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Research

Diabetes and its comorbidities

Diabetes and its comorbidities: a multidisciplinary approach to identify new ways to fight a global epidemic

Giordano Pula

Research specialisms

Cell Biology, Biochemistry, Imaging, Physiology and Pharmacology, Nutrition and Metabolism, Vascular Biology, Regenerative Medicine.

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Group lead

Dr Giordano Pula

Email: G.Pula@hull.ac.uk

Phone: 01482 464898 

The Challenge

Diabetes is a multifaceted disease that reduces life quality and expectancy through a plethora of health complications and comorbidities. Diabetes accounts for a large portion of the health expenditure in developed countries and the number of patients is predicted to rise sharply in the next decades.

In order to address the spectrum of health problems caused by diabetes, our PhD cluster brings together a multi-disciplinary team of Hull-based scientists and national industrial partners in the field of nutritional interventions for diabetes patients. 

The Approach

The complexity of diabetes requires a multidisciplinary research approach to understand its mechanisms and deliver novel therapeutic tools. 

This PhD cluster will therefore bring together a multidisciplinary team from five different Schools within the University of Hull to investigate four fundamental aspects of diabetes: 1) the effect on blood clotting and vascular health; 2) the association with kidney diseases; 3) the impairment of wound healing leading to peripheral limb diseases; 4) the effect of diabetes on vascular integrity and function.

The supervisory teams of each project have been selected to provide advanced multidisciplinary training for the PGRs, which will be a key asset for their success as future research leaders. The PhD students will gain an understanding of different research areas: preclinical science (including in vivo research ethics training), medical research (including training on REC and HTA ethics), clinical practice, clinical biochemistry, nutrition science, industrial research and business development. They will join established research teams, with cutting-edge expertise, significant external funding, existing resources, and relevant equipment. The resources available for this cluster include biochemistry and cell biology research infrastructures within the Allam and Hardy buildings (e.g. cell culture, imaging and flow cytometry setups), state of the art in vivo research infrastructures within Biological Service Unit, medical research platforms within NHS-trusts and clinical research-focused structures such as the Allam Diabetes Centre at HRI and the Daisy Appeal Medical Research Centre at Castle Hill Hospital, and industrial research/business development training through the interaction with the industrial partner and the Research Innovation Team. Short placements within the infrastructures of our industrial partner will be part of the formative experience for our PhD students. 

Healthcare_Science

Aims

  • Provide outstanding multi-disciplinary and industry-facing training
  • Identify novel pathophysiological and biochemical mechanisms underlying diabetes-related health complications
  • Determine the potential of novel forms of dietary supplementation to fight this disease
  • Promote diabetes research within the Universities of Hull and the North East. 

Projects

Blood cells

Diabetes and thrombosis: mechanistic links and novel interventional opportunities

Clinical Anatomy students

Development and characterisation of novel antioxidant H2S-releasing compounds to prevent diabetic kidney disease

student using microscope

The underlying causes of the diabetic foot: revascularisation deficit and novel strategies to boost healing

students using blood pressure monitors on each other

Vascular endothelial cell damage, its role in vascular complications of diabetes and the potential of dietary interventions

  • See all projects

    Project 1: Diabetes and thrombosis: mechanistic links and novel interventional opportunities

    Dr Giordano Pula (main supervisor), Prof Tim Palmer, Liz Wells, Dr Vicky Green, Dr Ahmed Aburima.

    Thrombosis is the occlusion of blood vessels by uncontrolled blood clotting. Being the cause of death for 70% of diabetes patients, thrombosis is a serious threat in diabetes. Blood platelets drive blood clotting and are hyperactive in diabetes. Our previous results (ERC #101025074) suggest that high blood glucose in diabetes patients causes oxidative stress, vesicle shedding and hyperactivity of platelets, which lead to uncontrolled blood clotting and increase the risk of thrombosis. In this project we will: 1) identify the molecular mechanisms linking high blood glucose with platelet oxidative stress, vesicle shedding and hyperactivity; 2) determine whether thrombosis, vesicle shedding and oxidative stress are recapitulated in vivo using animal models of diabetes; 3) assess whether selected dietary interventions can normalise platelet response in vitro. animal models of diabetes and in diabetes patients.

    Project 2: Development and characterisation of novel antioxidant H2S-releasing compounds to prevent diabetic kidney disease

    Dr Sam Xu (main supervisor), Prof Thozhukat Sathyapalan, Dr Andrew Boa, Dr Giordano Pula, Prof Sunil Bhandari.

    The mortality and morbidity of diabetes patients are due to the development of comorbidities, including kidney failure. The development of novel therapeutics to prevent kidney complications in diabetes is therefore an important biomedical research endeavour. Endogenous hydrogen sulphide (H2S) plays an essential role in maintaining kidney cell viability and function. Low levels of H2S have been implicated in the development of renal complications of diabetes. Thus, H2S-releasing compounds are promising therapeutic tools. To this end, we have synthesised GYY4137, a water-soluble H2S-releasing molecule, and several novel H2S-releasing compounds as part of an externally funded ERC IMI2 grant.This project aims to: 1) test the effectiveness of H2S-releasing compounds in preventing kidney cell damage in culture conditions modelling diabetes; 2) determine the molecular mechanisms underlying the protective effects of H2S-releasing compounds in vitro; 3) assess the protective effects of H2S-releasing compounds on kidney function in animal models of diabetes.

