Incretins Beyond the Pancreas: Exploring the Impact of GIP and GLP-1/2 on Bone Remodeling.

Incretin hormones, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 and 2 (GLP-1, 2), belong to the group of gastrointestinal hormones. Their actions occur through interaction with GIP and GLP-1/2 receptors, which are present in various target tissues. Apart from their well-established roles in pancreatic function and insulin regulation, incretins elicit significant effects that extend beyond the pancreas. Specifically, these hormones stimulate osteoblast differentiation and inhibit osteoclast activity, thereby promoting bone anabolism. Moreover, they play a pivotal role in bone mineralization and overall bone quality and function, making them potentially therapeutic for managing bone health. Thus, this review provides a summary of the crucial involvement of incretins in bone metabolism, influencing both bone formation and resorption processes. While existing evidence is persuasive, further studies are necessary for a comprehensive understanding of the therapeutic potential of incretins in modifying bone health.

Intestinal alterations and mild glucose homeostasis impairments in the offspring born to overweight rats.

The gut plays a crucial role in metabolism by regulating the passage of nutrients, water and microbial-derived substances to the portal circulation. Additionally, it produces incretins, such as glucose-insulinotropic releasing peptide (GIP) and glucagon-like derived peptide 1 (GLP1, encoded by gcg gene) in response to nutrient uptake. We aimed to investigate whether offspring from overweight rats develop anomalies in the barrier function and incretin transcription. We observed pro-inflammatory related changes along with a reduction in Claudin-3 levels resulting in increased gut-permeability in fetuses and offspring from overweight rats. Importantly, we found decreased gip mRNA levels in both fetuses and offspring from overweight rats. Differently, gcg mRNA levels were upregulated in fetuses, downregulated in female offspring and unchanged in male offspring from overweight rats. When cultured with high glucose, intestinal explants showed an increase in gip and gcg mRNA levels in control offspring. In contrast, offspring from overweight rats did not exhibit any response in gip mRNA levels. Additionally, while females showed no response, male offspring from overweight rats did exhibit an upregulation in gcg mRNA levels. Furthermore, female and male offspring from overweight rats showed sex-dependent anomalies when orally challenged with a glucose overload, returning to baseline glucose levels after 120 min. These results open new research questions about the role of the adverse maternal metabolic condition in the programming of impairments in glucose homeostasis, enteroendocrine function and gut barrier function in the offspring from overweight mothers and highlight the importance of a perinatal maternal healthy metabolism.

GLP1R (glucagon-like-peptide-1 incretin receptor), diabetes and obesity phenotypes: An in silico approach revealed new pathogenic variants.

OBJECTIVE: Glucagon-like peptide-1 receptor belongs to the B family of G protein-coupled receptors, serving as a binding protein in membranes and is widely expressed in human tissues. Upon stimulation by its agonist, the glucagon-like peptide-1, the receptor plays a role in glucose metabolism, enhancing insulin secretion, and regulating appetite in the hypothalamus. Mutations in the glucagon-like peptide-1 receptor gene can lead to physiological changes that may explain phenotypic variations in individuals with obesity and diabetes. Therefore, this study aimed to evaluate missense variants of the glucagon-like peptide-1 receptor gene. METHODS: Data mining was performed on the single nucleotide polymorphism database, retrieving a total of 16,399 variants. Among them, 356 were missense. These 356 variants were analyzed using the PolyPhen-2 and filtered based on allele frequency, resulting in 6 pathogenic variants. RESULTS: D344E, A239T, R310Q, R227H, R421P, and R176G were analyzed using four different prediction tools. The D344E and A239T resulted in larger amino acid residues compared to their wild-type counterparts. The D344E showed a slightly destabilized structure, while A239T affected the transmembrane helices. Conversely, the R310Q, R227H, R421P, and R176G resulted in smaller amino acid residues than the wild-type, leading to a loss of positive charge and increased hydrophobicity. Particularly, the R421P, due to the presence of proline, significantly destabilized the α-helix structure and caused severe damage to the receptor. CONCLUSION: Elucidating the glucagon-like peptide-1 receptor variants and their potentially detrimental effects on receptor functionality can contribute to an understanding of metabolic diseases and the response to available pharmacological treatments.

