Abstract
Type-2 Diabetes Mellitus (T2DM) is a growing pandemic that affects over 380 million people worldwide, especially in New Zealand where Māori and Pacifica populations are disproportionately affected. Besides insulin resistance, hallmarks of T2DM include the increase in pancreatic β-cell mass loss leading to reduced insulin secretion subsequently causing hyperglycaemia. Compelling new evidence suggests that the loss of insulin-producing pancreatic β-cells may be due to the increased conversion of β-cells to glucagon-secreting α-cells, known as β-cell plasticity.
The transforming growth factor-β (TGFβ) pathway maintains pancreatic β-cell identity. Its activation facilitates paired box 4 (Pax4) expression, a protein that is important to maintain β-cell identity and insulin production highlighting the importance of the TGFβ pathway for β-cell plasticity and T2DM development. A major negative regulator of the TGFβ pathway especially during inflammation is the transcription factor mothers against decapentaplegic homolog 7 (SMAD7).
Uric acid (UA), a metabolite of purine and fructose metabolism, increases significantly in pre-diabetic and diabetic patients. Furthermore, elevated UA levels (hyperuricemia) are known to inhibit the TGFβ pathway, however, the exact underlying mechanisms linking UA to the SMAD7-TGFβ signalling and to β-cell plasticity in T2DM is unknown and is the aim of this study.
Using the immunoblotting technique in fed and fasted, high fructose diet fed, and db/db mouse models, we found a significant reduction in Pax4 protein expression in high fructose fed mice (p = 0.034, n = 4) and db/db mice (p = 0.005, n = 6). Interestingly, we only detected a significant increase in Smad7 protein expression in db/db mice (p = 0.005, n = 6).
Findings in the Bahn lab (Dpt Physiology, Otago), revealed that elevated UA levels significantly down-regulated PAX4 expression and increased glucagon synthesis in pancreatic β-cells. High-fructose fed and db/db mice are hyperuricemic indicating a possible connection between hyperuricemia and changes in TGFβ-mediated β-cell plasticity in vivo. The changes in Smad7 protein expression we saw in db/db mice suggest that the increase in TGFβ signalling inhibition might be induced by increased inflammation, a condition known in the context of hyperuricemia as gout. Our results are the first step towards a better understanding of the real causes leading to the development of T2DM based on the observed disturbance of β-cell plasticity evolving as the main driver of T2DM. Ultimately, the answer to whether T2DM is an inflammatory or metabolic disease or both at different time points of the disease will lead to changes in T2DM treatment.