Platelet-activating factor (PAF) is a potent pro-inflammatory autacoid with diverse physiological and pathological actions. These actions are modulated by PAF acetylhydrolase, which hydrolyzes the sn-2 ester bond to yield the biologically inactive lyso-PAF. In contrast to most secreted phospholipase A 2 s, plasma PAF acetylhydrolase is calcium-independent and contains a GXSXG motif that is characteristic of the neutral lipases and serine esterases. In this study we tested whether the serine in this motif is part of the active site of plasma PAF acetylhydrolase and, if so, what the other components of the active site are. Using site-directed mutagenesis, we demonstrated that Ser-273 (of the GXSXG motif), Asp-296, and His-351 are essential for catalysis. These residues were conserved in PAF acetylhydrolase sequences isolated from bovine, dog, mouse, and chicken. The linear orientation and spacing of these catalytic residues are consistent with the ␣/␤ hydrolase conformation of other lipases and esterases. In support of this model, analysis of systematic truncations of PAF acetylhydrolase revealed that deletions beyond 54 amino acids from the NH 2 terminus and 21 from the COOH terminus resulted in a loss of enzyme activity. These observations demonstrate that although plasma PAF acetylhydrolase is a phospholipase A 2 it has structural properties characteristic of the neutral lipases and esterases.

automated insulin dosing continuous glucose monitoring continuous subcutaneous insulin infusion diabetes diabetes technology glucose sensors hybrid closed loop insulin pumps sensor-augmented pump low-glucose suspend predictive low-glucose suspend a b s t r a c t Objective: To provide evidence-based recommendations regarding the use of advanced technology in the management of persons with diabetes mellitus to clinicians, diabetes-care teams, health care professionals, and other stakeholders. Methods: The American Association of Clinical Endocrinology (AACE) conducted literature searches for relevant articles published from 2012 to 2021. A task force of medical experts developed evidence-based guideline recommendations based on a review of clinical evidence, expertise, and informal consensus, according to established AACE protocol for guideline development. Main Outcome Measures: Primary outcomes of interest included hemoglobin A1C, rates and severity of hypoglycemia, time in range, time above range, and time below range. Results: This guideline includes 37 evidence-based clinical practice recommendations for advanced diabetes technology and contains 357 citations that inform the evidence base.Recommendations: Evidence-based recommendations were developed regarding the efficacy and safety of devices for the management of persons with diabetes mellitus, metrics used to aide with the assessment of advanced diabetes technology, and standards for the implementation of this technology. Conclusions: Advanced diabetes technology can assist persons with diabetes to safely and effectively achieve glycemic targets, improve quality of life, add greater convenience, potentially reduce burden of Disclaimer: The American Association of Clinical Endocrinology medical guidelines for clinical practice are systematically developed statements to assist health care professionals in medical decision-making for specific clinical conditions. Most of the content herein is based on clinical evidence. In areas of uncertainty, or when clarification is required, expert opinion and professional judgment were applied.This guideline is a working document that reflects the state of the field at the time of publication. Because rapid changes are expected in this area, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made considering local resources and individual patient circumstances.

Studies have shown that effective diabetes management can delay or prevent the micro- and macrovascular complications of diabetes. Achieving optimal glycemic control often requires treatment with intensive insulin management. However, with intensive insulin management comes the risk of severe hypoglycemia. Hypoglycemia requiring emergency medical assistance is as common in patients with longstanding insulin-treated type 2 diabetes mellitus as in patients with type 1 diabetes mellitus, and is associated with a significant economic and personal burden; untreated, severe hypoglycemia can result in morbidity and death. Key contributors to severe hypoglycemia are asymptomatic hypoglycemia and nocturnal hypoglycemia; both conditions inhibit patients' ability to recognize hypoglycemia when it is occurring and take appropriate action. As a result, many patients with types 1 and 2 diabetes mellitus are reluctant to follow and/or adjust their insulin regimens as needed because of fear of hypoglycemia, resulting in exposure to chronic hyperglycemia, oxidative stress, and long-term complications. Severe hypoglycemia can be prevented through vigilance in identifying patients at risk, utilizing appropriate medications and medication regimens, and effective glucose monitoring strategies and technologies. The purpose of this article is to review our current understanding of hypoglycemia and its impact on diabetes management, and to provide guidance to health care providers when assisting patients who utilize insulin therapy to do so safely and effectively.

Clinicians and patients are rapidly adapting GLP-1 receptor agonists as efficacious and safe therapeutic options for managing type 2 diabetes (T2DM). GLP-1 receptor agonists stimulate insulin production and secretion from the pancreatic β cells in a glucose-dependent manner, improve gastric emptying, favor weight reduction, and reduce postabsorptive glucagon secretion from pancreatic α cells. GLP-1 receptor activity is impaired in patients with T2DM. GLP-1 secretion and subsequent physiologic actions in patients with type 1 diabetes (T1DM) is ill-defined. Some researchers have suggested that the use of GLP-1 receptor agonists in T1DM may reduce excessive postprandial glucagon secretion allowing patients to reduce their total daily dose of exogenous insulin. Hypoglycemia risk may also be minimized in T1DM as glucagon counter-regulation can be preserved to some degree via the glucose-dependent action of the GLP-1 receptor agonists. This paper will consider the physiologic and pharmacologic benefits of adding GLP-1 receptor agonists to therapeutic regimens of patients with T1DM.

Type 2 diabetes mellitus is a complicated metabolic disease affecting millions of individuals worldwide. The medications used to manage the disease are based on different pharmacologic approaches, including decreasing hepatic gluconeogenesis, stimulating pancreatic insulin production, slowing polysaccharide digestion, and increasing insulin sensitivity in muscle, liver, and fat to lower blood glucose. Incretin-based therapies, including glucagon-like peptide-1 (GLP-1) receptor agonists, mimic the effects of native GLP-1, while dipeptidyl peptidase-4 inhibitors increase circulating concentrations of endogenous GLP-1. This review focuses on means by which primary care physicians might evaluate the utility of pharmacologic agents based on their relation to the pathogenesis of type 2 diabetes. In general, patients with type 2 diabetes should be treated to their lowest targeted glycemic goals as soon as they are diagnosed, for as long as possible, as safely as possible, and as rationally as possible.