TY - JOUR AU - Birkenfeld, A.L. AU - Bergman, M.* C1 - 73580 C2 - 57117 SP - 265-267 TI - Bodyweight loss and remission of type 2 diabetes. JO - Lancet Diabet. Endocrinol. VL - 13 IS - 4 PY - 2025 SN - 2213-8587 ER - TY - JOUR AU - Bornstein, S.R. AU - Dey, A.K.* AU - Steenblock, C.* AU - Mohan, V.* AU - Anjana, R.M.* AU - Schwarz, P.E. C1 - 74802 C2 - 57580 SP - 552-554 TI - Artificial intelligence and diabetes: Time for action and caution. JO - Lancet Diabet. Endocrinol. VL - 13 IS - 7 PY - 2025 SN - 2213-8587 ER - TY - JOUR AU - Hummel, S. AU - Köger, M. AU - Bonifacio, E. AU - Ziegler, A.-G. C1 - 72688 C2 - 56698 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 10-12 TI - Dysglycaemia definitions and progression to clinical type 1 diabetes in children with multiple islet autoantibodies. JO - Lancet Diabet. Endocrinol. VL - 13 IS - 1 PB - Elsevier Science Inc PY - 2025 SN - 2213-8587 ER - TY - JOUR AU - Rubino, F.* AU - Cummings, D.E.* AU - Eckel, R.H.* AU - Cohen, R.V.* AU - Wilding, J.P.H.* AU - Brown, W.A.* AU - Stanford, F.C.* AU - Batterham, R.L.* AU - Farooqi, I.S.* AU - Farpour-Lambert, N.J.* AU - le Roux, C.W.* AU - Sattar, N.* AU - Baur, L.A.* AU - Morrison, K.M.* AU - Misra, A.* AU - Kadowaki, T.* AU - Tham, K.W.* AU - Sumithran, P.* AU - Garvey, W.T.* AU - Kirwan, J.P.* AU - Fernández-Real, J.M.* AU - Corkey, B.E.* AU - Toplak, H.* AU - Kokkinos, A.* AU - Kushner, R.F.* AU - Branca, F.* AU - Valabhji, J.* AU - Blüher, M. AU - Bornstein, S.R.* AU - Grill, H.J.* AU - Ravussin, E.* AU - Gregg, E.W.* AU - Al Busaidi, N.B.* AU - Alfaris, N.F.* AU - Al Ozairi, E.* AU - Carlsson, L.M.S.* AU - Clément, K.* AU - Després, J.P.* AU - Dixon, J.B.* AU - Galea, G.* AU - Kaplan, L.M.* AU - Laferrère, B.* AU - Laville, M.* AU - Lim, S.* AU - Luna Fuentes, J.R.* AU - Mooney, V.M.* AU - Nadglowski, J.* AU - Urudinachi, A.* AU - Olszanecka-Glinianowicz, M.* AU - Pan, A.* AU - Pattou, F.* AU - Schauer, P.R.* AU - Tschöp, M.H. AU - van der Merwe, M.T.* AU - Vettor, R.* AU - Mingrone, G.* C1 - 73108 C2 - 56915 SP - 221-262 TI - Definition and diagnostic criteria of clinical obesity. JO - Lancet Diabet. Endocrinol. VL - 13 IS - 3 PY - 2025 SN - 2213-8587 ER - TY - JOUR AB - The global epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. People with MASLD can progress to cirrhosis and hepatocellular carcinoma and are at increased risk of developing type 2 diabetes, cardiovascular disease, chronic kidney disease, and extrahepatic cancers. Most people with MASLD die from cardiac-related causes. This outcome is attributed to the shared pathogenesis of MASLD and cardiometabolic diseases, involving unhealthy dietary habits, dysfunctional adipose tissue, insulin resistance, and subclinical inflammation. In addition, the steatotic and inflamed liver affects the vasculature and heart via increased glucose production and release of procoagulant factors, dyslipidaemia, and dysregulated release of hepatokines and microRNAs. However, there is substantial heterogeneity in the contributors to the pathophysiology of MASLD, which might influence its rate of progression, its relationship with cardiometabolic diseases, and the response to therapy. The most effective non-pharmacological treatment approaches for people with MASLD include weight loss. Paradoxically, some effective pharmacological approaches to improve liver health in people with MASLD are associated with no change in bodyweight or even with weight gain, and similar response heterogeneity has been observed for changes in cardiometabolic risk factors. In this Review, we address the heterogeneity of MASLD with respect to its pathogenesis, outcomes, and metabolism-based treatment responses. Although there is currently insufficient evidence for the implementation of precision medicine for risk prediction, prevention, and treatment of MASLD, we discuss whether knowledge about this heterogeneity might help achieving this goal in the future. AU - Stefan, N. AU - Yki-Järvinen, H.* AU - Neuschwander-Tetri, B.A.* C1 - 72841 C2 - 56745 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 134-148 TI - Metabolic dysfunction-associated steatotic liver disease: heterogeneous pathomechanisms and effectiveness of metabolism-based treatment. JO - Lancet Diabet. Endocrinol. VL - 13 IS - 2 PB - Elsevier Science Inc PY - 2025 SN - 2213-8587 ER - TY - JOUR AU - Stefan, N. C1 - 74282 C2 - 57417 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 455-457 TI - Does tirzepatide treatment improve skeletal muscle composition? JO - Lancet Diabet. Endocrinol. VL - 13 IS - 6 PB - Elsevier Science Inc PY - 2025 SN - 2213-8587 ER - TY - JOUR AU - Bonifacio, E. AU - Winkler, C. AU - Achenbach, P. AU - Ziegler, A.-G. C1 - 70656 C2 - 55677 SP - 376-378 TI - Effect of population-wide screening for presymptomatic early-stage type 1 diabetes on paediatric clinical care. JO - Lancet Diabet. Endocrinol. VL - 12 IS - 6 PY - 2024 SN - 2213-8587 ER - TY - JOUR AB - BACKGROUND: The subjective experiences of individuals living with diabetes is commonly assessed with patient-reported outcomes (PROs; eg, depression symptoms, wellbeing, health-related quality of life [HRQOL], and diabetes-related distress). Cluster analyses have identified novel diabetes subtypes differing in phenotypic and metabolic characteristics. We aimed to investigate associations between these subtypes and PROs and whether subtype predicted PROs 5 years later. METHODS: Baseline (<12 months after a diabetes diagnosis) and 5-year follow-up data were collected from German Diabetes Study (GDS) participants. Multiple regressions were applied to analyse associations between diabetes subtypes and depression symptoms (Center for Epidemiologic Studies Depression Scale), wellbeing (WHO-5), HRQOL (SF-36), and diabetes-related distress (Problem Areas in Diabetes Scale). FINDINGS: Cluster analyses at baseline (n=1391) identified participants with severe autoimmune diabetes (SAID, 417 [30%]), severe insulin-deficient diabetes (SIDD, 33 [2%]), severe insulin-resistant diabetes (SIRD, 150 [11%]), mild obesity-related diabetes (MOD, 354 [25%]), and mild age-related diabetes (MARD, 437 [31%]). At baseline, multiple regression analyses showed that participants with SIRD had higher depression symptoms than participants with MARD and lower physical HRQOL than all other subtypes. Participants with SAID reported higher depression symptoms and lower mental HRQOL than participants with MARD, higher physical HRQOL than participants with MARD and MOD, and higher diabetes-related distress than most other subtypes. At the 5-year follow-up, clustering predicted no statistically significant changes in PROs after adjustment for multiple testing, whereas descriptive analyses demonstrated that individuals with SIRD were more likely to experience clinically relevant depression symptoms (16% vs 6%) and low wellbeing (31% vs 14%), respectively, than individuals with MARD. INTERPRETATION: Diabetes subtypes already differ in PROs at diabetes diagnosis. Our analyses had limited predictive power during follow-up. However, our findings suggest that clustering could predict future changes in depression symptoms. FUNDING: The GDS was initiated and financed by the German Diabetes Center, which is funded by the German Federal Ministry of Health, the Ministry of Culture and Science of the state of North Rhine-Westphalia, and by the German Federal Ministry of Education and Research to the German Center for Diabetes Research. TRANSLATION: For the German translation of the abstract see Supplementary Materials section. AU - Sommer, J.* AU - Borgmann, S.O.* AU - Gontscharuk, V.* AU - Zaharia, O.P.* AU - Maalmi, H.* AU - Herder, C.* AU - Wagner, R.* AU - Strassburger, K.* AU - Schön, M.* AU - Burkart, V.* AU - Szendroedi, J.* AU - Pfeiffer, A.F.H.* AU - Bornstein, S.* AU - Blüher, M.* AU - Seissler, J.* AU - Birkenfeld, A.L. AU - Meyhöfer, S.* AU - Roden, M.* AU - Icks, A.* C1 - 72218 C2 - 56494 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 890-903 TI - Depression symptoms, wellbeing, health-related quality of life, and diabetes-related distress in novel subtypes of recent-onset diabetes in Germany: A 5-year observational follow-up study. JO - Lancet Diabet. Endocrinol. VL - 12 IS - 12 PB - Elsevier Science Inc PY - 2024 SN - 2213-8587 ER - TY - JOUR AU - Stefan, N. AU - Schiborn, C.* AU - Machann, J. AU - Birkenfeld, A.L. AU - Schulze, M.B.* C1 - 71058 C2 - 55920 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 514-515 TI - Impact of higher BMI on cardiometabolic risk: Does height matter? JO - Lancet Diabet. Endocrinol. VL - 12 IS - 8 PB - Elsevier Science Inc PY - 2024 SN - 2213-8587 ER - TY - JOUR AB - Stress hyperglycaemia, hypoglycaemia, and diabetes are common in critically ill patients and related to clinical endpoints. To avoid complications related to hypoglycaemia and hyperglycaemia, it is recommended to start insulin therapy for the majority of critically ill patients with persistent blood glucose concentrations higher than 10·0 mmol/L (>180 mg/dL), targeting a range of 7·8-10·0 mmol/L (140-180 mg/dL). However, management and evidence-based targets for blood glucose control are under debate, particularly for patients with diabetes. Recent randomised controlled clinical trials now challenge current recommendations. In this Personal View, we aim to highlight these developments and the important differences between critically ill patients with and without diabetes, taking into account the considerable heterogeneity in this patient group. We critically discuss evidence from prospective randomised controlled trials and observational studies on the safety and efficacy of glycaemic control, specifically in the context of patients with diabetes in intensive care units. AU - von Loeffelholz, C.* AU - Birkenfeld, A.L. C1 - 70303 C2 - 55497 SP - 277-284 TI - Tight versus liberal blood-glucose control in the intensive care unit: Special considerations for patients with diabetes. JO - Lancet Diabet. Endocrinol. VL - 12 IS - 4 PY - 2024 SN - 2213-8587 ER - TY - JOUR AB - BACKGROUND: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. METHODS: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. FINDINGS: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04-0·12] or 0·9 mmol/mol lower reduction in HbA1c per serine, p=6·0 × 10-5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10-8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol  [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10-6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6-11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. INTERPRETATION: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists. FUNDING: Innovative Medicines Initiative and the Wellcome Trust. AU - Dawed, A.Y.