Magnesium and type 2 diabetes

Type 2 diabetes is frequently associated with both extracellular and intracellular magnesium(Mg) deficits. A chronic latent Mg deficit or an overt clinical hypomagnesemia is common in patients with type 2 diabetes, especially in those with poorly controlled glycemic profiles. Insulinand glucose are important regulators of Mg metabolism. Intracellular Mg plays a key role in regulating insulin action, insulin-mediated-glucose-uptake and vascular tone. Reduced intracellular Mg concentrations result in a defective tyrosine-kinase activity, postreceptorial impairment in insulin action and worsening of insulin resistance in diabetic patients. A low Mg intake and an increased Mg urinary loss appear the most important mechanisms that may favor Mg depletion in patients with type 2 diabetes. Low dietary Mg intake has been related to the development of type 2 diabetes and metabolic syndrome. Benefits of Mg supplementation on metabolic profiles in diabetic patients have been found in most, but not all clinical studies and larger prospective studies are needed to support the potential role of dietary Mg supplementation as a possible public health strategy in diabetes risk. The aim of this review is to revise current evidence on the mechanisms of Mg deficiency in diabetes and on the possible role of Mg supplementation in the prevention and management of the disease.     

Characteristics of autoimmunity in type 1 diabetes and type 1.5 overlap with type 2 diabetes

This presentation is an overview of mechanisms for developing and maintaining self-tolerance in mammalian organisms. Because this meeting is focused on type 1 diabetes and its mechanisms, the discussion deals primarily with mechanisms of T-cell tolerance, since type 1 diabetes in both effector and initiator phases is primarily a T-cell-mediated autoimmune disease. Emphasis is placed on more recently discovered mechanisms of maintaining self-tolerance (autoimmune regulator [AIRE]) and a new defect in T-cell negative selection. The emerging picture is that of a polygenic disease with various combinations of different alleles of many genes with important roles in the normal immune response or normal immune responses.     

Place of sodium-glucose co-transporter type 2 inhibitors for treatment of type 2 diabetes

Inhibitors of sodium-glucose co-transporter type 2 (SGLT2), such as canagliflozin and dapagliflozin, are recently approved for treatment of type 2 diabetes. These agents lower blood glucose mainly by increasing urinary glucose excretion. Compared with placebo, SGLT2 inhibitors reduce hemoglobin A1c (HbA1c) levels by an average of 0.5%-0.8% when used as monotherapy or add-on therapy. Advantages of this drug class include modest weight loss of approximately 2 kg, low risk of hypoglycemia, and decrease blood pressure of approximately 4 mmHg systolic and 2 mmHg diastolic. These characteristics make these agents potential add-on therapy in patients with HbA1c levels close to 7%-8.0%, particularly if these patients are obese, hypertensive, and/or prone for hypoglycemia. Meanwhile, these drugs are limited by high frequency of genital mycotic infections. Less common adverse effects include urinary tract infections, hypotension, dizziness, and worsening renal function. SGLT2 inhibitors should be used with caution in the elderly because of increased adverse effects, and should not be used in chronic kidney disease due to decreased or lack of efficacy and nephrotoxicity. Overall, SGLT2 inhibitors are useful addition for treatment of select groups of patients with type 2 diabetes, but their efficacy and safety need to be established in long-term clinical trials.     

Current perioperative treatment of patients with type 1 and type 2 diabetes

Diabetes mellitus is rapidly increasing, diabetic patients are likely to undergo surgical procedures more than non-diabetic patients, the hospital stay of diabetic patients is longer, and diabetic patients have increased mortality and morbidity. The correct treatment of diabetic patients in the perioperative period is crucial to improve clinical outcomes. Diabetic patients must be carefully evaluated for cardiovascular risk, keeping in mind micro- and macroangiopathic diabetic complications. Metabolic control deserves great attention because hyperglycemia is related to increased complications and worse outcomes. Insulin infusion regimens to achieve near normoglycemia must be implemented in surgical and critically ill patients.     

Intracranial meningiomas and neurofibromatosis type 2

Purpose

In spite of the few clinical studies regarding the occurrence of intracranial meningiomas, their prognosis in neurofibromatosis type 2 (NF2) has not been accurately assessed and their management remains controversial. This study aims to compare NF2 patients with intracranial meningiomas to those without, and consequently to identify prognostic factors in attempt to improve the management of these tumors.

