Diabetes and Infections-Hepatitis C: Is There Type 2 Diabetes Excess in Hepatitis C Infection?

Individual epidemiologic studies as well as the pooled analysis of observational studies have indicated the association between type 2 diabetes (T2D) and hepatitis C virus infection (HCV). Whether HCV infection is the cause of diabetes or diabetic patients are more prone to get HCV infection is still in question. The objective of the present review was to provide answers to this issue, based on available evidence from epidemiologic, molecular, experimental and therapeutic studies. Our current understanding of how chronic HCV infection could induce T2D is incomplete, but it seems twofold based on both direct and indirect roles of the virus. HCV may directly induce insulin resistance (IR) through its proteins. HCV core protein was shown to stimulate suppressor of cytokine signaling, resulting in ubiquitination and degradation of tyrosine kinase phosphorylated insulin receptor substrates (IRS1/2) in proteasomes. HCV-nonstructural protein could increase protein phosphatase 2A which has been shown to inactivate the key enzyme Akt by dephosphorylating it. Insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to IR, which leads to the development of T2D in patients with HCV infection. The peroxisome proliferator-activated receptors (PPARs) are also implicated. PPARα/γ, together with their obligate partner RXR, are the main nuclear receptors expressed in the liver. PPARα upregulates glycerol-3-phosphate dehydrogenase, glycerol kinase, and glycerol transport proteins, which allows for glucose synthesis during fasting states. Decreased activity of PPARs could attribute to HCV-induced IR. Immune-mediated mechanisms may be involved in the indirect role of HCV in inducing IR. It is speculated that TNF-alpha plays a major role in the pathogenesis of IR through lowering IRS1/2. Furthermore, HCV infection- triggered ER stress could lead to the activation of PP2A, which inhibits both Akt and the AMP-activated kinase, the regulators of gluconeogenesis. In summary, we illustrate that HCV infection is accompanied by multiple defects in the upstream insulin signaling pathway in the liver that may contribute to the observed prevalence of IR and diabetes. Future studies are needed to resolve this issue.     

Who Should We Target for Diabetes Prevention and Diabetes Risk Reduction?

Screening for individual diabetes risk is crucial to identify adult and pediatric high-risk target populations for referral into successful diabetes prevention programs. Determination of impaired glucose tolerance or elevated fasting glucose levels has been the “gold standard” to classify subjects at increased risk for and/or to diagnose type 2 diabetes (T2DM). However, this led to ignoring many individuals prone to develop the disease. Therefore, using a stepped strategy consisting of a preliminary assessment of risk factors, by using risk scores such as the Finnish Diabetes Risk Score (FINDRISC) adapted to the respective population, followed by a single blood test determining blood glucose or hemoglobin A_1c, respectively, or an oral glucose tolerance test is a feasible and pragmatic method to more accurately detect individuals at risk for T2DM. Inclusion of further risk factors into the assessment such as physical inactivity, waist circumference, and prenatal factors needs to be thoroughly discussed to establish a valid and reliable stepped approach applicable to real world health care. This article provides an overview of the current literature and is intentionally focused on the identification of high-risk populations (both adult and pediatric) that will help to address the key issues around the prevention of T2DM in health care settings.     

Is There a Role for Oral Antihyperglycemics in Gestational Diabetes and Type 2 Diabetes during Pregnancy?

Diabetes mellitus is a heterogeneous disorder of glucose intolerance that is generally classified into the following categories: type 1 and type 2 diabetes and gestational diabetes (GDM). Currently, the number of pregnancies complicated by type 2 diabetes and GDM exceed those affected by type 1 diabetes. Numerous studies have established a direct relationship between maternal glycemic control and neonatal outcomes for all types of diabetes. Therefore, modern treatment protocols during pregnancy emphasize strict glycemic control by a combination of diet and medication. Traditionally, insulin therapy has been considered the gold standard for management because of its efficacy in achieving tight glucose control and the fact that it does not cross the placenta. Since GDM and type 2 diabetes are characterized by insulin resistance and relatively decreased insulin secretion, treatment with oral antihyperglycemic agents that target these defects is of potential interest. However, because of concerns regarding transplacental passage and, therefore, the possibility of fetal teratogenesis and prolonged neonatal hypoglycemia, these agents are not currently recommended in pregnancy. There are no randomized controlled trials on which to draw conclusions regarding the teratogenicity of these oral agents. However, most retrospective studies and the published clinical experience have not demonstrated an increased risk of malformed infants among women treated with oral antihyperglycemic agents. Rather, the data indicate that the increased risk for major congenital anomalies appears to be related to maternal glycemic control prior to and during conception. These studies and currently available data on the use of both metformin and sulfonylureas in pregnancy have also failed to demonstrate an increased risk of neonatal hypoglycemia and other neonatal morbidities. To date, there has only been one randomized controlled trial to test the effectiveness and safety of sulfonylurea therapy (glyburide [glibenclamide]) in the management of women with GDM. Both the insulin- and glyburide-treated women were able to achieve satisfactory glucose control and had similar perinatal outcomes. Glyburide was not detected in the cord serum of any infant in the glyburide group. In summary, based on the currently available data, it appears that glyburide could be safely and effectively utilized in the management of GDM. However, more intensive investigation regarding the safety and feasibility of oral agents in pregnancies complicated by type 2 diabetes is necessary. It is important to emphasize that it is the level of metabolic control achieved and not the mode of therapy that is crucial to improving outcomes in these pregnancies.     

