Opportunities and challenges of incretin-based hypoglycemic agents treating type 2 diabetes mellitus from the perspective of physiological disposition

The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus (T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1, and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM. Here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug-drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug-drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.

The effects of macronutrients composition on hormones and substrates during a meal tolerance test in drug-naive and sitagliptin-treated individuals with type 2 diabetes: a randomized crossover study

ABSTRACT Objectives: To evaluate the effect of sitagliptin treatment in early type 2 diabetes mellitus (T2DM) and the impact of different macronutrient compositions on hormones and substrates during meal tolerance tests (MTT). Materials and methods: Half of the drug-naive patients with T2DM were randomly assigned for treatment with 100 mg of sitagliptin, q.d., or placebo for 4 weeks and then submitted to 3 consecutive MTT intercalated every 48 h. The MTTs differed in terms of macronutrient composition, with 70% of total energy from carbohydrates, proteins, or lipids. After 4 weeks of washout, a crossover treatment design was repeated. Both patients and researchers were blinded, and a repeated-measures ANOVA was employed for statistical analysis. Results: Sitagliptin treatment reduced but did not normalize fasting and post-meal glucose values in the three MTTs, with lowered area-under-glucose-curve values varying from 7% to 15%. The sitagliptin treatment also improved the insulinogenic index (+86%) and the insulin/glucose (+25%), glucagon-like peptide-1/glucose (+46%) incremental area under the curves. Patients with early T2DM maintained the lowest glucose excursion after a protein- or lipid-rich meal without any major change in insulin, C-peptide, glucagon, or NEFA levels. Conclusion: We conclude that sitagliptin treatment is tolerable and contributes to better control of glucose homeostasis in early T2DM, irrespective of macronutrient composition. The blood glucose excursion during meal ingestion is minimal in protein- or fat-rich meals, which can be a positive ally for the management of T2DM. Clinical trial no: NCT00881543

Immunohistochemical detection of l cells in gastrointestinal tract mucosa of patients after surgical treatment for control of type 2 diabetes mellitus / Detecção imunohistoquímica de células l na mucosa do trato gastrointestinal de pacientes após tratamento cirúrgico para controle de diabetes mellitus tipo 2

ABSTRACT - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a disease of global impact that has led to an increase in comorbidities and mortality in several countries. Immunoexpression of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (3-36) (PYY3-36) can be used as a scorer in the gastrointestinal tract to analyze L-cell activity in response to T2DM treatment. OBJECTIVE: This study aimed to investigate the presence, location, and secretion of L cells in the small intestine of patients undergoing the form of bariatric surgery denominated adaptive gastroenteromentectomy with partial bipartition. METHODS: Immunohistochemical assays, quantitative real-time polymerase chain reaction (qPCR), and Western blot analysis were performed on samples of intestinal mucosa from patients with T2DM in both the preoperative and postoperative periods. RESULTS: All results were consistent and indicated basal expression and secretion of GLP-1 and PYY3-36 incretins by L cells. A greater density of cells was demonstrated in the most distal portions of the small intestine. No significant difference was found between GLP-1 and PYY3-36 expression levels in the preoperative and postoperative periods because of prolonged fasting during which the samples were collected. CONCLUSION: The greater number of L cells in activity implies better peptide signaling, response, and functioning of the neuroendocrine system.