    Project 3: The underlying causes of the diabetic foot: revascularisation deficit and novel strategies to boost healing

    Dr Holly Wilkinson (main supervisor), Prof Matt Hardman, Dr Giordano Pula, Rebecca Vince.

    The diabetic foot is one of the most debilitating comorbidities of diabetes. It is caused by impaired tissue repair, which leads to limb dysfunction and ultimately amputation. Surgical interventions are commonlyutilised but are not suitable for all patients, which makes diabetic foot an unresolved medical emergency. In this project we aim to: 1) identify the molecular mechanisms impairing wound repair in diabetes using primary human cell cultures modelling diabetes (dermal endothelial cells for revascularisation studies and dermal fibroblasts/epithelial cells for repair studies); 2) confirm data from aim 1 in RNA-sequence data from animal models of diabetes and wound tissue explanted from diabetes foot patients; 3) test the effect on wound healing of pharmacological and dietary interventions using animal models of diabetes and wound tissue from diabetes foot patients cultured ex vivo.

    Project 4: Vascular endothelial cell damage, its role in vascular complications of diabetes and the potential of dietary interventions

    Prof Tim Palmer (main supervisor), Prof Thozhukat Sathyapalan, Dr Giordano Pula, Liz Wells.

    Increased oscillation of blood glucose levels or high glycaemic variability (GV) is associated with adverse clinical outcomes. The vascular endothelial cell injury caused by GV is a key cause of diabetes vascular complications. We hypothesise that GV causes metabolic and osmotic stress in vascular endothelial cells, leading to oxidative stress, functional impairment and ultimately vascular cell damage. We hypothesise that minimising the effect of GV on vascular endothelial cells may be beneficial for reducing the cardiovascular risk in diabetes.This project will: 1) characterise the effects of GV on vascular endothelial cell viability, motility, and function; 2) determine the molecular mechanisms mediating the effect of GV on vascular endothelial cells; 3) assess whether antioxidant dietary interventions protect endothelial cell and vascular function in cellular models of GV, in vivo models of diabetes and diabetes patient.

The Impact

Epidemiology projections warn regarding the increasing threat posed by diabetes, which is considered a “global health challenge” by the World Health Organization (WHO). Although uncontrolled blood clotting, vascular damage, kidney injury, poor wound repair and central nervous afflictions are key factors for the reduction of life quality and the increase in mortality in diabetes, the majority of current research addresses the onset mechanisms of the disease and focuses on pancreas or liver cells.

This leaves unaddressed important health risks for patients. Why are diabetes patients significantly more predisposed to certain diseases compared to the rest of the population? Why do current drugs have limited efficacy in protecting diabetes patients from blood vessel, kidney, skin or brain damage? Can we specifically target conditions associated to diabetes (i.e. comorbidities) and improve patients’ life quality and expectancy? At UoH, we have a unique opportunity to answer these questions.

Thanks to the wide spectrum of expertise (including synthetic chemistry, metabolism, biochemistry, nutrition, vascular biology, renal biology, wound healing and clinical practice), the focus on multidisciplinary research of the Biomedical Institute of Multimorbidity (BIM), and the access to clinical cohorts and data through our co-applicants based at HUTH and the Allam Diabetes Centre, we can make a real difference for diabetes patients and reduce the healthcare costs of this disease. 

  • Members

    Dr Giordano Pula

    Cluster lead | G.Pula@hull.ac.uk

    Dr Ahmed Aburima

    Supervisor | A.Aburima@hull.ac.uk

    Prof Sunil Bhandari

    Supervisor | SUNIL.BHANDARI@NHS.NET

    Dr Andrew Boa

    Supervisor | A.N.Boa@hull.ac.uk

    Dr Victoria Green

    Supervisor | V.L.Green@hull.ac.uk

    Prof Matt Hardman

    Supervisor | M.Hardman@hull.ac.uk

    Prof Tim Palmer

    Supervisor | Tim.Palmer@hull.ac.uk

    Prof Thozhukat Sathyapalan

    Supervisor | T.Sathyapalan@hull.ac.uk

    Dr Rebecca Vince

    Supervisor | Rebecca.Vince@hull.ac.uk

    Dr Sam Xu

    Supervisor | S.Xu@hull.ac.uk

    Ms Liz Wells

    Supervisor | Liz.Wells@hull.ac.uk

    Dr Holly Wilkinson

    Supervisor | H.N.Wilkinson@hull.ac.uk

  • Outputs and Publications

    1. Schulte C, Pieper L, Frye M, Waldeyer C, Neumann JT, Brunner FJ, Pula G (2023) Antiplatelet drugs do not protect from platelet-leukocyte aggregation in Coronary Artery Disease. J Thromb Haemost. S1538-7836(23)00408-7.

