Type 2 diabetes mellitus and the cardiometabolic syndrome: impact of incretin-based therapies

The rates of type 2 diabetes mellitus, obesity, and cardiovascular disease (CVD) continue to increase at epidemic proportions. It has become clear that these disease states are not independent but are frequently interrelated. By addressing conditions such as obesity, insulin resistance, stress hyperglycemia, impaired glucose tolerance, and diabetes mellitus, with its micro- and macrovascular complications, a specific treatment strategy can be developed. These conditions can be addressed by early identification of patients at high risk for type 2 diabetes, prompt and aggressive treatment of their hyperglycemia, recognition of the pleiotropic and synergistic benefits of certain antidiabetes agents on CVD, and thus, avoiding potential complications including hypoglycemia and weight gain. Incretin-based therapies, which include glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-IV (DPP-IV) inhibitors, have the potential to alter the course of type 2 diabetes and associated CVD complications. Advantages of these therapies include glucose-dependent enhancement of insulin secretion, infrequent instances of hypoglycemia, weight loss with GLP-1 receptor agonists, weight maintenance with DPP-IV inhibitors, decreased blood pressure, improvements in dyslipidemia, and potential beneficial effects on CV function

Intravenous immune globulin therapy of immune deficiency disorders

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29098/1/0000134.pd

Intravenous immunoglobulin (IVIG) for the therapy of autoimmune disorders

The weight of evidence from numerous clinical studies supports the use of IVIG, particularly at higher doses, in the treatment of a wide range of autoimmune disorders. Extensive experience has documented the safety of IVIG therapy but its present relatively high cost necessitates firmly establishing its efficacy. There is an acute need to define those disease states where IVIG is indicated and effective. Large-scale, possibly multicentered, clinical trials employing rigorous controls will resolve these questions. Concurrent fundamental immunologic studies will elucidate the mechanisms underlying the clinical effects. We are experiencing an exciting new era of effective immunotherapies and intravenous gamma-globulin preparations have already secured an important place in the therapeutic armamentarium. While one must guard against unsubstantiated applications, critical exploration of new uses for this unique product is warranted.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44840/1/10875_2004_Article_BF00918189.pd

Immunological assays for chemokine detection in in-vitro culture of CNS cells

Herein we review the various methods currently in use for determining the expression of chemokines by CNS cells in vitro. Chemokine detection assays are used in conjuction with one another to provide a comprehensive, biologically relevant assessment of the chemokines which is necessary for correct data interpretation of a specific observed biological effect. The methods described include bioassays for soluble chemokine receptors, RNA extraction, RT-PCR, Real - time quantitative PCR, gene array analysis, northern blot analysis, Ribonuclease Protection assay, Flow cytometry, ELISPOT, western blot analysis, and ELISA. No single method of analysis meets the criteria for a comprehensive, biologically relevant assessment of the chemokines, therefore more than one assay might be necessary for correct data interpretation, a choice that is based on development of a scientific rationale for the method with emphasis on the reliability and relevance of the method

Enhancement of human natural killer cells by interferon requires RNA and protein synthesis

An enriched population of human natural killer (NK) cells was obtained by density gradient centrifugation. The cytotoxic activity of these cells was enhanced by pretreatment with human leukocyte interferon (IF), and the metabolic requirements of this enhancement were examined. Augmentation of NK activity was initiated in a rapid, temperature-independent manner, requiring only a 10- to 15-min exposure to IF, and occurred at either 4 or 37[deg]C. Increased activity of the IF-treated NK effector cells was consistently observed after only 30 min of contact with target cells. Augmentation was inhibited by prior treatment of NK effector cells with actinomycin D (AD), but treatment with AD after 1 hr of IF treatment did not inhibit the IF-mediated increase in cytotoxicity, suggesting that the RNA species required for enhancement are synthesized within 1 hr of cell-IF interaction. Protein synthesis was required for at least 1 hr following cell-IF interaction, as shown by the ability of emetine and puromycin treatments to abrogate increased NK cell activity. Binding of IF to cells was independent of protein synthesis. IF-induced enhancement was unaffected by incubation of effector cells with mitomycin C either before or after IF treatment, indicating that IF acts primarily upon a population of preexisting cells of lower NK activity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23787/1/0000025.pd

Modulation of a human immunosuppressive lymphokine by monosaccharides

Soluble suppressor factor (SSF) is a recently purified human lymphokine produced by peripheral blood lymphocytes (PBL) in serum-free medium as a likely consequence of an autologous mixed lymphocyte reaction. Immunoregulatory actions of SSF include suppression of: polyclonal B cell activation, proliferative responses of normal PBL, and natural killer (NK) and antibody-dependent cellular cytotoxicity. We examined the ability of the monosaccharides fucose (Fuc), galactose (Gal), glucose (Glc), and mannose (Man) to reverse SSF-mediated suppression of NK activity. Fuc and Gal can partially or completely reverse SSF-mediated suppression at four effector:target cell ratios. Man and Glc were unable to significantly reverse SSF-mediated suppression. Fuc or Gal was added to PBL at various times after addition of SSF. SSF-mediated suppression of NK cytotoxicity becomes irreversible with respect to these monosaccharides during the first 24 hr of PBL exposure to SSF. To explore the mechanism behind this block of SSF-mediated suppression, Fuc or Gal (50 mM) was cultured with PBL for 24 hr before addition of SSF, or with SSF for 24 hr before addition to PBL. Our experiments indicate that SSF is directly interacting with these monosaccharides, and may function by recognizing specific sugar moieties on the surface of effector cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29181/1/0000234.pd

Reply to Dr. Goodwin

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23228/1/0000161.pd

Association of decreased T-cell-mediated natural cytotoxicity and interferon production in Down's Syndrome

Total peripheral blood lymphocytes (PBL) and isolated subpopulations from children with Down's Syndrome (DS) and age-matched healthy controls were investigated for their (1) natural killer (NK) and antibody-dependent cellular cytotoxic activities, (2) interleukin 2 (IL-2)-induced augmentation of NK activity, (3) lectin-dependent cellular cytotoxicity (LDCC), (4) ability of serum- and culture-derived soluble suppressor factor(s) to inhibit NK activity of normal lymphocytes, and (5) capacity to produce interferon (IFN) against tumor targets in vitro. T lymphocytes from DS patients demonstrated significantly decreased NK activity against K562 target cells compared to controls. DS lymphocytes also demonstrated a significant reduction in LDCC activity and IL-2-induced enhancement of NK activity. Furthermore, the ability of DS lymphocytes to produce IFN in vitro against K562 target cells was also significantly lower than that for normal PBL. Although sera from DS patients showed a significantly greater inhibitory effect on the NK activity of allogeneic normal PBL than normal sera, culture supernates from DS lymphocytes demonstrated suppressive effects comparable to culture supernates from normal PBL. These studies suggest an association between the decreased NK activity of T-cell subpopulations and lower IFN production by PBL from patients with DS.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24622/1/0000032.pd