RESUMO - RACIONAL: O diabetes tipo 2 (DM2) é uma doença de impacto mundial que tem levado ao aumento de comorbidades e mortalidade em vários países. A imunoexpressão dos hormônios incretínicos glp-1 e pyy3-36, pode ser usada como marcador no trato gastrointestinal para analisar a atividade da célula L em resposta ao tratamento do DM2. OBJETIVO: O presente estudo teve como objetivo investigar a presença, localização e secreção de células L no intestino delgado de pacientes submetidos à forma de cirurgia bariátrica denominada gastroenteromentectomia adaptativa com bipartição parcial. MÉTODOS: Ensaios imunohistoquímicos, reação quantitativa em cadeia de polimerase em tempo real (qPCR) e análise de manchas ocidentais foram realizados em amostras de mucosa intestinal de pacientes com diabetes tipo 2 nos períodos pré- e pós-operatório. RESULTADOS: Todos os resultados foram consistentes e indicaram expressão basal e secreção de peptídeos glucagon-1 (GLP-1) e peptídeos YY (PYY3-36) incretinas por células L. Uma maior densidade de células foi demonstrada nas porções mais distais do intestino delgado. Não foi encontrada diferença significativa entre os níveis de expressão GLP-1 e PYY3-36 nos períodos pré-operatório e pós-operatório, provavelmente devido ao estado de jejum prolongado durante o qual as amostras foram coletadas CONCLUSÃO: O maior número de células L em atividade implica melhor sinalização de peptídeo, resposta e funcionamento do sistema neuroendócrino.

STUDY OF PALM OIL AND GLUTAMINE AS FUNCTIONAL FOODS ON PEPTIDE TYROSINE TYROSINE AND GLUCAGON-LIKE PEPTIDE 1 IN OBESE PATIENTS FOLLOWING UP ON THE AMBULATORY HEALTH SERVICES OF A PUBLIC HOSPITAL

Incretin-based therapies are an alternative for the treatment of type 2 diabetes and weight reduction. In this respect, functional foods such as palm oil and glutamine are dietary strategies for the stimulation of intestinal peptides. Objective: The aim of this study was to evaluate whether the palm oil capsules of ileal release (LI) and of glutamine (LI) result in increased secretion of glucagon-like peptide-1 (GLP-1) and Peptide tyrosine tyrosine (PYY). Method: Nineteen obese patients follow-up of the Ambulatory Health Services, received nutritional guidance and supplementation with ileal release capsules containing palm oil and glutamine. Result: Prospective analysis showed an increase in median GLP-1 levels between T0 (before treatment) and T2 (after 2 months of treatment) from 21.9 pmol/liter (2-93) to 25.7 pmol/liter (3-92.5) (p= 0.564). The baseline of peptide YY increased between T0 68.5 pg / mL (46.5 to 150) to 71 pg / mL (46-181) in T2 (p= 0.909). The significant level established for all analyses was 5% (p <0.05). Conclusion: The daily intake of palm oil capsules (LI) and of glutamine (LI) by a period of 2 months did not influence the secretion of GLP-1 and PYY in obese patients. However, weight maintenance was observed during the evaluated period. Further studies are needed for inferences in this population, to determine if functional foods such as palm oil and glutamine are associated with other specific health benefits.

TCF7L2 gene variant rs7903146 affects the risk of Type 2 Diabetes by modulating incretin secretion

Background: Type2 diabetes mellitus (T2DM) is a highly inheritable disease. Transcription factor 7- like 2 (TCF7L2) gene regulates the expression of glucagon-like peptide 1 (GLP-1) in L cells of small intestine. GLP1 plays a critical role in blood glucose homeostasis by stimulating postprandial insulin secretion and increasing insulin sensitivity. Aim of the study: TCF7L2 gene variants may affect the susceptibility to Type 2 diabetes by altering GLP-1 levels. Materials and methods: This case-control study was conducted with 90 newly diagnosed patients with Type2 diabetes mellitus as cases and 90 age and sex-matched healthy volunteers as controls. TCF7L2 rs7903146 genotyping was done and we also estimated Fasting and postprandial GLP -1 level, Fasting and Postprandial insulin level and calculated HOMA-IR in both cases and controls. Results: Out study showed that T+ genotype, lower fasting GLP-1 level and lower postprandial GLP1 levels were more observed among cases as compared to controls. Low mean GLP 1 activity, high Mean HOMA-IR, low postprandial insulin, low percentage rise in insulin were observed among T+ genotype than among T- genotypic individuals. Conclusion: Hence, the study concludes that T+ genotype causes a decrease in GLP-1 levels, which in turn by decreasing postprandial insulin levels and by increasing insulin resistance increases the risk of Type2 diabetes.

