Kálmán Bódis

Differential Patterns of Impaired Cardiorespiratory Fitness and Cardiac Autonomic Dysfunction in Recently Diagnosed Type 1 and Type 2 Diabetes

OBJECTIVE Both impaired cardiorespiratory fitness (CRF) and heart rate variability (HRV) are predictors of mortality, but their relative roles in recent-onset diabetes are unknown. We determined to which extent CRF and HRV are reduced and interrelated in recent-onset diabetes. RESEARCH DESIGN AND METHODS Participants from the German Diabetes Study with type 1 (n = 163) or type 2 (n = 188) diabetes with known diabetes duration <1 year and two age-matched glucose-tolerant control groups (n = 40 each) underwent spiroergometry and HRV assessment during a hyperinsulinemic-euglycemic clamp. RESULTS Compared with control subjects, patients with type 2 diabetes showed reduced VO2max (median [1st–3rd quartiles] 19.3 [16.5–22.9] vs. 25.6 [20.7–29.9] mL/kg body weight/min; P < 0.05), diminished VCO2max (23.0 [19.1–26.8] vs. 30.9 [24.5–34.4] mL/kg body weight/min; P < 0.05), blunted heart rate recovery after 2 min (−29.0 [−35.0 to −23.0] vs. −36.0 [−42.8 to −28.0] beats/min; P < 0.05), and reduced HRV in four of nine indices, whereas patients with type 1 diabetes had unaltered CRF but reduced HRV in three of nine indices (P < 0.05), indicating diminished vagal and sympathetic HRV modulation. HRV measures correlated with VO2max in patients with type 1 diabetes (r >0.34; P < 0.05) but not in those with type 2 diabetes. CONCLUSIONS CRF is reduced in recently diagnosed type 2 diabetes but preserved in type 1 diabetes, whereas cardiac autonomic function is reduced in both diabetes types but is strongly associated with CRF only in type 1 diabetes. These results support the therapeutic concept of promoting physical fitness in the early course of diabetes.

Deep subcutaneous adipose tissue lipid unsaturation associates with intramyocellular lipid content

BACKGROUND Obese twins have lower saturated and higher long-chain polyunsaturated fatty acids (FA) in subcutaneous adipose tissue (SAT) compared to their lean monozygotic (MZ) co-twin. Whether this holds for metabolically distinct deep (DSAT) and superficial (SSAT) depots is unknown. Here we use non-invasive magnetic resonance spectroscopy (MRS) to measure the FA unsaturation in body mass index (BMI) discordant MZ twins in DSAT and SSAT and their relationship to ectopic fat content and body fat distribution. The main finding is further confirmed in an independent cohort using standardized measurement times. METHODS MRS and magnetic resonance imaging were used to measure DSAT and SSAT unsaturation and their relationship to intramyocellular lipids (IMCL), hepatocellular lipids (HCL) and the amount of subcutaneous (SAT) and visceral adipose tissue (VAT) in 16 pairs of healthy monozygotic twins (MZ) discordant for BMI. A second independent cohort of 12 healthy volunteers was used to measure DSAT unsaturation and IMCL with standardized measurement time. One volunteer also underwent repeated random measurements of DSAT unsaturation and IMCL. RESULTS In accordance with biopsy studies SSAT unsaturation was higher in the heavier twins (15.2±1.0% vs. 14.4±1.5%, P=0.024) and associated with SAT volume (R=0.672, P=0.001). DSAT unsaturation did not differ between twins (11.4±0.8 vs. 11.0±1.0, P=0.267) and associated inversely with IMCL content (R=-0.462, P=0.001). The inverse association between DSAT unsaturation and IMCL was also present in the participants of the second cohort (R=-0.641, P=0.025) and for the repeated sampling at random of one person (R=-0.765, P=0.027). CONCLUSIONS DSAT and SSAT FA unsaturation shows distinct associations with obesity and IMCL in MZ twins, reflecting compartment-specific metabolic activities. The FA unsaturation in the DSAT depot associates inversely with IMCL content, which raises the possibility of cross talk between the DSAT depot and the rapid turnover IMCL depot.

