The emergence of the glucoregulatory hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide has expanded our understanding of glucose homeostasis. In particular, the glucoregulatory actions of the incretin hormone GLP-1 include enhancement of glucosedependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. Two approaches have been developed to overcome rapid degradation of GLP-1. One is the use of agents that mimic the enhancement of glucose-dependent insulin secretion, and potentially other antihyperglycemic actions of incretins, and the other is the use of dipeptidyl peptidase-IV inhibitors, which reduce the inactivation of GLP-1, increasing the concentration of endogenous GLP-1. The development of incretin mimetics and dipeptidyl peptidase-IV inhibitors opens the door to a new generation of antihyperglycemic agents to treat several otherwise unaddressed pathophysiologic defects of type 2 diabetes mellitus. We review the physiology of glucose homeostasis, emphasizing the role of GLP-1, the pathophysiology of type 2 diabetes mellitus, the clinical shortcomings of current therapies, and the potential of new therapies -- including the newly approved incretin mimetic exenatide -- that elicit actions similar to those of GLP-1.
". Variations in white cell count (l −1 ) over time, in relation to concurrent infections and supportive therapies. of glucagon-like peptide-1 (GLP-1) , an insulin secretagogue synthesized by gut wall cells in response to food. "
[Show abstract][Hide abstract] ABSTRACT: Hematopoietic stem cell (HSC) transplantation fails if grafted HSCs fail to find and settle in an appropriate bone marrow niche where they can receive required trophic factors from stromal cells. Since intravenously injected HSCs are known to migrate into the bone marrow mainly in response to gradients of the CXCL12 chemokine, we reasoned that drugs that inhibit catabolism of CXCL12 could eventually increase the CXCL12 gradient and enhance engraftment. dipeptidyl peptidase IV (DPP-IV) catalyzes the first step in CXCL12 degradation, and oral DPP-IV inhibitors, such as sitagliptin, have been recently approved for type II diabetes mellitus. We report here a case of delayed graft failure in a T-cell-depleted (TCD) HSC transplant recipient, which was refractory to both retransplantation and high-dose granulocyte-colony stimulating factor (G-CSF). After beginning sitagliptin therapy our patient showed a sustained neutrophil rise and a reduction in transfusion dependence, which worsened again after drug discontinuation. Since these changes were paralleled by fluctuations in CXCL12 levels in serial peripheral blood samples, we discuss here the potential benefit of this class of drugs.
Leukemia Research 06/2008; 33(1):178-81. DOI:10.1016/j.leukres.2008.04.019 · 2.35 Impact Factor
"One is the use of GLP-1 receptor agonists which maintain the physiologic effects of native GLP-1, but are resistant to the actions of DPP-4 and the other is the use of DPP-4 inhibitors which decrease the inactivation of GLP-1, thereby increasing its concentration as well as its duration of action on target tissue.[1126–28] Several investigators have concentrated on the second approach, i.e. inhibition of DPP-4 action leading to increase in the plasma concentration of GLP-1 along with an increase in its half-life and hence, prolongation of its duration of action.[111326–28] Administration of specific DPP-4 inhibitors has been found to inhibit the pathway of incretin degradation along with an increase in insulin secretion. "
[Show abstract][Hide abstract] ABSTRACT: Proper control of blood sugar in type 2 diabetes mellitus (T2DM) is not adequate till now in spite of use of well-planned dosage regimens containing oral hypoglycemic agents/insulin or both. Recently, the role of 'incretins,' particularly that of glucagon-like peptide-1 (GLP-1) in glucose homeostasis has been firmly established. The peptide (GLP-1) increases insulin secretion while decreasing that of glucagon in response to rise in plasma glucose in addition to delay of gastric emptying time, reduction of appetite, preservation of beta-cell function, and increase in beta-cell mass all of which will contribute toward lowering of blood sugar in T2DM. But the peptide hormone cannot be used orally as such because of its very short plasma half-life (2 min) and chemical nature, which needs continuous i.v. infusion or repeated s.c. or i.v. injections at short intervals. Hence, to prolong the duration of action of endogenous GLP-1, compounds have been synthesized which inhibit the enzyme dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for metabolic degradation of GLP-1. One such compound is vildagliptin. In this article, an attempt has been made to compile some of the established recent advances in the therapeutic utility of vildagliptin along with a discussion about the physiological role of endogenous GLP-1 and its metabolism by DPP-4.
Indian Journal of Pharmacology 03/2008; 40(1):10-4. DOI:10.4103/0253-7613.40482 · 0.69 Impact Factor
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