Asian Subpopulations May Exhibit Greater Cardiovascular Benefit from Long-Acting Glucagon-Like Peptide 1 Receptor Agonists: A Meta-Analysis of Cardiovascular Outcome Trials

BACKGROUND: Based on reported results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major adverse cardiovascular events (MACEs) and to identify subpopulations exhibiting the greatest cardiovascular (CV) benefit. METHODS: Three CVOTs reporting effects of long-acting GLP-1 RAs were included: LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide once weekly). In all studies, the primary endpoint was three-point MACE, comprising CV death, non-fatal myocardial infarction, and non-fatal stroke. Overall effect estimates were calculated as hazard ratios and 95% confidence intervals (CIs) using the random-effects model; subgroup analyses reported in the original studies were similarly analyzed. RESULTS: Overall, statistically significant risk reductions in MACE and CV death were observed. Subgroup analysis indicated a significant racial difference with respect to CV benefit (P for interaction <0.001), and more substantial risk reductions were observed in subjects of African origin (relative risk [RR], 0.78; 95% CI, 0.60 to 0.99) and in Asians (RR, 0.35; 95% CI, 0.09 to 1.32). However, post hoc analysis (Bonferroni method) revealed that only Asians exhibited a significantly greater CV benefit from treatment, compared with white subjects (P<0.0001). CONCLUSION: Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in high-risk patients with type 2 diabetes mellitus. Our findings of a particularly effective reduction in CV events with GLP-1 RA in Asian populations merits further exploration and dedicated trials in specific populations.

Changes in Glucose Metabolism with Aging / 임상당뇨병

The increasing risk of glucose intolerance and diabetes associated with aging is well established. However, it is difficult to determine whether changes in glucose metabolism result from biological aging itself or due to various environmental factors that occur during the aging process. Many epidemiologic studies have shown that plasma glucose levels after oral glucose tolerance test rise consecutively for every decade of age, but many of these studies also demonstrated the effects of environmental factors including obesity and exercise. In some studies, the development of insulin resistance and insulin secretion defects due to biological aging itself have also been identified as major etiologic factors of glucose intolerance. However, the rate of diabetes development due to these factors is expected to be very slow and largely preventable by addressing environmental risk factors.

Manejo de pacientes diabéticos hospitalizados / Management of diabetes in hospitals

Resumen La diabetes es una enfermedad con importante prevalencia en todo el mundo. Se calcula que cerca de 415 millones de personas la padecen en la actualidad y que para el año 2040 esta cifra aumentará poco más del 50%. Debido a esto, se estima que gran parte de los ingresos por urgencias serán de pacientes diabéticos o sujetos a los cuales esta patología se les diagnosticará en dicha hospitalización; esta situación hace necesario conocer los lineamientos y las recomendaciones de las guías para el manejo intrahospitalario de los pacientes con hiperglucemia. El pilar fundamental del manejo hospitalario de diabetes es la monitorización intensiva, junto con la educación al paciente y la administración de insulina. El control glicémico es clave debido a que disminuye complicaciones intrahospitalarias. Cabe resaltar que el control estricto puede llevar a hipoglucemias, por lo que los episodios deben ser debidamente documentados y su causa corregida de inmediato.

Abstract Diabetes is a disease with significant prevalence worldwide. According to the latest estimates, about 415 million people suffer from this condition and this figure will almost double by 2040. For this reason, a large part of emergency admissions will be related to diabetic patients or subjects who will be diagnosed with this pathology while hospitalized. Hospital-related hyperglycemia due to stress, medications and parenteral nutrition are also a common finding. In consequence, it is imperative for health care providers to become familiar with inpatient hyperglycemia management. Intensive glucose monitoring, patient education and insulin administration are essential for treating this condition. Glycemic control is fundamental as it decreases nosocomial complications. It should be noted that strict control may lead to hypoglycemia, so episodes should be properly documented and their cause corrected immediately.