* AU - Mari, A.* AU - Brown, A.* AU - McDonald, T.J.* AU - Li, L.* AU - Wang, S.* AU - Hong, M.G.* AU - Sharma, S. AU - Robertson, N.R.* AU - Mahajan, A.* AU - Wang, X.* AU - Walker, M.* AU - Gough, S.C.* AU - Hart, L.M.'.* AU - Zhou, K.* AU - Forgie, I.* AU - Ruetten, H.* AU - Pavo, I.* AU - Bhatnagar, P.* AU - Jones, A.G.* AU - Pearson, E.R.* AU - DIRECT Consortium (Adamski, J. AU - Fritsche, A. AU - Grallert, H.) C1 - 66973 C2 - 53362 SP - 33-41 TI - Pharmacogenomics of GLP-1 receptor agonists: A genome-wide analysis of observational data and large randomised controlled trials. JO - Lancet Diabet. Endocrinol. VL - 11 IS - 1 PY - 2023 SN - 2213-8587 ER - TY - JOUR AU - Hummel, J.* AU - Kullmann, S. AU - Wagner, R.* AU - Heni, M.* C1 - 68710 C2 - 54919 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 883-884 TI - Glycaemic fluctuations across the menstrual cycle: Possible effect of the brain. JO - Lancet Diabet. Endocrinol. VL - 11 IS - 12 PB - Elsevier Science Inc PY - 2023 SN - 2213-8587 ER - TY - JOUR AU - Körner, A. AU - Stein, R. AU - Landgraf, K.* C1 - 67536 C2 - 54099 SP - 143-144 TI - Beyond genetic screening-functionality-based precision medicine in monogenic obesity. JO - Lancet Diabet. Endocrinol. VL - 11 IS - 3 PY - 2023 SN - 2213-8587 ER - TY - JOUR AB - Viruses have been present during all evolutionary steps on earth and have had a major effect on human history. Viral infections are still among the leading causes of death. Another public health concern is the increase of non-communicable metabolic diseases in the last four decades. In this Review, we revisit the scientific evidence supporting the presence of a strong bidirectional feedback loop between several viral infections and metabolic diseases. We discuss how viruses might lead to the development or progression of metabolic diseases and conversely, how metabolic diseases might increase the severity of a viral infection. Furthermore, we discuss the clinical relevance of the current evidence on the relationship between viral infections and metabolic disease and the present and future challenges that should be addressed by the scientific community and health authorities. AU - Perakakis, N. AU - Harb, H.* AU - Hale, B.G.* AU - Varga, Z.* AU - Steenblock, C.* AU - Kanczkowski, W.* AU - Alexaki, V.I.* AU - Ludwig, B. AU - Mirtschink, P.* AU - Solimena, M. AU - Toepfner, N.* AU - Zeissig, S.* AU - Gado, M. AU - Abela, I.A.* AU - Beuschlein, F.* AU - Spinas, G.A.* AU - Cavelti-Weder, C.* AU - Gerber, P.A.* AU - Huber, M.* AU - Trkola, A.* AU - Puhan, M.A.* AU - Wong, W.W.* AU - Linkermann, A.* AU - Mohan, V.* AU - Lehnert, H.* AU - Nawroth, P.* AU - Chavakis, T. AU - Mingrone, G.* AU - Wolfrum, C.* AU - Zinkernagel, A.S.* AU - Bornstein, S.R. C1 - 68045 C2 - 54523 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 675-693 TI - Mechanisms and clinical relevance of the bidirectional relationship of viral infections with metabolic diseases. JO - Lancet Diabet. Endocrinol. VL - 11 IS - 9 PB - Elsevier Science Inc PY - 2023 SN - 2213-8587 ER - TY - JOUR AB - BACKGROUND: Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes. METHODS: In this prespecified post-hoc analysis, weight loss-induced resolution of prediabetes in the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) was assessed, and the results were validated against participants from the Diabetes Prevention Program (DPP) study. For PLIS, between March 1, 2012, and Aug 31, 2016, participants were recruited from eight clinical study centres (including seven university hospitals) in Germany and randomly assigned to receive either a control intervention, a standard lifestyle intervention (ie, DPP-based intervention), or an intensified lifestyle intervention for 12 months. For DPP, participants were recruited from 23 clinical study centres in the USA between July 31, 1996, and May 18, 1999, and randomly assigned to receive either a standard lifestyle intervention, metformin, or placebo. In both PLIS and DPP, only participants who were randomly assigned to receive lifestyle intervention or placebo and who lost at least 5% of their bodyweight were included in this analysis. Responders were defined as people who returned to normal fasting plasma glucose (FPG; <5·6 mmol/L), normal glucose tolerance (<7·8 mmol/L), and HbA1c less than 39 mmol/mol after 12 months of lifestyle intervention or placebo or control intervention. Non-responders were defined as people who had FPG, 2 h glucose, or HbA1c more than these thresholds. The main outcomes for this analysis were insulin sensitivity, insulin secretion, visceral adipose tissue (VAT), and intrahepatic lipid content (IHL) and were evaluated via linear mixed models. FINDINGS: Of 1160 participants recruited to PLIS, 298 (25·7%) had weight loss of 5% or more of their bodyweight at baseline. 128 (43%) of 298 participants were responders and 170 (57%) were non-responders. Responders were younger than non-responders (mean age 55·6 years [SD 9·9] vs 60·4 years [8·6]; p<0·0001). The DPP validation cohort included 683 participants who lost at least 5% of their bodyweight at baseline. Of these, 132 (19%) were responders and 551 (81%) were non-responders. In PLIS, BMI reduction was similar between responders and non-responders (responders mean at baseline 32·4 kg/m2 [SD 5·6] to mean at 12 months 29·0 kg/m2 [4·9] vs non-responders 32·1 kg/m2 [5·9] to 29·2 kg/m2 [5·4]; p=0·86). However, whole-body insulin sensitivity increased more in responders than in non-responders (mean at baseline 291 mL/[min × m2], SD 60 to mean at 12 months 378 mL/[min × m2], 56 vs 278 mL/[min × m2], 62, to 323 mL/[min × m2], 66; p<0·0001), whereas insulin secretion did not differ within groups over time or between groups (responders mean at baseline 175 pmol/mmol [SD 64] to mean at 12 months 163·7 pmol/mmol [60·6] vs non-responders 158·0 pmol/mmol [55·6] to 154·1 pmol/mmol [56·2]; p=0·46). IHL decreased in both groups, without a difference between groups (responders mean at baseline 10·1% [SD 8·7] to mean at 12 months 3·5% [3·9] vs non-responders 10·3% [8·1] to 4·2% [4·2]; p=0·34); however, VAT decreased more in responders than in non-responders (mean at baseline 6·2 L [SD 2·9] to mean at 12 months 4·1 L [2·3] vs 5·7 L [2·3] to 4·5 L [2·2]; p=0·0003). Responders had a 73% lower risk of developing type 2 diabetes than non-responders in the 2 years after the intervention ended. INTERPRETATION: By contrast to remission of type 2 diabetes, resolution of prediabetes was characterised by an improvement in insulin sensitivity and reduced VAT. Because return to normal glucose regulation (NGR) prevents development of type 2 diabetes, we propose the concept of remission of prediabetes in analogy to type 2 diabetes. We suggest that remission of prediabetes should be the primary therapeutic aim in individuals with prediabetes. FUNDING: German Federal Ministry for Education and Research via the German Center for Diabetes Research; the Ministry of Science, Research and the Arts Baden-Württemberg; the Helmholtz Association and Helmholtz Munich; the Cluster of Excellence Controlling Microbes to Fight Infections; and the German Research Foundation. AU - Sandforth, A. AU - Jumpertz von Schwartzenberg, R. AU - Arreola, E.V.* AU - Hanson, R.L.* AU - Sancar, G. AU - Katzenstein, S. AU - Lange, K. AU - Preissl, H. AU - Dreher, S. AU - Weigert, C. AU - Wagner, R.* AU - Kantartzis, K. AU - Machann, J. AU - Schick, F. AU - Lehmann, R. AU - Peter, A. AU - Katsouli, N. AU - Ntziachristos, V. AU - Dannecker, C. AU - Fritsche, L. AU - Perakakis, N.* AU - Heni, M. AU - Nawroth, P.P.* AU - Kopf, S.* AU - Pfeiffer, A.F.H.* AU - Kabisch, S.* AU - Stumvoll, M.* AU - Schwarz, P.E.H.* AU - Hauner, H* AU - Lechner, A.* AU - Seissler, J.* AU - Yurchenko, I.* AU - Icks, A.* AU - Solimena, M. AU - Häring, H.-U. AU - Szendroedi, J.* AU - Schürmann, A.* AU - Hrabě de Angelis, M. AU - Blüher, M.* AU - Roden, M.* AU - Bornstein, S.* AU - Stefan, N. AU - Fritsche, A. AU - Birkenfeld, A.L. C1 - 68637 C2 - 54826 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 798-810 TI - Mechanisms of weight loss-induced remission in people with prediabetes: A post-hoc analysis of the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS). JO - Lancet Diabet. Endocrinol. VL - 11 IS - 11 PB - Elsevier Science Inc PY - 2023 SN - 2213-8587 ER - TY - JOUR AB - BACKGROUND: Heterogeneity in type 2 diabetes can be represented by a tree-like graph structure by use of reversed graph-embedded dimensionality reduction. We aimed to examine whether this approach can be used to stratify key pathophysiological components and diabetes-related complications during longitudinal follow-up of individuals with recent-onset type 2 diabetes. METHODS: For this cohort analysis, 927 participants aged 18-69 years from the German Diabetes Study (GDS) with recent-onset type 2 diabetes were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualised for age and sex. Insulin sensitivity was assessed by a hyperinsulinaemic-euglycaemic clamp, insulin secretion was assessed by intravenous glucose tolerance test, hepatic lipid content was assessed by 1 H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 were assessed by ELISA, and peripheral and autonomic neuropathy were assessed by functional and clinical measures. Participants were followed up for up to 16 years. We also investigated heart failure and all-cause mortality in 794 individuals with type 2 diabetes undergoing invasive coronary diagnostics from the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort. FINDINGS: There were gradients of clamp-measured insulin sensitivity (both dimensions: p<0·0001) and insulin secretion (pdim1<0·0001, pdim2=0·00097) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest hepatic lipid content (n=205, pdim1<0·0001, pdim2=0·037), pro-inflammatory biomarkers (IL-6: n=348, pdim1<0·0001, pdim2=0·013; IL-18: n=350, pdim1<0·0001, pdim2=0·38), and elevated cardiovascular risk (nevents=143, pdim1=0·14, pdim2<0·00081), whereas individuals positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (nevents=85, pdim1=0·032, pdim2=0·12) and had the highest risk of diabetic sensorimotor polyneuropathy (nevents=184, pdim1=0·012, pdim2=0·044) and cardiac autonomic neuropathy (nevents=118, pdim1=0·0094, pdim2=0·06). In the LURIC cohort, all-cause mortality was highest in the tree branch showing insulin resistance (nevents=488, pdim1=0·12, pdim2=0·0032). Significant gradients differentiated individuals having heart failure with preserved ejection fraction from those who had heart failure with reduced ejection fraction. INTERPRETATION: These data define the pathophysiological underpinnings of the tree structure, which has the potential to stratify diabetes-related complications on the basis of routinely available variables and thereby expand the toolbox of precision diabetes diagnosis. FUNDING: German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, European Community, German Research Foundation, and Schmutzler Stiftung. AU - Schön, M.