An adrenal incidentaloma is now established as a common endocrine diagnosis that requires a multidisciplinary approach for effective management. The majority of patients can be reassured and discharged, but a personalized approach based upon image analysis, endocrine workup and clinical symptoms and signs are required in every case. ACC remains a real concern but is restricted to <2% of all cases. Functional AI lesions are commoner (but still probably <10% of total) and the greatest challenge remains the diagnosis and optimum management of autonomous cortisol secretion. Modern-day surgery has improved outcomes and novel radiological and urinary biomarkers will improve early detection and patient stratification in future years to come.

OBJECTIVEIn mice, haploinsufficiency of the IGF-1 receptor (IGF-1R+/−), at a whole-body level, increases resistance to inflammation and oxidative stress, but the underlying mechanisms are unclear. We hypothesized that by forming insulin-resistant heterodimers composed of one IGF-1Rαβ and one insulin receptor (IR), IRαβ complex in endothelial cells (ECs), IGF-1R reduces free IR, which reduces EC insulin sensitivity and generation of the antioxidant/anti-inflammatory signaling radical nitric oxide (NO).RESEARCH DESIGN AND METHODSUsing a number of complementary gene-modified mice with reduced IGF-1R at a whole-body level and specifically in EC, and complementary studies in EC in vitro, we examined the effect of changing IGF-1R/IR stoichiometry on EC insulin sensitivity and NO bioavailability.RESULTSIGF-1R+/− mice had enhanced insulin-mediated glucose lowering. Aortas from these mice were hypocontractile to phenylephrine (PE) and had increased basal NO generation and augmented insulin-mediated NO release from EC. To dissect EC from whole-body effects we generated mice with EC-specific knockdown of IGF-1R. Aortas from these mice were also hypocontractile to PE and had increased basal NO generation. Whole-body and EC deletion of IGF-1R reduced hybrid receptor formation. By reducing IGF-1R in IR-haploinsufficient mice we reduced hybrid formation, restored insulin-mediated vasorelaxation in aorta, and insulin stimulated NO release in EC. Complementary studies in human umbilical vein EC in which IGF-1R was reduced using siRNA confirmed that reducing IGF-1R has favorable effects on NO bioavailability and EC insulin sensitivity.CONCLUSIONSThese data demonstrate that IGF-1R is a critical negative regulator of insulin sensitivity and NO bioavailability in the endothelium.

Low concentrations of insulin-like growth factor (IGF) binding protein-1 (IGFBP1) are associated with insulin resistance, diabetes, and cardiovascular disease. We investigated whether increasing IGFBP1 levels can prevent the development of these disorders. Metabolic and vascular phenotype were examined in response to human IGFBP1 overexpression in mice with diet-induced obesity, mice heterozygous for deletion of insulin receptors (IR+/−), and ApoE−/− mice. Direct effects of human (h)IGFBP1 on nitric oxide (NO) generation and cellular signaling were studied in isolated vessels and in human endothelial cells. IGFBP1 circulating levels were markedly suppressed in dietary-induced obese mice. Overexpression of hIGFBP1 in obese mice reduced blood pressure, improved insulin sensitivity, and increased insulin-stimulated NO generation. In nonobese IR+/− mice, overexpression of hIGFBP1 reduced blood pressure and improved insulin-stimulated NO generation. hIGFBP1 induced vasodilatation independently of IGF and increased endothelial NO synthase (eNOS) activity in arterial segments ex vivo, while in endothelial cells, hIGFBP1 increased eNOS Ser1177 phosphorylation via phosphatidylinositol 3-kinase signaling. Finally, in ApoE−/− mice, overexpression of hIGFBP1 reduced atherosclerosis. These favorable effects of hIGFBP1 on insulin sensitivity, blood pressure, NO production, and atherosclerosis suggest that increasing IGFBP1 concentration may be a novel approach to prevent cardiovascular disease in the setting of insulin resistance and diabetes.

ObjectivesCharacterize patients with diabetes with severe hypoglycemia requiring emergency services intervention at home and investigate 12-month mortality.Research design and methodsEmergency services call-outs for hypoglycemia were recorded between 2005 and 2013 in an area covering 34 000 patients with diabetes. Patient characteristics were documented together with capillary blood glucose (CBG), glycated hemoglobin (HbA1c), and treatment for hypoglycemia; 12-month mortality and variables influencing survival were analyzed.ResultsIn 1835 episodes among 1156 patients, 45% had type 1 diabetes (68.2% males) and 44% had type 2 diabetes (49.4% males), with a minority unclassified. CBG at presentation (mean±SD) was 1.76±0.72 mmol/L in patients with type 1 diabetes and 1.96±0.68 mmol/L in patients with type 2 diabetes (p<0.0001), with a higher HbA1c in the former group (8.3±1.52% (67.5±16.4 mmol/mol) and 7.8±1.74% (61.6±19.0 mmol/mol), respectively; p<0.0001). A third of patients with type 2 diabetes were not on insulin therapy and displayed lower HbA1c compared with insulin users. Glucagon was used in 37% of patients with type 1 diabetes and 28% of patients with type 2 diabetes (p<0.0001). One-year mortality was 4.45% in type 1 diabetes and 22.1% in type 2 diabetes. Age and type of diabetes were predictive of mortality in multivariable analysis, whereas CBG levels/frequency of hypoglycemia had no effect.ConclusionsSevere hypoglycemia in the community is common with a male predominance in type 1 diabetes. Severe hypoglycemia in non-insulin treated patients with type 2 diabetes is associated with lower HbA1c compared with insulin users. Severe hypoglycemia appears to be associated with increased mortality at 12 months, particularly in type 2 diabetes.

Objective-Circulating progenitor cells (CPC) have emerged as potential mediators of vascular repair. In experimental models, CPC mobilization is critically dependent on nitric oxide (NO