Comparação dos níveis de proteína C reativa, GLP-1 e GLP-2 entre indivíduos diabéticos, obesos mórbidos e controles saudáveis: um estudo exploratório / Comparison of the levels of c-reactive protein, glp-1 and glp-2 among individuals with diabetes, morbid obesity and healthy controls: an exploratory study

ABSTRACT BACKGROUND: The glucagon-like peptides 1 and 2 (GLP-1/GLP-2) are gut hormones that may directly affect the glucose homeostasis and their activity seems to be significantly affected by chronic inflammation. OBJECTIVE: To evaluate the postprandial levels of glucagon-like peptides 1 and 2 (GLP-1/GLP-2), C-reactive protein (CRP), and the postprandial glucose and insulin levels among individuals with obesity, type 2 diabetes, and healthy controls. METHODS: An exploratory cross-sectional study, which involved individuals awaiting for bariatric/metabolic surgery and healthy controls. Postprandial levels of GLP-1, GLP-2, glucose, and insulin were obtained after a standard meal tolerance test. Inflammation was assessed by means of CRP. RESULTS: There were 30 individuals enrolled in the study, divided into three groups: non-diabetic with morbid obesity (NDO; n=11 individuals), diabetic with mild obesity (T2D; n=12 individuals), and healthy controls (C; n=7 individuals). The mean CRP levels were significantly higher in the NDO group (6.6±4.7 mg/dL) than in the T2D (3.3±2.2 mg/dL) and C groups (2.5±3.2 mg/dL) (P=0.038). The GLP-1 levels following standard meal tolerance test and the area under the curve of GLP-1 did not differ among the three groups. The GLP-2 levels were significantly lower in the NDO and T2D than in the C group following standard meal tolerance test at all the times evaluated. The area under the curve of the GLP-2 was significantly lower in the NDO and T2D groups than in the C group (P=0.05 and P=0.01, respectively). CONCLUSION: GLP-2 levels were impaired in the individuals with obesity and diabetes. This mechanism seems to be enrolled in preventing the worsening of the glucose homeostasis in these individuals.

RESUMO CONTEXTO: Os peptídeos semelhantes ao glucagon 1 e 2 (GLP-1/GLP-2) são hormônios gastrointestinais que podem afetar diretamente a homeostase glicêmica; a atividade de ambos parece ser significativamente afetada pela inflamação crônica. OBJETIVO: Avaliar os níveis pós-prandiais dos peptídeos semelhantes ao glucagon 1 e 2 (GLP-1/GLP-2), proteína C reativa (PCR) e as curvas pós-prandiais de glucose e insulina entre indivíduos com obesidade, diabetes tipo 2 e controles saudáveis. MÉTODOS: Estudo piloto transversal, que envolveu indivíduos aguardando a realização de cirurgia bariátrica/metabólica e controles saudáveis. Os níveis de GLP-1, GLP-2, glucose e insulina foram obtidos após um teste de refeição padrão. A inflamação foi avaliada através dos níveis de PCR. RESULTADOS: Houve 30 indivíduos avaliados no estudo, divididos em três grupos: obesos mórbidos sem diabetes (NDO; n=11 pacientes), diabéticos com obesidade leve (T2D; n=12 pacientes) e controles (C; n=7 pacientes). Os níveis médios de PCR foram significativamente maiores no grupo NDO (6,6±4,7 mg/dL) do que nos grupos T2D (3,3±2,2 mg/dL) e C (2,5±3,2 mg/ dL) (P=0,038). Os níveis de GLP-1 após o teste de refeição padrão e a área sob a curva do GLP-1 não diferiram significativamente entre os grupos. Os níveis de GLP-2 foram significativamente mais baixos nos grupos NDO e T2D do que no grupo C em todos os tempos avaliados. A área sob a curva do GLP-2 foi significativamente menor nos grupos NDO e T2D do que no grupo C (P=0,05 and P=0,01, respectivamente). CONCLUSÃO: Os níveis de GLP-2 encontram-se alterados em indivíduos com obesidade e diabetes. Este mecanismo parece estar envolvido na prevenção da piora da homeostase glicêmica nestes indivíduos.