* AU - Prystupa, K.* AU - Mori, T.* AU - Zaharia, O.P.* AU - Bódis, K.* AU - Bombrich, M.* AU - Moser, C.* AU - Yurchenko, I.* AU - Kupriyanova, Y.* AU - Strassburger, K.* AU - Bobrov, P.* AU - Nair, A.T.N.* AU - Bönhof, G.J.* AU - Strom, A.* AU - Delgado, G.E.* AU - Kaya, S.* AU - Guthoff, R.* AU - Stefan, N.* AU - Birkenfeld, A.L.* AU - Hauner, H.* AU - Seissler, J.* AU - Pfeiffer, A.* AU - Blüher, M. AU - Bornstein, S.* AU - Szendroedi, J.* AU - Meyhöfer, S.* AU - Trenkamp, S.* AU - Burkart, V.* AU - Schrauwen-Hinderling, V.B.* AU - Kleber, M.E.* AU - Niessner, A.* AU - Herder, C.* AU - Kuss, O.* AU - März, W.* AU - Pearson, E.R.* AU - Roden, M.* AU - Wagner, R.* C1 - 69036 C2 - 53820 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 119-131 TI - Analysis of type 2 diabetes heterogeneity with a tree-like representation: Insights from the prospective German Diabetes Study and the LURIC cohort. JO - Lancet Diabet. Endocrinol. VL - 12 IS - 2 PB - Elsevier Science Inc PY - 2023 SN - 2213-8587 ER - TY - JOUR AB - Among 20 leading global risk factors for years of life lost in 2040, reference forecasts point to three metabolic risks-high blood pressure, high BMI, and high fasting plasma glucose-as being the top risk variables. Building upon these and other risk factors, the concept of metabolic health is attracting much attention in the scientific community. It focuses on the aggregation of important risk factors, which allows the identification of subphenotypes, such as people with metabolically unhealthy normal weight or metabolically healthy obesity, who strongly differ in their risk of cardiometabolic diseases. Since 2018, studies that used anthropometrics, metabolic characteristics, and genetics in the setting of cluster analyses proposed novel metabolic subphenotypes among patients at high risk (eg, those with diabetes). The crucial point now is whether these subphenotyping strategies are superior to established cardiometabolic risk stratification methods regarding the prediction, prevention, and treatment of cardiometabolic diseases. In this Review, we carefully address this point and conclude, firstly, regarding cardiometabolic risk stratification, in the general population both the concept of metabolic health and the cluster approaches are not superior to established risk prediction models. However, both subphenotyping approaches might be informative to improve the prediction of cardiometabolic risk in subgroups of individuals, such as those in different BMI categories or people with diabetes. Secondly, the applicability of the concepts by treating physicians and communication of the cardiometabolic risk with patients is easiest using the concept of metabolic health. Finally, the approaches to identify cardiometabolic risk clusters in particular have provided some evidence that they could be used to allocate individuals to specific pathophysiological risk groups, but whether this allocation is helpful for prevention and treatment still needs to be determined. AU - Stefan, N. AU - Schulze, M.B.* C1 - 67762 C2 - 54240 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 426-440 TI - Metabolic health and cardiometabolic risk clusters: Implications for prediction, prevention, and treatment. JO - Lancet Diabet. Endocrinol. VL - 11 IS - 6 PB - Elsevier Science Inc PY - 2023 SN - 2213-8587 ER - TY - JOUR AU - Stefan, N. AU - Schulze, M.B.* C1 - 68036 C2 - 54514 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 636-637 TI - Achieving replicable subphenotypes of adult-onset diabetes - Authors' reply. JO - Lancet Diabet. Endocrinol. VL - 11 IS - 9 PB - Elsevier Science Inc PY - 2023 SN - 2213-8587 ER - TY - JOUR AB - Current evidence suggests that severity and mortality of COVID-19 is higher in men than in women, whereas women might be at increased risk of COVID-19 reinfection and development of long COVID. Differences between sexes have been observed in other infectious diseases and in the response to vaccines. Sex-specific expression patterns of proteins mediating virus binding and entry, and divergent reactions of the immune and endocrine system, in particular the hypothalamic-pituitary-adrenal axis, in response to acute stress might explain the higher severity of COVID-19 in men. In this Personal View, we discuss how sex hormones, comorbidities, and the sex chromosome complement influence these mechanisms in the context of COVID-19. Due to its role in the severity and progression of SARS-CoV-2 infections, we argue that sexual dimorphism has potential implications for disease treatment, public health measures, and follow-up of patients predisposed to the development of long COVID. We suggest that sex differences could be considered in future pandemic surveillance and treatment of patients with COVID-19 to help to achieve better disease stratification and improved outcomes. AU - Bechmann, N.* AU - Barthel, A.* AU - Schedl, A.* AU - Herzig, S. AU - Varga, Z.* AU - Gebhard, C.* AU - Mayr, M.* AU - Hantel, C.* AU - Beuschlein, F.* AU - Wolfrum, C.* AU - Perakakis, N.* AU - Poston, L.* AU - Andoniadou, C.L.* AU - Siow, R.* AU - Gainetdinov, R.R.* AU - Dotan, A.* AU - Shoenfeld, Y.* AU - Mingrone, G.* AU - Bornstein, S.R.* C1 - 64247 C2 - 51911 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 221-230 TI - Sexual dimorphism in COVID-19: Potential clinical and public health implications. JO - Lancet Diabet. Endocrinol. VL - 10 IS - 3 PB - Elsevier Science Inc PY - 2022 SN - 2213-8587 ER - TY - JOUR AB - BACKGROUND: Early prediction of childhood type 1 diabetes reduces ketoacidosis at diagnosis and provides opportunities for disease prevention. However, only highly efficient approaches are likely to succeed in public health settings. We sought to identify efficient strategies for initial islet autoantibody screening in children younger than 15 years. METHODS: We harmonised data from five prospective cohorts from Finland (DIPP), Germany (BABYDIAB), Sweden (DiPiS), and the USA (DAISY and DEW-IT) into the Type 1 Diabetes Intelligence (T1DI) cohort. 24 662 children at high risk of diabetes enrolled before age 2 years were included and followed up for islet autoantibodies and diabetes until age 15 years, or type 1 diabetes onset, whichever occurred first. Islet autoantibodies measured included those against glutamic acid decarboxylase, insulinoma antigen 2, and insulin. Main outcomes were sensitivity and positive predictive value (PPV) of detected islet autoantibodies, tested at one or two fixed ages, for diagnosis of clinical type 1 diabetes. FINDINGS: Of the 24 662 participants enrolled in the Type 1 Diabetes Intelligence cohort, 6722 total were followed up to age 15 years or until onset of type 1 diabetes. Type 1 diabetes developed by age 15 years in 672 children, but did not develop in 6050 children. Optimal screening ages for two measurements were 2 years and 6 years, yielding sensitivity of 82% (95% CI 79-86) and PPV of 79% (95% CI 75-80) for diabetes by age 15 years. Autoantibody positivity at the beginning of each test age was highly predictive of diagnosis in the subsequent 2-5·99 year or 6-15-year age intervals. Autoantibodies usually appeared before age 6 years even in children diagnosed with diabetes much later in childhood. INTERPRETATION: Our results show that initial screening for islet autoantibodies at two ages (2 years and 6 years) is sensitive and efficient for public health translation but might require adjustment by country on the basis of population-specific disease characteristics. FUNDING: Juvenile Diabetes Research Foundation. AU - Ghalwash, M.* AU - Dunne, J.L.* AU - Lundgren, M.* AU - Rewers, M.* AU - Ziegler, A.-G. AU - Anand, V.* AU - Toppari, J.* AU - Veijola, R.* AU - Hagopian, W.* C1 - 65650 C2 - 52850 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 589-596 TI - Two-age islet-autoantibody screening for childhood type 1 diabetes: A prospective cohort study. JO - Lancet Diabet. Endocrinol. VL - 10 IS - 8 PB - Elsevier Science Inc PY - 2022 SN - 2213-8587 ER - TY - JOUR AB - Non-alcoholic fatty liver disease (NAFLD) has become an epidemic, much like other non-communicable diseases (NCDs), such as cancer, obesity, diabetes, and cardiovascular disease. The pathophysiology of NAFLD, particularly involving insulin resistance and subclinical inflammation, is not only closely linked to that of those NCDs but also to a severe course of the communicable disease COVID-19. Genetics alone cannot explain the large increase in the prevalence of NAFLD during the past 2 decades and the increase that is projected for the next decades. Impairment of glucose and lipid metabolic pathways, which has been propelled by the worldwide increase in the prevalence of obesity and type 2 diabetes, is most likely behind the increase in people with NAFLD. As the prevalence of NAFLD varies among subgroups of patients with diabetes and prediabetes identified by cluster analyses, stratification of people with diabetes and prediabetes by major pathological mechanistic pathways might improve the diagnosis of NAFLD and prediction of its progression. In this Review, we aim to understand how diabetes can affect the development of hepatic steatosis and its progression to advanced liver damage. First, we emphasise the extent to which NAFLD and diabetes jointly occur worldwide. Second, we address the major mechanisms that are involved in the pathogenesis of NAFLD and type 2 diabetes, and we discuss whether these mechanisms place NAFLD in an important position to better understand the pathogenesis of NCDs and communicable diseases, such as COVID-19. Third, we address whether this knowledge can be used for personalised treatment of NAFLD in the future. Finally, we discuss the current treatment strategies for people with type 2 diabetes and their effectiveness in treating the spectrum of hepatic diseases from simple steatosis to non-alcoholic steatohepatitis and hepatic fibrosis. AU - Stefan, N. AU - Cusi, K.