Many patients with diabetes mellitus (both type 1 and type 2) require therapy to maintain normal fasting glucose levels. To develop a novel treatment for these individuals, we used phage display technology to target the insulin receptor (INSR) complexed with insulin and identified a high affinity, allosteric, human monoclonal antibody, XMetA, which mimicked the glucoregulatory, but not the mitogenic, actions of insulin. Biophysical studies with cultured cells expressing human INSR demonstrated that XMetA acted allosterically and did not compete with insulin for binding to its receptor. XMetA was found to function as a specific partial agonist of INSR, eliciting tyrosine phosphorylation of INSR but not the IGF-IR. Although this antibody activated metabolic signaling, leading to enhanced glucose uptake, it neither activated Erk nor induced proliferation of cancer cells. In an insulin resistant, insulinopenic model of diabetes, XMetA markedly reduced elevated fasting blood glucose and normalized glucose tolerance. After 6 weeks, significant improvements in HbA1c, dyslipidemia, and other manifestations of diabetes were observed. It is noteworthy that hypoglycemia and weight gain were not observed during these studies. These studies indicate, therefore, that allosteric monoclonal antibodies have the potential to be novel, ultra-long acting, agents for the regulation of hyperglycemia in diabetes.

[1] We used a new, 100-year, 1 Â 1°global fire map and a carbon cycle model (CASA) to provide a yearly gridded estimate of the temporal trend in carbon emissions due to wildfires through the 20th century. 2700-3325 Tg C y À1 burn at the end of the 20th century, compared to 1500 -2700 Tg C y À1 at the beginning, with increasing uncertainty moving backward in time. There have been major changes in the regional distribution of emissions from fires, as a consequence of i) increased burning in tropical savannas and ii) a switch of emissions from temperate and boreal forests towards the tropics. The frequently-used assumption that pre-industrial emissions were 10% of present biomass burning is clearly inadequate, in terms of both the total amount and the spatial distribution of combustion.

LDL receptor-null (LDLR 2/2 ) mice on a Western diet (WD) develop endothelial dysfunction and atherosclerosis, which are improved by the apolipoprotein A-I (apoA-I) mimetic peptide D-4F. Focusing on the kidney, LDLR 2/2 mice were fed a WD with D-4F or the inactive control peptide scrambled D-4F (ScD-4F) added to their drinking water. The control mice (ScD-4F) developed glomerular changes, increased immunostaining for MCP-1/CCL2 chemokine, increased macrophage CD68 and F4/80 antigens, and increased oxidized phospholipids recognized by the EO6 monoclonal antibody in both glomerular and tublointerstitial areas. All of these parameters were significantly reduced by D-4F treatment, approaching levels found in wildtype C57BL/6J or LDLR 2/2 mice fed a chow diet. Sterolregulatory element binding protein-1c (SREBP-1c) mRNA levels and triglyceride levels were elevated in the kidneys of the control mice (ScD-4F) fed the WD compared with C57BL/6J and LDLR 2/2 mice on chow (P , 0.001 and P , 0.001, respectively) and compared with D-4F-treated mice on the WD (P , 0.01). There was no significant difference in plasma lipids, lipoproteins, glucose, blood pressure, or renal apoB levels between D-4F-and ScD-4F-treated mice. We conclude that D-4F reduced renal oxidized phospholipids, resulting in lower expression of SREBP-1c, which, in turn, resulted in lower triglyceride content and reduced renal inflammation. ) mice has been shown to induce atherosclerosis, endothelial dysfunction, and inflammation of brain arterioles associated with cognitive dysfunction, all of which have been reported to be significantly ameliorated by treatment with the oral apolipoprotein A-I (apoA-I) mimetic peptide D-4F without a change in plasma lipid levels or blood pressure (1-3).In addition to hyperlipidemia, feeding a WD to LDLR 2/2 mice results in insulin resistance and elevated plasma glucose levels (4, 5). A major problem facing Western societies is an increase in chronic renal disease that appears to be associated with dyslipidemia and diabetes in addition to hypertension (6). Dyslipidemia has been emphasized as a factor that can exacerbate hypertension-induced renal damage as well as a factor that by itself may have adverse effects on the kidney (6). Diet-induced obesity in C57BL/6J mice has been reported to cause lipid accumulation in kidneys and glomerulosclerosis via a sterol-regulatory element binding protein 1c (SREBP-1c)-dependent pathway (7). Oxidized phospholipids have been identified as potent mediators of inflammation (8,9). Berliner and colleagues have reported that oxidized phospholipids induce cytokine production in endothelial cells through induction of SREBP (10) via an endothelial nitric oxide synthase (eNOS)-mediated mechanism (11).Pritchard and colleagues reported that the apoA-I mimetic peptide L-4F (identical to D-4F except that the peptide is synthesized from L-amino acids) restored the balance between nitric oxide and superoxide anion production by eNOS in LDL-treated endothelial cells in culture (12). Injection of ...

XMetA, a high-affinity, fully human monoclonal antibody, allosterically binds to and activates the insulin receptor (INSR). Previously, we found that XMetA normalized fasting glucose and glucose tolerance in insulinopenic mice. To determine whether XMetA is also beneficial for reducing hyperglycaemia due to the insulin resistance of obesity, we have now evaluated XMetA in hyperinsulinemic mice with diet-induced obesity. XMetA treatment of these mice normalized fasting glucose for 4 weeks without contributing to weight gain. XMetA also corrected glucose tolerance and improved non-high density lipoprotein cholesterol. These studies indicate, therefore, that monoclonal antibodies that allosterically activate the INSR, such as XMetA, have the potential to be novel agents for the treatment of hyperglycaemia in conditions associated with the insulin resistance of obesity.

Objective-The role of myeloid cell cyclooxygenase-2 (COX-2) in the progression of atherosclerosis has not been clearly defined. Methods and Results-We investigated the role of COX-2 expressed in the myeloid lineage in the development of atherosclerosis using a myeloid-specific COX-2