A long-term "memory" of HIF induction in response to chronic mild decreased oxygen after oxygen normalization

Background Endothelial dysfunction (ED) is functionally characterized by decreased vasorelaxation, increased thrombosis, increased inflammation, and altered angiogenic potential, has been intimately associated with the progression and severity of cardiovascular disease. Patients with compromised cardiac function oftentimes have a state of chronic mild decreased oxygen at the level of the vasculature and organs, which has been shown to exacerbate ED. Hypoxia inducible factor (HIF) is a transcription factor complex shown to be the master regulator of the cellular response to decreased oxygen levels and many HIF target genes have been shown to be associated with ED. Methods Human endothelial and aortic smooth muscle cells were exposed either to A) normoxia (21% O2) for three weeks, or to B) mild decreased oxygen (15% O2) for three weeks to mimic blood oxygen levels in patients with heart failure, or to C) mild decreased oxygen for two weeks followed by one week of normoxia ("memory" treatment). Levels of HIF signaling genes (HIF-1α, HIF-2α, VEGF, BNIP3, GLUT-1, PAI-1 and iNOS) were measured both at the protein and mRNA levels. Results It was found that chronic exposure to mild decreased oxygen resulted in significantly increased HIF signaling. There was also a "memory" of HIF-1α and HIF target gene induction when oxygen levels were normalized for one week, and this "memory" could be interrupted by adding a small molecule HIF inhibitor to the last week of normalized oxygen. Finally, levels of ubiquitylated HIF-1α were reduced in response to chronic mild decreased oxygen and were not full restored after oxygen normalization. Conclusion These data suggest that HIF signaling may be contributing to the pathogenesis of endothelial dysfunction and that normalization of oxygen levels may not be enough to reduce vascular stress

Big data and diabetes: the applications of big data for diabetes care now and in the future

Aims: Review the current applications of Big Data in diabetes care and consider the future potential. Methods: Scoping study of the academic literature on Big Data and diabetes care. Results: Healthcare data are being produced at ever-increasing rates, and this information has the potential to transform the provision of diabetes care. Big Data is beginning to have an impact on diabetes care through data research. The use of Big Data for routine clinical care is still a future application. Conclusions: Vast amounts of healthcare data are already being produced, and the key is harnessing these to produce actionable insights. Considerable development work is required to achieve these goals

The glucose triad and its role in comprehensive glycaemic control: current status, future management

The prevalence of type 2 diabetes across the world has been described as a global pandemic. Despite significant efforts to limit both the increase in the number of cases and the long-term impact on morbidity and mortality, the total number of people with diabetes is projected to continue to rise and most patients still fail to achieve adequate glycaemic control. Optimal management of type 2 diabetes requires an understanding of the relationships between glycosylated haemoglobin (HbA1c), fasting plasma glucose and postprandial glucose (the glucose triad), and how these change during development and progression of the disease. Early and sustained control of glycaemia remains important in the management of type 2 diabetes. The contribution of postprandial glucose levels to overall glycaemic control and the role of postprandial glucose targets in disease management are currently debated. However, many patients do not reach HbA1C targets set according to published guidelines. As recent data suggest, if driving HbA1C down to lower target levels is not the answer, what other factors involved in glucose homeostasis can or should be targeted? Has the time come to change the treatment paradigm to include awareness of the components of the glucose triad, the existence of glucose variability and their potential influence on the choice of pharmacological treatment? It is becomingly increasingly clear that physicians are likely to have to consider plasma glucose levels both after the overnight fast and after meals as well as the variability of glucose levels, in order to achieve optimal glycaemic control for each patient. When antidiabetic therapy is initiated, physicians may need to consider selection of agents that target both fasting and postprandial hyperglycaemia

