fatty acids

    Proc Soc Exp Biol Med

    (1970)
  • R.H. Unger et al.

    Physiology and pathophysiology of glucagon

    Physiol Rev

    (1976)
  • Cited by (34)

    • Glucagon and the metabolic syndrome

      2023, Metabolic Syndrome: From Mechanisms to Interventions
    • Mesenchymal stem cell-conditioned medium alleviates high fat-induced hyperglucagonemia via miR-181a-5p and its target PTEN/AKT signaling

      2021, Molecular and Cellular Endocrinology
      Citation Excerpt :

      Fasting glucagon concentrations are associated with a longitudinal decline of β-cell function in non-diabetics (Adams et al., 2020). Free fatty acids increase glucagon secretion from α-cell lines and primary islets (Hong et al., 2007; Bollheimer et al., 2004; Olofsson et al., 2004; Collins et al., 2008; Piro et al., 2010). α-Cells exposed to fatty acids exhibit insulin resistance, manifested as impaired IRS-1/PI3K/Akt pathway, which participates in glucagon secretion regulation (Piro et al., 2010).

    • Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis through Adipose Tissue Crosstalk

      2016, Cell Metabolism
      Citation Excerpt :

      Given the insulin-sensitizing actions of adiponectin on multiple cell types, along with its protective capacity in the β cell, the role of adiponectin in the α cell provides for an exciting potential target to treat the hyperglycemia associated with type 1 and type 2 diabetes. Fatty Acids: Recent studies suggest that short-term exposure to fatty acids stimulates glucagon exocytosis (Bollheimer et al., 2004; Hong et al., 2007; Olofsson et al., 2004). Similar to the stimulatory effect of low glucose concentrations, palmitate has been shown to increase Ca2+-mediated glucagon release by opening Ca2+ channels.

    View all citing articles on Scopus

    Supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (Bo 1379/2-1, Bo 1379/2-2).

    View full text