Glucose-Lowering Agents in the Management of Nonalcoholic Fatty Liver Disease / 임상당뇨병

Nonalcoholic fatty liver disease (NAFLD) is more prevalent in diabetic patients than in non-diabetic subjects, because the two diseases share a common pathophysiological mechanism. Associated abnormalities can be observed from the pre-diabetic stage. Lifestyle intervention, including diet, exercise, and weight loss, is the primary recommended therapy for NAFLD. Among the therapeutic drugs for NAFLD treatment, anti-diabetic agents are aimed at improving or slowing the progression of NAFLD in addition to lowering blood glucose. In this paper, we systemically review the evidence surrounding antidiabetic medications and their ability to improve disease progression in patients with NAFLD.

Effect of Nutrient Preload and Food Order on Glucose, Insulin, and Gut Hormones / 임상당뇨병

Postprandial hyperglycemia is associated with the risk of diabetes mellitus, cardiovascular disease, and mortality. Nutrition therapy is an important component of the management of postprandial hyperglycemia. Postprandial glucose levels are determined by several factors, such as the quantity and composition of nutrients, gastric emptying rates, secretion of incretin hormones, insulin secretion, glucose uptake by peripheral tissues, and endogenous glucose production. Nutrient preload and food order (or meal sequence) are dietary approaches targeting these factors. Nutrient preload reduces postprandial glucose excursion by enhancing insulin secretion, augmenting the secretion of glucagonlike peptide-1, and delaying gastric emptying. Carbohydrates-last food order improves glycemic control, increases the secretion of glucagon-like peptide-1, and decreases insulin requirements. Therefore, both nutrient preload and manipulation of food order can be an effective, safe, and feasible strategy for treating hyperglycemia in individuals with diabetes mellitus.

Bipartición de tránsito intestinal, la nueva era de la cirugía metabólica para la diabetes mellitus de tipo 2 / Intestinal transit bipartition, the new era in metabolic surgery for type 2 diabetes

Antecedentes. La diabetes mellitus de tipo 2 es el principal reto de salud pública que enfrentamos actualmente, constituye la primera causa de discapacidad y es o está asociada a las principales causas de muerte en nuestro país. En Ciudad de México, se reportó que más del 79 % de los pacientes diabéticos no tienen cifras óptimas de HbA1c (<6,5 %), mientras que el 47 % presentan descontrol importante (HbA1c >9 %). La cirugía metabólica es el mejor tratamiento en términos de remisión, sin embargo, los mecanismos involucrados no son los tradicionalmente considerados. Objetivo. Ofrecer actualización acerca de los mecanismos involucrados en la remisión de la diabetes mellitus de tipo 2 después de la cirugía metabólica. Metodos. Se hizo una revisión bibliográfica utilizando las palabras clave en términos MeSH; hasta el 1° de junio del 2018, se encontraron 83 artículos de referencia considerados como pertinentes. Resultados. La remisión de la diabetes mellitus de tipo 2 lograda por procedimientos quirúrgicos, depende de complejas interacciones entre la microbiota, los ácidos biliares y el epitelio intestinal, más que de procesos malabsortivos o restrictivos. La bipartición de tránsito intestinal es una opción quirúrgica basada en los principios fisiológicos responsables en la remisión de la diabetes, y es la más sencilla y segura para el manejo de la diabetes mellitus. Conclusiones. La cirugía metabólica ofrece mejores tasas de remisión y control de complicaciones de la diabetes tipo 2 al modificar la secreción de enterohormonas, la concentración e interacciones de los ácidos biliares y al modificar la microbiota

