Pub Date : 2024-09-30DOI: 10.1007/s00125-024-06282-6
Sapna Sharma, Qiuling Dong, Mark Haid, Jonathan Adam, Roberto Bizzotto, Juan J Fernandez-Tajes, Angus G Jones, Andrea Tura, Anna Artati, Cornelia Prehn, Gabi Kastenmüller, Robert W Koivula, Paul W Franks, Mark Walker, Ian M Forgie, Giuseppe Giordano, Imre Pavo, Hartmut Ruetten, Manolis Dermitzakis, Mark I McCarthy, Oluf Pedersen, Jochen M Schwenk, Konstantinos D Tsirigos, Federico De Masi, Soren Brunak, Ana Viñuela, Andrea Mari, Timothy J McDonald, Tarja Kokkola, Jerzy Adamski, Ewan R Pearson, Harald Grallert
<p><strong>Aims/hypothesis: </strong>Type 2 diabetes is a chronic condition that is caused by hyperglycaemia. Our aim was to characterise the metabolomics to find their association with the glycaemic spectrum and find a causal relationship between metabolites and type 2 diabetes.</p><p><strong>Methods: </strong>As part of the Innovative Medicines Initiative - Diabetes Research on Patient Stratification (IMI-DIRECT) consortium, 3000 plasma samples were measured with the Biocrates AbsoluteIDQ p150 Kit and Metabolon analytics. A total of 911 metabolites (132 targeted metabolomics, 779 untargeted metabolomics) passed the quality control. Multivariable linear and logistic regression analysis estimates were calculated from the concentration/peak areas of each metabolite as an explanatory variable and the glycaemic status as a dependent variable. This analysis was adjusted for age, sex, BMI, study centre in the basic model, and additionally for alcohol, smoking, BP, fasting HDL-cholesterol and fasting triacylglycerol in the full model. Statistical significance was Bonferroni corrected throughout. Beyond associations, we investigated the mediation effect and causal effects for which causal mediation test and two-sample Mendelian randomisation (2SMR) methods were used, respectively.</p><p><strong>Results: </strong>In the targeted metabolomics, we observed four (15), 34 (99) and 50 (108) metabolites (number of metabolites observed in untargeted metabolomics appear in parentheses) that were significantly different when comparing normal glucose regulation vs impaired glucose regulation/prediabetes, normal glucose regulation vs type 2 diabetes, and impaired glucose regulation vs type 2 diabetes, respectively. Significant metabolites were mainly branched-chain amino acids (BCAAs), with some derivatised BCAAs, lipids, xenobiotics and a few unknowns. Metabolites such as lysophosphatidylcholine a C17:0, sum of hexoses, amino acids from BCAA metabolism (including leucine, isoleucine, valine, N-lactoylvaline, N-lactoylleucine and formiminoglutamate) and lactate, as well as an unknown metabolite (X-24295), were associated with HbA<sub>1c</sub> progression rate and were significant mediators of type 2 diabetes from baseline to 18 and 48 months of follow-up. 2SMR was used to estimate the causal effect of an exposure on an outcome using summary statistics from UK Biobank genome-wide association studies. We found that type 2 diabetes had a causal effect on the levels of three metabolites (hexose, glutamate and caproate [fatty acid (FA) 6:0]), whereas lipids such as specific phosphatidylcholines (PCs) (namely PC aa C36:2, PC aa C36:5, PC ae C36:3 and PC ae C34:3) as well as the two n-3 fatty acids stearidonate (18:4n3) and docosapentaenoate (22:5n3) potentially had a causal role in the development of type 2 diabetes.</p><p><strong>Conclusions/interpretation: </strong>Our findings identify known BCAAs and lipids, along with novel N-lactoyl-amino acid metabolites, signific
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Pub Date : 2024-09-27DOI: 10.1007/s00125-024-06262-w
Naomi Holman, Arthur C. Yelland, Bob Young, Jonathan Valabhji, William Jeffcoate, Fran Game
Aims/hypothesis
People with diabetes-related foot ulcers (DFUs) have high mortality rates. This analysis assesses the impact of selected risk factors on short-term mortality using a population registered in the National Diabetes Foot Care Audit (NDFA).
Methods
Mortality rates at 12, 26 and 52 weeks was assessed in people with a new DFU registered by a specialist diabetes footcare service in the NDFA in England and Wales between April 2017 and March 2022. Poisson regression models were created to explore risk factors for mortality.
Results
In 71,000 people registered with a new DFU, mortality rates at 12, 26 and 52 weeks was 4.2%, 8.2% and 14.4%, respectively. At 26 weeks, higher mortality rates was associated with older age (rate ratio 2.15; 95% CI 2.03, 2.28, for age ≥80 years vs age 65–79 years), certain ulcer characteristics (area ≥1 cm2 [1.50; 95% CI 1.42, 1.59], deep ulcers [1.26; 95% CI 1.18, 1.35] or hindfoot location [1.53; 95% CI 1.44, 1.62]) and recorded evidence of ischaemia in the lower limb (1.78; 95% CI 1.69, 1.88) and various comorbidities (heart failure [2.13; 95% CI 2.00, 2.26], myocardial infarction [1.45; 95% CI 1.29, 1.63], stroke [1.37; 95% CI 1.22, 1.53], renal replacement therapy [2.34; 95% CI 2.09, 2.61] and chronic kidney disease stage 3 or greater [1.20; 95% CI 1.12, 1.29]). The 26-week mortality rate exceeded 25% for 7.3% of all individuals, rising to 11.5% of those aged 65 years and older, and 22.1% of those aged 80 years and over.
Conclusions/interpretation
Short-term mortality rates in people with a DFU is high. Teams managing people with DFUs should consider modifying the burdensome interventions and care required to heal such ulcers so maximising the quality of residual life, rather than focusing exclusively on healing.