* C1 - 64344 C2 - 51906 SP - 284-296 TI - A global view of the interplay between non-alcoholic fatty liver disease and diabetes. JO - Lancet Diabet. Endocrinol. VL - 10 IS - 4 PY - 2022 SN - 2213-8587 ER - TY - JOUR AB - Up to 50% of the people who have died from COVID-19 had metabolic and vascular disorders. Notably, there are many direct links between COVID-19 and the metabolic and endocrine systems. Thus, not only are patients with metabolic dysfunction (eg, obesity, hypertension, non-alcoholic fatty liver disease, and diabetes) at an increased risk of developing severe COVID-19 but also infection with SARS-CoV-2 might lead to new-onset diabetes or aggravation of pre-existing metabolic disorders. In this Review, we provide an update on the mechanisms of how metabolic and endocrine disorders might predispose patients to develop severe COVID-19. Additionally, we update the practical recommendations and management of patients with COVID-19 and post-pandemic. Furthermore, we summarise new treatment options for patients with both COVID-19 and diabetes, and highlight current challenges in clinical management. AU - Steenblock, C.* AU - Schwarz, P.E. AU - Ludwig, B. AU - Linkermann, A.* AU - Zimmet, P.* AU - Kulebyakin, K.* AU - Tkachuk, V.A.* AU - Markov, A.G.* AU - Lehnert, H.* AU - Hrabě de Angelis, M. AU - Rietzsch, H.* AU - Rodionov, R.N.* AU - Khunti, K.* AU - Hopkins, D.* AU - Birkenfeld, A.L. AU - Boehm, B.* AU - Holt, R.I.G.* AU - Skyler, J.S.* AU - deVries, J.H.* AU - Renard, E.* AU - Eckel, R.H.* AU - Alberti, K.G.M.M.* AU - Geloneze, B.* AU - Chan, J.C.* AU - Mbanya, J.C.* AU - Onyegbutulem, H.C.* AU - Ramachandran, A.* AU - Basit, A.* AU - Hassanein, M.T.* AU - Bewick, G.A.* AU - Spinas, G.A.* AU - Beuschlein, F.* AU - Landgraf, R.* AU - Rubino, F.* AU - Mingrone, G.* AU - Bornstein, S.R. C1 - 63296 C2 - 51278 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 786-798 TI - COVID-19 and metabolic disease: Mechanisms and clinical management. JO - Lancet Diabet. Endocrinol. VL - 9 IS - 11 PB - Elsevier Science Inc PY - 2021 SN - 2213-8587 ER - TY - JOUR AB - Diabetes is one of the most important comorbidities linked to the severity of all three known human pathogenic coronavirus infections, including severe acute respiratory syndrome coronavirus 2. Patients with diabetes have an increased risk of severe complications including Adult Respiratory Distress Syndrome and multi-organ failure. Depending on the global region, 20-50% of patients in the coronavirus disease 2019 (COVID-19) pandemic had diabetes. Given the importance of the link between COVID-19 and diabetes, we have formed an international panel of experts in the field of diabetes and endocrinology to provide some guidance and practical recommendations for the management of diabetes during the pandemic. We aim to briefly provide insight into potential mechanistic links between the novel coronavirus infection and diabetes, present practical management recommendations, and elaborate on the differential needs of several patient groups. AU - Bornstein, S.R. AU - Rubino, F.* AU - Khunti, K.* AU - Mingrone, G.* AU - Hopkins, D.* AU - Birkenfeld, A.L. AU - Boehm, B.* AU - Amiel, S.* AU - Holt, R.I.* AU - Skyler, J.S.* AU - deVries, J.H.* AU - Renard, E.* AU - Eckel, R.H.* AU - Zimmet, P.* AU - Alberti, K.G.* AU - Vidal, J.* AU - Geloneze, B.* AU - Ludwig, B. C1 - 58995 C2 - 48588 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 546-550 TI - Practical recommendations for the management of diabetes in patients with COVID-19. JO - Lancet Diabet. Endocrinol. VL - 8 IS - 6 PB - Elsevier Science Inc PY - 2020 SN - 2213-8587 ER - TY - JOUR AB - Insulin acts on the CNS to modulate behaviour and systemic metabolism. Disturbances in brain insulin action represent a possible link between metabolic and cognitive health. Current findings from human research suggest that boosting central insulin action in the brain modulates peripheral metabolism, enhancing whole-body insulin sensitivity and suppressing endogenous glucose production. Moreover, central insulin action curbs food intake by reducing the salience of highly palatable food cues and increasing cognitive control. Animal models show that the mesocorticolimbic circuitry is finely tuned in response to insulin, driven mainly by the dopamine system. These mechanisms are impaired in people with obesity, which might increase their risk of developing type 2 diabetes and associated diseases. Overall, current findings highlight the role of insulin action in the brain and its consequences on peripheral metabolism and cognition. Hence, improving central insulin action could represent a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases. AU - Kullmann, S. AU - Kleinridders, A.* AU - Small, D.M. AU - Fritsche, A. AU - Häring, H.-U. AU - Preissl, H. AU - Heni, M. C1 - 59230 C2 - 48674 SP - 524-534 TI - Central nervous pathways of insulin action in the control of metabolism and food intake. JO - Lancet Diabet. Endocrinol. VL - 8 IS - 6 PY - 2020 SN - 2213-8587 ER - TY - JOUR AU - Kurz, C.F. AU - König, A. C1 - 57771 C2 - 46668 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 101-103 TI - The causal influence of maternal obesity on preterm birth. JO - Lancet Diabet. Endocrinol. VL - 8 IS - 2 PB - Elsevier Science Inc PY - 2020 SN - 2213-8587 ER - TY - JOUR AB - The coronavirus disease 2019 pandemic is wreaking havoc on society, especially health-care systems, including disrupting bariatric and metabolic surgery. The current limitations on accessibility to non -urgent care undermine postoperative monitoring of patients who have undergone such operations. Furthermore, like most elective surgery, new bariatric and metabolic procedures are being postponed worldwide during the pandemic. When the outbreak abates, a backlog of people seeking these operations will exist. Hence, surgical candidates face prolonged delays of beneficial treatment. Because of the progressive nature of obesity and diabetes, delaying surgery increases risks for morbidity and mortality, thus requiring strategies to mitigate harm. The risk of harm, however, varies among patients, depending on the type and severity of their comorbidities. A triaging strategy is therefore needed. The traditional weight -centric patient -selection criteria do not favour cases based on actual clinical needs. In this Personal View, experts from the Diabetes Surgery Summit consensus conference series provide guidance for the management of patients while surgery is delayed and for postoperative surveillance. We also offer a strategy to prioritise bariatric and metabolic surgery candidates on the basis of the diseases that are most likely to be ameliorated postoperatively. Although our system will be particularly germane in the immediate future, it also provides a framework for long-term clinically meaningful prioritisation. AU - Rubino, F.* AU - Cohen, R.V.* AU - Mingrone, G.* AU - le Roux, C.W.* AU - Mechanick, J.I.* AU - Arterburn, D.E.* AU - Vidal, J.* AU - Alberti, G.* AU - Amiel, S.A.* AU - Batterham, R.L.* AU - Bornstein, S.R. AU - Chamseddine, G.* AU - Del Prato, S.* AU - Dixon, J.B.* AU - Eckel, R.H.* AU - Hopkins, D.* AU - McGowan, B.M.* AU - Pan, A.* AU - Patel, A.* AU - Pattou, F.* AU - Schauer, P.R.* AU - Zimmet, P.Z.* AU - Cummings, D.E.* C1 - 59154 C2 - 48667 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 640-648 TI - Bariatric and metabolic surgery during and after the COVID-19 pandemic: DSS recommendations for management of surgical candidates and postoperative patients and prioritisation of access to surgery. JO - Lancet Diabet. Endocrinol. VL - 8 IS - 7 PB - Elsevier Science Inc PY - 2020 SN - 2213-8587 ER - TY - JOUR AU - Rubino, F. AU - Zimmet, P.* AU - Ludwig, B. C1 - 59765 C2 - 49006 SP - 669-670 TI - Management of diabetes in patients with COVID-19 – Authors' reply. JO - Lancet Diabet. Endocrinol. VL - 8 IS - 8 PY - 2020 SN - 2213-8587 ER - TY - JOUR AU - Stefan, N. C1 - 59810 C2 - 49055 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 616-627 TI - Causes, consequences, and treatment of metabolically unhealthy fat distribution. JO - Lancet Diabet. Endocrinol. VL - 8 IS - 7 PB - Elsevier Science Inc PY - 2020 SN - 2213-8587 ER - TY - JOUR AB - Background Microalbuminuria is an early sign of kidney disease in people with diabetes and indicates increased risk of cardiovascular disease. We tested whether a urinary proteolnic risk classifier (CKD273) score was associated with development of microalbuminuria and whether progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone.Methods In this multicentre, prospective, observational study with embedded randomised controlled trial (PRIORITY), we recruited people with type 2 diabetes, normal urinary albumin excretion, and preserved renal function from 15 specialist centres in ten European countries. All participants (observational cohort) were tested with the CKD273 classifier and classified as high risk (CKD273 classifier score >0 - 154) or low risk (<= 0.154). Participants who were classified as high risk were entered into a randomised controlled trial and randomly assigned (1:1), by use of an interactive webresponse system, to receive spironolactone 25 mg once daily or matched placebo (trial cohort). The primary endpoint was development of confirmed microalbuminuria in all individuals with available data (observational cohort). Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone (trial cohort, intention-to-treat population) and association between CKD273 risk score and measures of impaired renal function based on estimated glomerular filtration rate (eGFR; observational cohort). Adverse events (particularly gynaecomastia and hyperkalaemia) and serious adverse events were recorded for the intention-to-treat population (trial cohort). This study is registered with the EU Clinical Trials Register (EudraCT 20120-004523-4) and ClinicalTrials.gov (NCT02040441) and is completed.Findings Between March 25, 2014, and Sept 30, 2018, we enrolled and followed-up 1775 participants (observational cohort), 1559 (88%) of 1775 participants had a low-risk urinary proteomic pattern and 216 (12%) had a high-risk pattern, of whom 209 were included in the trial cohort and assigned to spironolactone (n=102) or placebo (n=107). The overall median follow-up time was 2.51 years (IQR 2. 