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Mol Cell Biochem. 2019 Feb;452(1-2):17-27. doi: 10.1007/s11010-018-3408-7. Epub 2018 Jul 23.

Bacterial supernatants elevate glucose-dependent insulin secretion in rat pancreatic INS-1 line and islet β-cells via PI3K/AKT signaling.

Author information

1
Clinic of Preventive Dentistry, Periodontology and Cariology, Center of Dental Medicine, University of Zurich, Plattenstrasse 11, 8032, Zurich, Switzerland.
2
Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.
3
Department for Statistics, Ludwig-Maximilians-University Munich, Theresienstrasse 39/I, 80333, Munich, Germany.
4
Clinic of Preventive Dentistry, Periodontology and Cariology, Center of Dental Medicine, University of Zurich, Plattenstrasse 11, 8032, Zurich, Switzerland. patrick.schmidlin@zzm.uzh.ch.

Abstract

Diabetes and periodontitis are considered associated chronic diseases, and hyperinsulinemia in prediabetes has been shown to be present in normoglycemic animals with periodontitis. As periodontal bacterial species are significant sources of endotoxemia and may directly stimulate insulin secretion, we hypothesized that increased bacterial virulence may exert an adverse effect on rat pancreatic β-cell function via PI3K/AKT signaling. INS-1 cells and isolated pancreatic islets were cultured separately with the following supernatants: Streptococcus anginosus, Streptococcus mutans, Fusobacterium nucleatum, Prevotella intermedia, Porphyromonas gingivalis (P.g), and Treponema denticola (T.d). Supernatants were purified from single bacterial cultures and prepared at different dilutions (100 pg/ml, 50 ng/ml, 200 ng/ml, and 500 ng/ml) to challenge INS-1 and islets. Gene expression (IL-1β, TNFα, IL-6, TLR2, TLR4, Ins1, and Ins2) and insulin secretion were measured. The results showed upregulation of gene expression up to 5.5-fold, not only as a result of the different dilutions used, but also due to bacterial virulence (p < 0.05). P.g and T.d supernatants demonstrated an increase in insulin secretion to fivefold at hypo- and hyperglycemia, yet stimulation from hypo- to hyperglycemia stays in the same ratio. Activation of TLR4/PI3K/AKT signaling by supernatants in INS-1 cells resulted in increased IL-1β, TNFα, IL-6 gene expression levels, and AKT phosphorylation, which were abolished by TLR4 and PI3K/AKT signaling inhibitor. We demonstrated that bacterial supernatants derived from gram-negative species increasingly stimulate insulin secretion in β-cells and TLR4 may promote inflammation by activating the PI3K/AKT signaling pathway to induce pro-inflammatory molecules. Bacterial species, depending on their virulence, appear to play a role in the relationship between periodontitis and prediabetes by promoting insulin resistance and β-cell compensatory response.

KEYWORDS:

Cytokines; Gene expression; Insulin; Microbiology; Signaling pathway

PMID:
30039349
PMCID:
PMC6373304
DOI:
10.1007/s11010-018-3408-7
[Indexed for MEDLINE]
Free PMC Article

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