In this issue
Risk of vascular complications: from the “Cube” to the “Pyramid”
Current guidelines for the treatment of diabetes suggest as goal for glycemic control an HbA1c value below 7% (6.5%, if possible), in order to reduce the incidence/progression of diabetes-related micro and macrovascular complications. However, fasting plasma glucose (FPG), post-prandial glucose (PPG) and, more recently, glycemic variability (GV) have been recognized as HbA1c-independent risk factors of diabetic vascular disease. Therefore, the optimal glycemic control should address all of the four targets: HbA1c, FPG, PPG and GV. In this review we highlight the role of each target (in particular glycemic variability) and suggest a simple “geometric” model showing the global vascular risk as the sum of the four variables.
Control of type 1 diabetes by CD4 + Foxp3+ regulatory T cells
CD4+ regulatory T (Treg) cells represent a critical switch in the modulation of various immune responses, including autoimmune responses and immunity to transplants, allergens, tumours and infectious microbes. Treg cells are diverse in their ontogeny, phenotype and mechanism(s) of action, and as such, may constitute many cell subsets with varying degrees of regulatory potential. Here, we summarize research from various laboratories, including our own, showing that CD4 + Foxp3+ Treg cells are critical in the control of type 1 diabetes onset and progression in mouse models and humans. Moreover, cellular and genetic factors impact CD4 + Foxp3+ Treg cell development and function and consequential resistance to organ-specific autoimmunity. Recent advances also show great promise in the use of CD4 + Foxp3+ Treg cells for the treatment of autoimmune diseases in the absence of long-term generalized immunosuppression.
C-reactive protein and pre-diabetic status
Serum C-reactive protein (CRP) levels are associated with body mass index (BMI) and the development of type 2 diabetes. In this cross-sectional study, we evaluated the relationship between CRP levels and glucose tolerance in a relatively lean Chinese population. CRP levels tended to be low in this population, but the odds of having impaired fasting glucose and impaired glucose tolerance both increased with increasing quartiles of CRP. These results suggest that elevated C-reactive protein is a risk factor for glucose intolerance and the development of type 2 diabetes, even in a population with low baseline BMI levels.
Insulin regimens, metformin, and hypoglycemia in type 2 diabetes
In patients with diabetes on insulin therapy, as HbA1c approaches normal, the risk of hypoglycemia increases. This relationship between hypoglycemia and HbA1c has been quantified in patients with type 1 diabetes but has yet to be quantified in patients with type 2 diabetes. In the present post-hoc analysis, previous findings have been extended by describing the relationship between HbA1c and confirmed hypoglycemia for patients with type 2 diabetes treated with metformin in combination with insulin in a clinical trial setting.
E-cadherin as a novel biomarker for diabetic nephropathy
Currently, early diagnosis of diabetic nephropathy (DN) remains a major challenge. In the present study, urinary proteomic approaches of differential gel electrophoresis (DIGE) and mass spectrometry were employed to identify novel nephropathy-related biomarkers. Urinary soluble E- cadherin was identified by proteomic methods in patients with diabetic nephropathy. The ELISA analysis also demonstrated urinary sE-cadherin was significantly increased in diabetic nephropathy group versus control group. The sensitivity and specificity of urinary sE-cadherin for diagnosis of diabetic nephropathy were calculated as 78.8% (95%CI, 74-83%) and 80% (95%CI, 65-91%). Besides, immunohistochemical stain showed E-cadherin expression was markedly decreased in renal tubular epithelial cells of patients with diabetic nephropathy versus healthy controls.
Involvement of dimethylarginine dimethylaminohydrolase (DDAH2) in visfatin-enhanced angiogenic function of endothelial cells
The novel adipocytokine visfatin was recently shown to promote angiogenesis and to be involved in the process of atherosclerosis. DDAH2, which regulates the expression of vascular endothelial growth factor (VEGF) is thought to be a novel modulator of angiogenesis. Therefore, the role of DDAH2 in visfatin-induced angiogenesis was investigated in human umbilical cord endothelial cells. The results suggest that PI3K/Akt-mediated upregulation of DDAH2 expression plays a critical role in visfatin-promoted angiogenesis through VEGF-dependent pathway.