Methods

This retrospective study includes a total of 80 NF2 patients followed at Lille Hospital Center between 1987 and 2011. The diagnosis of NF2 was confirmed either because the patient met the Manchester criteria or by the presence of genetic mutation. Clinical, radiological and genetic data were retrospectively recorded and analyzed. Patients underwent annual cranial and spinal MRI. Both location and size of each tumor were reported.

Results

The mean follow-up period was 8.8 years (range 1–24 years; SD: ±0.8) and the mean age at diagnosis was 27.2 years (range 6–73 years; SD: ±1.7). Among all patients, 34 harbored intracranial meningiomas. Patients with intracranial meningiomas had a higher number of intracranial schwannomas, spinal tumors and cutaneous tumors (p?<?0.05). They underwent more surgical procedures (p?<?0.012). Twenty five intracranial meningiomas were surgically removed in 17 patients. The decision to perform surgery was taken in 10 cases for symptomatic tumors and in 15 cases for growing asymptomatic tumors determined by radiology. The histological analysis found a high rate of fibroblastic, transitional or grade 2 meningiomas preferentially located at the cerebri falx.

Conclusion

Intracranial meningiomas are common in NF2. They are associated with poor prognosis factors. Clinical and radiological monitoring could lead to early treatment of these tumors both when clinical symptoms are present and in case of proven radiological evolution, and thus trying to maintain a favorable functional prognosis for as long as possible.     

Prorenin and angiotensin-dependent renal vasoconstriction in type 1 and type 2 diabetes

Prorenin is a powerful marker for risk of nephropathy and retinopathy in diabetes, but the responsible mechanism remains unclear. Studied were 35 patients with diabetes (18 with type 1 and 17 with type 2) and 69 age-matched healthy subjects with para-aminohippurate and inulin clearances and their response to captopril. All patients with diabetes had normal renal function and no microalbuminuria. Prorenin was calculated as the difference between total renin and active renin. Active renin level in patients with diabetes (11.6 +/- 0.9 microU/ml) was significantly lower than in normal subjects (14.5 +/- 1.3 microU/ml; P < 0.05); despite this, the renal vascular response to captopril was much larger (82.9 +/- 11.5 versus 13.6 +/- 5.8 ml/min per 1.73 m(2); P < 0.01). Prorenin in both patients with type 1 and type 2 diabetes (175.7 +/- 15.1 microU/ml) also was significantly higher than in normal subjects (128 +/- 5.8 microU/ml; P < 0.01). Active renin correlated with prorenin in normal subjects (r = 0.44, P = 0.0002), and this correlation was much more striking in patients with diabetes (r = 0.72, P = 0.0001). The active renin and prorenin correlation was identical in type 1 and type 2 diabetes. There was a clear correlation between plasma prorenin and the renovascular response to captopril in patients with diabetes (P < 0.01) but not in normal subjects (P > 0.13). The strong correlation between plasma prorenin concentration and the renovascular response to captopril in diabetes supports the hypothesis of a direct effect of prorenin, but the unanticipated high degree of correlation between plasma prorenin and active renin limits the conclusions that can be drawn.     

Hepatitis C virus infection and type 1 and type 2 diabetes mellitus

Hepatitis C virus(HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus(T1DM) and T2 DM. T2 DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1 DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2 DM and chronic hepatitis C(CHC) infection. The processes through which CHC is associated with T2 DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immunemediated mechanisms. Few data have been reported on the association of CHC and T1 DM and reports on the potential association between T1 DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-α therapy can stimulate pancreatic autoim-munity and in certain cases lead to the development of T1 DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with nondiabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effec-tive programmes for the surveillance and treatment of diabetic CHC patients.     

Genetics of type 2 diabetes

Type 2 diabetes (T2D) is the result of interaction between environmental factors and a strong hereditary component. We review the heritability of T2D as well as the history of genetic and genomic research in this area. Very few T2D risk genes were identified using candidate gene and linkage-based studies, but the advent of genome-wide association studies has led to the identification of multiple genes, including several that were not previously known to play any role in T2D. Highly replicated genes, for example TCF7L2, KCNQ1 and KCNJ11, are discussed in greater detail. Taken together, the genetic loci discovered to date explain only a small proportion of the observed heritability. We discuss possible explanations for this “missing heritability”, including the role of rare variants, gene-environment interactions and epigenetics. The clinical utility of current findings and avenues of future research are also discussed.     

Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes

Many diabetic patients suffer from a cardiomyopathy that cannot be explained by poor coronary perfusion. Reactive oxygen species (ROS) have been proposed to contribute to this cardiomyopathy. Consistent with this we found evidence for induction of the antioxidant genes for catalase in diabetic OVE26 hearts. To determine whether increased antioxidant protection could reduce diabetic cardiomyopathy, we assessed cardiac morphology and contractility, Ca(2+) handling, malondialdehyde (MDA)-modified proteins, and ROS levels in individual cardiomyocytes isolated from control hearts, OVE26 diabetic hearts, and diabetic hearts overexpressing the antioxidant protein catalase. Diabetic hearts showed damaged mitochondria and myofibrils, reduced myocyte contractility, slowed intracellular Ca(2+) decay, and increased MDA-modified proteins compared with control myocytes. Overexpressing catalase preserved normal cardiac morphology, prevented the contractile defects, and reduced MDA protein modification but did not reverse the slowed Ca(2+) decay induced by diabetes. Additionally, high glucose promoted significantly increased generation of ROS in diabetic cardiomyocytes. Chronic overexpression of catalase or acute in vitro treatment with rotenone, an inhibitor of mitochondrial complex I, or thenoyltrifluoroacetone, an inhibitor of mitochondrial complex II, eliminated excess ROS production in diabetic cardiomyocytes. The structural damage to diabetic mitochondria and the efficacy of mitochondrial inhibitors in reducing ROS suggest that mitochondria are a source of oxidative damage in diabetic cardiomyocytes. We also found that catalase overexpression protected cardiomyocyte contractility in the agouti model of type 2 diabetes. These data show that both type 1 and type 2 diabetes induce damage at the level of individual myocytes, and that this damage occurs through mechanisms utilizing ROS.     

Fetal programming of obesity and type 2 diabetes

The prevalence of obesity and type 2 diabetes mellitus has increased rapidly over the past few decades, and prevention efforts have not been successful. Fetal programming involves the earliest stage of obesity development, and provides a novel concept to complement other strategies for lifelong prevention of obesity and type 2 diabetes mellitus. The World Health Organization now advocates a life-course approach to prevent/control obesity, starting with pre-conceptional and antenatal maternal health. Maternal overnutrition, gestational diabetes mellitus and excessive gestational weight gain lead to fetal overgrowth, and “programs” the offspring with an increased risk of obesity and type 2 diabetes mellitus in childhood and adulthood. This review summarizes current data on fetal programming of obesity and type 2 diabetes mellitus including potential causative factors, mechanisms and interventions to reduce its impact.     

Angiotensin type 1 and type 2 receptor blockade in chronic allograft nephropathy

Angiotensin-II (Ang-II) type 1 (AT(1)) receptor blockers may delay the progression of chronic allograft nephropathy (CAN). However, neither the optimal time for initiating AT(1) receptor blockade in order to delay CAN potentially nor the role of Ang-II type 2 (AT(2)) receptors under AT(1) receptor blockade is known. Both AT receptors can regulate p53 expression and apoptosis. We investigated what time of initiation with AT(1) blockers most effectively delayed CAN as well as the role of the AT(2) receptor, and how angiotensin receptor blockade affected apoptosis and its regulating factors in this context in a rat model. Kidneys of Fisher (F344) rats were transplanted into Lewis rats. Animals were treated with AT(1) (candesartan) and/or AT(2) (PD123319) receptor antagonists, a calcium channel blocker, or vehicle (treatment periods: day -7 before to week 24 after transplantation (long term), week 12 to week 24 (late), day -7 to day +5 (early)) and observed the animals for 24 weeks. Reduction of proteinuria, grade of CAN, and number of apoptotic cells was most pronounced in animals receiving long-term AT(1) receptor blockade. A combined AT(1)/AT(2) blocker treatment reduced CAN similarly to AT(1) blocker treatment alone. The number of apoptotic cells and the level of p53 mRNA were significantly lower in long-term AT(1) blocker-treated animals. In summary, AT(1) receptor blockade delayed the progression of CAN, particularly in animals treated long term. Reduction of apoptosis could be related to these beneficial effects. The AT(2) receptor does not appear to play an important role in CAN.