Background: Diabetes mellitus type 2 (DM2) is a major public health challenge that we face today; it is the first cause of disability and is associated with the main causes of death in our country. In Mexico City, it was reported that more than 79% of diabetic patients did not have optimal levels of HbA1c (<6.5%), while 47% are not properly controlled (HbA1c> 9%). Metabolic surgery is the best treatment option for DM2, yet the presumed involved mechanisms are not traditionally considered. Objective: To provide an update on the mechanisms involved in the remission of DM2 following metabolic surgery. Methods: Narrative review of the literature, using MeSH terms, until June 1, 2018, encountering 83 articles considered pertinent. Methods: Narrative review of the literature, using MeSH terms, until June 1, 2018, encountering 83 articles considered pertinent. Results: DM2 remission after surgery depends on complex interactions between the microbiota, biliary acids and the intestinal epithelium, more so than of malabsortion or restrictive processes. Bipartition of the intestinal transit constitutes a surgical option based on the physiologic principles responsible of the remission of diabetes, and it is a simple and most secure procedure for the management of diabetes. Mechanisms include restoration/ enhancement of incretin secretion; as well as an improvement of bile acid concentration and microbiome manipulation, rather than the commonly accepted restriction and malabsorption. Intestinal transit bipartition is a novel and simple procedure that complies with the actual involved mechanisms, with comparable results in terms of safety and efficacy with the more complex and demanding techniques, such as the gastric bypass. Conclusions: Metabolic surgery is the best treatment for DM2 in terms of remission and prevention of complications, modifying the secretion of enterohormones, the concentration of biliary acids, and the modification of the microbiota

New therapeutic agents in diabetic nephropathy

Studies investigating diabetic nephropathy (DN) have mostly focused on interpreting the pathologic molecular mechanisms of DN, which may provide valuable tools for early diagnosis and prevention of disease onset and progression. Currently, there are few therapeutic drugs for DN, which mainly consist of antihypertensive and antiproteinuric measures that arise from strict renin-angiotensin-aldosterone system inactivation. However, these traditional therapies are suboptimal and there is a clear, unmet need for treatments that offer effective schemes beyond glucose control. The complexity and heterogeneity of the DN entity, along with ambiguous renal endpoints that may deter accurate appraisal of new drug potency, contribute to a worsening of the situation. To address these issues, current research into original therapies to treat DN is focusing on the intrinsic renal pathways that intervene with intracellular signaling of anti-inflammatory, antifibrotic, and metabolic pathways. Mounting evidence in support of the favorable metabolic effects of these novel agents with respect to the renal aspects of DN supports the likelihood of systemic beneficial effects as well. Thus, when translated into clinical use, these novel agents would also address the comorbid factors associated with diabetes, such as obesity and risk of cardiovascular disease. This review will provide a discussion of the promising and effective therapeutic agents for the management of DN.

Inhibidores de la dipeptidil peptidasa 4 y una nueva estrategia farmacológica en la diabetes mellitus tipo 2 / Inhibitors of dipeptidil peptidase 4 new pharmacologic strategic in the diabetes mellitus type 2

La diabetes mellitus sigue siendo una enfermedad temible. El uso adecuado de la farmacoterapia para el control metabólico, ayudaría a disminuir la incidencia de complicaciones. Actualmente se dispone de variados grupos farmacológicos para el control temporal de las cifras de glucemias de pacientes con diabetes mellitus tipo 2, entre ellos están los inhibidores de la dipeptidil peptidasa 4 caracterizados por estimular el aumento de la concentración del péptido similar a glucagón tipo 1 GLP-1 y la secreción de insulina en la célula beta del islote pancreático. La eficacia, en términos de hemoglobina glucosilada, ha mostrado ser inferior a la de la insulina, pero sin el potencial del peligro de hipoglucemia, así como el efecto neutro o la disminución del peso corporal. Se realizó esta revisión bibliográfica con el objetivo de actualizar los conocimientos sobre el papel de las sustancias con acción incretinas en el control metabólico de los pacientes con diabetes mellitus tipo 2 y específicamente la acción de los IDPP4, ya que es creciente el problema de dicha enfermedad y se requiere, cada vez más, una mejor información de los fármacos a utilizar, aunque en el futuro los datos obtenidos concluirán su efectividad(AU)

Diabetes mellitus remains a fearsome disease. Proper use of pharmacotherapy for metabolic control, would help reduce the incidence of complications. Currently there are various pharmacological groups for temporary control of blood glycemia of patients with diabetes mellitus type 2. One of them is dipeptidyl peptidase-4 inhibitor characterized by stimulating increased concentration like peptide glucagon type 1 GLP -1 and insulin secretion in pancreatic islet beta cell. The effectiveness in terms of glycosylated hemoglobin has shown to be less than that of insulin, but without the potential danger of hypoglycaemia and the neutral effect or decrease in body weight. These facts prompt this literature review which was conducted to update the knowledge on the role of substances with incretin action in the metabolic control of patients with diabetes mellitus type 2, specifically the action of IDPP4, as this disease is an growing problem requiring better information on drug use(AU)

