Macrovascular and microvascular type 2 diabetes complications are interrelated in a mouse model.

AIM: Evaluate the development of multiple complications, their interactions, and common mechanisms in the same individual with T2D. MATERIAL AND METHODS: 4-week-old male C57BL/6J mice were divided into: control (n = 6) and T2D (n = 6). T2D was induced through a high-carbohydrate-diet and low doses of streptozotocin. T2D was validated by metabolic parameters. Diabetic neuropathy was evaluated by mechanical and thermal sensitivity tests. We performed a histopathological analysis of the heart, kidney, liver, and parotid salivary glands and changes in bone microarchitecture by µCT. We calculated the relative risk (RR), odd ratios (OR) and Pearson correlation coefficients between the different complications and metabolic features. RESULTS: T2D mice have cardiomyopathy, neuropathy, nephropathy, liver steatosis and fibrosis, structural damage in parotid salivary glands, and bone porosity. RR analysis shows that all complications are interrelated by hyperglycaemia, insulin resistance, obesity, and systemic inflammation. CONCLUSIONS: T2D mice develop multiple complications simultaneously, which are related to each other, and this is associated with metabolic alterations. Our findings open up new approaches for the study and new therapeutic approaches of the pathophysiology of T2D and its complications.

CD4+ T-cell activation of bone marrow causes bone fragility and insulin resistance in type 2 diabetes.

Type 2 diabetes mellitus (T2DM) causes an increased risk of bone fractures. However, the pathophysiology of diabetic bone fragility is not completely understood. It has been proposed that an inflammatory microenvironment in bone could be a major mechanism by inducing uncontrolled bone resorption, inadequate bone formation and consequently more porous bones. We propose that activated T-cells in the bone marrow cause a pro-inflammatory microenvironment in bone, and cause bone fragility in T2DM. We induced T2DM in C57BL/6 male mice through a hypercaloric diet rich in carbohydrates and low doses of streptozocin. In T2DM mice we inhibited systemic activation of T-cells with a fusion protein between the extracellular domain of Cytotoxic T-Lymphocyte Antigen 4 and the Fc domain of human immunoglobulin G (CTLA4-Ig). We analysed the effects of T2DM or CTLA4-Ig in lymphocyte cell subsets and antigen-presenting cells in peripheral blood and femoral bone marrow; and their effect on the metabolic phenotype, blood and bone cytokine concentration, femoral bone microarchitecture and biomechanical properties, and the number of osteoblast-like cells in the femoral endosteum. We performed a Pearson multiple correlation analysis between all variables in order to understand the global mechanism. Results demonstrated that CTLA4-Ig decreased the number of activated CD4+ T-cells in the femoral bone marrow and consequently decreased TNF-α and RANK-L concentration in bone, notably improved femoral bone microarchitecture and biomechanical properties, increased the number of osteoblast-like cells, and reduces osteoclastic activity compared to T2DM mice that did not receive the inhibitor. Interestingly, we observed that blood glucose levels and insulin resistance may be related to the increase in activated CD4+ T-cells in the bone marrow. We conclude that bone marrow activated CD4+ T-cells cause poor bone quality and insulin resistance in T2DM.