HSD1 effects on muscle metabolism
Impairments in glucocorticoid metabolism in adipose and liver have been linked to the development of obesity and insulin resistance. Using primary cultures of human skeletal muscle, the direct effects of glucocorticoids on skeletal muscle to suppress glucose metabolism and enhance lipid metabolism, are demonstrated, as well as the efficacy of targeting 11 β-hydroxysteroid dehydrogenase 1 in prevention of cortisol mediated effects. The results highlight that skeletal muscle is likely to be an important tissue underlying glucocorticoid-mediated derangements in metabolism.
Low serum adiponectin as a useful marker for metabolic syndrome in type 2 diabetic patients
Although low adiponectin is known as a predictor of metabolic syndrome, potential of adiponectin as a predictor for metabolic syndrome in type 2 diabetes is debated. This study found an association between low adiponectin and metabolic syndrome risk among 1,013 type 2 diabetes Korean patients. Metabolic syndrome was defined by the National Cholesterol Education Program's Adult Treatment Panel III. Insulin sensitivity was directly assessed using the short insulin tolerance test. Metabolic syndrome risk was higher in subjects with lower adiponectin levels and stronger in those with low adiponectin and severe insulin resistance simultaneously. Therefore, measurement of adiponectin levels can be useful in future risk assessment and disease prevention.
Anti-platelet effects of pigment epithelium-derived factor (PEDF) in experimental diabetes
Pigment epithelium-derived factor (PEDF) inhibits thrombus formation in rats through its anti-oxidative properties. However, effects of PEDF on platelet activation and aggregation in diabetic or advanced glycation end products (AGEs)-injected rats are not understood. In this paper, PEDF inhibited platelet activation and aggregation in diabetic or AGEs-injected rats by suppressing NADPH oxidase-driven superoxide generation. The present study suggests that PEDF may play a protective role against diabetic vascular complications by attenuating the deleterious effects of AGEs on platelets.
Rosuvastatin positively changes nerve electrophysiology in diabetic rats
The authors examine the effect of rosuvastatin on peripheral nerve function in diabetic rats using electrophysiological measurements. At T1 there was a trend to lower amplitude of compound motor action potential (CMAP) in the 3 diabetic groups as compared to controls, but no difference for motor nerve conduction velocity (MNCV), amplitude of sensory nerve action potential (SNAP), or sensory nerve conduction velocity (SNCV) between diabetic groups and controls. At T2, the amplitude of CMAP was significantly lower in groups treated with rosuvastatin or with rosuvastatin plus mevalonate versus untreated diabetic group and control rats. MNCV was significantly and similarly decreased in the 3 diabetic groups. The results of the study show that rosuvastatin exerts a beneficial effect on the conduction of the fastest sensory fibers, and that these effects are independent of blood pressure and lipid changes.
Acetaminophen prevents hyperglycemia
Aging is associated with a higher incidence of hyperglycemia and reactive oxygen species (ROS). Whether direct links exist between aging-related hyperglycemia, Glut4 and ROS is not well understood. Here we show that aged F344BN rats (33-month old) that had been treated daily with acetaminophen (30mg/kg) for 6 months exhibit normal blood glucose, increased Glut4 levels and diminished skeletal muscle ROS, and that these improvements are associated with diminished age-related p38 MAPK hyperactivation. These results indicate that aging-related increases of ROS may play an important role in the development of hyperglycemia, and more importantly, that age-associated hyperglycemia may be reversed by pharmacological intervention.
α -Lipoic acid reduces anomalies in diabetic mice
In spite of improvements in the treatment of diabetes with glucose monitoring, the incidence of congenital malformations in diabetic pregnancies remains higher than in non-diabetic pregnancies. Therefore, new countermeasures need to be developed to prevent the occurrence of diabetes-induced congenital malformations. In this work, we demonstrate that α-lipoic acid (LA), a potent antioxidant, reduces not only neural tube defects, but also cardiovascular malformations and skeletal malformations in the offspring of streptozotocin-induced diabetic mice. Our results imply that LA is useful for investigation into causes and possible prevention of malformations in diabetic pregnancy.
