There is increasing evidence for a role of the metabolic syndrome (MetS) during development of distal sensorimotor polyneuropathy (DSPN). We hypothesized that MetS components are differentially associated with measures of DSPN in individuals with normal glucose tolerance (NGT) and early type 2 diabetes (T2D). Electrophysiological and quantitative sensory testing was performed in 180 participants with NGT and 355 with recent-onset T2D (known diabetes duration <1 year) matched for age from the German Diabetes Study (NGT/T2D [mean±SD]: age: 43.9±14.0/45.1±7.7 years; sex: 61/65% male; BMI: 26.8±5.0/32.3±6.5 kg/m²; HbA1c: 5.2±0.3/6.5±1.0%). Intraepidermal nerve fiber density (IENFD) was assessed in 218 individuals (NGT/T2D: n=117/101). Subsets of participants were followed for 5 years (NGT/T2D: n=48/53). MetS was defined according to International Diabetes Federation (2006) and DSPN according to Toronto consensus criteria (2011). After adjustment for age, sex, height, smoking and HbA1c, a lower IENFD was associated with higher weight (β=-0.306), number of MetS components (NMetSC; β=-0.222) and presence of central obesity (β=-0.292), while higher malleolar vibration perception threshold was associated with weight (β=0.219) in NGT (P<0.05), but not in T2D. Median motor nerve conduction velocity and sural sensory nerve action potential were inversely associated with weight (β=-0.182/-0.286), NMetSC (β=-0.127/-0.128), presence of central obesity (β=-0.163/-0.165), and MetS (β=-0.169/-0.203) in T2D (P<0.05). Higher weight predicted the presence of DSPN at 5 years (β=0.652, P=0.001) in NGT, while increasing NMetSC and MetS prevalence predicted a decline in IENFD over 5 years (β=-0.533/-0.388, P=0.001/0.013) in T2D. This suggests that obesity indices can predict DSPN over 5 years in NGT, while MetS and its components are differentially associated with measures of DSPN in early, well-controlled type 2 diabetes compared with NGT. Disclosure G.Sipola: None. A.Strom: None. M.Bombrich: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. D.Ziegler: None. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. G.J.Bönhof: None. Gds group: n/a. Funding German Federal Ministry of Health; Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia; German Federal Ministry of Education and Research
There is a lack of evidence on the long-term changes of nerve function in individuals with type 2 diabetes (T2D) compared to those with normal glucose tolerance (NGT). Therefore, we assessed motor and sensory nerve conduction velocities (MNCV, SNCV), sensory nerve action potentials, vibration perception threshold (VPT) and thermal detection threshold of lower extremities in 45 individuals with T2D (known diabetes duration [mean±SD]: 164±95 days) and NGT from the German Diabetes Study (GDS) at baseline (BL) and 5-year follow-up. Individuals were matched pairwise for age (T2D/NGT: 52.9±10.4/52.9±10.3 years) and sex (64/64% male). In addition, 103 individuals with T2D were followed over 10 years. At BL, 1/6 indices was lower in T2D vs NGT (peroneal MNCV: 45.6±4.0 vs 47.2±2.8 m/s; P<0.05). After five years, one index deteriorated in T2D (peroneal MNCV: 45.3±4.1 vs 43.5±3.8 m/s) and one in NGT (malleolar VPT: 1.29±1.88 vs 2.25±3.06 µm) (all P<0.05). After adjustment for BL values and pairwise matching, nerve function similarly declined over the first five years in T2D and NGT (e.g. Δperoneal