Long-Term Voriconazole and Skin Cancer: Is There Cause for Concern?

Skin toxicity due to voriconazole is well recognized. Recently, several series have reported skin cancer, particularly cutaneous squamous cell carcinoma (C-SCC), following photosensitivity reactions among patients receiving long-term voriconazole (>12 months). Almost all patients were immunosuppressed, including stem cell and solid organ transplant recipients. A case-control study of lung transplant recipients identified long-term voriconazole (median cumulative dose: 76 grams) and residence in areas of strong sun exposure as independent risk factors for C-SCC. The mechanism(s) by which voriconazole may predispose to skin cancer is not clear. Moreover, the relative contribution of voriconazole and other factors such as immunosuppression, ultraviolet exposure, advanced age and skin type is unknown. Until further data are available, voriconazole should be used carefully for durations >6–9 months, particularly among patients with risk factors for skin cancer. In patients requiring prolonged voriconazole, diligent skin examinations, avoidance of excess sunlight, and liberal use of UV protectants are advisable.     

Is There Evidence for Vasculitis in Systemic Sclerosis?

Systemic sclerosis (SSc) is a devastating and potentially life-threatening multi-organ system disease. SSc is marked by skin thickening and tightening, Raynaud??s phenomenon and digital ischemia with ulceration, gastrointestinal dysmotility, cardiopulmonary involvement with pulmonary fibrosis and pulmonary arterial hypertension, as well as renal failure. Fibrosis is the most obvious manifestation of SSc. Vascular involvement and inflammation are other prominent components of SSc pathology, and both features are also seen in vasculitis. This review analyzes whether there is evidence for vasculitis especially with particular organ manifestations and subgroups of patients.     

Is There a Role for Antiplatelet Therapy in Infective Endocarditis? A Review of Current Scientific Evidence

Recently, interest has emerged regarding adjuvant antiplatelet therapy in infective endocarditis (IE) and its impact on clinical outcomes. Despite ongoing research, the role of antiplatelet therapy in this setting remains unclear. Generally, investigations of IE are limited by the low incidence of the disease, practical issues related to diagnosis, and the highly variable latency period between symptom onset and definitive diagnosis. This article reviews the rationale for using antiplatelet therapy in the setting of IE and the contemporary literature that investigates its use.     

Should smallpox vaccine be tested in children?

Following the terrorist attacks on 11 September 2001 there has been increased concern about bioterrorism, much of it focused on smallpox. Routine smallpox vaccination in the USA was discontinued in 1972 and most US citizens are susceptible to smallpox. The last natural case of smallpox occurred in 1978 but the virus has been stocked in freezers. If a terrorist had access to stored smallpox virus a release could produce a chaotic situation. In response the USA has developed a program for vaccinating adults but children have been left out. The only available vaccine has recently been tested in adults but a proposal for testing children was not approved. We need to know if available vaccines are safe for children so children can be safely and effectively vaccinated in an emergency situation.     

Controversies in the treatment of hypercholesterolemia in the elderly: who should be treated and how?

High levels of low-density lipoprotein cholesterol may contribute to the development of coronary heart disease in the absence of other risk factors. This paper reviews major cholesterol prevention trials since 1994 concerning possible beneficial results of lowering cholesterol in persons over 65 years of age.     

Are There Pleiotropic Effects of Antihypertensive Medications or Is It All About the Blood Pressure in the Patient With Diabetes and Hypertension?

Many small studies with varied surrogate end points and numerous preclinical data have suggested the likelihood of there being specific benefits that exceed simple blood pressure control with drug classes such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers, which may be particularly relevant to the patient with diabetes and hypertension. Large clinical trials, however, have provided only token support for this idea. Likewise, meta-analyses that have incorporated varied clinical trials, albeit with somewhat heterogeneous data, have not been particularly forthcoming in their support of this concept. In the patient with diabetes and hypertension, tight blood pressure control, more so than using a specific drug class, is the most important aspect of therapy.