Gidon J. Bönhof

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.

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.

Constant hepatic ATP concentrations during prolonged fasting and absence of effects of Cerbomed Nemos® on parasympathetic tone and hepatic energy metabolism

Objective Brain insulin-induced improvement in glucose homeostasis has been proposed to be mediated by the parasympathetic nervous system. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) activating afferent branches of the vagus nerve may prevent hyperglycemia in diabetes models. We examined the effects of 14-min taVNS vs sham stimulation by Cerbomed Nemos® on glucose metabolism, lipids, and hepatic energy homeostasis in fasted healthy humans (n = 10, age 51 ± 6 yrs, BMI 25.5 ± 2.7 kg/m2). Methods Heart rate variability (HRV), reflecting sympathetic and parasympathetic nerve activity, was measured before, during and after taVNS or sham stimulation. Endogenous glucose production was determined using [6,6-2H2]glucose, and hepatic concentrations of triglycerides (HCL), adenosine triphosphate (ATP), and inorganic phosphate (Pi) were quantified from 1H/31P magnetic resonance spectroscopy at baseline and for 180 min following stimulation. Results taVNS did not affect circulating glucose, free fatty acids, insulin, glucagon, or pancreatic polypeptide. Rates of endogenous glucose production (P = 0.79), hepatic HCL, ATP, and Pi were also not different (P = 0.91, P = 0.48 and P = 0.24) between taVNS or sham stimulation. Hepatic HCL, ATP, and Pi remained constant during prolonged fasting for 3 h. No changes in heart rate or shift in cardiac autonomic function from HRV towards sympathetic or parasympathetic predominance were detected. Conclusion Non-invasive vagus stimulation by Cerbomed Nemos® does not acutely modulate the autonomic tone to the visceral organs and thereby does not affect hepatic glucose and energy metabolism. This technique is therefore unable to mimic brain insulin-mediated effects on peripheral homeostasis in humans.

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.

Emerging biomarkers, tools, and treatments for diabetic polyneuropathy

Diabetic neuropathy, with its major clinical sequels, notably neuropathic pain, foot ulcers, and autonomic dysfunction, is associated with substantial morbidity, increased risk of mortality, and reduced quality of life. Despite its major clinical impact, diabetic neuropathy remains underdiagnosed and undertreated. Moreover, the evidence supporting a benefit for causal treatment is weak at least in patients with type 2 diabetes, and current pharmacotherapy is largely limited to symptomatic treatment options. Thus, a better understanding of the underlying pathophysiology is mandatory for translation into new diagnostic and treatment approaches. Improved knowledge about pathogenic pathways implicated in the development of diabetic neuropathy could lead to novel diagnostic techniques that have the potential of improving the early detection of neuropathy in diabetes and prediabetes to eventually embark on new treatment strategies. In this review, we first provide an overview on the current clinical aspects and illustrate the pathogenetic concepts of (pre)diabetic neuropathy. We then describe the biomarkers emerging from these concepts and novel diagnostic tools and appraise their utility in the early detection and prediction of predominantly distal sensorimotor polyneuropathy. Finally, we discuss the evidence for and limitations of the current and novel therapy options with particular emphasis on lifestyle modification and pathogenesis-derived treatment approaches. Altogether, recent years have brought forth a multitude of emerging biomarkers reflecting different pathogenic pathways such as oxidative stress and inflammation and diagnostic tools for an early detection and prediction of (pre)diabetic neuropathy. Ultimately, these insights should culminate in improving our therapeutic armamentarium against this common and debilitating or even life-threatening condition.

Myeloperoxidase, superoxide dismutase-3, cardiometabolic risk factors, and distal sensorimotor polyneuropathy: The KORA F4/FF4 study

Oxidative stress has been proposed as important pathomechanism of cardiometabolic diseases and distal sensorimotor polyneuropathy (DSPN). However, the relevance of biomarkers of oxidative stress has not been investigated in this context. Therefore, this study aimed to assess the association of the prooxidant myeloperoxidase (MPO) and the antioxidant extracellular superoxide dismutase (SOD3) with cardiometabolic risk factors and with prevalence and incidence of DSPN.

A Systemic Inflammatory Signature Reflecting Cross Talk Between Innate and Adaptive Immunity Is Associated With Incident Polyneuropathy: KORA F4/FF4 Study

Prospective analyses of biomarkers of inflammation and distal sensorimotor polyneuropathy (DSPN) are scarce and limited to innate immunity. We therefore aimed to assess associations between biomarkers reflecting multiple aspects of immune activation and DSPN. The study was based on 127 case subjects with incident DSPN and 386 noncase subjects from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (follow-up 6.5 years). Proximity extension assay technology was used to measure serum levels of biomarkers of inflammation. Of 71 biomarkers assessed, 26 were associated with incident DSPN. After adjustment for multiple testing, higher levels of six biomarkers remained related to incident DSPN. Three of these proteins (MCP-3/CCL7, MIG/CXCL9, IP-10/CXCL10) were chemokines, and the other three (DNER, CD40, TNFRSF9) were soluble forms of transmembrane receptors. The chemokines had neurotoxic effects on neuroblastoma cells in vitro. Addition of all six biomarkers improved the C statistic of a clinical risk model from 0.748 to 0.783 (P = 0.011). Pathway analyses indicated that multiple cell types from innate and adaptive immunity are involved in the development of DSPN. We thus identified novel associations between biomarkers of inflammation and incident DSPN pointing to a complex cross talk between innate and adaptive immunity in the pathogenesis of the disease.

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.

Cardiorespiratory Fitness and Cardiac Autonomic Function in Diabetes

Purpose of ReviewThis review summarizes the current knowledge on the relationship of physical activity, exercise, and cardiorespiratory fitness (CRF) with cardiovascular autonomic neuropathy (CAN) based on epidemiological, clinical, and interventional studies.Recent FindingsThe prevalence of CAN increases with age and duration of diabetes. Further risk factors for CAN comprise poor glycemic control, dyslipidemia, abdominal obesity, hypertension, and the presence of diabetic complications. CAN has been also linked to reduced CRF. We recently showed that CRF parameters (e.g., maximal oxidative capacity or oxidative capacity at the anaerobic threshold) are associated with cardiac autonomic function in patients recently diagnosed with type 1 or type 2 diabetes. Exercise interventions have shown that physical activity can increase cardiovagal activity and reduce sympathetic overactivity. In particular, long-term and regularly, but also supervised, performed endurance and high-intense and high-volume exercise improves cardiac autonomic function in patients with type 2 diabetes. By contrast, the evidence in those with type 1 diabetes and also in individuals with prediabetes or metabolic syndrome is weaker.SummaryOverall, the studies reviewed herein addressing the question whether favorably modulating the autonomic nervous system may improve CRF during exercise programs support the therapeutic concept to promote physical activity and to achieve physical fitness. However, high-quality exercise interventions, especially in type 1 diabetes and metabolic syndrome including prediabetes, are further required to better understand the relationship between physical activity, fitness, and cardiac autonomic function.