Monocytes rolling on the endothelial cell layer interact with monocyte chemoattractant protein-1 (MCP-1) that is tethered to the proteoglycans on the luminal side of the endothelial cells and consequently initiate adhesion of monocytes in the early phase of immune response. The amino acid residues in MCP-1 involved in tethering to the proteoglycans have not been elucidated. MCP-1 showed binding to [3 H]heparin with a K D of 1.5 M. We substituted lysine or histidine residues at the C-terminal end of MCP-1 with alanine residues and tested these mutants for their ability to bind heparin, heparan sulfate, hyaluronic acid, and chondroitin sulfate-C. Substitution of Lys-58 or His-66 drastically reduced glycosaminoglycan binding. Substitution of Lys-56 or deletion of the five amino acid residues at the C terminus, including Lys-75, did not alter the heparin binding ability, suggesting that the other lysine residues at the C terminus are not involved in glycosaminoglycan binding. MCP-1 and its mutants did not bind hyaluronic acid as strongly as the other subunits of the GAGs. Substitution of Lys-58 or His-66 by alanine that prevented glycosaminoglycan binding did not affect Ca 2؉ influx, receptor binding, or chemotactic activity elicited by the chemokine on monocytic THP-1 cells. Therefore, we conclude that the Lys-58 and His-66 residues in the C-terminal ␣-helix of MCP-1 are essential for glycosaminoglycan binding and probably for the binding to the endothelial surface proteoglycans.
Nocturnal hypoglycemia is common in aggressively treated type 1 diabetes. Bedtime administration of a conventional snack or of uncooked cornstarch does not prevent it. That of terbutaline prevents nocturnal hypoglycemia but causes hyperglycemia the following morning. The efficacy of a lower dose of terbutaline remains to be determined.
OBJECTIVE -Bedtime administration of 5.0 mg of the  2 -adrenergic agonist terbutaline prevents nocturnal hypoglycemia but causes morning hyperglycemia in type 1 diabetes. We tested the hypothesis that 2.5 mg terbutaline prevents nocturnal hypoglycemia without causing morning hyperglycemia.RESEARCH DESIGN AND METHODS -This was a randomized double-blind crossover pilot study (placebo, 2.5 mg terbutaline, and 5.0 mg terbutaline) in 15 patients with type 1 diabetes.RESULTS -Mean Ϯ SE nadir nocturnal plasma glucose concentrations were 87 Ϯ 14 mg/dl following placebo, 100 Ϯ 14 mg/dl following 2.5 mg terbutaline, and 122 Ϯ 13 mg/dl following 5.0 mg terbutaline (P Ͻ 0.05 vs. placebo). Nadir levels were Ͻ50 mg/dl in 5, 2, and 0 patients (P Ͻ 0.05 vs. placebo), respectively. Morning levels were 113 Ϯ 18, 127 Ϯ 17, and 183 Ϯ 19 mg/dl (P Ͻ 0.02 vs. placebo), respectively. CONCLUSIONS -Terbutaline may be shown to be effective and safe in the prevention of nocturnal hypoglycemia in type 1 diabetes in a suitably powered randomized controlled trial. Diabetes Care 31:2271-2272, 2008I atrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes (1). Most episodes of hypoglycemia occur at night, specifically during sleep, in type 1 diabetes-a finding in the Diabetes Control and Complications Trial (2) that continues to be documented (3,4). Sympathoadrenal responses to hypoglycemia are reduced further during sleep (5,6), and, probably because of their markedly reduced sympathoadrenal responses, patients with type 1 diabetes are substantially less likely to be awakened by hypoglycemia than nondiabetic individuals (6,7).Among the approaches to the prevention of nocturnal hypoglycemia in type 1 diabetes, we found bedtime administration of a conventional snack, uncooked cornstarch, or an ␣-glucosidase inhibitor to be ineffective (3). In contrast, bedtime administration of the epinephrinesimulating  2 -adrenergic agonist terbutaline in a dose of 5.0 mg prevented nocturnal hypoglycemia (3). However, it also caused hyperglycemia the following morning. Therefore, we used a randomized double-blind crossover design (placebo, 2.5 mg terbutaline, and 5.0 mg terbutaline) in a pilot study to test the hypothesis that bedtime administration of 2.5 mg terbutaline prevents nocturnal hypoglycemia without causing morning hypoglycemia in patients with aggressively treated type 1 diabetes. RESEARCH DESIGN ANDMETHODS -Fifteen patients (seven women) with type 1 diabetes gave their written consent to participate in this study, which was approved by the Washington University Human Research Protection Office and conducted at the institution's General Clinical Research Center. Mean Ϯ SD age was 28.6 Ϯ 7.5 years, BMI 29.3 Ϯ 5.6 kg/m 2 , duration of type 1 diabetes 14.9 Ϯ 7.0 years, and A1C 7.1 Ϯ 0.5%. Subjects were selected for an A1C Յ8.0% and the absence of diabetes complications or use of a potentially interfering medication. Nine subjects were using continuous subcutaneous insulin infusion with insulin analogs, and six were using ...
Conclusions drawn from the pancreatic (or islet) clamp technique (suppression of endogenous insulin, glucagon, and growth hormone secretion with somatostatin and replacement of basal hormone levels by intravenous infusion) are critically dependent on the biological appropriateness of the selected doses of the replaced hormones. To assess the appropriateness of representative doses we infused saline alone, insulin (initially 0.20 mU.kg(-1).min(-1)) alone, glucagon (1.0 ng.kg(-1).min(-1)) alone, and growth hormone (3.0 ng.kg(-1).min(-1)) alone intravenously for 4 h in 13 healthy individuals. That dose of insulin raised plasma insulin concentrations approximately threefold, suppressed glucose production, and drove plasma glucose concentrations down to subphysiological levels (65 +/- 3 mg/dl, P < 0.0001 vs. saline), resulting in nearly complete suppression of insulin secretion (P < 0.0001) and stimulation of glucagon (P = 0.0059) and epinephrine (P = 0.0009) secretion. An insulin dose of 0.15 mU.kg(-1).min(-1) caused similar effects, but a dose of 0.10 mU.kg(-1).min(-1) did not. The glucagon and growth hormone infusions did not alter plasma glucose levels or those of glucoregulatory factors. Thus, insulin "replacement" doses of 0.20 and even 0.15 mU.kg(-1).min(-1) are excessive, and conclusions drawn from the pancreatic clamp technique using such doses may need to be reassessed.
A 59-year old man, who had a hypertensive crisis during transsphenoidal surgery for a pituitary macroadenoma, was subsequently found to have an adrenal pheochromocytoma. A total of twenty-five cases describing the coexistence of a pituitary adenoma and pheochromocytoma have been reported in the literature over the past 40 years. Among pituitary tumors, acromegaly has been the most common. In an effort to identify the relationship between the two tumors, multiple theories have been suggested including fortuitous association, overlap or variants of MEN syndromes, and ectopic production of a trophic hormone by the pheochromocytoma. The high risk of mortality and morbidity associated with undiagnosed pheochromocytoma warrants careful attention to the possibility of such a coexistence.
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