Fetuin-A and risk of diabetes-related vascular complications: a prospective study

Background Fetuin-A is a hepatokine which has the capacity to prevent vascular calcification. Moreover, it is linked to the induction of metabolic dysfunction, insulin resistance and associated with increased risk of diabetes. It has not been clarified whether fetuin-A associates with risk of vascular, specifically microvascular, complications in patients with diabetes. We aimed to investigate whether pre-diagnostic plasma fetuin-A is associated with risk of complications once diabetes develops. Methods Participants with incident type 2 diabetes and free of micro- and macrovascular disease from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (n = 587) were followed for microvascular and macrovascular complications (n = 203 and n = 60, respectively, median follow-up: 13 years). Plasma fetuin-A was measured approximately 4 years prior to diabetes diagnosis. Prospective associations between baseline fetuin-A and risk of complications were assessed with Cox regression. Results In multivariable models, fetuin-A was linearly inversely associated with incident total and microvascular complications, hazard ratio (HR, 95% CI) per standard deviation (SD) increase: 0.86 (0.74; 0.99) for total, 0.84 (0.71; 0.98) for microvascular and 0.92 (0.68; 1.24) for macrovascular complications. After additional adjustment for cardiometabolic plasma biomarkers, including triglycerides and high-density lipoprotein, the associations were slightly attenuated: 0.88 (0.75; 1.02) for total, 0.85 (0.72; 1.01) for microvascular and 0.95 (0.67; 1.34) for macrovascular complications. No interaction by sex could be observed (p > 0.10 for all endpoints). Conclusions Our data show that lower plasma fetuin-A levels measured prior to the diagnosis of diabetes may be etiologically implicated in the development of diabetes-associated microvascular disease.

Fracture Patterns in Type 1 and Type 2 Diabetes Mellitus: A Narrative Review of Recent Literature

Purpose of Review In this narrative review, we have summarized the literature on fracture risk in T1DM and T2DM with a special focus on fracture site, time patterns, glucose-lowering drugs, and micro- and macrovascular complications. Recent Findings T1DM and T2DM were associated with an overall increased fracture risk, with preferent locations at the hip, vertebrae, humerus, and ankle in T1DM and at the hip, vertebrae, and likely humerus, distal forearm, and foot in T2DM. Fracture risk was higher with longer diabetes duration and the presence of micro- and macrovascular complications. In T2DM, fracture risk was higher with use of insulin, sulfonylurea, and thiazolidinediones and lower with metformin use. Summary The increased fracture risk in T1DM and T2DM concerns specific fracture sites, and is higher in subjects with longer diabetes duration, vascular complications, and in T2DM with the use of specific glucose-lowering medication.

The Neoepitopes on Methylglyoxal- (MG-) Glycated Fibrinogen Generate Autoimmune Response: Its Role in Diabetes, Atherosclerosis, and Diabetic Atherosclerosis Subjects

Objectives. In diabetes mellitus, hyperglycemia-mediated nonenzymatic glycosylation of fibrinogen protein plays a crucial role in the pathogenesis of micro- and macrovascular complications especially atherosclerosis via the generation of advanced glycation end products (AGEs). Methylglyoxal (MG) induces glycation of fibrinogen, resulting in structural alterations that lead to autoimmune response via the generation of neoepitopes on protein molecules. The present study was designed to probe the prevalence of autoantibodies against MG-glycated fibrinogen (MG-Fib) in type 2 diabetes mellitus (T2DM), atherosclerosis (ATH), and diabetic atherosclerosis (T2DM-ATH) patients. Design and Methods. The binding affinity of autoantibodies in patients’ sera (T2DM, n = 100 ; ATH, n = 100 ; and T2DM-ATH, n = 100 ) and isolated immunoglobulin G (IgG) against native fibrinogen (N-Fib) and MG-Fib to healthy subjects (HS, n = 50 ) was accessed by direct binding ELISA. The results of direct binding were further validated by competitive/inhibition ELISA. Moreover, AGE detection, ketoamines, protein carbonyls, hydroxymethylfurfural (HMF), thiobarbituric acid reactive substances (TBARS), and carboxymethyllysine (CML) concentrations in patients’ sera were also determined. Furthermore, free lysine and free arginine residues were also estimated. Results. The high binding affinity was observed in 54% of T2DM, 33% of ATH, and 65% of T2DM-ATH patients’ samples with respect to healthy subjects against MG-Fib antigen in comparison to N-Fib ( p < 0.05 to p < 0.0001 ). HS sera showed nonsignificant binding ( p > 0.05 ) with N-Fib and MG-Fib. Other biochemical parameters were also found to be significant ( p < 0.05 ) in the patient groups with respect to the HS group. Conclusions. These findings in the future might pave a way to authenticate fibrinogen as a biomarker for the early detection of diabetes-associated micro- and macrovascular complications.