    2. Wolska N, Celikag M, Failla AV, Tarafdar A, Renné T, Torti M, Canobbio I, Pula G (2023) Human platelets release amyloid peptides β1-40 and β1-42 in response to haemostatic, immune, and hypoxic stimuli. Research and Practice in Thrombosis and Haemostasis (RPTH) 7(4):100154.

    3. Wallis S, Wolska N, Englert H, Posner M, Upadhyay A, Renné T, Eggleston I, Bagby S, Pula G. (2022) A peptide from the staphylococcal protein Efb binds P-selectin and inhibits the interaction of platelets with leukocytes. J Thromb Haemost. 20(3):729-741.

    4. Vara D, Mailer RK, Tarafdar A, Wolska N, Heestermans M, Konrath S, Spaeth M, Renné M, Schröder K, Pula G. (2021) NADPH oxidases are required for full platelet activation in vitro and thrombosis in vivo, but dispensable for plasma coagulation and haemostasis. Arteriosclerosis, Thrombosis and Vascular Biology 41(2):683-697.

    5. Aburima A, Berger M, Spurgeon B, Webb B, Wraith KS, Febbraio M, Poole A, and Naseem KM. (2021) Platelet-Derived Thrombospondin-1 Modulates cAMP Signaling To Promote Platelet Activation in a CD36-dependent manner”. Blood 137 (5): 678-689.

    6. Kahal H, Aburima A, Spurgeon B, Wraith KS, Rigby AS, Sathyapalan T, Kilpatrick ES, Naseem KM, Atkin SL. (2018) Platelet function following induced hypoglycaemia in type 2 diabetes. Diabetes Metab. 44(5):431-436.

    7. Crompton RA, Williams H, Campbell L, Kheng LH, Saville C, Ansell D, Reid A, Wong J, Vardy LA, Hardman MJ, Cruickshank S (2022). A novel epidermal-specific role for arginase1 during cutaneous wound repair. J Invest Dermatol. 42, 1206-1216.

    8. Wilkinson HN, Clowes C, Banyard KL, Matteucci P, Mace KA, Hardman MJ. (2019) Elevated Local Senescence in Diabetic Wound Healing Is Linked to Pathological Repair via CXCR2. J Invest Dermatol. 139:1171-1181.

    9. Williams JJL, Alotaiq N, Liu L, Baillie GS, Schaper F, Pilch PF, Palmer TM (2018) Interaction of suppressor of cytokine signalling 3 (SOCS3) with cavin-1 links SOCS3 function and cavin-1 stability. Nat Commun. 9:168.

    10. Mosenzon O, Blicher TM, Rosenlund S, Eriksson JW, Heller S, Hels OH, Pratley R, Sathyapalan T, Desouza C; PIONEER 5 Investigators. (2019) Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 7: 515-527.

    11. Al-Qaissi A, Papageorgiou M, Deshmukh H, Madden LA, Rigby A, Kilpatrick ES, Atkin SL, Sathyapalan T. (2019) Effects of acute insulin-induced hypoglycaemia on endothelial microparticles in adults with and without type 2 diabetes. Diabetes Obes Metab. 21: 533-540.

    12. Chattopadhyay S, George A, John J, Sathyapalan T. (2018) Adjustment of the GRACE score by 2-hour post-load glucose improves prediction of long-term major adverse cardiac events in acute coronary syndrome in patients without known diabetes. Eur Heart J. 39:2740-2745.

    13. Wilkinson HN, Upson SE, Banyard KL, Knight R, Mace KA, Hardman MJ. (2019) Reduced iron in diabetic wounds: An oxidative stress-dependent role for STEAP3 in extracellular matrix deposition and remodelling. J Invest Dermatol. 189(11): 2368-2377.

    14. Zaibi N, Li P, Xu SZ. (2021) Protective effects of dapagliflozin against oxidative stress-induced cell injury in human proximal tubular cells. PLoS One 16:e0247234.

    15. Farmer LK, Desideri S, Rollason R, Whitcomb DJ, Goodliff A, Neal CR, Lay AC, Birnbaumer L, Foster RR, Heesom KJ, Xu SZ, Saleem MA, Welsh GI. (2019) TRPC6 binds and activates calpain independent of its channel activity to regulate podocyte dynamics. J Am Soc Nephrol 30(10):1910-1924.

    16. Zeng B, Chen GL, Garcia-Vaz E, Bhandari S, Daskoulidou N, Berglund LM, Jiang H, Hallett T, Zhou LP, Huang L, Xu ZH, Nair V, Nelson RG, Ju W, Kretzler M, Atkin SL, Gomez MF, Xu SZ. (2017) ORAI channels are critical for receptor-mediated endocytosis of albumin. Nat Commun. 8:1920. 

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