Improving Effect of the Acute Administration of Dietary Fiber-Enriched Cereals on Blood Glucose Levels and Gut Hormone Secretion

Dietary fiber improves hyperglycemia in patients with type 2 diabetes through its physicochemical properties and possible modulation of gut hormone secretion, such as glucagon-like peptide 1 (GLP-1). We assessed the effect of dietary fiber-enriched cereal flakes (DC) on postprandial hyperglycemia and gut hormone secretion in patients with type 2 diabetes. Thirteen participants ate isocaloric meals based on either DC or conventional cereal flakes (CC) in a crossover design. DC or CC was provided for dinner, night snack on day 1 and breakfast on day 2, followed by a high-fat lunch. On day 2, the levels of plasma glucose, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and insulin were measured. Compared to CC, DC intake exhibited a lower post-breakfast 2-hours glucose level (198.5±12.8 vs. 245.9±15.2 mg/dL, P<0.05) and a lower incremental peak of glucose from baseline (101.8±9.1 vs. 140.3±14.3 mg/dL, P<0.001). The incremental area under the curve (iAUC) of glucose after breakfast was lower with DC than with CC (P<0.001). However, there were no differences in the plasma insulin, glucagon, GLP-1, and GIP levels. In conclusion, acute administration of DC attenuates postprandial hyperglycemia without any significant change in the representative glucose-regulating hormones in patients with type 2 diabetes (ClinicalTrials.gov. NCT 01997281).

Incretin hormone glucagon-like peptide 1 and gut microbiota / 中国药理学与毒理学杂志

There are more than two dozens of peptide hormones that are produced and released from the gastrointestinal (GI) tract. Among them, the incretin hormone glucagon-like peptide 1 (GLP-1) has received the most intensive attention for the past 30 years. Functional studies on GLP-1 and anoth?er gut incretin hormone glucose-dependent insulinotropic peptide (GIP) have led to the development of novel diabetes therapeutic agents known as GLP-1 receptor agonists and DPP-Ⅵinhibitors. Instead of forming endocrine glands, the gut hormone producing endocrine cells are widely spread throughout the entire GI tract, permitting vital interactions with the″external″environment. Here a brief introduction on GLP-1 and how nutritional components regulate its secretion were made, followed by reviewing some key development on how gut environment affects the production and secretion of GLP-1, including the contribution of gut microbiota.

An Update on the Effect of Incretin-Based Therapies on β-Cell Function and Mass

Type 2 diabetes mellitus (T2DM) is a multifactorial disease with a complex and progressive pathogenesis. The two primary mechanisms of T2DM pathogenesis are pancreatic β-cell dysfunction and insulin resistance. Pancreatic β-cell dysfunction is recognized to be a prerequisite for the development of T2DM. Therapeutic modalities that improve β-cell function are considered critical to T2DM management; however, blood glucose control remains a challenge for many patients due to suboptimal treatment efficacy and the progressive nature of T2DM. Incretin-based therapies are now the most frequently prescribed antidiabetic drugs in Korea. Incretin-based therapies are a favorable class of drugs due to their ability to reduce blood glucose by targeting the incretin hormone system and, most notably, their potential to improve pancreatic β-cell function. This review outlines the current understanding of the incretin hormone system in T2DM and summarizes recent updates on the effect of incretin-based therapies on β-cell function and β-cell mass in animals and humans.

