Biomedical subjects

Peter A Gottlieb

Publications and source records attributed to Peter A Gottlieb.

23 records · Page 2Linked to original sources

PubMed2002

Cytokine and immunosuppressive therapies of type 1 diabetes mellitus.

In this article, the authors covered a number of issues that affect how researchers approach prevention of diabetes. The focus has been the use of cytokines and immunosuppressive therapies. The historical understanding of cytokine and immunosuppressive approaches, new developments in using these agents in humans, and the issues involved in designing diabetes prevention trials were reviewed. Although progress at times appears slow, the current research activities predict new developments in the next few years that may improve the understanding of the progression of diabetes and possible ways to intervene.

Animals↗

PubMed2002

Testing the NKT cell hypothesis of human IDDM pathogenesis.

Defects in IL-4-producing CD1d-autoreactive NKT cells have been implicated in numerous Th1-mediated autoimmune diseases, including diabetes, multiple sclerosis, rheumatoid arthritis, lupus, and systemic sclerosis. Particular attention has been focused on autoimmune insulin-dependent diabetes mellitus (IDDM) because nonobese diabetic (NOD) mice and humans with IDDM are both reported to express severe deficiencies in the frequency and Th2 functions of NKT cells. Furthermore, experimental manipulations of the NKT defect in the NOD mouse induced corresponding changes in disease. Taken together, these converging studies suggested a general role of NKT cells in natural protection against destructive autoimmunity. However, in previous reports the identification of NKT cells was based on indirect methods. We have now devised a direct, highly specific CD1d tetramer-based methodology to test whether humans with IDDM have associated NKT cell defects. Surprisingly, although we find marked and stable differences in NKT cells between individuals, our study of IDDM patients and healthy controls, including discordant twin pairs, demonstrates that NKT cell frequency and IL-4 production are conserved during the course of IDDM. These results contradict previous conclusions and refute the hypothesis that NKT cell defects underlie most autoimmune diseases.

Adolescent↗

PubMed2002

Optimizing insulin therapy in pregnant women with type 1 diabetes mellitus.

Pregnancy complicated by type 1 diabetes mellitus is associated with an increased risk of complications in the mother and infant. Normal or near normal glycemic control prior to and during pregnancy reduces many of these risks to levels observed in the general population. This degree of glycemic control is generally achievable only with intensive insulin therapy: multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) via an insulin pump. These therapeutic regimens have been found to result in comparable glycemic control, although CSII provides increased flexibility in terms of patient lifestyle, and may reduce the incidence of hypoglycemia. Frequent home blood glucose monitoring is imperative during pregnancy in order to optimize glycemic control and reduce the risk of hypoglycemia. Furthermore, insulin requirements change significantly over the course of pregnancy. The new short-acting insulin analogs, insulin lispro and insulin aspart, have pharmacodynamic properties which make them ideal for use during pregnancy. Although the number of published studies evaluating the use of insulin lispro during pregnancy is limited, the majority support its safety. No studies of insulin aspart in pregnancy have been published in full. In addition to optimization of glycemic control, frequent assessment for development and/or progression of microvascular complications is necessary during pregnancy.

Diabetes Mellitus, Type 1↗

PubMed2002

Immunological characterization and therapeutic activity of an altered-peptide ligand, NBI-6024, based on the immunodominant type 1 diabetes autoantigen insulin B-chain (9-23) peptide.

The nonobese diabetic (NOD) mouse is a good model for human type 1 diabetes, which is characterized by autoreactive T-cell-mediated destruction of insulin-producing islet beta-cells of the pancreas. The 9-23 amino acid region of the insulin B-chain [B((9-23))] is an immunodominant T-cell target antigen in the NOD mouse that plays a critical role in the disease process. By testing a series of B((9-23)) peptide analogs with single or double alanine substitutions, we identified a set of altered peptide ligands (APLs) capable of inhibiting B((9-23))-induced proliferative responses of NOD pathogenic T-cell clones. These APLs were unable to induce proliferation of these clones. However, vaccinations with the APLs induced strong cellular responses, as measured by in vitro lymphocyte proliferation and Th2 cytokine production (i.e., interleukin [IL]-4 and IL-10, but not gamma-interferon [IFN-gamma]). These responses were cross-reactive with the native antigen, B((9-23)), suggesting that the APL-induced Th2 responses may provide protection by controlling endogenous B((9-23))-specific Th1 (i.e., IFN-gamma-producing) pathogenic responses. One of these APLs that contained alanine substitutions at residues 16 and 19 (16Y-->A, 19C-->A; NBI-6024) was further characterized for its therapeutic activity because it consistently induced T-cell responses (e.g., T-cell lines and clones) that were of the Th2 type and that were cross-reactive with B((9-23)). Subcutaneous injections of NBI-6024 to NOD mice administered either before or after the onset of disease substantially delayed the onset and reduced the incidence of diabetes. This study is the first to report therapeutic activity of an APL derived from an islet beta-cell-specific antigen in type 1 diabetes.

Amino Acid Substitution↗

PubMedDate not supplied

Insulin lispro therapy in pregnancies complicated by type 1 diabetes: glycemic control and maternal and fetal outcomes.

OBJECTIVE: To evaluate glycemic control and maternal and fetal outcomes of patients with type 1 diabetes treated with insulin lispro before and during pregnancy. METHODS: We undertook a retrospective review of medical records of 62 women with type 1 diabetes who were treated with insulin lispro before and during pregnancy in an outpatient center specializing in the care of patients with diabetes. Outcome measures included maternal glycemic control, hypoglycemic episodes, microvascular complications, duration of gestation, fetal birth weight, and major congenital malformations. RESULTS: The mean hemoglobin A1c level (+/- standard error) was reduced from 7.2 +/- 0.2% at conception to 5.8 +/- 0.1% at the time of delivery. Of the 62 patients, 14 experienced at least one episode of severe hypoglycemia. No significant change was found in mean eye grade score for retinopathy or in albumin excretion rate during pregnancy. The mean duration of gestation was 37 weeks. The mean infant birth weight was 3.4 kg, with 24% of the pregnancies resulting in macrosomia. Major congenital malformations occurred in 2 of the 62 infants (3.2%). CONCLUSION: In our experience, insulin lispro therapy during pregnancy in patients with type 1 diabetes resulted in normalization of glycemic control and had no detectable adverse effects on maternal or fetal outcomes. A prospective, randomized study with adequate sample size needs to be performed in order to confirm these conclusions.

Adult↗