The condition of oxidative stress arises when oxidant production exceeds antioxidant activity in cells and plasma. The overabundance of oxidants is mechanistically connected with the multifactorial etiology of insulin resistance, primarily in skeletal muscle tissue, and the subsequent development of type 2 diabetes. Two important mechanisms for this oxidant excess are 1) the mitochondrial overproduction of hydrogen peroxide and superoxide ion in conditions of energy surplus and 2) the enhanced activation of cellular NADPH oxidase via angiotensin II (AT1) receptors. Several recent studies are reviewed that support the concept that direct exposure of mammalian skeletal muscle to an oxidant stress (including hydrogen peroxide) results in stimulation of the serine kinase p38 mitogen-activated protein kinase (p38 MAPK), and that the engagement of this stress-activated p38 MAPK signaling is mechanistically associated with diminished insulin-dependent stimulation of insulin signaling elements and glucose transport activity. The beneficial interactions between the antioxidant α-lipoic acid and the advanced glycation end product inhibitor pyridoxamine to ameliorate oxidant stress-associated defects in whole-body and skeletal muscle insulin action in the obese Zucker rat, a model of pre-diabetes, are also addressed. Overall, this review highlights the importance of oxidative stress in the development of insulin resistance in mammalian skeletal muscle tissue, at least in part via a p38 MAPK-dependent mechanism, and indicates that interventions that reduce this oxidative stress and oxidative damage can improve insulin action in insulin-resistant animal models. Strategies to prevent and ameliorate oxidative stress remain important in the overall treatment of insulin resistance and type 2 diabetes.

The majority of penile carcinoma is squamous cell carcinoma. Although uncommon in the United States, it represents a larger proportion of cancers in the underdeveloped world. Invasive squamous cell carcinoma may arise from precursor lesions or de novo , and has been associated with lack of circumcision and HPV infection. Early diagnosis is imperative as lymphatic spread is associated with a poor prognosis. Radical surgical treatment is no longer the mainstay, and penile sparing treatments now are often used, including Mohs micrographic surgery. Therapeutic decisions should be made with regard to the size and location of the tumor, as well as the functional desires of the patient. It is critical for the dermatologist to be familiar with the evaluation, grading/staging, and treatment advances of penile squamous cell carcinoma. Herein, we present a review of the literature regarding penile squamous cell carcinoma, as well as a case report of invasive squamous cell carcinoma treated with Mohs micrographic surgery.

Increased cellular exposure to oxidants may contribute to the development of insulin resistance and type 2 diabetes. Skeletal muscle is the primary site of insulin-dependent glucose disposal in the body; however, the effects of oxidative stress on insulin signaling and glucose transport activity in mammalian skeletal muscle are not well understood. We therefore studied the effects of a low-level in vitro oxidant stress (30-40 μM H 2 O 2 ) on basal and insulin-stimulated (5 mU/ml) glucose transport activity and insulin signaling at 2, 4, and 6 hr in isolated rat soleus muscle. H 2 O 2 increased basal glucose transport activity at 2 and 4 hr, but not at 6 hr. This lowlevel oxidant stress significantly impaired insulin-stimulated glucose transport activity at all time points, and was associated with inhibition of insulin-stimulated phosphorylation of Akt Ser 473 and GSK-3β Ser 9 . In the presence of insulin, H 2 O 2 decreased total protein expression of IRS-1 at 6 hr and IRS-2 at 4 and 6 hr. Phosphorylation of p38 MAPK Thr 180 /Tyr 182 was transiently increased by H 2 O 2 in the presence and absence of insulin at 2 and 4 hr, but not at 6 hr. Selective inhibition of p38 MAPK with A304000 partially rescued the H 2 O 2 -induced reduction in insulin-stimulated glucose transport activity. These results indicate that direct in vitro exposure of isolated mammalian skeletal muscle to a low-level oxidant stress impairs distal insulin signaling and insulin-stimulated glucose transport activity, at least in part, due to a p38 MAPK-dependent mechanism.

We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker (fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser(473) phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the strategy of targeting the RAS to improve both blood pressure regulation and insulin action in conditions of insulin resistance.

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