Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort

Martin Schön; Katsiaryna Prystupa; Tim Mori; Oana P. Zaharia; Kálmán Bódis; Maria Bombrich; Clara Möser; Iryna Yurchenko; Yuliya Kupriyanova; Klaus Strassburger; Pavel Bobrov; Anand T.N. Nair; Gidon J. Bönhof; Alexander Strom; Graciela E. Delgado; Sema Kaya; Rainer Guthoff; Norbert Stefan; Andreas L. Birkenfeld; Hans Hauner; Jochen Seissler; Andreas Pfeiffer; Matthias Blüher; Stefan Bornstein; Julia Szendroedi; Svenja Meyhöfer; Sandra Trenkamp; Volker Burkart; Vera B. Schrauwen-Hinderling; Marcus E. Kleber; Alexander Niessner; Christian Herder; Oliver Kuss; Winfried März; Ewan R. Pearson; Michael Roden; Robert Wagner; German Diabetes Study Group

doi:10.1016/S2213-8587(23)00329-7

Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort

Martin Schön, Katsiaryna Prystupa, Tim Mori, Oana P. Zaharia, Kálmán Bódis, Maria Bombrich, Clara Möser, Iryna Yurchenko, Yuliya Kupriyanova, Klaus Strassburger, Pavel Bobrov, Anand T.N. Nair, Gidon J. Bönhof, Alexander Strom, Graciela E. Delgado, Sema Kaya, Rainer Guthoff, Norbert Stefan, Andreas L. Birkenfeld, Hans HaunerJochen Seissler, Andreas Pfeiffer, Matthias Blüher, Stefan Bornstein, Julia Szendroedi, Svenja Meyhöfer, Sandra Trenkamp, Volker Burkart, Vera B. Schrauwen-Hinderling, Marcus E. Kleber, Alexander Niessner, Christian Herder, Oliver Kuss, Winfried März, Ewan R. Pearson, Michael Roden, Robert Wagner (Lead / Corresponding author), German Diabetes Study Group

Population Health and Genomics

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Abstract

Background: Heterogeneity in type 2 diabetes (T2D) can be represented by a tree-like structure using reversed graph-embedded dimensionality reduction. We examined whether this approach stratifies key pathophysiological components and diabetes-related complications during longitudinal follow-up of recent-onset T2D.

Methods: Participants (n=927) of the German Diabetes Study (GDS) with recent-onset T2D were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualized for age and sex. Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp, insulin secretion by intravenous glucose tolerance test, hepatic lipid content (HLC) by 1H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 by ELISA as well as peripheral and autonomic neuropathy by functional and clinical measures. Participants were followed-up for up to 16 years. In the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort in persons with diabetes undergoing invasive coronary diagnostics (n=794), we also investigated heart failure and all-cause mortality.

Findings: There were gradients of clamp-measured insulin sensitivity (both dimensions: p<0·001) and insulin secretion (both dimensions: p<0·001) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest HLC (pdim1<0·001, pdim2=0·037), proinflammatory biomarkers (IL-6: pdim1<0·001, pdim2=0·013; IL-18: pdim1<0·001, pdim2=0·376) and elevated cardiovascular hazard (nevents=143, pdim1=0·144, pdim2<0·001), whereas persons positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (nevents=85, pdim1=0·032, pdim2=0·116) and had the highest risk of peripheral (nevents=184, pdim1=0·012, pdim2=0·044) and autonomic neuropathy (nevents=118, pdim1=0·009, pdim2=0·060). In the LURIC cohort, mortality was highest in the tree branch exhibiting insulin resistance (nevents=448, pdim1=0·120, pdim2=0·003). Significant gradients differentiated persons having heart failure with preserved from those with reduced ejection fraction.

Interpretation: These data define the pathophysiological underpinnings of the tree structure, with the potential to stratify diabetes-related complications based on routinely available variables and thereby extend the toolbox of precision diabetes diagnosis.