In Vivo Models for Incretin Research: From the Intestine to the Whole Body

Incretin hormones are produced by enteroendocrine cells (EECs) in the intestine in response to ingested nutrient stimuli. The incretin effect is defined as the difference in the insulin secretory response between the oral glucose tolerance test and an isoglycemic intravenous glucose infusion study. The pathophysiology of the decreased incretin effect has been studied as decreased incretin sensitivity and/or β-cell dysfunction per se. Interestingly, robust increases in endogenous incretin secretion have been observed in many types of metabolic/bariatric surgery. Therefore, metabolic/bariatric surgery has been extensively studied for incretin physiology, not only the hormones themselves but also alterations in EECs distribution and genetic expression levels of gut hormones. These efforts have given us an enormous understanding of incretin biology from synthesis to in vivo behavior. Further innovative studies are needed to determine the mechanisms and targets of incretin hormones.

Inhibidores de dipeptidil dipeptidasa-IV: de la teoría a la práctica / Dipeptidil dipeptidase-IV inhibidors: from the theory to the practice

Esta revisión de los inhibidores de dipeptidil peptidasa-IV busca motivar el uso racional de tal grupo farmacológico en la práctica diaria. Este grupo es una nueva opción terapéutica en monoterapia o terapia combinada para el tratamiento de los pacientes con diabetes mellitus tipo 2. En Colombia, se encuentran disponibles: sitagliptina, vildagliptina, saxagliptina y linagliptina. Si bien todas las gliptinas tienen el mismo mecanismo de acción-aumentan la vida media del péptido similar al glucagón-, esta revisión presenta las diferencias entre sus propiedades farmacológicas, eventos adversos y perfil de seguridad. Estos medicamentos son de segunda o tercera línea para el tratamiento oral de los pacientes con diabetes mellitus tipo 2, o primera línea en los pacientes intolerantes a la metformina. Además, algunas de las ventajas que tienen son que: generan menor riesgo de hipoglucemia, tienen efecto neutro sobre el peso, son seguros en adultos mayores, disminuyen la variabilidad de la glucemia y, adicionalmente, se pueden utilizar en la enfermedad renal crónica avanzada, con o sin terapia de reemplazo renal, y en la insuficiencia hepática.

This review of dipeptidyl peptidase-IV inhibitors seeks to encourage the rational use of these drugs in daily practice; this group is a new therapeutic option in monotherapy or combination therapy for the treatment of patients with diabetes mellitus type 2. Sitagliptin, vildagliptin, saxagliptin and linagliptin are available in Colombia. While all gliptins have the same mechanism of action-they increase the average life of glucagon-like peptide-, this review presents the differences among their pharmacological properties, adverse events and safety profile. These drugs are second or third-line for the oral treatment of patients with diabetes mellitus type 2, or first-line in patients intolerant to metformin. They also have some advantages like lower risk of hypoglycemia, neutral effect on weight, safety for the elderly, reduction of glycaemia variability; additionally, they can be used in advanced chronic kidney disease, with or without renal replacement therapy, and in liver failure.

Vaciamiento gástrico y diabetes mellitus tipo 2 / Gastric emptying and Type 2 diabetes mellitus

El adecuado control de la diabetes mellitus tiene una gran importancia desde muchos puntos de vista. En los últimos años, se ha destacado el impacto que tienen los niveles de la glucemia postprandial sobre el manejo y las complicaciones de esta enfermedad. Controlar la hiperglucemia postprandial y, por lo tanto, su participación en el deterioro clínico de los pacientes con diabetes puede conseguirse retardando el vaciamiento gástrico y estimulando el efecto incretina, los cuales se pueden promover utilizando los análogos del péptido similar al glucagón tipo 1 (GLP-1). En este artículo se revisa el concepto del efecto incretina y la utilidad de los análogos GLP-1 en el control de la glicemia en los pacientes con diabetes mellitus tipo 2.

Proper control of diabetes mellitus is very important from many points of view. In recent years, the impact of postprandial blood glucose levels on the treatment and complications of this disease has been highlighted. Controlling postprandial hyperglycemia-and, therefore, its participation in the clinical deterioration of patients with diabetes-can be achieved by delaying gastric emptying and stimulating the incretin effect, which can be promoted using the analogues of glucagon-like peptide-1 (GLP-1). In this article, the concept of the incretin effect and usefulness of GLP-1 analogues for glycemic control in patients with type 2 diabetes mellitus is reviewed.