High MBL-expressing genotypes are associated with deterioration in renal function in type 2 diabetes.

Introduction: Accumulating evidence support that mannan-binding lectin (MBL) is a promising prognostic biomarker for risk-stratification of diabetic micro- and macrovascular complications. Serum MBL levels are predominately genetically determined and depend on MBL genotype. However, Type 1 diabetes (T1D) is associated with higher MBL serum levels for a given MBL genotype, but it remains unknown if this is also the case for patients with T2D. In this study, we evaluated the impact of MBL genotypes on renal function trajectories serum MBL levels and compared MBL genotypes in newly diagnosed patients with T2D with age- and sex-matched healthy individuals. Furthermore, we evaluated differences in parameters of insulin resistance within MBL genotypes. Methods: In a cross-sectional study, we included 100 patients who were recently diagnosed with T2D and 100 age- and sex-matched individuals. We measured serum MBL levels, MBL genotype, standard biochemistry, and DEXA, in all participants. A 5-year clinical follow-up study was conducted, followed by 12-year data on follow-up biochemistry and clinical status for the progression to micro- or macroalbuminuria for the patients with T2D. Results: We found similar serum MBL levels and distribution of MBL genotypes between T2D patients and healthy individuals. The serum MBL level for a given MBL genotype did not differ between the groups neither at study entry nor at 5-year follow-up. We found that plasma creatinine increased more rapidly in patients with T2D with the high MBL expression genotype than with the medium/low MBL expression genotype over the 12-year follow-up period (p = 0.029). Serum MBL levels did not correlate with diabetes duration nor with HbA1c. Interestingly, serum MBL was inversely correlated with body fat percentage in individuals with high MBL expression genotypes both at study entry (p=0.0005) and 5-years follow-up (p=0.002). Discussion: Contrary to T1D, T2D is not per se associated with increased MBL serum level for a given MBL genotype or with diabetes duration. Serum MBL was inversely correlated with body fat percentage, and T2D patients with the high MBL expression genotype presented with deterioration of renal function.

Differential vascular effects of aspirin in people with Type 2 diabetes without cardiovascular disease and matched controls without diabetes.

AIM: We investigated whether the effect of low-dose aspirin on endothelium-dependent vasodilation and arterial stiffness in people with Type 2 diabetes is different from a matched control group. We examined acute and chronic effects, and effects over the 24h dosing interval. METHODS: In an open-label parallel group intervention study, we included 21 participants with Type 2 diabetes and 21 age- and sex-matched controls. Endothelium-dependent vasodilation was assessed as the reactive hyperaemia index (lnRHI) measured by peripheral arterial tonometry (EndoPAT® ). Arterial stiffness was assessed as pulse wave velocity (PWV) measured by applanation tonometry (SphygmoCor® ). Measurements were performed prior to aspirin intake and 1h after aspirin administration (75 mg). Participants were then treated for 6 days, and measurements were repeated at 24 h and 1 h after aspirin intake. RESULTS: Baseline lnRHI did not differ between groups. The controls had an immediate increase in lnRHI after the first aspirin tablet. This was not observed in participants with diabetes (difference between groups; P < 0.05). After 1 week, both groups demonstrated increased lnRHI compared with baseline (P < 0.01). In participants with diabetes, lnRHI was significantly lower 24 h after aspirin administration compared with 1 h after administration (P < 0.05). This difference was not observed in controls (P = 0.84, difference between groups; P = 0.12). The effect on PWV did not differ between groups. CONCLUSION: Aspirin had a reduced immediate effect on endothelium-dependent vasodilation in participants with diabetes. Both groups had improved endothelial function after 1 week of treatment. Further, the effect of aspirin on endothelial function may be declining during a 24 h dosing interval in people with Type 2 diabetes. (Clinical Trial Registry No: 2016-000515-32).

Arterial stiffness in people with Type 2 diabetes and obstructive sleep apnoea.

