Liraglutide treatment reduced interleukin-6 in adults with type 1 diabetes but did not improve established autonomic or polyneuropathy.

AIMS: Type 1 diabetes can be complicated with neuropathy that involves immune-mediated and inflammatory pathways. Glucagon-like peptide-1 receptor agonists such as liraglutide, have shown anti-inflammatory properties, and thus we hypothesized that long-term treatment with liraglutide induced diminished inflammation and thus improved neuronal function. METHODS: The study was a randomized, double-blinded, placebo-controlled trial of adults with type 1 diabetes and confirmed symmetrical polyneuropathy. They were randomly assigned (1:1) to receive either liraglutide or placebo. Titration was 6 weeks to 1.2-1.8 mg/d, continuing for 26 weeks. The primary endpoint was change in latency of early brain evoked potentials. Secondary endpoints were changes in proinflammatory cytokines, cortical evoked potential, autonomic function and peripheral neurophysiological testing. RESULTS: Thirty-nine patients completed the study, of whom 19 received liraglutide. In comparison to placebo, liraglutide reduced interleukin-6 (-22.6%; 95% confidence interval [CI]: -38.1, -3.2; P = .025) with concomitant numerical reductions in other proinflammatory cytokines. However neuronal function was unaltered at the central, autonomic or peripheral level. Treatment was associated with -3.38 kg (95% CI: -5.29, -1.48; P < .001] weight loss and a decrease in urine albumin/creatinine ratio (-40.2%; 95% CI: -60.6, -9.5; P = .02). CONCLUSION: Hitherto, diabetic neuropathy has no cure. Speculations can be raised whether mechanism targeted treatment, e.g. lowering the systemic level of proinflammatory cytokines may lead to prevention or treatment of the neuroinflammatory component in early stages of diabetic neuropathy. If ever successful, this would serve as an example of how fundamental mechanistic principles are translated into clinical practice similar to those applied in the cardiovascular and nephrological clinic.

The degree of autonomic modulation is associated with the severity of microvascular complications in patients with type 1 diabetes.

OBJECTIVE: The objective of this study was to elucidate whether the degree of autonomic modulation is associated with the degree of microvascular complications in patients with type 1 diabetes. METHODS: A total of 290 type 1 individuals with diabetes were randomly recruited during normal visits to outpatient clinics at 4 Danish hospitals. The degree of autonomic modulations was quantified by measuring heart rate variability (HRV) during passive spectral analysis and active tests (valsalva ratio [VT], response to standing [RT], and deep breathing [E:I]). To describe possible associations between severity of microvascular complications and measures of autonomic modulation, multivariate analysis was performed. RESULTS: After adjusting for diabetes duration, sex, age, pulse pressure, heart rate, and smoking, autonomic dysfunction remained significantly correlated with severity of retinopathy, nephropathy, and peripheral neuropathy in individuals with type 1 diabetes patients. CONCLUSIONS: Autonomic dysfunction is present in early stages of retinopathy, nephropathy, and peripheral neuropathy in patients with type 1 diabetes.

Cardiovascular autonomic neuropathy is associated with macrovascular risk factors in type 2 diabetes: new technology used for routine large-scale screening adds new insight.

The objective was to identify the presence of cardiovascular autonomic neuropathy (CAN) in a cohort of individuals with diabetes in outpatient clinics from 4 different parts of Denmark and to explore the difference between type 1 and type 2 diabetes in relation to CAN. The DAN-Study is a Danish multicenter study focusing on diabetic autonomic neuropathy. Over a period of 12 months, 382 type 1 and 271 type 2 individuals with diabetes were tested for CAN. Patients were randomly recruited and tested during normal visits to outpatient clinics at 4 Danish hospitals. The presence of CAN was quantified by performing 3 cardiovascular reflex tests (response to standing, deep breathing, and valsalva). To describe possible associations, multivariate analysis with CAN as the dependent variable was performed. The prevalence of CAN was higher among patients with type 2 diabetes (35%) compared to patients with type 1 diabetes (25%). Multivariate analysis revealed significant associations between CAN and different risk markers in the 2 populations. In type 1 diabetes patients CAN was associated with microalbuminuria (P < .001), macroalbuminuria (P = .011), simplex retinopathy (P < .001), proliferative retinopathy (P < .001), and peripheral neuropathy (P = .041). Among type 2 diabetes patients CAN was independently associated with high pulse pressure (P < .01), BMI (P = .006), and smoking (P = .025). In this cross-sectional observational study CAN was independently associated with microvascular complication in type 1, whereas in type 2 CAN was associated with macrovascular risk factors.

Lifestyle diseases and cardiovascular risk factors are interrelated to deficiencies of major substrates in ATP synthesis.

Recent studies on diabetes and metabolic syndrome indicate a common disturbance of inorganic phosphate (Pi) metabolism. Pi is an important substrate in the formation of adenosine triphosphate (ATP), and many lifestyle diseases and cardiovascular risk factors similarly show deficiencies in either 1 or 2 major components of ATP synthesis. Age, male gender, hypertension, obesity, hypertriglyceridemia, metabolic syndrome, and diabetes mellitus are all associated with hypophosphatemia. In addition, tobacco smoking, hyperchylomicronemia, hypertension, and diabetes may involve defects in tissue oxygen delivery. Hypophosphatemia may lead to a critical decrease in intracellular Pi and to mitochondrial dysfunction, which might be counter-acted by the pharmacological use of fructose 1,6-diphosphate.

The North Jutland County Diabetic Retinopathy Study (NCDRS).

PURPOSE: This study set out to map the associations between retinal lesions, visual acuity (VA) and the presence of clinically significant macular oedema (CSMO) in diabetes subjects. METHODS: This cross-sectional study comprised 656 type 1 and 328 type 2 diabetes subjects undergoing retinopathy screening in the County of North Jutland, Denmark. Numbers of specific retinal lesions were quantified from retinal photographic recordings. Associations between CSMO, number of specific retinal lesions and VA were established. The percentages of eyes with CSMO ascribed to retinal lesions were calculated. RESULTS: The presence of CSMO, number of specific retinal lesions and VA were all significantly associated. The parameter with the highest statistical association with CSMO measured by Spearman's correlation coefficient was hard exudates (type 1: 0.524; type 2: 0.715), followed by microaneurysms (type 1: 0.298; type 2: 0.508), retinal haemorrhages (type 1: 0.227; type 2: 0.595), cottonwool spots (type 1: 0.207; type 2: 0.259) and VA (type 1: - 0.137; type 2: - 0,175). CONCLUSIONS: All retinal lesions are significantly associated with CSMO and together can predict for up to 42.3% (in type 1 diabetes) and 64.3% (in type 2 diabetes) of CSMO cases.

[Photographic screening for diabetic retinopathy in the county of North Jutland. The first fully digitalized telemedicine-screening clinic]. / Fotoscreening for diabetisk retinopati i Nordjyllands Amt. Landets første fuldt digitaliserede telemedicinske screeningsklinik.

Screening for diabetic retinopathy was introduced in Denmark in 1988. At present, screening is carried out in four of the 14 counties, thus being available to a minority of diabetic subjects. According to the WHO but also the National Board of Health, all diabetic patients should undergo screening for diabetic retinopathy. Not only does screening pay off in terms of preservation of vision, it is also cost-effective, as confirmed in the present study. The first fully digitized clinic for retinopathic screening in diabetic patients was recently introduced in the County of North Jutland. Preliminary results from this clinic indicate that all procedures can be handled in this fully digitized system. We therefore predict that fully digitized clinics for retinopathic screening will be introduced throughout Denmark in the future.