0-3 - 0). Progression to microalbuminuria was seen in 61(28%) of 216 high-risk participants and 139 (9%) of 1559 low-risk participants (hazard ratio [HR] 2.48, 95% CI 1-80-3.42; p<0.0001, after adjustment for baseline variables of age, sex, HbA(1c) systolic blood pressure, retinopathy, urine albumin-to-creatinine ratio [UACR], and eGFR). Development of impaired renal function (eGFR <60 mL/min per 1.73 m(2)) was seen in 48 (26%) of 184 high-risk participants and 119 (8%) of 1423 low-risk participants (HR 3.50; 95% CI 2- 50-490, after adjustment for baseline variables). A 30% decrease in eGFR from baseline (post-hoc endpoint) was seen in 42 (19%) of 216 high-risk participants and 62 (4%) of 1559 low-risk participants (HR 5.15, 95% CI 3.41-7.76; p<0.0001, after adjustment for basline eGFR and UACR). In the intention-to-treat trial cohort, development of microalbuminuria was seen in 35 (33%) of 107 in the placebo group and 26 (25%) of 102 in the spironolactone group (HR 0.81, 95% CI 0.49-1.34; p=0.41). In the safety analysis (intention-to-treat trial cohort), events of plasma potassium concentrations of more than 5.5 mmol/L were seen in 13 (13%) of 102 participants in the spironolactone group and four (4%) of 107 participants in the placebo group, and gynaecomastia was seen in three (3%) participants in the spironolactone group and none in the placebo group. One patient died in the placebo group due to a cardiac event (considered possibly related to study drug) and one patient died in the spironolactone group due to cancer, deemed unrelated to study drug.Interpretation In people with type 2 diabetes and normoalbuminuria, a high-risk score from the urinary proteomic classifier CKD273 was associated with an increased risk of progression to microalbuminuria over a median of 2.5 years, independent of clinical characteristics. However, spironolactone did not prevent progression to microalbuminuria in high-risk patients. AU - Tofte, N.* AU - Lindhardt, M.* AU - Adamova, K.* AU - Bakker, S.J.L.* AU - Beige, J.* AU - Beulens, J.W.J.* AU - Birkenfeld, A.L. AU - Currie, G.* AU - Delles, C.* AU - Dimos, I.* AU - Francová, L.* AU - Frimodt-Møller, M.* AU - Girman, P.* AU - Göke, R.* AU - Havrdova, T.* AU - Heerspink, H.J.L.* AU - Kooy, A.* AU - Laverman, G.D.* AU - Mischak, H.* AU - Navis, G.* AU - Nijpels, G.* AU - Noutsou, M.* AU - Ortiz, A.* AU - Parvanova, A.* AU - Persson, F.* AU - Petrie, J.R.* AU - Ruggenenti, P.L.* AU - Rutters, F.* AU - Rychlík, I.* AU - Siwy, J.* AU - Spasovski, G.* AU - Speeckaert, M.* AU - Trillini, M.* AU - Zürbig, P.* AU - von der Leyen, H.* AU - Rossing, P.* AU - PRIORITY investigators* C1 - 58657 C2 - 48359 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 301-312 TI - Early detection of diabetic kidney disease by urinary proteomics and subsequent intervention with spironolactone to delay progression (PRIORITY): A prospective observational study and embedded randomised placebo-controlled trial. JO - Lancet Diabet. Endocrinol. VL - 8 IS - 4 PB - Elsevier Science Inc PY - 2020 SN - 2213-8587 ER - TY - JOUR AU - Turcu, A.F.* AU - Walch, A.K. C1 - 59913 C2 - 48950 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 733-734 TI - A multi-test strategy for adrenal tumours. JO - Lancet Diabet. Endocrinol. VL - 8 IS - 9 PB - Elsevier Science Inc PY - 2020 SN - 2213-8587 ER - TY - JOUR AB - The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. In some patients with NAFLD, isolated steatosis can progress to advanced stages with non-alcoholic steatohepatitis (NASH) and fibrosis, increasing the risk of cirrhosis and hepatocellular carcinoma. Furthermore, NAFLD is believed to be involved in the pathogenesis of common disorders such as type 2 diabetes and cardiovascular disease. In this Review, we highlight novel concepts related to diagnosis, risk prediction, and treatment of NAFLD. First, because NAFLD is a heterogeneous disease, the advanced stages of which seem to be strongly affected by comorbidities such as insulin resistance and type 2 diabetes, early use of reliable, non-invasive diagnostic tools is needed, particularly in patients with insulin resistance or diabetes, to allow the identification of patients at different disease stages. Second, although the strongest genetic risk alleles for NAFLD (ie, the 148Met allele in PNPLA3 and the 167Lys allele in TM6SF2) are associated with increased liver fat content and progression to NASH and cirrhosis, these alleles are also unexpectedly associated with an apparent protection from cardiovascular disease. If consistent across diverse populations, this discordance in NAFLD-related risk prediction between hepatic and extrahepatic disease might need to be accounted for in the management of NAFLD. Third, drug treatments assessed in NAFLD seem to differ with respect to cardiometabolic and antifibrotic efficacy, suggesting the need to better identify and tailor the most appropriate treatment approach, or to use a combination of approaches. These emerging concepts could contribute to the development of a multidisciplinary approach for endocrinologists and hepatologists working together in the management of NAFLD. AU - Stefan, N. AU - Häring, H.-U. AU - Cusi, K.* C1 - 54224 C2 - 45444 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 313-324 TI - Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. JO - Lancet Diabet. Endocrinol. VL - 7 IS - 4 PB - Elsevier Science Inc PY - 2019 SN - 2213-8587 ER - TY - JOUR AB - Background Cluster analyses have proposed different diabetes phenotypes using age, BMI, glycaemia, homoeostasis model estimates, and islet autoantibodies. We tested whether comprehensive phenotyping validates and further characterises these clusters at diagnosis and whether relevant diabetes-related complications differ among these clusters, during 5-years of follow-up.Methods Patients with newly diagnosed type 1 or type 2 diabetes in the German Diabetes Study underwent comprehensive phenotyping and assessment of laboratory variables. Insulin sensitivity was assessed using hyperinsulinaemic-euglycaemic clamps, hepatocellular lipid content using magnetic resonance spectroscopy, hepatic fibrosis using non-invasive scores, and peripheral and autonomic neuropathy using functional and clinical criteria. Patients were reassessed after 5 years. The German Diabetes Study is registered with ClinicalTrials.gov , number NCT01055093, and is ongoing.Findings 1105 patients were classified at baseline into five clusters, with 386 (35%) assigned to mild age-related diabetes (MARD), 323 (29%) to mild obesity-related diabetes (MOD), 247 (22%) to severe autoimmune diabetes (SAID), 121 (11%) to severe insulin-resistant diabetes (SIRD), and 28 (3%) to severe insulin-deficient diabetes (SIDD). At 5-year follow-up, 367 patients were reassessed, 128 (35%) with MARD, 106 (29%) with MOD, 88 (24%) with SAID, 35 (10%) with SIRD, and ten (3%) with SIDD. Whole-body insulin sensitivity was lowest in patients with SIRD at baseline (mean 4.3 mg/kg per min [SD 2.0]) compared with those with SAID (8.4 mg/kg per min [3.2]; p<0.0001), MARD (7.5 mg/kg per min [2.5]; p<0.0001), MOD (6.6 mg/kg per min [2.6]; p=0.0011), and SIDD (5.5 mg/kg per min [2.4]; p=0.0035). The fasting adipose-tissue insulin resistance index at baseline was highest in patients with SIRD (median 15.6 [IQR 9.3-20-9]) and MOD (11.6 [7-4-17.9]) compared with those with MARD (6.0 [3.9-10-3]; both p<0.0001) and SAID (6.0 [3.0-9.5]; both p<0.0001). In patients with newly diagnosed diabetes, hepatocellular lipid content was highest at baseline in patients assigned to the SIRD cluster (median 19% [IQR 11-22]) compared with all other clusters (7% [2-15] for MOD, p=0.00052; 5% [2-11] for MARD, p<0 . 0001; 2% [0-13] for SIDD, p=0 . 0083; and 1% [0-3] for SAID, p<0.0001), even after adjustments for baseline medication. Accordingly, hepatic fibrosis at 5-year follow-up was more prevalent in patients with SIRD (n=7 [26%]) than in patients with SAID (n=5 [7%], p=0.0011), MARD (n=12 [12%], p=0.012), MOD (n=13 [15%], p=0.050), and SIDD (n=0 [0%], p value not available). Confirmed diabetic sensorimotor polyneuropathy was more prevalent at baseline in patients with SIDD (n=9 [36%]) compared with patients with SAID (n=10 [5%], p<0.0001), MARD (n=39 [15%], p=0.00066), MOD (n=26 [11%], p<0.0001), and SIRD (n=10 [17%], p<0-0001).Interpretation Cluster analysis can characterise cohorts with different degrees of whole-body and adipose-tissue insulin resistance. Specific diabetes clusters show different prevalence of diabetes complications at early stages of non-alcoholic fatty liver disease and diabetic neuropathy. These findings could help improve targeted prevention and treatment and enable precision medicine for diabetes and its comorbidities. AU - Zaharia, O.P.* AU - Strassburger, K.* AU - Strom, A.* AU - Bönhof, G.J.* AU - Karusheva, Y.* AU - Antoniou, S.* AU - Bódis, K.* AU - Markgraf, D.F.* AU - Burkart, V.* AU - Müssig, K.* AU - Hwang, J.H.* AU - Asplund, O.* AU - Groop, L.* AU - Ahlqvist, E.* AU - Seissler, J. AU - Nawroth, P.P.* AU - Kopf, S.* AU - Schmid, S.M.* AU - Stumvoll, M.* AU - Pfeiffer, A.F.H.* AU - Kabisch, S.* AU - Tselmin, S.* AU - Häring, H.-U. AU - Ziegler, D.* AU - Kuss, O.* AU - Szendroedi, J.* AU - Roden, M.* C1 - 56656 C2 - 47187 CY - Ste 800, 230 Park Ave, New York, Ny 10169 Usa SP - 684-694 TI - Risk of diabetes-associated diseases in subgroups of patients with recent-onset diabetes: A 5-year follow-up study. JO - Lancet Diabet. Endocrinol. VL - 7 IS - 9 PB - Elsevier Science Inc PY - 2019 SN - 2213-8587 ER - TY - JOUR AB - Background Cardiovascular disease risk among individuals across different categories of BMI might depend on their metabolic health. It remains unclear to what extent metabolic health status changes over time and whether this affects cardiovascular disease risk. In this study, we aimed to examine the association between metabolic health and its change over time and cardiovascular disease risk across BMI categories.Methods Between June and December, 1976, 121 701 female nurses were recruited to the Nurses' Health Study (NHS) of whom 103 298 returned a questionnaire in 1980 used as baseline in this study. After excluding women with a history of cardiovascular disease or cancer, with missing body weight and with underweight. 