Original language	English
Pages (from-to)	119-131
Number of pages	23
Journal	The Lancet Diabetes and Endocrinology
Volume	12
Issue number	2
Early online date	21 Dec 2023
DOIs	https://doi.org/10.1016/S2213-8587(23)00329-7
Publication status	Published - 21 Dec 2023

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Endocrinology

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Schön, M., Prystupa, K., Mori, T., Zaharia, O. P., Bódis, K., Bombrich, M., Möser, C., Yurchenko, I., Kupriyanova, Y., Strassburger, K., Bobrov, P., Nair, A. T. N., Bönhof, G. J., Strom, A., Delgado, G. E., Kaya, S., Guthoff, R., Stefan, N., Birkenfeld, A. L., ... German Diabetes Study Group (2023). Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort. The Lancet Diabetes and Endocrinology, 12(2), 119-131. https://doi.org/10.1016/S2213-8587(23)00329-7

@article{567a4c33648b4c23afc341bbc776da73,

title = "Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort",

abstract = "Background: Heterogeneity in type 2 diabetes (T2D) can be represented by a tree-like structure using reversed graph-embedded dimensionality reduction. We examined whether this approach stratifies key pathophysiological components and diabetes-related complications during longitudinal follow-up of recent-onset T2D.Methods: Participants (n=927) of the German Diabetes Study (GDS) with recent-onset T2D were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualized for age and sex. Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp, insulin secretion by intravenous glucose tolerance test, hepatic lipid content (HLC) by 1H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 by ELISA as well as peripheral and autonomic neuropathy by functional and clinical measures. Participants were followed-up for up to 16 years. In the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort in persons with diabetes undergoing invasive coronary diagnostics (n=794), we also investigated heart failure and all-cause mortality.Findings: There were gradients of clamp-measured insulin sensitivity (both dimensions: p<0·001) and insulin secretion (both dimensions: p<0·001) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest HLC (pdim1<0·001, pdim2=0·037), proinflammatory biomarkers (IL-6: pdim1<0·001, pdim2=0·013; IL-18: pdim1<0·001, pdim2=0·376) and elevated cardiovascular hazard (nevents=143, pdim1=0·144, pdim2<0·001), whereas persons positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (nevents=85, pdim1=0·032, pdim2=0·116) and had the highest risk of peripheral (nevents=184, pdim1=0·012, pdim2=0·044) and autonomic neuropathy (nevents=118, pdim1=0·009, pdim2=0·060). In the LURIC cohort, mortality was highest in the tree branch exhibiting insulin resistance (nevents=448, pdim1=0·120, pdim2=0·003). Significant gradients differentiated persons having heart failure with preserved from those with reduced ejection fraction.Interpretation: These data define the pathophysiological underpinnings of the tree structure, with the potential to stratify diabetes-related complications based on routinely available variables and thereby extend the toolbox of precision diabetes diagnosis.",

author = "Martin Sch{\"o}n and Katsiaryna Prystupa and Tim Mori and Zaharia, {Oana P.} and K{\'a}lm{\'a}n B{\'o}dis and Maria Bombrich and Clara M{\"o}ser and Iryna Yurchenko and Yuliya Kupriyanova and Klaus Strassburger and Pavel Bobrov and Nair, {Anand T.N.} and B{\"o}nhof, {Gidon J.} and Alexander Strom and Delgado, {Graciela E.} and Sema Kaya and Rainer Guthoff and Norbert Stefan and Birkenfeld, {Andreas L.} and Hans Hauner and Jochen Seissler and Andreas Pfeiffer and Matthias Bl{\"u}her and Stefan Bornstein and Julia Szendroedi and Svenja Meyh{\"o}fer and Sandra Trenkamp and Volker Burkart and Schrauwen-Hinderling, {Vera B.} and Kleber, {Marcus E.} and Alexander Niessner and Christian Herder and Oliver Kuss and Winfried M{\"a}rz and Pearson, {Ewan R.} and Michael Roden and Robert Wagner and {German Diabetes Study Group} and Hadi Al-Hasani and Belgardt, {Bengt Frederik} and B{\"o}nhof, {Gidon J.} and Gerd Geerling and Andrea Icks and Karin Jandeleit-Dahm and J{\"o}rg Kotzka and Eckhard Lammert and Wolfgang Rathmann and Sabrina Schlesinger and Vera Schrauwen-Hinderling",