Metabolic Characteristics of Recently Diagnosed Adult-Onset Autoimmune Diabetes Mellitus

Context and Objective Among patients diagnosed with type 2 diabetes, autoimmune diabetes often remains undetected. Metabolic features of these patients are insufficiently characterized at present. Design, Setting, and Patients This study compared age- and sex-matched adult (aged 41 to 62 years) humans with recent-onset diabetes: patients positive for antibodies against glutamic acid decarboxylase (GAD) and/or cytoplasmic islet-cell antigen with an insulin-free period of >6 months [antibody positive/insulin negative (ab+/ins-); previously termed latent autoimmune diabetes of adults], type 1 diabetes [antibody positive/insulin positive (ab+/ins+)], and type 2 diabetes [antibody negative/insulin negative (ab-/ins-)], as well as glucose-tolerant humans (controls) of the German Diabetes Study (n = 41/group). β-Cell function was assessed from glucagon tests and intravenous glucose tolerance tests (IVGTTs), and insulin sensitivity was determined from hyperinsulinemic-euglycemic clamps. Results Of the ab+/ins- patients, 33 (81%) were initially diagnosed as having type 2 diabetes. In ab+/ins-, body mass index (BMI) was higher than in ab+/ins+ (27.8 ± 5.3 kg/m2 vs 25.0 ± 3.5 kg/m2, P < 0.05), lower than in ab-/ins- (31.9 ± 5.8 kg/m2, P < 0.05), and similar to controls (29.4 ± 6.6 kg/m2). In ab+/ins-, GAD antibody titers correlated negatively with BMI (r = -0.40, P < 0.05) and with C-peptide secretion in glucagon stimulation tests (r = -0.33, P < 0.05). β-Cell function from IVGTT was 228% higher in ab+/ins- than in ab+/ins+ but 35% lower than in ab-/ins- and 61% lower than in controls (all P < 0.05). Insulin sensitivity in ab+/ins- was comparable to ab+/ins+ and controls but 41% higher than in ab-/ins- (P < 0.05) after adjustment for BMI and fasting blood glucose or hemoglobin A1c. Conclusion Even shortly after diagnosis, ab+/ins- patients feature partly preserved β-cell function and chronic hyperglycemia, which possibly contributes to the observed impairment of whole-body insulin sensitivity.

Association of Lower Cardiovagal Tone and Baroreflex Sensitivity With Higher Liver Fat Content Early in Type 2 Diabetes

Context Cardiovascular autonomic neuropathy (CAN) diagnosed by diminished heart rate variability (HRV) is prevalent and carries an increased risk of mortality in patients with diabetes and chronic liver diseases. Objective To determine whether lower HRV is associated with increased liver fat content in recent-onset diabetes. Design Cross-sectional study. Setting German Diabetes Study (GDS), Düsseldorf, Germany. Participants Individuals with type 1 diabetes (n = 97) or type 2 diabetes (n = 109) with known diabetes duration ≤1 year and two age- and sex-matched glucose-tolerant control groups from the GDS baseline cohort. Main Outcome Measures Four time and frequency domain HRV indices each were measured over 3 hours during a hyperinsulinemic-euglycemic clamp, whereas spontaneous cross-correlation baroreflex sensitivity (xBRS) was computed over 5 minutes. Hepatic fat content was determined by 1H magnetic resonance spectroscopy, and values >5.56% were defined as hepatic steatosis. Results Hepatic steatosis was observed in 52% and 5% of patients with type 2 and type 1 diabetes, respectively. After adjustment for sex, age, body mass index, smoking, diabetes duration, hemoglobin A1c, M-value, and triglycerides, all four vagus-mediated time domain HRV indices, three of four frequency domain indices, and xBRS were inversely associated with liver fat content in participants with type 2 diabetes (all P < 0.05) but not in the group with type 1 diabetes. Conclusions Both lower cardiovagal tone and baroreflex sensitivity are strongly associated with prevalent hepatic steatosis in patients with recent-onset type 2 as opposed to type 1 diabetes, suggesting a role for hepatic steatosis in the early development of parasympathetic CAN in type 2 diabetes.

Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival

Angiocrine signals derived from endothelial cells are an important component of intercellular communication and have a key role in organ growth, regeneration and disease1–4. These signals have been identified and studied in multiple organs, including the liver, pancreas, lung, heart, bone, bone marrow, central nervous system, retina and some cancers1–4. Here we use the developing liver as a model organ to study angiocrine signals5,6, and show that the growth rate of the liver correlates both spatially and temporally with blood perfusion to this organ. By manipulating blood flow through the liver vasculature, we demonstrate that vessel perfusion activates β1 integrin and vascular endothelial growth factor receptor 3 (VEGFR3). Notably, both β1 integrin and VEGFR3 are strictly required for normal production of hepatocyte growth factor, survival of hepatocytes and liver growth. Ex vivo perfusion of adult mouse liver and in vitro mechanical stretching of human hepatic endothelial cells illustrate that mechanotransduction alone is sufficient to turn on angiocrine signals. When the endothelial cells are mechanically stretched, angiocrine signals trigger in vitro proliferation and survival of primary human hepatocytes. Our findings uncover a signalling pathway in vascular endothelial cells that translates blood perfusion and mechanotransduction into organ growth and maintenance.In mouse and human liver models, blood vessel perfusion and mechanical stretching release angiocrine signals from endothelial cells that lead to hepatocyte survival and liver growth.

Reduced expression of stearoyl-CoA desaturase-1, but not free fatty acid receptor 2 or 4 in subcutaneous adipose tissue of patients with newly diagnosed type 2 diabetes mellitus

BackgroundIn subcutaneous adipose tissue (SAT), higher stearoyl-CoA desaturase-1 (SCD1) expression has been related to improved insulin sensitivity in thiazolidinedione-treated type 2 diabetes mellitus patients. In animal models, deficiency of the free fatty acid receptor (FFAR) 2 associated with higher and FFAR4-deficiency with lower insulin sensitivity. We hypothesized that increased FFAR2 expression and reductions in FFAR4 and SCD1 expression in SAT of type 2 diabetes mellitus patients associate positively with insulin resistance and impaired beta cell function.MethodsTwenty-five type 2 diabetes mellitus patients and 25 glucose-tolerant humans (CON) matched for sex, age, and BMI underwent mixed-meal tests to assess insulin sensitivity (OGIS) and beta cell function (ΔAUC(C-peptide)0–180 min/ΔAUC(glucose)0–180 min) in a cross-sectional study. Gene and protein expression of SCD1 and FFAR2/4 were quantified in SAT biopsies.ResultsInsulin sensitivity was 14% and beta cell function 71% (both p < 0.001) lower in type 2 diabetes mellitus patients. In type 2 diabetes mellitus, SCD1 mRNA was fivefold (p < 0.001) and protein expression twofold (p < 0.01) lower. While FFAR2/4 mRNA and protein expression did not differ between groups, FFAR2 protein levels correlated negatively with beta cell function only in CON (r = −0.74, p < 0.01). However, neither SCD1 nor FFAR2/4 protein expression correlated with insulin sensitivity in both groups.ConclusionsType 2 diabetes patients have lower SCD1, which does not associate with insulin resistance. Only in non-diabetic humans, FFAR2 associated with impaired beta cell function.

Differential associations of lower cardiac vagal tone with insulin resistance and insulin secretion in recently diagnosed type 1 and type 2 diabetes