Hypothesis: the "metabolic memory" - the new challenge of diabetes

W dużych randomizowanych badaniach wykazano, że intensywne wyrównywanie glikemii od samego początku po rozpoznaniu cukrzycy zmniejsza ryzyko rozwoju powikłań cukrzycy zarówno mikro-, jak i makroangiopatii. Jednak wyniki badań epidemiologicznych i dane prospektywne wskazują, że wpływ kontroli metabolicznej we wczesnej fazie na efekty kliniczne jest długofalowy. To zjawisko określono ostatnio jako "pamięć metaboliczną". Do potencjalnych mechanizmów propagacji tej "pamięci" należą nieenzymatyczna glikacja białek i lipidów komórkowych oraz nadmiar reaktywnego tlenu i azotu w komórce, w szczególności powstający na poziomie glikowanych białek mitochondriów, które prawdopodobnie współdziałają w celu utrzymania procesów sygnałowania w komórce. Sformułowanie teorii "pamięci metabolicznej" wskazuje na konieczność wczesnego intensywnego leczenia cukrzycy, którego celem jest normalizacja glikemii, oraz włączania do terapii substancji redukujących reaktywne związki w komórkach oraz zmniejszających glikację, aby zminimalizować odległe powikłania tej choroby.Large randomized studies have established that early intensive glycaemic control reduces the risk of diabetic complications, both micro- and macrovascular. However, epidemiological and prospective data support a long-term influence of early metabolic control on clinical outcomes. This phenomenon has recently been defined as 'metabolic memory'. Potential mechanisms for propagating this 'memory' are the non-enzymatic glycation of cellular proteins and lipids, and an excess of cellular reactive oxygen and nitrogen species, in particular originated at the level of glycated-mitochondrial proteins, perhaps acting in concert with one another to maintain stress signalling. Furthermore, the emergence of this 'metabolic memory' suggests the need for very early aggressive treatment aiming to 'normalize' glycaemic control and the addition of agents which reduce cellular reactive species and glycation in order to minimize long-term diabetic complications

Natural history and risk factors for diabetic kidney disease in patients with T2D: lessons from the AMD-annals

The Associazione Medici Diabetologi (AMD) annals initiative is an ongoing observational survey promoted by AMD. It is based on a public network of about 700 Italian diabetes clinics, run by specialists who provide diagnostic confirmation and prevention and treatment of diabetes and its complications. Over the last few years, analysis of the AMD annals dataset has contributed several important insights on the clinical features of type-2 diabetes kidney disease and their prognostic and therapeutic implications. First, non-albuminuric renal impairment is the predominant clinical phenotype. Even though associated to a lower risk of progression compared to overt albuminuria, it contributes significantly to the burden of end-stage renal disease morbidity. Second, optimal blood pressure control provides significant but incomplete renal protection. It reduces albuminuria but there may be a J curve phenomenon with eGFR at very low blood pressure values. Third, hyperuricemia and diabetic hyperlipidemia, namely elevated triglycerides and low HDL cholesterol, are strong independent predictors of chronic kidney disease (CKD) onset in diabetes, although the pathogenetic mechanisms underlying these associations remain uncertain. Fourth, the long-term intra-individual variability in HbA1c, lipid parameters, uric acid and blood pressure plays a greater role in the appearance and progression of CKD than the absolute value of each single variable. These data help clarify the natural history of CKD in patients with type 2 diabetes and provide important clues for designing future interventional studies

Increased glycation and oxidative damage to apolipoprotein B100 of LDL cholesterol in patients with type 2 diabetes and effect of metformin

OBJECTIVE The aim of this study was to investigate whether apolipoprotein B100 of LDL suffers increased damage by glycation, oxidation, and nitration in patients with type 2 diabetes, including patients receiving metformin therapy. RESEARCH DESIGN AND METHODS For this study, 32 type 2 diabetic patients and 21 healthy control subjects were recruited; 13 diabetic patients were receiving metformin therapy (median dose: 1.50 g/day). LDL was isolated from venous plasma by ultracentrifugation, delipidated, digested, and analyzed for protein glycation, oxidation, and nitration adducts by stable isotopic dilution analysis tandem mass spectrometry. RESULTS Advanced glycation end product (AGE) content of apolipoprotein B100 of LDL from type 2 diabetic patients was higher than from healthy subjects: arginine-derived AGE, 15.8 vs. 5.3 mol% (P < 0.001); and lysine-derived AGE, 2.5 vs. 1.5 mol% (P < 0.05). Oxidative damage, mainly methionine sulfoxide residues, was also increased: 2.5 vs. 1.1 molar equivalents (P < 0.001). 3-Nitrotyrosine content was decreased: 0.04 vs. 0.12 mol% (P < 0.05). In diabetic patients receiving metformin therapy, arginine-derived AGE and methionine sulfoxide were lower than in patients not receiving metformin: 19.3 vs. 8.9 mol% (P < 0.01) and 2.9 vs. 1.9 mol% (P < 0.05), respectively; 3-nitrotyrosine content was higher: 0.10 vs. 0.03 mol% (P < 0.05). Fructosyl-lysine residue content correlated positively with fasting plasma glucose. Arginine-derived AGE residue contents were intercorrelated and also correlated positively with methionine sulfoxide. CONCLUSIONS Patients with type 2 diabetes had increased arginine-derived AGEs and oxidative damage in apolipoprotein B100 of LDL. This was lower in patients receiving metformin therapy, which may contribute to decreased oxidative damage, atherogenicity, and cardiovascular disease