Diabetes continues to be a global burden, affecting over 450 million people worldwide and is associated with chronic health impairment and premature mortality in adults. The Diabetes Research Center (DRC) at the Qatar Biomedical Research Institute (QBRI) supports the Qatar national strategy in diabetes research in pursuing translational and innovative basic research to develop novel biomarkers and therapies for diabetes and its vascular complications and comorbidities. Dr. Paul J Thornalley, Scientific Director at the DRC-QBRI, highlights key research programs in his group in collaboration with other DRC and Qatar-based investigators towards this goal.
Diabetic kidney disease (DKD) is one of the most feared associated health impairments or complications of diabetes, leading to a decline in kidney function and dialysis, with an increased risk of fatal heart disease. Identification of patients at risk of DKD and early-stage preventive treatment is important but risk predictive biomarkers are unknown. Using artificial intelligence machine learning, Dr. Thornalley’s team, in collaboration with investigator Prof. Naila Rabbani at Qatar University, discovered that fractional excretion of glycated amino acids are risk predictors of DKD and including only three glycated amino acids in blood and urine in algorithms gave strong, often conclusive evidence of future risk of DKD. With further validation, this diagnostic method may markedly improve risk prediction and prevention of DKD.
Patients with diabetes have an increased risk of developing severe COVID-19 disease following infection with SARS-CoV-2 coronavirus in the ongoing global pandemic. Dr. Thornalley’s team has developed a dietary supplement for the treatment of insulin resistance to prevent and reverse type 2 diabetes. During a clinical trial, the supplement had a strong anti-inflammatory effect – decreasing inflammatory mediators, interleukin-8 (IL8) and monocyte chemoattractant protein-1 (MCP-1), in overweight and obese subjects. IL8, and MCP1 were identified as risk predictors and potential risk factors of severe COVID-19. The team considered repurposing the dietary supplement for the prevention and treatment of severe COVID-19. Further studies revealed that the supplement decreases expression of IL8, MCP-1, and also proteases in human lung alveolar epithelial cells considered essential for infectivity of SARS-CoV-2. Research is now ongoing with collaborators to assess the prevention of infectivity by SARS-CoV-2 and progression of COVID-19 by the supplement. Repurposing of the supplement, trans-resveratrol and hesperetin combination (tRES-HESP) – an inducer of glyoxalase 1 expression or “Glo1 inducer”, was patented. tRES-HESP was developed to decrease protein glycation by the reactive metabolite, methylglyoxal, and thereby suppress activation of the Unfolded Protein Response (UPR) and drivers of insulin resistance and inflammation (Figure 1). The UPR is required for the correct folding of viral proteins in SARS-CoV-2 replication and also likely contributes to the inflammatory response driving the development of severe symptoms of COVID-19. This project is part of the QBRI research response to counter the COVID-19 pandemic.
Dr.Thornalley’s team, in collaboration with Dr. Abdelilah Arredouani (DRC) and QBRI Executive Director, Dr. Omar El-Agnaf, are also investigating diagnostic biomarkers for diagnosis of co-morbidities of type 2 diabetes – cardiovascular disease, stroke, and dementia. This translational research is in collaboration with Qatar Biobank, HBKU’s Qatar Computing Research Institute (QCRI), Hamad Medical Corporation (HMC), and Weill Cornell College of Medicine-Qatar (WCM-Q). Blood-based biomarkers for diagnosis of cardiovascular disease, stroke, and early-stage dementia in patients with and without type 2 diabetes are being investigated and combined in diagnostic algorithms to improve co-morbidity diagnosis in patients with type 2 diabetes. It is likely that some biomarkers may be mechanistic and suggest new strategies for improved prevention and treatment in selected patient groups. The lead investigator is Dr. Thornalley. Clinical collaborators in DRC translational research in precision medicine include Dr. Khalid Hussain (Sidra Medicine); Dr. Shahrad Taheri and Dr. Rayaz Malik (WCM-Q); and Dr. Abou-Samra, Dr. Jassim Al Suwaidi, Dr. Ashfaq Shuaib, Dr. Naveed Akhtar, and Dr. Aijaz Parray (HMC).
Figure 1. Proposed mechanism of action of Glo1 inducer, tRES-HESP, through suppression of the unfolded protein response. Key: yellow filled arrows – mechanism of health improvement by; red filled arrows – damaging processes suppressed. From: Rabbani et al., Nutrients 13, 2374, 2021, where the definition of abbreviations is also given.
A major research effort of the DRC is a collaboration with Harvard Stem Cell Research Institute (HSCI), Boston, USA. Human-induced pluripotent stem cell (iPSC) technology is used to advance understanding of the molecular and cellular mechanisms underlying the progression of type 1 and type 2 diabetes and development of iPSC-derived pancreatic beta-cells for cell therapy of type 1 diabetes. Dr. Thornalley’s team is contributing to two of the four projects in this collaboration: studies on the role of transcription factors in the production of iPSC-derived pancreatic beta-cells – a project coordinated by Dr. Essam Abdelalim in collaboration with other DRC investigators, Dr. Al-Siddiqi, Dr. Kolatkar, and Dr. Arredouani; and a project on metabolic inflammation in the pancreatic beta-cell – coordinated by Dr. Thornalley in collaboration with Dr. Abdelalim.
This year has seen increased recognition of DRC research at major international diabetes research conferences, with three oral presentations at the 81st American Diabetes Association (ADA) Scientific Sessions, and forthcoming oral presentations at the 57th European Association for the Study of Diabetes (EASD) Annual Meeting and International Diabetes Federation (IDF) Congress on Diabetes, Complications and COVID-19 later this year. Dr. Thornalley in collaboration with other DRC investigators and Prof. Rabbani (Qatar University) is organizing and hosting an international symposium and a conference on diabetes-related themes:
IMARS-14 is sponsored by Qatar National Research Fund and the International Maillard Reaction Society. Protein glycation provides one of the most important biomarkers, glycated hemoglobin or “A1C”, in the diagnosis and care of people at risk of developing diabetes and for control of blood glucose and prevention of vascular complications of patients with diabetes. The keynote speaker will be Professor Kazutoshi Mori (Lasker Laureate, Kyoto University, Japan). There will be over 120 presentations at IMARS-14 by leading diabetes and glycation researchers. DRC investigators will be presenting – including a session on “Methods and Models in Glycation Research” with collaborators from Qatar University.
Figure 2. IMARS-14 - Protein glycation in food, health, and disease. A virtual conference online, hosted from Doha, Qatar, September 20-24, 2021.
Contribution by: Dr. Paul J Thornalley (Scientific Director, Diabetes Research Center, QBRI)
Arabic text validation: Rowaida Z. Taha, Research Associate at QBRI
Editors: Dr. Adviti Naik (Postdoctoral Researcher, QBRI), Dr. Prasanna Kolatkar (Senior Scientist, QBRI),