AIMS: To examine whether people with Type 2 diabetes with concurrent obstructive sleep apnoea have increased arterial stiffness as compared with people with Type 2 diabetes without obstructive sleep apnoea. METHODS: In a study with a case-control design, 40 people with Type 2 diabetes and treatment-naïve moderate to severe obstructive sleep apnoea (Apnoea-Hypopnoea Index ≥15) and a control group of 31 people with Type 2 diabetes without obstructive sleep apnoea (Apnoea-Hypopnoea Index <5) were examined. Obstructive sleep apnoea status was evaluated using the ApneaLink® + home-monitoring device (Resmed Inc., San Diego, CA, USA), providing the Apnoea-Hypopnoea Index scores. Arterial stiffness was assessed according to carotid-femoral pulse wave velocity using the Sphygmocor device and the oscillometric Mobil-O-Graph® (I.E.M. GmbH, Stolberg, Germany). RESULTS: Carotid-femoral pulse wave velocity was not significantly different between participants with Type 2 diabetes with obstructive sleep apnoea and those without obstructive sleep apnoea (10.7±2.2 m/s vs 10.3±2.1 m/s; P=0.513), whereas oscillometric pulse wave velocity was significantly higher in participants with Type 2 diabetes with obstructive sleep apnoea than in those without obstructive sleep apnoea (9.5±1.0 m/s vs 8.6±1.4 m/s; P=0.002). In multiple regression analysis, age (P=0.002), gender (men; P=0.018) and HbA1c (P=0.027) were associated with carotid-femoral pulse wave velocity, and systolic blood pressure (P=0.004) and age (P<0.001) were associated with oscillometric pulse wave velocity. After adjustment, presence of obstructive sleep apnoea was not independently associated with pulse wave velocity whether assessed by tonometry or oscillometry. CONCLUSION: In conclusion, the present study did not find an age- and blood pressure-independent association between moderate to severe obstructive sleep apnoea and arterial stiffness in non-sleepy people with Type 2 diabetes. (Clinical trial registration number: NCT02482584).

Plasma levels of MASP-1, MASP-3 and MAp44 in patients with type 2 diabetes: influence of glycaemic control, body composition and polymorphisms in the MASP1 gene.

Mounting evidence indicates that adverse activation of the complement system plays a role in the development of diabetic vascular complications. Plasma levels of the complement proteins mannan-binding lectin (MBL) and its associated serine proteases (MASP-1 and MASP-2) are elevated in diabetes. We hypothesized that single nucleotide polymorphisms (SNPs) in the MASP1 gene may contribute to altered plasma levels of the belonging gene products; MASP-1, MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44) in patients with type 2 diabetes. To investigate this, we compared plasma levels of MASP-1, MASP-3 and MAp44 in 100 patients with type 2 diabetes and 100 sex- and age-matched controls. Ten carefully selected SNPs were analysed using TaqMan® genotyping assay. Additionally, we included a streptozotocin-induced diabetes mouse model to directly examine the effect of inducing diabetes on MASP-1 levels. MASP-1 levels were significantly higher among patients with type 2 diabetes compared with healthy controls (P = 0·017). Five SNPs (rs874603, rs72549254, rs3774275, rs67143992, rs850312) in the MASP1 gene were associated with plasma levels of MASP-1, MASP-3 and MAp44. In the diabetes mouse model, diabetic mice had significantly higher MASP-1 levels than control mice (P = 0·003). In conclusion, MASP-1 levels were higher among patients with type 2 diabetes and diabetic mice. The mechanism behind this increase remains elusive.

Latent autoimmune diabetes of the adult: current knowledge and uncertainty.

Patients with adult-onset autoimmune diabetes have less Human Leucocyte Antigen (HLA)-associated genetic risk and fewer diabetes-associated autoantibodies compared with patients with childhood-onset Type 1 diabetes. Metabolic changes at diagnosis reflect a broad clinical phenotype ranging from diabetic ketoacidosis to mild non-insulin-requiring diabetes, also known as latent autoimmune diabetes of the adult (LADA). This latter phenotype is the most prevalent form of adult-onset autoimmune diabetes and probably the most prevalent form of autoimmune diabetes in general. Although LADA is associated with the same genetic and immunological features as childhood-onset Type 1 diabetes, it also shares some genetic features with Type 2 diabetes, which raises the question of genetic heterogeneity predisposing to this form of the disease. The potential value of screening patients with adult-onset diabetes for diabetes-associated autoantibodies to identify those with LADA is emphasized by their lack of clinically distinct features, their different natural history compared with Type 2 diabetes and their potential need for a dedicated management strategy. The fact that, in some studies, patients with LADA show worse glucose control than patients with Type 2 diabetes, highlights the need for further therapeutic studies. Challenges regarding classification, epidemiology, genetics, metabolism, immunology, clinical presentation and treatment of LADA were discussed at a 2014 workshop arranged by the Danish Diabetes Academy. The presentations and discussions are summarized in this review, which sets out the current ideas and controversies surrounding this form of diabetes.