90 257 women were followed-up from 1980 to 2010 for incident cardiovascular disease. Participants were cross-classified by BMI categories, metabolic health (defined by absence of diabetes, hypertension and hypercholesterolaemia), and change in metabolic health status during follow-up. The cardiovascular component of the NHS is registered with ClinicalTrials.gov,number NCT00005152.Findings During 2 127 391 person-years of follow-up with a median follow-up of 24 years, we documented 6306 cases of cardiovascular disease including 3304 myocardial infarction cases and 3080 strokes. Cardiovascular disease risk of women with metabolically healthy obesity was increased compared with women with metabolically healthy normal weight (HR 1.39, 95% CI 1.15-1.68), but risk was considerably higher in women with metabolically unhealthy normal weight (2.43, 2.19-2.68), overweight (2.61, 2.36-2.89) and obesity (3.15, 2.83-3.50). The majority of metabolically healthy women converted to unhealthy phenotypes (2555 [84%] of 3027 women with obesity, 22 215 [68%] of 32 882 women with normal-weight after 20 years). Women who maintained metabolically healthy obesity during follow-up were still at a higher cardiovascular disease risk compared with women with stable healthy normal weight (HR 1.57, 1.03-2.38), yet this risk was lower than for initially metabolically healthy women who converted to an unhealthy phenotype (normal-weight 1.90, 1.66-2.17 vs obesity 2.74, 2.30-3.27). Particularly incident diabetes and hypertension increased the risk among women with initial metabolic health.Interpretation Even when metabolic health is maintained during long periods of time, obesity remains a risk factor for cardiovascular disease. However, risks are highest for metabolically unhealthy women across all BMI categories. A large proportion of metabolically healthy women converted to an unhealthy phenotype over time across all BMI categories, which is associated with an increased cardiovascular disease risk. AU - Eckel, N.* AU - Li, Y.* AU - Kuxhaus, O.* AU - Stefan, N. AU - Hu, F.B.* AU - Schulze, M.B.* C1 - 53599 C2 - 44919 CY - 360 Park Ave South, New York, Ny 10010-1710 Usa SP - 714-724 TI - Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses' Health Study): 30 year follow-up from a prospective cohort study. JO - Lancet Diabet. Endocrinol. VL - 6 IS - 9 PB - Elsevier Science Inc PY - 2018 SN - 2213-8587 ER - TY - JOUR AB - BACKGROUND: Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. METHODS: DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18-75 years and had inadequately controlled type 1 diabetes (HbAbetween ≥7·7% and ≤11·0% [≥61·0 mmol/mol and ≤97·0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA. The primary efficacy outcome was the change from baseline in HbAafter 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing. FINDINGS: Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg [n=277] vs dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbAwas 8·53% (70 mmol/mol; SD 0·67% [7·3 mmol/mol]). At week 24, both doses of dapagliflozin significantly reduced HbAcompared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was -0·42% [95% CI -0·56 to -0·28; p<0·0001] and for dapagliflozin 10 mg vs placebo was -0·45% [-0·58 to -0·31; p<0·0001]). Among patients in the dapagliflozin 5 mg (n=277), dapagliflozin 10 mg (n=296), and placebo (n=260) groups, the most common adverse events were nasopharyngitis (38 [14%] vs 36 [12%] vs 39 [15%]), urinary tract infection (19 [7%] vs 11 [4%] vs 13 [5%]), upper respiratory tract infection (15 [5%] vs 15 [5%] vs 11 [4%]), and headache (12 [4%] vs 17 [6%] vs 11 [4%]). Hypoglycaemia occurred in 220 (79%), 235 (79%), and 207 (80%) patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups, respectively; severe hypoglycaemia occurred in 21 (8%), 19 (6%), and 19 (7%) patients, respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%) patients in the dapagliflozin 5 mg group, five (2%) in the dapagliflozin 10 mg group, and three (1%) in the placebo group. INTERPRETATION: Our results suggest that dapagliflozin is a promising adjunct treatment to insulin to improve glycaemic control in patients with inadequately controlled type 1 diabetes. AU - Dandona, P.* AU - Mathieu, C.* AU - Phillip, M.* AU - Hansen, L.* AU - Griffen, S.C.* AU - Tschöpe, D.* AU - Thorén, F.* AU - Xu, J.* AU - Langkilde, A.M.* AU - DEPICT-1 Investigators (Ziegler, A.-G.) C1 - 53006 C2 - 44259 SP - 864-876 TI - Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. JO - Lancet Diabet. Endocrinol. VL - 5 IS - 11 PY - 2017 SN - 2213-8587 ER - TY - JOUR AB - Obesity increases the risk of several other chronic diseases and, because of its epidemic proportions, has become a major public health problem worldwide. Alarmingly, a lower proportion of adults have tried to lose weight during the past decade than during the mid-1980s to 1990s. The first-line treatment option for obesity is lifestyle intervention. Although this approach can decrease fat mass in the short term, these beneficial effects typically do not persist. If a large amount of weight loss is not an easily achievable goal, other goals that might motivate people with obesity to adopt a healthy lifestyle should be considered. In this setting, the concept of metabolically healthy obesity is useful. Accumulating evidence suggests that, although the risk of all-cause mortality and cardiovascular events might be higher in people with metabolically healthy obesity compared with metabolically healthy people of a normal weight, the risk is substantially lower than in individuals with metabolically unhealthy obesity. Therefore, every person with obesity should be motivated to achieve a normal weight in the long term, but more moderate weight loss sufficient for the transition from metabolically unhealthy obesity to metabolically healthy obesity might also lower the risk of adverse outcomes. However, how much weight needs to be lost for this transition to occur is under debate. This transition might be supported by lifestyle factors-such as the Mediterranean diet-that affect cardiovascular risk, independent of body fat. In this Series paper, we summarise available information about the concept of metabolically healthy obesity, highlight gaps in research, and discuss how this concept can be implemented in clinical care. AU - Stefan, N. AU - Häring, H.-U. AU - Schulze, M.B.* C1 - 51909 C2 - 43570 CY - New York SP - 249-258 TI - Metabolically healthy obesity: The low-hanging fruit in obesity treatment? JO - Lancet Diabet. Endocrinol. VL - 6 IS - 3 PB - Elsevier Science Inc PY - 2017 SN - 2213-8587 ER - TY - JOUR AB - BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention. FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7. AU - EUMODIC Consortium (Peters, A. AU - Heid, I.) C1 - 49822 C2 - 40940 SP - 840-849 TI - Natriuretic peptides and integrated risk assessment for cardiovascular disease: An individual-participant-data meta-analysis. JO - Lancet Diabet. Endocrinol. VL - 4 IS - 10 PY - 2016 SN - 2213-8587 ER - TY - JOUR AB - Among chronic non-communicable diseases, cardiometabolic diseases and cancer are the most important causes of morbidity and mortality worldwide. Although high BMI and waist circumference, as estimates of total and abdominal fat mass, are now accepted as predictors of the increasing incidence of these diseases, adult height, which also predicts mortality, has been neglected. Interestingly, increasing evidence suggests that height is associated with lower cardiometabolic risk, but higher cancer risk, associations supported by mendelian randomisation studies. Understanding the complex epidemiology, biology, and pathophysiology related to height, and its association with cardiometabolic diseases and cancer, is becoming even more important because average adult height has increased substantially in many countries during recent generations. Among the mechanisms driving the increase in height and linking height with cardiometabolic diseases and cancer are insulin and insulin-like growth factor signalling pathways. These pathways are thought to be activated by overnutrition, especially increased intake of milk, dairy products, and other animal proteins during different stages of child development. Limiting overnutrition during pregnancy, early childhood, and puberty would avoid not only obesity, but also accelerated growth in children-and thus might reduce risk of cancer in adulthood. AU - Stefan, N. AU - Häring, H.-U. AU - Hu, F.B.* AU - Schulze, M.B.* C1 - 47799 C2 - 39504 CY - New York SP - 457-467 TI - Divergent associations of height with cardiometabolic disease and cancer: Epidemiology, pathophysiology, and global implications. JO - Lancet Diabet. Endocrinol. VL - 4 IS - 5 PB - Elsevier Science Inc PY - 2016 SN - 2213-8587 ER - TY - JOUR AB - Prediabetes is associated with increased risks of type 2 diabetes, cardiovascular disease, dementia, and cancer, and its prevalence is increasing worldwide. Lifestyle and pharmacological interventions in people with prediabetes can prevent the development of diabetes and possibly cardiovascular disease. However, prediabetes is a highly heterogeneous metabolic state, both with respect to its pathogenesis and prediction of disease. Improved understanding of these features and precise phenotyping of prediabetes could help to improve stratification of disease risk. In this Personal View, we focus on the extreme metabolic phenotypes of metabolically healthy obesity and metabolically unhealthy normal weight, insulin secretion failure, insulin resistance, visceral obesity, and non-alcoholic fatty liver disease. We present new analyses aimed at improving characterisation of phenotypes in lean, overweight, and obese people with prediabetes. We discuss evidence from lifestyle intervention studies to explore whether these phenotypes can also be used for individualised prediction and prevention of cardiometabolic diseases. AU - Stefan, N. AU - Fritsche, A. AU - Schick, F. AU - Häring, H.