OBJECTIVE It is unclear to which extent altered insulin sensitivity/secretion contribute to the development of diabetic cardiovascular autonomic neuropathy (CAN) characterized by diminished heart rate variability (HRV). We hypothesised that lower HRV is differentially associated with measures of insulin resistance and insulin secretion in recent-onset type 1 and type 2 diabetes. MATERIALS/METHODS This cross-sectional study included participants from the German Diabetes Study with type 1 (n=275) or type 2 diabetes (n=450) with known diabetes duration ≤1year and glucose-tolerant controls (n=81). Four time domain and frequency domain HRV measures each, reflecting vagal and/or sympathetic modulation were determined over 3h during a hyperinsulinaemic-euglycaemic clamp. Insulin sensitivity was calculated as the M-value, while insulin secretion was determined by glucagon-stimulated incremental C-peptide (ΔC-peptide). RESULTS After adjustment for sex, age, BMI, smoking, and HbA1c, both M-value and ΔC-peptide were lower in the diabetes groups compared to controls (P<0.05). In multiple linear regression analyses after Bonferroni correction, vagus-mediated HRV indices were positively associated with M-value in both diabetes types (P<0.05) and inversely associated with ΔC-peptide only in participants with type 1 diabetes (P<0.05). In type 2 diabetes, the low-frequency/high-frequency (LF/HF) power as an indicator of sympathovagal balance was weakly inversely associated with M-value. CONCLUSIONS Insulin resistance may contribute to the development of early cardiovagal suppression rather than sympathetic predominance in both diabetes types, while in type 1 diabetes a lower glucagon-stimulated insulin secretion is linked to a possibly compensatory higher parasympathetic tone. Whether interventions aimed at reducing insulin resistance could also reduce the risk of CAN remains to be established.

Energy metabolism of white adipose tissue and insulin resistance in humans

Insulin resistance not only occurs in obesity, but also in lipodystrophy. Although adipose tissue mass affects metabolic fluxes and participates in interorgan crosstalk, the role of energy metabolism within white adipose tissue for insulin resistance is less clear.

Impaired Baroreflex Sensitivity in Patients with Recent-Onset Type 2 Diabetes

Impaired baroreflex sensitivity (BRS) is a sign of diabetic cardiovascular autonomic neuropathy (CAN) which often remains undiscovered during the early course of diabetes. We aimed to determine whether BRS alterations can be detected in patients with recent-onset type 1 and type 2 diabetes. Continuous plethysmographic arterial pressure and R-R intervals were recorded using the Finometer (Finapres Medical Systems) from the left middle finger in 586 participants from the baseline German Diabetes Study (GDS) cohort with type 1 or type 2 diabetes and a known diabetes duration ≤1 year (T1D/T2D [mean±SD]: n=208/378; age: 34.7±11.1/51.6±10.3 years; male: 60/74%; BMI: 24.7±4.2/31.7±6.3 kg/m²; diabetes duration: 6.3±3.3/5.9±3.5 months; HbA1c: 6.5±1.1/6.5±0.9%) and corresponding controls (CON1/CON2: n=74/208; age: 36.4±10.1/49.4±14.8 years; male: 64/64%; BMI: 26.5±4.9/26.6±4.9 kg/m²; HbA1c: 5.2±0.3/5.3±0.3%). BRS parameters included the alpha index of spectral power (BRSα), transfer function cross spectrum (xBRS), and sequence analyses (BRSseq). After adjustment for sex, age, BMI, and smoking, all three BRS measures were reduced in T2D vs. CON2 (BRSα: 10.1±8.6 vs. 15.4±10.2 ms/mmHg; xBRS: 7.84±6.94 vs. 10.4±8.2 ms/mmHg; BRSseq: 9.85±9.07 vs. 13.3±9.6 ms/mmHg) (P≤0.01), while no such differences were observed in T1D vs. CON1. Multiple regression analyses revealed, that systolic blood pressure (SBP) was the strongest determinant of lower BRS in T2D (xBRS/BRSseq/BRSα: β=-0.32/-0.23/-0.22) followed by age (xBRS: β=-0.18) and lower HDL cholesterol (BRSseq: β=-0.23), while in T1D it was age (xBRS/BRSseq/BRSα: β=-0.37/-0.36/-0.34), SBP (xBRS/BRSα: β=-0.26), and BMI (BRSseq: β=-0.24) (all P≤0.01). In conclusion, reduced baroreflex sensitivity indicates early CAN in recent-onset type 2 diabetes in relation to modifiable risk factors such as higher systolic blood pressure and lower HDL cholesterol. Disclosure G.J. Bonhof: None. A. Strom: None. K. Bodis: None. K. Mussig: None. J. Szendroedi: None. M. Roden: Speaker9s Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. D. Ziegler: None.