Objective measurements of activity patterns in people with newly diagnosed Type 2 diabetes demonstrate a sedentary lifestyle.

AIMS: To evaluate physical activity in people with newly diagnosed Type 2 diabetes using objective measures. METHODS: We analysed data from a study aimed at assessing carotid femoral pulse wave velocity in which a piezoelectric accelerometer was worn by 100 people with newly diagnosed Type 2 diabetes and by 100 age- and sex-matched control subjects. Differences in physical activity patterns were investigated. RESULTS: Compared with the control group, the people with Type 2 diabetes spent significantly more time engaged in sedentary or lower level activities during the day, with a mean (sd) time of 926 (44) vs 898 (70) min, P < 0.001). This difference remained significant after correction for differences in BMI between the two groups. CONCLUSIONS: Using objective measurements, our findings demonstrate that people with newly diagnosed Type 2 diabetes have a more sedentary lifestyle compared with well-matched controls.

Pulse pressure and systolic night-day ratio interact in prediction of macrovascular disease in patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease (CVD). We examined the predictive ability of 24-hour ambulatory pulse pressure (24-h PP), ambulatory arterial stiffness index (AASI) and diurnal blood pressure (BP) parameters for fatal and non-fatal CVD in patients with type 2 diabetes mellitus. A total of 108 patients with type 2 diabetes mellitus (mean duration 6.6 years) were followed for 9.5 (0.5-14.5) years. At baseline, all patients underwent ambulatory BP monitoring. During follow-up, 45 patients had cardiovascular (CV) events (35 non-fatal and 10 fatal). In bivariate analysis, events during follow-up were predicted by 24-h PP (P<0.01), AASI, 24-h systolic BP and systolic and diastolic night-day BP ratio (P<0.05 for all). In Cox regression analysis adjusted for established risk markers, only 24-h PP and systolic night-day BP ratio predicted CV events, P<0.05 for both. A significant interaction between the two parameters was found, P<0.05; thus, the higher the systolic night-day ratio, the greater the increase in hazard ratio (HR) per mmHg increase in 24-h PP and vice versa. A combined 10 mmHg increase in 24-h PP and 10%-point increase in systolic night-day ratio from the 25th percentile increased the adjusted HR (95% confidence interval) for CV events with 1.29 (0.53; 3.12), whereas a similar increase from the 75th percentile increased the HR with 4.2 (1.54; 11,51). Our study showed that 24-h PP and systolic night-day ratio interact as predictors of CV events in type 2 diabetes patients, and should be considered in conjunction when evaluating the risk of CVD.

Ambulatory pulse pressure, decreased nocturnal blood pressure reduction and progression of nephropathy in type 2 diabetic patients.

AIMS/HYPOTHESIS: We followed type 2 diabetic patients over a long period to evaluate the predictive value of ambulatory pulse pressure (PP) and decreased nocturnal BP reduction (non-dipping) for nephropathy progression. METHODS: Type 2 diabetic patients (n = 112) were followed for an average of 9.5 (range 0.5-14.5) years. At baseline, all patients underwent 24 h ambulatory BP measurement. Urinary albumin excretion rate was evaluated by three urinary albumin:creatinine ratio measurements at baseline and follow-up. RESULTS: At baseline, patients who subsequently progressed to a more advanced nephropathy stage (n = 35) had reduced diastolic night/day BP variation and higher 24 h systolic BP and PP values; they also had more advanced nephropathy and were more likely to smoke than those with no progression of nephropathy (n = 77). In a Cox regression analysis, independent predictors of nephropathy progression were 24 h PP (p < 0.01), diastolic night:day BP ratio (p = 0.02) and smoking (p = 0.02). The adjusted hazards ratio (95% CI) for each mmHg increment in 24 h PP was 1.04 (1.01-1.07), whereas the adjusted hazards ratio (95% CI) for each 1% increase in diastolic night:day BP ratio was 1.06 (1.01-1.11). Only one of 33 patients (3.0%) with both a diastolic night:day BP ratio and a 24 h PP below the median progressed, whereas 17 of 32 patients (53.1%) with both a diastolic night:day BP ratio and a 24 h PP equal to or above the median progressed to a more advanced nephropathy stage (p < 0.001). CONCLUSIONS/INTERPRETATION: Ambulatory PP, impaired nocturnal BP decline and smoking are strong, independent predictors of nephropathy progression in type 2 diabetic patients.