MNCV; figure). A comparable deterioration was observed in individuals with T2D over 10 years (figure). Parallel decline in small and large fiber function in both NGT and well controlled T2D indicates that the main events leading to impaired nerve function in well controlled T2D might occur earlier than previously assumed. Disclosure A.Strom: None. K.Strassburger: None. G.Sipola: None. D.Ziegler: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. G.J.Bönhof: None. Gds group: n/a. Funding German Federal Ministry of Health; Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia; German Federal Ministry of Education and Research
Adult-onset type 1 diabetes (T1D) is a chronic disease with progressive beta-cell destruction. However, individuals with adult-onset T1D are metabolically dissimilar. We aimed to identify metabolically distinct groups in a comprehensively phenotyped cohort of individuals with recent-onset T1D. Participants with T1D (n=550) were split by presence of glutamic-acid decarboxylase antibody (GADA) into a GADA- (n=95) and GADA+ groups (n=455). GADA+ was clustered using partitioning around medoids based on fasting C-peptide, glucose, triglycerides and HDL resulting in 2 distinguished GADA+ clusters. All 3 clusters were compared at baseline (first year of diabetes diagnosis) and after five years of follow-up using ANOVA, chi-squared test and logistic regression adjusted for age and sex. The larger GADA+ cluster (n=285) with younger age, lower BMI and lower C-peptide was termed “classic T1D”. The other GADA+ cluster (n=170) combined features of type 1 and type 2 diabetes and was named “mixed T1D”. Patients of the “mixed T1D” cluster did not gain weight over 5 years (p=0.29), which was not the case for “classic T1D” cluster (p<0.001, increased BMI with an effect size 0.07) and GADA-cluster (p=0.01, effect size 0.04) participants. The “classic T1D” cluster had the highest insulin sensitivity at baseline (p<0.001) that sharply decreased during five years of follow-up. At five years, there was no difference in insulin sensitivity across the 3 clusters (p=0.78). There were no differences in HbA1c levels across clusters neither at baseline (p=0.48) nor after 5 years (p=0.64). Classic T1D participants reported a higher incidence of hypoglycemia (OR 4.92, 95% CI 1.9-13.5, p=0.001). The incidence of both distal peripheral sensory (OR 2.89, 95%CI1.05-8.29, p= 0.041) and cardiac autonomic neuropathy (OR 9.61, 95%CI 2.35-49.8, p= 0.003), was higher in “mixed T1D”. Based on rapidly available laboratory variables, individuals with recent-onset adult type 1 diabetes can be stratified into clusters with different clinical course and complication risk Disclosure K.Prystupa: Other Relationship; Berlin-Chemie AG. S.M.Meyhöfer: Speaker's Bureau; Novo Nordisk, AstraZeneca, Lilly, Amgen Inc., Boehringer-Ingelheim, Novartis. O.P.Zaharia: None. N.Saatmann: None. M.Huttasch: None. K.Strassburger: None. V.Burkart: None. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. G.J.Bönhof: None. A.Strom: None. M.Heni: Advisory Panel; Boehringer-Ingelheim, Sanofi, Research Support; Boehringer Ingelheim Inc., Speaker's Bureau; Lilly, Bayer Inc., Sanofi, Boehringer-Ingelheim, Novo Nordisk, Amryt Pharma Plc. J.Seissler: None. J.Szendroedi: None. A.F.Pfeiffer: Advisory Panel; Abbott Diabetes, Speaker's Bureau; Novo Nordisk, Sanofi-Aventis Deutschland GmbH. M.W.Stumvoll: None.