Brain access of incretins and incretin receptor agonists to their central targets relevant for appetite suppression and weight loss.

New incretin-based pharmacotherapies provide efficient and safe therapeutic options to curb appetite and produce weight loss in patients with obesity. Delivered systemically, these molecules produce pleiotropic metabolic benefits, but the target sites mediating their weight-suppressive action are located within the brain. Recent research has increased our understanding of the neural circuits and behavioral mechanisms involved in the anorectic and metabolic consequences of glucagon-like peptide 1 (GLP-1)-based weight loss strategies, yet little is known about how these drugs access their functional targets in the brain to produce sustained weight loss. The majority of brain cells expressing incretin receptors are located behind the blood-brain barrier, shielded from the circulation and fluctuations in the availability of peripheral signals, which is a major challenge for the development of CNS-targeted therapeutic peptides. GLP-1 receptor (GLP-1R) agonists with increased half-life and enhanced therapeutic benefit do not cross the blood-brain barrier, yet they manage to access discrete brain sites relevant to the regulation of energy homeostasis. In this review, we give a brief overview of the different routes for peptide hormones to access the brain. We then examine the evidence informing the routes employed by incretins and incretin receptor agonists to access brain targets relevant for their appetite and weight-suppressive actions. We highlight existing controversies and suggest future directions to further establish the functionally relevant access routes for GLP-1-based weight loss compounds, which might guide the development and selection of the future generation of incretin receptor polypharmacologies.

Potential Role of GLP-1 Based Therapeutics in Coronary Artery Disease.

Glucagon-like peptide-1 (GLP-1), an incretin hormone primarily secreted by intestinal L cells, regulates glucose metabolism by increasing insulin synthesis and secretion, decreasing plasma glucagon levels, reducing food intake, and slowing gastric emptying. This has led to the development of GLP-1 receptor (GLP-1R) agonists as a treatment for diabetes and obesity. In addition to being present in beta cells, GLP-1R has also been identified in blood vessels and the heart, suggesting that GLP-1R agonists may have an impact on cardiovascular health. There is now substantial evidence supporting GLP-1's protective effects on the cardiovascular system. This review summarizes the current research on GLP-1-based therapy for coronary artery disease (CAD) by examining its protective effects against inflammation and ischemia/reperfusion injury and analyzing clinical trials on GLP-1-based therapies for CAD. Although results from various studies were inconsistent, the challenge of transitioning GLP-1-based therapies from the laboratory to the clinical setting remains. Further well-designed and high-quality studies are necessary to determine the efficacy and safety of GLP-1 for patients with CAD.

A specific gut microbiota signature is associated with an enhanced GLP-1 and GLP-2 secretion and improved metabolic control in patients with type 2 diabetes after metabolic Roux-en-Y gastric bypass.