Risk management of micro- and macrovascular complications of diabetes mellitus: the importance of glycemic self-control

As the incidence of obesity, unhealthy lifestyles and an aging population increases, the global prevalence of diabetes mellitus (DM) is projected to rise sharply in the coming decades. A significant part of the burden of DM is associated with the development of micro- and macrovascular complications, which are the cause of a deterioration in the quality of life, disability and premature death of patients with DM. Cardiovascular disease (CVD) is the leading cause of death in patients with DM, especially those with type 2 DM The risk of CVD in people with DM is 2–4 times higher than in people without DM, and this risk increases with the deterioration of glycemic control. Disorders of the glycemic profile such as hyperglycemia, hypoglycemia and high variability of glycemia negatively affect the prognosis of patients with DM. Self-monitoring of blood glucose is an effective tool for managing DM, which allows not only achieving the target level of glycated hemoglobin and minimizing glycemic variability, but predicting the risk of severe hypoglycemia.

Time in range is a tool for assessing the quality of glycemic control in diabetes

The presence of continuous glucose monitoring (CGM) systems has expanded diagnostic capabilities. The implementation of this technology into clinical practice allowed to determine the patterns and tendencies of excursions in glucose levels, to obtain reliable data concerning short-term glycemic control. Taking into consideration the large amount of obtained information using CGM systems, more than 30 different indicators characterizing glycemic variability were proposed. However, it is very difficult for a practitioner to interpret the data obtained due to the variety of indicators and the lack of their target values. The first step in the standardization of indices was the creation of the International Guidelines for CGM in 2017, where the Time in Range (TIR) (3,9–10,0 mmol/l, less often 3,9–7,8 mmol/l) was significant. To complement the agreed parameters and simplify the interpretation of obtained data using CGM, in 2019 the recommendations were prepared for the International Consensus on Time in Range, where TIR was validated as an additional component of the assessment of glycemic control along with HbA1c. In the literature review the issues of the association of TIR with the development of micro- and macrovascular complications in type 1 and 2 diabetes are considered. The relationship with other indicators of the glycemic control assessment was also analyzed and the dependence of insulin therapy on TIR was shown. TIR is a simple and convenient indicator, it has a proven link with micro- and macrovascular complications of diabetes and can be recommended as a new tool for assessing the glycemic control. The main disadvantage of TIR usage is the insufficient apply of CGM technology by the majority of patients with diabetes.

Relationship between time in range, glycemic variability, HbA1c and complications in adults with type 1 diabetes mellitus

Purpose Real-time continuous glucose monitoring (RT-CGM) provides information on glycaemic variability (GV), time in range (TIR) and guidance to avoid hypoglycemia, thereby complimenting HbA1c for diabetes management. We investigated whether GV and TIR were independently associated with chronic and acute diabetes complications. Methods Between September 2014 and January 2017 515 subjects with type 1 diabetes using sensor-augmented pump therapy were followed for 24 months. The link between baseline HbA1c and CGM-derived glucometrics (TIR [70-180 mg/dL], coefficient of variation [CV] and standard deviation [SD]) obtained from the first 2 weeks of RT-CGM use and the presence of complications was investigated. Complications were defined as: composite microvascular complications (presence of neuropathy, retinopathy or nephropathy), macrovascular complications, and hospitalization for hypoglycemia and/or ketoacidosis. Results Individuals with microvascular complications were older (P&lt;0.001), had a longer diabetes duration (P&lt;0.001), a higher HbA1c (7.8±0.9 vs 7.5±0.9%, P&lt;0.001) and spent less time in range (60.4±12.2 vs 63.9±13.8%, P=0.022) compared to those without microvascular complication. Diabetes duration (OR=1.12 [1.09-1.15],P&lt;0.001) and TIR (OR=0.97 [0.95-0.99], P=0.005) were independent risk factors for composite microvascular complications, while SD and CV were not. Age (OR=1.08 [1.03-1.14],P=0.003) and HbA1c (OR=1.80 [1.02-3.14], P=0.044) were risk factors for macrovascular complications. TIR (OR=0.97 [0.95-0.99], P=0.021) was the only independent risk factor for hospitalizations for hypoglycaemia or ketoacidosis. Conclusions Lower TIR was associated with the presence of composite microvascular complications and with hospitalization for hypoglycemia or ketoacidosis. TIR, SD and CV were not associated with macrovascular complications.