note = "Copyright: {\textcopyright} 2023 Elsevier Ltd.",

year = "2023",

month = dec,

day = "21",

doi = "10.1016/S2213-8587(23)00329-7",

language = "English",

volume = "12",

pages = "119--131",

journal = "The Lancet Diabetes and Endocrinology",

issn = "2213-8587",

publisher = "Elsevier",

number = "2",

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Schön, M, Prystupa, K, Mori, T, Zaharia, OP, Bódis, K, Bombrich, M, Möser, C, Yurchenko, I, Kupriyanova, Y, Strassburger, K, Bobrov, P, Nair, ATN, Bönhof, GJ, Strom, A, Delgado, GE, Kaya, S, Guthoff, R, Stefan, N, Birkenfeld, AL, Hauner, H, Seissler, J, Pfeiffer, A, Blüher, M, Bornstein, S, Szendroedi, J, Meyhöfer, S, Trenkamp, S, Burkart, V, Schrauwen-Hinderling, VB, Kleber, ME, Niessner, A, Herder, C, Kuss, O, März, W, Pearson, ER, Roden, M, Wagner, R & German Diabetes Study Group 2023, 'Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort', The Lancet Diabetes and Endocrinology, vol. 12, no. 2, pp. 119-131. https://doi.org/10.1016/S2213-8587(23)00329-7

TY - JOUR

T1 - Analysis of type 2 diabetes heterogeneity with a tree-like representation

T2 - insights from the prospective German Diabetes Study and the LURIC cohort

AU - Schön, Martin

AU - Prystupa, Katsiaryna

AU - Mori, Tim

AU - Zaharia, Oana P.

AU - Bódis, Kálmán

AU - Bombrich, Maria

AU - Möser, Clara

AU - Yurchenko, Iryna

AU - Kupriyanova, Yuliya

AU - Strassburger, Klaus

AU - Bobrov, Pavel

AU - Nair, Anand T.N.

AU - Bönhof, Gidon J.

AU - Strom, Alexander

AU - Delgado, Graciela E.

AU - Kaya, Sema

AU - Guthoff, Rainer

AU - Stefan, Norbert

AU - Birkenfeld, Andreas L.

AU - Hauner, Hans

AU - Seissler, Jochen

AU - Pfeiffer, Andreas

AU - Blüher, Matthias

AU - Bornstein, Stefan

AU - Szendroedi, Julia

AU - Meyhöfer, Svenja

AU - Trenkamp, Sandra

AU - Burkart, Volker

AU - Schrauwen-Hinderling, Vera B.

AU - Kleber, Marcus E.

AU - Niessner, Alexander

AU - Herder, Christian

AU - Kuss, Oliver

AU - März, Winfried

AU - Pearson, Ewan R.

AU - Roden, Michael

AU - Wagner, Robert

AU - German Diabetes Study Group

AU - Al-Hasani, Hadi

AU - Belgardt, Bengt Frederik

AU - Bönhof, Gidon J.

