A Novel Mediator connects Diabetes and Periodontitis
Type-2 diabetic (T2D) patients are prone to developing periodontitis, which involves an elevated inflammatory response and greater bone resorption by osteoclasts. The International Diabetes Federation estimates that the number of people with diabetes will continue to increase, and at least 55% will develop chronic periodontitis. Diabetes is a metabolic disorder that alters metabolites. We recently reported that succinate is significantly elevated by hyperglycemia and in T2D patients. Levels of succinate, a Krebs cycle intermediate, increase after dysregulated energy metabolism (such as diabetes and aging), which binds to its cognate receptor, SucnR1, to activate downstream signaling pathways promoting inflammation. Meanwhile succinate alters microbiome directly by supporting the growth of pathogenic bacterial species.
Figure 1. Working model of how succinate elevation in diabetes increases periodontitis.
Succinate signaling mediated neuroinflammation
Patients with periodontitis and type 2 diabetes (T2D) have a higher risk of developing Alzheimer's disease (AD). AD is a degenerative brain disorder that gradually destroys the ability to remember, reason, learn, and imagine. It is estimated that almost 6 million Americans of all ages are living with Alzheimer's dementia currently. As the number of senior Americans grows rapidly, so will the numbers of new and existing cases of patients with T2D and periodontitis who will be at higher risk of developing Alzheimer's. We have shown that succinate, a tricarboxylic acid cycle intermediate, significantly increased in diabetes, periodontitis and aging. It is intriguing to determine whether neuroinflammation, including neurodegeneration, microglial activation and production of inflammatory cytokines occur in response to elevated succinate levels.
Figure 2. Immunofluorescent of SucnR1 and neuron marker MAP2 in A-D) Primary neurons and E) Hippocampal CA3 pyramidal cells.
Metformin: the most prescribed T2D medicine and what else?
Metformin acts as a chemopreventive agent to impede prostate cancer initiation and progression in prostate cancer mouse models. We further studied the molecular mechanism of metformin's anti-neoplasia effects in prostate cancer development. Our data suggest that metformin targets c-Myc oncogene, miR708, H3K9 methyltransferase (Suv39H1) and importins (KPNA4 and KPNB1) to regulate cell proliferation, apoptosis, and migration.
Figure 3. The malignancy of prostate in Hi-Myc mice is reduced by metformin.
Metformin inhibits oral malignancy by down-regulating c-Myc and interfering cell metabolism
Figure 4. Metformin reduced the tumor burden in mice with salivary gland adenocarcinoma xenografts.
Rescues impaired osteogenesis in diabetes
Figure 5. Metformin treatment improved bone healing in diabetic mice (MKR).
Rebalances the metabolite profile in diabetes
Figure 6. Alterations of TCA and urea cycle metabolites revealed by LC-MS. Only significant changes at p<0.05, as indicated by a post-ANOVA t-test, are marked with arrows. Red arrow: regulated in MKR vs. WT; Blue arrow: regulated by metformin vs. PBS in MKR mice. Light blue oval: enzyme.
Experimental Tools and Approaches
- Transgenic mouse models for prostate cancer and diabetes
- Surgery models mimicking postmenopausal, periodontitis, fracture, and brain injury etc.
- In vitro primary culture and assays of osteoblasts, osteoclasts, gingival tissues, microglial cells, astrocytes and neurons.
- Histology and microCT
- Genetic, epigenetic, metabolomics, RNA seq analysis, and Flow cytometry