Incretin mimetics and dipeptidyl peptidase-4 inhibitors: innovative treatment therapies for type 2 diabetes

Abstract

the prevalence of diabetes and impaired glucose tolerance is predicted to dramatically increase over the next two decades. clinical therapies for type 2 diabetes mellitus (t2dM) have traditionally included lifestyle modification, oral anti-diabetic agents, and ultimately insulin initiation. In this report, we review the clinical trial results of two innovative t2dM treatment therapies that are based on the glucoregulatory effects of incretin hormones. Incretin mimetics are peptide drugs that mimic several of the actions of glucagon-like peptide-1 (gLP-1) and have been shown to lower glycated hemoglobin (A1c) levels in patients with t2dM. Additionally, incretin mimetics lower postprandial and fasting glucose, suppress elevated glucagon release, and are associated with progressive weight reduction. dipeptidyl peptidase-4 (dPP-4) inhibitors increase endogenous gLP-1 levels by inhibiting the enzymatic degradation of gLP-1. clinical studies in patients with t2dM have shown that dPP-4 inhibitors reduce elevated A1c, lower postprandial and fasting glucose, suppress glucagon release, and are weight neutral. collectively, these new drugs, given in combination with other antidiabetic agents, such as metformin, sulfonylureas, and/or thiazolidinediones, can help restore glucose homeostasis in poorly controlled patients with t2dM. É previsto que a prevalência de diabetes e a intolerância à glicose aumente dramaticamente ao longo das próximas duas décadas. As terapias clínicas para diabetes melito tipo 2 (dM2) têm tradicionalmente incluído modificação do estilo de vida, agentes antidiabéticos orais e, por último, o início da insulina. neste artigo, revisamos os resultados dos estudos clínicos de duas terapias inovadoras no tratamento do dM2 baseadas nos efeitos glicorregulatórios dos hormônios incretina. Os incretinomiméticos são medicamentos peptídeos que mimetizam várias das ações do peptídeo semelhante ao glucagon-1 (gLP-1) e têm demonstrado reduzir níveis de hemoglobina glicada (A1c) em pacientes com dM2. Adicionalmente, incretinomiméticos reduzem as glicemias pós-prandial e de jejum, suprimem a liberação elevada do glucagon, e são associados com redução de peso. Os inibidores da dipeptidil peptidase-4 (dPP-4) aumentam os níveis de gLP-1 endógeno pela inibição da degradação enzimática do gLP-1. Estudos clínicos em pacientes com dM2 têm demonstrado que inibidores da dPP-4 reduzem A1c elevada, reduzem as glicemias pós-prandial e de jejum, suprimem a liberação elevada do glucagon e são neutros quanto ao peso. coletivamente, estas novas medicações, administradas em combinação com outros agentes antidiabéticos, como metformina, sulfoniluréias e/ou tiazolidinedionas (tZds), podem ajudar a recuperar a homeostase glicêmica de pacientes com dM2 não-controlados. (Arq Bras Endocrinol Metab

DPP4‐inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high‐fat diet consumption

“…Glucagon‐like‐peptide 1 (GLP‐1) is an incretin hormone, secreted by enteroendocrine cells during ingestion of nutrients (Pratley & Salsali, ; Verspohl, ). GLP‐1 plays an important role in insulinotropic and insulinomimetic activity (Davidson et al ., ), by stimulating insulin secretion, suppressing glucagon production, and improving beta‐cell function in type‐2 diabetes mellitus (T2DM) and insulin resistance models (Gault & Holscher, ; McClean et al ., ). GLP‐1 has a very short half‐life (< 2 min) as it is rapidly degraded by a dipeptidyl peptidase‐4 (DPP‐4) enzyme in the circulation (Drucker & Nauck, ; Davidson et al ., ; Ranganath, ; Akarte et al ., ).…”

“…GLP‐1 plays an important role in insulinotropic and insulinomimetic activity (Davidson et al ., ), by stimulating insulin secretion, suppressing glucagon production, and improving beta‐cell function in type‐2 diabetes mellitus (T2DM) and insulin resistance models (Gault & Holscher, ; McClean et al ., ). GLP‐1 has a very short half‐life (< 2 min) as it is rapidly degraded by a dipeptidyl peptidase‐4 (DPP‐4) enzyme in the circulation (Drucker & Nauck, ; Davidson et al ., ; Ranganath, ; Akarte et al ., ). Therefore, DPP‐4 inhibitors have been used to improve glycemic control (Drucker & Nauck, ; Verspohl, ).…”

Enhanced Incretin Effects of Exendin-4 Expressing Chimeric Plasmid Based On Two-Step Transcription Amplification System with Dendritic Bioreducible Polymer for the Treatment of Type 2 Diabetes

“…The anti-hyperglycemic effects of incretin hormones are mediated by the key actions of enhancement of glucose-dependent insulin secretion [7,37]. Our results demonstrate that exendin-4 expressed by chimeric DNA system with PAM-ABP can induce enhancement of insulin secretion and has insulin secretion-inducing ability in diabetic mice ( Figure 5B).…”

Delivery of two-step transcription amplification exendin-4 plasmid system with arginine-grafted bioreducible polymer in type 2 diabetes animal model

“…The anti-hyperglycemic effects of incretin hormones are mediated by the enhanced insulin secretion in a glucose dependent manner [27, 28]. We next verified whether exendin-4 or GLP-1 expressed by TSTA system with ABP polymer had insulin secretion-inducing ability as incretin action against diabetes.…”