Objective: To determine changes in incretins, systemic inflammation, intestinal permeability and microbiome modifications 12 months after metabolic RYGB (mRYGB) in patients with type 2 diabetes (T2D) and their relationship with metabolic improvement. Materials and methods: Prospective single-center non-randomized controlled study, including patients with class II-III obesity and T2D undergoing mRYGB. At baseline and one year after surgery we performed body composition measurements, biochemical analysis, a meal tolerance test (MTT) and lipid test (LT) with determination of the area under the curve (AUC) for insulin, C-peptide, GLP-1, GLP-2, and fasting determinations of succinate, zonulin, IL-6 and study of gut microbiota. Results: Thirteen patients aged 52.6 ± 6.5 years, BMI 39.3 ± 1.4 kg/m2, HbA1c 7.62 ± 1.5% were evaluated. After mRYGB, zonulin decreased and an increase in AUC after MTT was observed for GLP-1 (pre 9371 ± 5973 vs post 15788 ± 8021 pM, P<0.05), GLP-2 (pre 732 ± 182 vs post 1190 ± 447 ng/ml, P<0.001) and C- peptide, as well as after LT. Species belonging to Streptococaceae, Akkermansiacea, Rickenellaceae, Sutterellaceae, Enterobacteriaceae, Oscillospiraceae, Veillonellaceae, Enterobacterales_uc, and Fusobacteriaceae families increased after intervention and correlated positively with AUC of GLP-1 and GLP-2, and negatively with glucose, HbA1c, triglycerides and adiposity markers. Clostridium perfringens and Roseburia sp. 40_7 behaved similarly. In contrast, some species belonging to Lachnospiraceae, Erysipelotricaceae, and Rumnicocaceae families decreased and showed opposite correlations. Higher initial C-peptide was the only predictor for T2D remission, which was achieved in 69% of patients. Conclusions: Patients with obesity and T2D submitted to mRYGB show an enhanced incretin response, a reduced gut permeability and a metabolic improvement, associated with a specific microbiota signature.

Endoplasmic reticulum stress in pancreatic ß cells induces incretin desensitization and ß-cell dysfunction via ATF4-mediated PDE4D expression.

Pancreatic ß-cell dysfunction and eventual loss are key steps in the progression of type 2 diabetes (T2D). Endoplasmic reticulum (ER) stress responses, especially those mediated by the protein kinase RNA-like ER kinase and activating transcription factor 4 (PERK-ATF4) pathway, have been implicated in promoting these ß-cell pathologies. However, the exact molecular events surrounding the role of the PERK-ATF4 pathway in ß-cell dysfunction remain unknown. Here, we report our discovery that ATF4 promotes the expression of PDE4D, which disrupts ß-cell function via a downregulation of cAMP signaling. We found that ß-cell-specific transgenic expression of ATF4 led to early ß-cell dysfunction and loss, a phenotype that resembles accelerated T2D. Expression of ATF4, rather than C/EBP homologous protein (CHOP), promoted PDE4D expression, reduced cAMP signaling, and attenuated responses to incretins and elevated glucose. Furthermore, we found that ß-cells of leptin receptor-deficient diabetic (db/db) mice had elevated nuclear localization of ATF4 and PDE4D expression, accompanied by impaired ß-cell function. Accordingly, pharmacological inhibition of the ATF4 pathway attenuated PDE4D expression in the islets and promoted incretin-simulated glucose tolerance and insulin secretion in db/db mice. Finally, we found that inhibiting PDE4 activity with selective pharmacological inhibitors improved ß-cell function in both db/db mice and ß-cell-specific ATF4 transgenic mice. In summary, our results indicate that ER stress causes ß-cell failure via ATF4-mediated PDE4D production, suggesting the ATF4-PDE4D pathway could be a therapeutic target for protecting ß-cell function during the progression of T2D.NEW & NOTEWORTHY Endoplasmic reticulum stress has been implied to cause multiple ß-cell pathologies during the progression of type 2 diabetes (T2D). However, the precise molecular events underlying this remain unknown. Here, we discovered that elevated ATF4 activity, which was seen in T2D ß cells, attenuated ß-cell proliferation and impaired insulin secretion via PDE4D-mediated downregulation of cAMP signaling. Additionally, we demonstrated that pharmacological inhibition of the ATF4 pathway or PDE4D activity alleviated ß-cell dysfunction, suggesting its therapeutic usefulness against T2D.

Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets.