AU - Geerling, Gerd

AU - Icks, Andrea

AU - Jandeleit-Dahm, Karin

AU - Kotzka, Jörg

AU - Lammert, Eckhard

AU - Rathmann, Wolfgang

AU - Schlesinger, Sabrina

AU - Schrauwen-Hinderling, Vera

PY - 2023/12/21

Y1 - 2023/12/21

N2 - Background: Heterogeneity in type 2 diabetes (T2D) can be represented by a tree-like structure using reversed graph-embedded dimensionality reduction. We examined whether this approach stratifies key pathophysiological components and diabetes-related complications during longitudinal follow-up of recent-onset T2D.Methods: Participants (n=927) of the German Diabetes Study (GDS) with recent-onset T2D were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualized for age and sex. Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp, insulin secretion by intravenous glucose tolerance test, hepatic lipid content (HLC) by 1H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 by ELISA as well as peripheral and autonomic neuropathy by functional and clinical measures. Participants were followed-up for up to 16 years. In the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort in persons with diabetes undergoing invasive coronary diagnostics (n=794), we also investigated heart failure and all-cause mortality.Findings: There were gradients of clamp-measured insulin sensitivity (both dimensions: p<0·001) and insulin secretion (both dimensions: p<0·001) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest HLC (pdim1<0·001, pdim2=0·037), proinflammatory biomarkers (IL-6: pdim1<0·001, pdim2=0·013; IL-18: pdim1<0·001, pdim2=0·376) and elevated cardiovascular hazard (nevents=143, pdim1=0·144, pdim2<0·001), whereas persons positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (nevents=85, pdim1=0·032, pdim2=0·116) and had the highest risk of peripheral (nevents=184, pdim1=0·012, pdim2=0·044) and autonomic neuropathy (nevents=118, pdim1=0·009, pdim2=0·060). In the LURIC cohort, mortality was highest in the tree branch exhibiting insulin resistance (nevents=448, pdim1=0·120, pdim2=0·003). Significant gradients differentiated persons having heart failure with preserved from those with reduced ejection fraction.Interpretation: These data define the pathophysiological underpinnings of the tree structure, with the potential to stratify diabetes-related complications based on routinely available variables and thereby extend the toolbox of precision diabetes diagnosis.

AB - Background: Heterogeneity in type 2 diabetes (T2D) can be represented by a tree-like structure using reversed graph-embedded dimensionality reduction. We examined whether this approach stratifies key pathophysiological components and diabetes-related complications during longitudinal follow-up of recent-onset T2D.Methods: Participants (n=927) of the German Diabetes Study (GDS) with recent-onset T2D were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualized for age and sex. Insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamp, insulin secretion by intravenous glucose tolerance test, hepatic lipid content (HLC) by 1H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 by ELISA as well as peripheral and autonomic neuropathy by functional and clinical measures. Participants were followed-up for up to 16 years. In the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort in persons with diabetes undergoing invasive coronary diagnostics (n=794), we also investigated heart failure and all-cause mortality.Findings: There were gradients of clamp-measured insulin sensitivity (both dimensions: p<0·001) and insulin secretion (both dimensions: p<0·001) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest HLC (pdim1<0·001, pdim2=0·037), proinflammatory biomarkers (IL-6: pdim1<0·001, pdim2=0·013; IL-18: pdim1<0·001, pdim2=0·376) and elevated cardiovascular hazard (nevents=143, pdim1=0·144, pdim2<0·001), whereas persons positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (nevents=85, pdim1=0·032, pdim2=0·116) and had the highest risk of peripheral (nevents=184, pdim1=0·012, pdim2=0·044) and autonomic neuropathy (nevents=118, pdim1=0·009, pdim2=0·060). In the LURIC cohort, mortality was highest in the tree branch exhibiting insulin resistance (nevents=448, pdim1=0·120, pdim2=0·003). Significant gradients differentiated persons having heart failure with preserved from those with reduced ejection fraction.Interpretation: These data define the pathophysiological underpinnings of the tree structure, with the potential to stratify diabetes-related complications based on routinely available variables and thereby extend the toolbox of precision diabetes diagnosis.

UR - http://www.scopus.com/inward/record.url?scp=85180327829&partnerID=8YFLogxK

U2 - 10.1016/S2213-8587(23)00329-7

DO - 10.1016/S2213-8587(23)00329-7

M3 - Article

C2 - 38142707

AN - SCOPUS:85180327829

SN - 2213-8587

VL - 12

SP - 119

EP - 131

JO - The Lancet Diabetes and Endocrinology

JF - The Lancet Diabetes and Endocrinology

IS - 2

ER -

Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort

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