-U. C1 - 48615 C2 - 41222 CY - New York SP - 789-798 TI - Phenotypes of prediabetes and stratification of cardiometabolic risk. JO - Lancet Diabet. Endocrinol. VL - 4 IS - 9 PB - Elsevier Science Inc PY - 2016 SN - 2213-8587 ER - TY - JOUR AB - To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods: We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1α and IL-1β); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings: For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0·22 SD (95% CI 0·18-0·25; 12·5%; p=9·3 × 10-33), concentrations of interleukin 6 decreased by 0·02 SD (-0·04 to -0·01; -1·7%; p=3·5 × 10-3), and concentrations of C-reactive protein decreased by 0·03 SD (-0·04 to -0·02; -3·4%; p=7·7 × 10-14). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1·15 (1·08-1·22; p=1·8 × 10-6) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1·03 (1·02-1·04; p=3·9 × 10-10). Per-allele odds ratios were 0·97 (0·95-0·99; p=9·9 × 10-4) for rheumatoid arthritis, 0·99 (0·97-1·01; p=0·47) for type 2 diabetes, 1·00 (0·98-1·02; p=0·92) for ischaemic stroke, and 1·08 (1·04-1·12; p=1·8 × 10-5) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation: Human genetic data suggest that long-term dual IL-1α/β inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Funding: UK Medical Research Council, British Heart Foundation, UK National Institute for Health Research, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7. AU - Interleukin 1 Genetics Consortium AU - Freitag, D.F.* AU - Butterworth, A.S.* AU - Willeit, P.* AU - Howson, J.M.M.* AU - Burgess, S.L.* AU - Kaptoge, S.K.* AU - Young, R.* AU - Ho, W.K.* AU - Wood, A.M.* AU - Sweeting, M.* AU - Spackman, S.* AU - Staley, J.R.* AU - Ramond, A.* AU - Harshfield, E.* AU - Nielsen, S.F.* AU - Grande, P.* AU - Lange, L.A.* AU - Bown, M.* AU - Jones, G.T.* AU - Scott, R.A.H.* AU - Bevan, S.N.* AU - Porcu, E.* AU - Thorleifsson, G.* AU - Zeng, L.M.* AU - Kessler, T.* AU - Nikpay, M.* AU - Do, R.* AU - Zhang, W.* AU - Hopewell, J.C.* AU - Kleber, M.E.* AU - Delgado, G.E.* AU - Nelson, C.P.* AU - Goel, A.* AU - Bis, J.C.M.* AU - Dehghan, A.J.* AU - Ligthart, S.* AU - Smith, A.V.* AU - Qu, L.* AU - van 'T Hof, F.* AU - de Bakker, P.I.W.* AU - Baas, A.F.* AU - van Rij, A.M.* AU - Tromp, G.* AU - Kuivaniemi, H.* AU - Ritchie, M.D.* AU - Verma, S.S.* AU - Crawford, D.C.* AU - Malinowski, J.* AU - de Andrade, M.* AU - Kullo, I.J.* AU - Peissig, P.L.* AU - McCarty, C.A.* AU - Bottinger, E.P.* AU - Gottesman, O.* AU - Crosslin, D.R.* AU - Carrell, D.S.* AU - Rasmussen-Torvik, L.J.* AU - Pacheco, J.A.* AU - Huang, J.* AU - Timpson, N.J.* AU - Kettunen, J.A.* AU - Ala-Korpela, M.* AU - Mitchell, G.F.* AU - Parsa, A.* AU - Wilkinson, I.B.* AU - Gorski, M.* AU - Li, Y.* AU - Franceschini, N.C.* AU - Keller, M.F.* AU - Ganesh, S.K.* AU - Langefeld, C.D.* AU - Bruijn, L.* AU - Brown, M.A.* AU - Evans, D.M.D.* AU - Baltic, S.* AU - Ferreira, M.A.R.* AU - Baurecht, H.J.* AU - Weidinger, S.* AU - Franke, A.* AU - Lubitz, S.A.* AU - Müller-Nurasyid, M. AU - Felix, J.F.* AU - Smith, N.L.* AU - Sudman, M.* AU - Thompson, S.D.* AU - Zeggini, E.* AU - Panoutsopoulou, K.* AU - Nalls, M.A.* AU - Singleton, A.B.* AU - Polychronakos, C.* AU - Bradfield, J.P.* AU - Hakonarson, H.H.* AU - Easton, D.F.* AU - Thompson, D.J.* AU - Tomlinson, I.P.M.* AU - Dunlop, M.G.* AU - Hemminki, K.L.* AU - Morgan, G.* AU - Eisen, T.* AU - Goldschmidt, H.P.* AU - Allan, J.M.* AU - Henrion, M.* AU - Whiffin, N.* AU - Wang, Y.* AU - Chubb, D.* AU - Iles, M.M.* AU - Bishop, D.T.* AU - Law, M.H.* AU - Hayward, N.K.* AU - Luo, Y.* AU - Nejentsev, S.* AU - Barbalic, M.* AU - Crossman, D.C.* AU - Sanna, S.* AU - Soranzo, N.* AU - Markus, H.S.* AU - Wareham, N.J.* AU - Rader, D.J.* AU - Reilly, M.P.* AU - Assimes, T.L.* AU - Harris, T.B.* AU - Hofman, A.* AU - Franco, O.H.* AU - Gudnason, V.G.* AU - Tracy, R.P.* AU - Psaty, B.M.* AU - Farrall, M.J.* AU - Watkins, H.* AU - Hall, A.S.* AU - Samani, N.J.* AU - Marz, W.* AU - Clarke, R.* AU - Collins, R.E.* AU - Kooner, J.S.* AU - Chambers, J.C.* AU - Kathiresan, S.* AU - McPherson, R.* AU - Erdmann, J.* AU - Kastrati, A.* AU - Schunkert, H.* AU - Stefansson, K.* AU - Thorsteinsdottir, U.* AU - Walston, J.D.* AU - Tybjærg-Hansen, A.* AU - Alam, D.S.* AU - Al Shafi Majumder, A.* AU - Angelantonio, E.D.* AU - Chowdhury, R.* AU - Nørdestgaard, B.G.* AU - Saleheen, D.* AU - Thompson, S.G.* AU - Danesh, J.* AU - Houlston, R.S.* C1 - 44067 C2 - 36750 CY - New York SP - 243-253 TI - Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: A mendelian randomisation analysis. JO - Lancet Diabet. Endocrinol. VL - 3 IS - 4 PB - Elsevier Science Inc PY - 2015 SN - 2213-8587 ER - TY - JOUR AB - BACKGROUND: Indian Asians, who make up a quarter of the world's population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes. METHODS: We did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p<1 × 10(-7). We compared methylation levels between Indian Asian and European controls without type 2 diabetes at baseline to estimate the potential contribution of DNA methylation to increased risk of future type 2 diabetes incidence among Indian Asians. FINDINGS: 1608 (11·9%) of 13 535 Indian Asians and 306 (4·3%) of 7066 Europeans developed type 2 diabetes over a mean of 8·5 years (SD 1·8) of follow-up. The age-adjusted and sex-adjusted incidence of type 2 diabetes was 3·1 times (95% CI 2·8-3·6; p<0·0001) higher among Indian Asians than among Europeans, and remained 2·5 times (2·1-2·9; p<0·0001) higher after adjustment for adiposity, physical activity, family history of type 2 diabetes, and baseline glycaemic measures. The mean absolute difference in methylation level between type 2 diabetes cases and controls ranged from 0·5% (SD 0·1) to 1·1% (0·2). Methylation markers at five loci were associated with future type 2 diabetes incidence; the relative risk per 1% increase in methylation was 1·09 (95% CI 1·07-1·11; p=1·3 × 10(-17)) for ABCG1, 0·94 (0·92-0·95; p=4·2 × 10(-11)) for PHOSPHO1, 0·94 (0·92-0·96; p=1·4 × 10(-9)) for SOCS3, 1·07 (1·04-1·09; p=2·1 × 10(-10)) for SREBF1, and 0·92 (0·90-0·94; p=1·2 × 10(-17)) for TXNIP. A methylation score combining results for the five loci was associated with future type 2 diabetes incidence (relative risk quartile 4 vs quartile 1 3·51, 95% CI 2·79-4·42; p=1·3 × 10(-26)), and was independent of established risk factors. Methylation score was higher among Indian Asians than Europeans (p=1 × 10(-34)). INTERPRETATION: DNA methylation might provide new insights into the pathways underlying type 2 diabetes and offer new opportunities for risk stratification and prevention of type 2 diabetes among Indian Asians. FUNDING: The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health. AU - Chambers, J.C.* AU - Loh, M.* AU - Lehne, B.* AU - Drong, A.* AU - Kriebel, J. AU - Motta, V.* AU - Wahl, S. AU - Elliott, H.R.* AU - Rota, F.* AU - Scott, W.R.* AU - Zhang, W.* AU - Tan, S.T.* AU - Campanella, G.* AU - Chadeau-Hyam, M.* AU - Yengo, L.* AU - Richmond, R.C.* AU - Adamowicz-Brice, M.* AU - Afzal, U.* AU - Bozaoglu, K.* AU - Mok, Z.Y.* AU - Ng, H.K.* AU - Pattou, F.* AU - Prokisch, H. AU - Rozario, M.A.* AU - Tarantini, L.* AU - Abbott, J.* AU - Ala-Korpela, M.* AU - Albetti, B.* AU - Ammerpohl, O.* AU - Bertazzi, P.A.* AU - Blancher, C.* AU - Caiazzo, R.* AU - Danesh, J.* AU - Gaunt, T.R.* AU - de Lusignan, S.* AU - Gieger, C. AU - Illig, T.* AU - Jha, S.* AU - Jones, S.* AU - Jowett, J.* AU - Kangas, A.J.* AU - Kasturiratne, A.* AU - Kato, N.* AU - Kotea, N.* AU - Kowlessur, S.* AU - Pitkäniemi, J.* AU - Punjabi, P.* AU - Saleheen, D.* AU - Schafmayer, C.* AU - Soininen, P.* AU - Tai, E.S.* AU - Thorand, B. AU - Tuomilehto, J.* AU - Wickremasinghe, A.R.* AU - Kyrtopoulos, S.A.* AU - Aitman, T.J.* AU - Herder, C.* AU - Hampe, J.* AU - Cauchi, S.* AU - Relton, C.L.* AU - Froguel, P.* AU - Soong, R.* AU - Vineis, P.* AU - Jarvelin, M.R.* AU - Scott, J.* AU - Grallert, H. AU - Bollati, V.* AU - Elliott, P.* AU - McCarthy, M.I.* AU - Kooner, J.S.* C1 - 45385 C2 - 37338 CY - New York SP - 526-534 TI - Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: A nested case-control study. JO - Lancet Diabet. Endocrinol. VL - 3 IS - 7 PB - Elsevier Science Inc PY - 2015 SN - 2213-8587 ER - TY - JOUR AB - BACKGROUND: Diabetes has been defined on the basis of different biomarkers, including fasting plasma glucose (FPG), 2-h plasma glucose in an oral glucose tolerance test (2hOGTT), and HbA1c. We assessed the effect of different diagnostic definitions on both the population prevalence of diabetes and the classification of previously undiagnosed individuals as having diabetes versus not having diabetes in a pooled analysis of data from population-based health examination surveys in different regions. METHODS: We used data from 96 population-based health examination surveys that had measured at least two of the biomarkers used for defining diabetes. Diabetes was defined using HbA1c (HbA1c ≥6·5% or history of diabetes diagnosis or using insulin or oral hypoglycaemic drugs) compared with either FPG only or FPG-or-2hOGTT definitions (FPG ≥7·0 mmol/L or 2hOGTT ≥11·1 mmol/L or history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated diabetes prevalence, taking into account complex survey design and survey sample weights. We compared the prevalences of diabetes using different definitions graphically and by regression analyses. We calculated sensitivity and specificity of diabetes diagnosis based on HbA1c compared with diagnosis based on glucose among previously undiagnosed individuals (ie, excluding those with history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated sensitivity and specificity in each survey, and then pooled results using a random-effects model. We assessed the sources of heterogeneity of sensitivity by meta-regressions for study characteristics selected a priori. FINDINGS: Population prevalence of diabetes based on FPG-or-2hOGTT was correlated with prevalence based on FPG alone (r=0·98), but was higher by 2-6 percentage points at different prevalence levels. Prevalence based on HbA1c was lower than prevalence based on FPG in 42·8% of age-sex-survey groups and higher in another 41·6%; in the other 15·6%, the two definitions provided similar prevalence estimates. The variation across studies in the relation between glucose-based and HbA1c-based prevalences was partly related to participants' age, followed by natural logarithm of per person gross domestic product, the year of survey, mean BMI, and whether the survey population was national, subnational, or from specific communities. Diabetes defined as HbA1c 6·5% or more had a pooled sensitivity of 52·8% (95% CI 51·3-54·3%) and a pooled specificity of 99·74% (99·71-99·78%) compared with FPG 7·0 mmol/L or more for diagnosing previously undiagnosed participants; sensitivity compared with diabetes defined based on FPG-or-2hOGTT was 30·5% (28·7-32·3%). None of the preselected study-level characteristics explained the heterogeneity in the sensitivity of HbA1c versus FPG. INTERPRETATION: Different biomarkers and definitions for diabetes can provide different estimates of population prevalence of diabetes, and differentially identify people without previous diagnosis as having diabetes. Using an HbA1c-based definition alone in health surveys will not identify a substantial proportion of previously undiagnosed people who would be considered as having diabetes using a glucose-based test. FUNDING: Wellcome Trust, US National Institutes of Health. AU - NCD Risk Factors Collaboration (Müller-Nurasyid, M. AU - Peters, A. AU - Stöckl, D. AU - Ezzati, M.