Simultaneous activation of the incretin G-protein-coupled receptors (GPCRs) via unimolecular dual-receptor agonists (UDRA) has emerged as a new therapeutic approach for type 2 diabetes. Recent studies also advocate triple agonism with molecules also capable of binding the glucagon receptor. In this scoping review, we discuss the cellular mechanisms of action (MOA) underlying the actions of these novel and therapeutically important classes of peptide receptor agonists. Clinical efficacy studies of several UDRAs have demonstrated favorable results both as monotherapies and when combined with approved hypoglycemics. Although the additive insulinotropic effects of dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) agonism were anticipated based on the known actions of either glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP) alone, the additional benefits from GCGR were largely unexpected. Whether additional synergistic or antagonistic interactions among these G-protein receptor signaling pathways arise from simultaneous stimulation is not known. The signaling pathways affected by dual- and tri-agonism require more trenchant investigation before a comprehensive understanding of the cellular MOA. This knowledge will be essential for understanding the chronic efficacy and safety of these treatments.

Emerging therapeutic options in the management of diabetes: recent trends, challenges and future directions.

Diabetes is a serious health issue that causes a progressive dysregulation of carbohydrate metabolism due to insufficient insulin hormone, leading to consistently high blood glucose levels. According to the epidemiological data, the prevalence of diabetes has been increasing globally, affecting millions of individuals. It is a long-term condition that increases the risk of various diseases caused by damage to small and large blood vessels. There are two main subtypes of diabetes: type 1 and type 2, with type 2 being the most prevalent. Genetic and molecular studies have identified several genetic variants and metabolic pathways that contribute to the development and progression of diabetes. Current treatments include gene therapy, stem cell therapy, statin therapy, and other drugs. Moreover, recent advancements in therapeutics have also focused on developing novel drugs targeting these pathways, including incretin mimetics, SGLT2 inhibitors, and GLP-1 receptor agonists, which have shown promising results in improving glycemic control and reducing the risk of complications. However, these treatments are often expensive, inaccessible to patients in underdeveloped countries, and can have severe side effects. Peptides, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are being explored as a potential therapy for diabetes. These peptides are postprandial glucose-dependent pancreatic beta-cell insulin secretagogues and have received much attention as a possible treatment option. Despite these advances, diabetes remains a major health challenge, and further research is needed to develop effective treatments and prevent its complications. This review covers various aspects of diabetes, including epidemiology, genetic and molecular basis, and recent advancements in therapeutics including herbal and synthetic peptides.

Dietary Vitamin A Affects the Function of Incretin-Producing Enteroendocrine Cells in Male Mice Fed a High-Fat Diet.

BACKGROUND: Retinol-binding protein 2 (RBP2) is an intracellular carrier for vitamin A in the absorptive enterocytes. Mice lacking RBP2 (Rbp2-/-) display an unexpected phenotype of obesity, glucose intolerance, and elevated glucose-dependent insulinotropic polypeptide (GIP) levels. GIP and glucagon-like peptide 1 (GLP-1) are incretin hormones secreted by enteroendocrine cells (EECs). We recently demonstrated the presence of RBP2 and other retinoid-related proteins in EECs. OBJECTIVES: Given RBP2's role in intracellular retinoid trafficking, we aimed to evaluate whether dietary vitamin A affects incretin-secreting cell function and gene expression. METHODS: Male Rbp2-/- mice and sex- and age-matched controls (n = 6-9) were fed a high-fat diet (HFD) for 18 wk containing normal (VAN, 4000 IU/kg of diet) or low (VAL, 25% of normal) vitamin A concentrations. Body weight was recorded biweekly. Plasma GIP and GLP-1 levels were obtained fasting and 30 min after an oral fat gavage at week 16. Glucose tolerance tests were also performed. Mice were killed at week 18, and blood and tissue samples were obtained. RESULTS: Rbp2-/- mice displayed greater weight gain on the VAN compared with the VAL diet from week 7 of the intervention (P ≤ 0.01). Stimulated GIP levels were elevated in Rbp2-/- mice compared with their controls fed the VAN diet (P = 0.02), whereas their GIP response was lower when fed the VAL diet (P = 0.03). Although no differences in GLP-1 levels were observed in the VAN diet group, a lower GLP-1 response was seen in Rbp2-/- mice fed the VAL diet (P = 0.02). Changes in incretin gene expression and that of other genes associated with EEC lineage and function were consistent with these observations. Circulating and hepatic retinoid levels revealed no systemic vitamin A deficiency across dietary groups. CONCLUSIONS: Our data support a role for RBP2 and dietary vitamin A in incretin secretion and gene expression in mice fed a HFD.