Heterogeneity in type 2 diabetes (T2D) can be represented by a tree-like structure using reverse graph-embedded dimensionality reduction. We aimed to validate this approach and study if intensified phenotyping stratifies complications. Participants (n=927) of the German Diabetes Study (GDS) with recent-onset T2D were mapped onto a two-dimensional tree based on HbA1c, BMI, total and HDL cholesterol, triglycerides, alanine aminotransferase, creatinine, systolic and diastolic blood pressure, residualized for age and sex. A subset (n=447) had follow-up examinations after 5 years. Phenotypic variability rendered on a tree structure showed gradients for insulin sensitivity (hyperinsulinemic-euglycemic clamp, both dimensions: p<0.001) and insulin secretion (intravenous glucose tolerance test, both dimensions: p<0.001) (Fig 1). Individuals in the tree branch with the lowest insulin sensitivity had the highest liver fat content (1H-MR spectroscopy, pdim1<0.001, pdim2=0.04), elevated cardiovascular hazard (nevents=147, HRmax 4.0, pdim1=0.2, pdim2<0.001) and diabetic retinopathy (nevents=36, fundus photography, HRmax 2.5, pdim1=0.04, pdim2=0.2). This method provides an alternative approach to discrete clusters in identifying persons at high risk of certain diabetes-related diseases, potentially providing a framework for precision diabetology. Disclosure M.Schön: None. G.J.Bönhof: None. A.L.Birkenfeld: None. J.Seissler: None. A.F.Pfeiffer: Advisory Panel; Abbott Diabetes, Speaker's Bureau; Novo Nordisk, Sanofi-Aventis Deutschland GmbH. M.Blüher: Advisory Panel; Boehringer Ingelheim Inc., Lilly, Novo Nordisk, Consultant; Novo Nordisk Foundation, Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo, Novartis, Sanofi-Aventis Deutschland GmbH. S.R.Bornstein: None. J.Szendroedi: None. S.Meyhoefer: None. V.Burkart: None. V.Schrauwen-hinderling: None. K.Prystupa: Other Relationship; Berlin-Chemie AG. O.Kuss: Consultant; Berlin-Chemie AG. E.Pearson: Speaker's Bureau; Novo Nordisk, Lilly, Illumina. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. The german diabetes study (gds) group: n/a. T.Mori: None. O.P.Zaharia: None. K.Bódis: None. Y.Kupriyanova: None. A.Nair: None. A.Strom: None. R.Guthoff: Other Relationship; Alimera, Bayer Inc., Novartis, Allergan. Funding German Diabetes Center; German Federal Ministry of Health (Berlin, Germany); Ministry of Culture and Science of the state North Rhine-Westphalia (Düsseldorf, Germany); German Federal Ministry of Education and Research; German Center for Diabetes Research
Increased hepatocellular lipid content (HCL) is generally linked to insulin resistance, which contributes to greater risk of type 2 diabetes and cardiovascular complications. Conversely, a single-nucleotide polymorphism (TM6SF2EK; rs58542926) in the transmembrane 6 superfamily member 2 gene has been associated with nonalcoholic fatty liver disease (NAFLD), but lower cardiovascular risk. Thus, this case-control study tested the role of this polymorphism for tissue-specific insulin sensitivity during the early course of diabetes. Males with recent-onset type 2 diabetes with (TM6SF2EK: n=16) or without (TM6SF2EE: n=16) the heterozygous TM6SF2 polymorphism of similar age and BMI, underwent Botnia-clamps with [6,6-2H2]glucose to measure whole-body, hepatic and adipose tissue insulin sensitivity. HCL and liver fibrosis were assessed with 1H-magnetic resonance spectroscopy and non-invasive tests (FIB4, APRI, AST/ALT), respectively. A subset of both groups (n=24) was re-evaluated after 5 years. Despite doubled HCL, TM6SF2EK had similar hepatic and adipose tissue insulin sensitivity and even 27% higher whole-body insulin sensitivity than TM6SF2EE. The novel diabetes endotypes were equally distributed among both groups. After 5 years, whole-body insulin sensitivity, HCL and liver fibrosis indices were similar, while adipose tissue insulin sensitivity decreased by 87% and 55% both in TM6SF2EK and TM6SF2EE and circulating triacylglycerol increased in TM6SF2EE only. The TM6SF2 gene polymorphism rs58542926 dissociates ectopic fat content from insulin resistance in recent-onset type 2 diabetes, which is however attenuated by disease duration. This suggests that diabetes-related metabolic alterations dominate over the effects of the TM6SF2 gene polymorphism during the early course of diabetes and NAFLD. Disclosure K.Bódis: None. R.Guthoff: Other Relationship; Alimera, Bayer Inc., Novartis, Allergan. V.Schrauwen-hinderling: None. H.Al-hasani: None. V.Burkart: None. J.Szendroedi: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. D.F.Markgraf: Employee; Boehringer Ingelheim Pharma GmbH&Co.KG. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. M.Bombrich: None. M.Schön: None. B.Knebel: None. O.P.Zaharia: None. G.J.Bönhof: None. Y.Karusheva: None. Y.Kupriyanova: None. J.Kotzka: None.
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