*) C1 - 46433 C2 - 37515 CY - New York SP - 624-637 TI - Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: A pooled analysis of 96 population-based studies with 331 288 participants. JO - Lancet Diabet. Endocrinol. VL - 3 IS - 8 PB - Elsevier Science Inc PY - 2015 SN - 2213-8587 ER - TY - JOUR AB - In parallel with the increasing prevalence of obesity and type 2 diabetes, sleep loss has become common in modern societies. An increasing number of epidemiological studies show an association between short sleep duration, sleep disturbances, and circadian desynchronisation of sleep with adverse metabolic traits, in particular obesity and type 2 diabetes. Furthermore, experimental studies point to distinct mechanisms by which insufficient sleep adversely affects metabolic health. Changes in the activity of neuroendocrine systems seem to be major mediators of the detrimental metabolic effects of insufficient sleep, through favouring neurobehavioural outcomes such as increased appetite, enhanced sensitivity to food stimuli, and, ultimately, a surplus in energy intake. The effect of curtailed sleep on physical activity and energy expenditure is less clear, but changes are unlikely to outweigh increases in food intake. Although long-term interventional studies proving a cause and effect association are still scarce, sleep loss seems to be an appealing target for the prevention, and probably treatment, of metabolic disease. AU - Schmid, S.M.* AU - Hallschmid, M. AU - Schultes, B.* C1 - 31026 C2 - 34095 CY - New York SP - 52-62 TI - The metabolic burden of sleep loss. JO - Lancet Diabet. Endocrinol. VL - 3 IS - 1 PB - Elsevier Science Inc PY - 2015 SN - 2213-8587 ER - TY - JOUR AB - BACKGROUND: The prevalence of non-alcoholic fatty liver disease is increasing worldwide and an effective and safe pharmacological treatment is needed. We investigated whether inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, also known as HSD11B1) by RO5093151 could safely and effectively decrease liver-fat content in patients with this disorder. METHODS: We did this phase 1b trial at four centres in Germany and Austria. Participants with non-alcoholic fatty liver disease (defined as (1)H magnetic resonance spectroscopy liver-fat content >5·56%), insulin resistance (homoeostatic model assessment of insulin resistance [HOMA-IR] of at least 2·0 mmol/L·mU/L), BMI greater than 27 kg/m(2), and aged 35-65 years were randomly assigned by interactive voice response system in a 1:1 ratio, stratified for triglyceride concentration (<1·7 mmol/L or ≥1·7 mmol/L), to oral RO5093151 (200 mg twice daily) or matching placebo for 12 weeks. The main exclusion criteria were other liver diseases, aspartate aminotransferase or alanine aminotransferase concentrations of more than two and a half times the upper limit of normal, history of diabetes or bariatric surgery, and use of weight lowering drugs. Participants and investigators were masked to assignment throughout the study. The primary endpoint was change in liver-fat content from baseline to week 12. Efficacy analysis was by modified intention to treat, including all patients who received at least one dose of study drug and had a baseline and follow-up measurement of liver-fat content. Safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01277094. FINDINGS: We did this trial between Jan 13, 2011, and March 28, 2012. 41 patients were randomly assigned to RO5093151 and 41 to placebo. 35 patients in the RO5093151 group and 39 in the placebo group were included in the efficacy analysis. Mean liver-fat content decreased in the RO5093151 group (from 16·75% [SD 8·67] to 14·28% [8·89]), but not in the placebo group (from 18·53% [10·00] to 18·46% [10·78], p=0·02 for between group difference). 26 participants (65%) in the RO5093151 group had adverse events, compared with 21 (53%) in the placebo group. The most common adverse events were gastrointestinal disorders (12 patients [30%] in the RO5093151 group vs seven [18%] in the placebo group), and infections and infestations (eight [20%] vs nine [23%]). Nervous system disorders occurred in significantly more patients in the RO5093151 group than in the placebo group (nine [23%] vs two [5%]; p=0·02); all other differences in adverse events were non-significant. One participant (3%) in the placebo group and three participants (8%) in the RO5093151 group had serious adverse events. All serious adverse events were deemed unrelated to study treatment. INTERPRETATION: Inhibition of 11β-HSD1 by RO5093151 was effective and safe in reducing liver-fat content, suggesting that targeting of 11β-HSD1 might be a promising approach for the treatment of non-alcoholic fatty liver disease. AU - Stefan, N.* AU - Ramsauer, M.* AU - Jordan, P.* AU - Nowotny, B.* AU - Kantartzis, K. AU - Machann, J. AU - Hwang, J.H. AU - Nowotny, P. AU - Kahl, S. AU - Harreiter, J.* AU - Hornemann, S. AU - Sanyal, A.J.* AU - Stewart, P.M.* AU - Pfeiffer, A.F. AU - Kautzky-Willer, A.* AU - Roden, M.* AU - Häring, H.-U. AU - Fürst-Recktenwald, S.* C1 - 31528 C2 - 34511 CY - New York SP - 406-416 TI - Inhibition of 11β-HSD1 with RO5093151 for non-alcoholic fatty liver disease: A multicentre, randomised, double-blind, placebo-controlled trial. JO - Lancet Diabet. Endocrinol. VL - 2 IS - 5 PB - Elsevier Science Inc PY - 2014 SN - 2213-8587 ER - TY - JOUR AB - BACKGROUND: Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. METHODS: In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. FINDINGS: In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002). INTERPRETATION: Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study. FUNDING: British Heart Foundation, UK Medical Research Council, and Academy of Finland. AU - Vimaleswaran, K.S.* AU - Cavadino, A.* AU - Berry, D.J.* AU - Jorde, R.* AU - Dieffenbach, A.K.* AU - Lu, C.* AU - Alves, A.C.* AU - Heerspink, H.J.* AU - Tikkanen, E.* AU - Eriksson, J.* AU - Wong, A.* AU - Mangino, M.* AU - Jablonski, K.A.* AU - Nolte, I.M.* AU - Houston, D.K.* AU - Ahluwalia, T.S.* AU - van der Most, P.J.* AU - Pasko, D.* AU - Zgaga, L.* AU - Thiering, E. AU - Vitart, V.* AU - Fraser, R.M.* AU - Huffman, J.E.* AU - de Boer, R.A.* AU - Schöttker, B.* AU - Saum, K.U.* AU - McCarthy, M.I.* AU - Dupuis, J.* AU - Herzig, K.H.* AU - Sebert, S.* AU - Pouta, A.* AU - Laitinen, J.* AU - Kleber, M.E.* AU - Navis, G.* AU - Lorentzon, M.* AU - Jameson, K.* AU - Arden, N.* AU - Cooper, J.A.* AU - Acharya, J.* AU - Hardy, R.* AU - Raitakari, O.* AU - Ripatti, S.* AU - Billings, L.K.* AU - Lahti, J.* AU - Osmond, C.* AU - Penninx, B.W.* AU - Rejnmark, L.* AU - Lohman, K.K.* AU - Paternoster, L.* AU - Stolk, R.P.* AU - Hernandez, D.G.* AU - Byberg, L.* AU - Hagström, E.* AU - Melhus, H.* AU - Ingelsson, E.* AU - Mellström, D.* AU - Ljunggren, O.* AU - Tzoulaki, I.* AU - McLachlan, S.* AU - Theodoratou, E.* AU - Tiesler, C.M. AU - Jula, A.* AU - Navarro, P.* AU - Wright, A.F.* AU - Polasek, O.* AU - ICBP Consortium (*) AU - CHARGE Consortium (*) AU - Global BPgen Consortium (*) AU - Wilson, J.F.* AU - Rudan, I.* AU - Salomaa, V.* AU - Heinrich, J. AU - Campbell, H.* AU - Price, J.F.* AU - Karlsson, M.* AU - Lind, L.* AU - Michaelsson, K.* AU - Bandinelli, S.* AU - Frayling, T.M.* AU - Hartman, C.A.* AU - Sørensen, T.I.* AU - Kritchevsky, S.B.* AU - Langdahl, B.L.* AU - Eriksson, J.G.* AU - Florez, J.C* AU - Spector, T.D.* AU - Lehtimäki, T.* AU - Kuh, D.* AU - Humphries, S.E.* AU - Cooper, C.* AU - Ohlsson, C.* AU - Marz, W.* AU - de Borst, M.H.* AU - Kumari, M.* AU - Kivimaki, M.* AU - Wang, T.J.* AU - Power, C.* AU - Brenner, H.* AU - Grimnes, G.* AU - van der Harst, P.* AU - Snieder, H.* AU - Hingorani, A.D.* AU - Pilz, S.* AU - Whittaker, J.C.* AU - Jarvelin, M.R.* AU - Hyppönen, E.* C1 - 31706 C2 - 34687 CY - New York SP - 719-729 TI - Association of vitamin D status with arterial blood pressure and hypertension risk: A mendelian randomisation study. JO - Lancet Diabet. Endocrinol. VL - 2 IS - 9 PB - Elsevier Science Inc PY - 2014 SN - 2213-8587 ER - TY - JOUR AB - Obesity has become a worldwide epidemic that poses substantial health problems for both individuals and society. However, a proportion of obese individuals might not be at an increased risk for metabolic complications of obesity and, therefore, their phenotype can be referred to as metabolically healthy obesity. This novel concept of metabolically healthy obesity might become increasingly important to stratify individuals in the clinical treatment of obesity. However, no universally accepted criteria exist to define metabolically healthy obesity. Furthermore, many questions have been raised regarding the biological basis of this phenotype, the transitory nature of metabolically healthy obesity over time, and predictors of this phenotype. We describe the observational studies that gave rise to the idea of metabolically healthy obesity and the key parameters that can help to distinguish it from the general form of obesity. We also discuss potential biological mechanisms underlying metabolically healthy obesity and its public health and clinical implications. AU - Stefan, N. AU - Häring, H.-U. AU - Hu, F.B.* AU - Schulze, M.B. C1 - 28618 C2 - 33490 CY - New York SP - 152-162 TI - Metabolically healthy obesity: Epidemiology, mechanisms, and clinical implications. JO - Lancet Diabet. Endocrinol. VL - 1 IS - 2 PB - Elsevier PY - 2013 SN - 2213-8587 ER -