Alterations of adipokines, pancreatic hormones and incretins in acute and convalescent COVID-19 children.

BACKGROUND: The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), accountable for Coronavirus disease 2019 (COVID-19), may cause hyperglycemia and additional systemic complexity in metabolic parameters. It is unsure even if the virus itself causes type 1 or type 2 diabetes mellitus (T1DM or T2DM). Furthermore, it is still unclear whether even recuperating COVID-19 individuals have an increased chance to develop new-onset diabetes. METHODS: We wanted to determine the impact of COVID-19 on the levels of adipokines, pancreatic hormones, incretins and cytokines in acute COVID-19, convalescent COVID-19 and control children through an observational study. We performed a multiplex immune assay analysis and compared the plasma levels of adipocytokines, pancreatic hormones, incretins and cytokines of children presenting with acute COVID-19 infection and convalescent COVID-19. RESULTS: Acute COVID-19 children had significantly elevated levels of adipsin, leptin, insulin, C-peptide, glucagon and ghrelin in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had elevated levels of adipsin, leptin, insulin, C-peptide, glucagon, ghrelin and Glucagon-like peptide-1 (GLP-1) in comparison to control children. On the other hand, acute COVID-19 children had significantly decreased levels of adiponectin and Gastric Inhibitory Peptide (GIP) in comparison to convalescent COVID-19 and controls. Similarly, convalescent COVID-19 children had decreased levels of adiponectin and GIP in comparison to control children. Acute COVID-19 children had significantly elevated levels of cytokines, (Interferon (IFN)) IFNγ, Interleukins (IL)-2, TNFα, IL-1α, IL-1ß, IFNα, IFNß, IL-6, IL-12, IL-17A and Granulocyte-Colony Stimulating Factors (G-CSF) in comparison to convalescent COVID-19 and controls. Convalescent COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IL-1ß, IFNα, IFNß, IL-6, IL-12, IL-17A and G-CSF in comparison to control children. Additionally, Principal component Analysis (PCA) analysis distinguishes acute COVID-19 from convalescent COVID-19 and controls. The adipokines exhibited a significant correlation with the levels of pro-inflammatory cytokines. CONCLUSION: Children with acute COVID-19 show significant glycometabolic impairment and exaggerated cytokine responses, which is different from convalescent COVID-19 infection and controls.

The expanding incretin universe: from basic biology to clinical translation.

Incretin hormones, principally glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1(GLP-1), potentiate meal-stimulated insulin secretion through direct (GIP + GLP-1) and indirect (GLP-1) actions on islet ß-cells. GIP and GLP-1 also regulate glucagon secretion, through direct and indirect pathways. The incretin hormone receptors (GIPR and GLP-1R) are widely distributed beyond the pancreas, principally in the brain, cardiovascular and immune systems, gut and kidney, consistent with a broad array of extrapancreatic incretin actions. Notably, the glucoregulatory and anorectic activities of GIP and GLP-1 have supported development of incretin-based therapies for the treatment of type 2 diabetes and obesity. Here we review evolving concepts of incretin action, focusing predominantly on GLP-1, from discovery, to clinical proof of concept, to therapeutic outcomes. We identify established vs uncertain mechanisms of action, highlighting biology conserved across species, while illuminating areas of active investigation and uncertainty that require additional clarification.

Individuals with type 2 diabetes have higher density of small intestinal neurotensin-expressing cells.

Neurotensin (NT) is a gastro-intestinal hormone involved in several pathways that regulate energy and glucose homeostasis. NT was hypothesized to act in synergy with incretin hormones to potentiate its anti-diabetic effects. Additionally, circulating NT levels were shown to rise after bariatric surgery-induced weight loss. Knowledge of NT-secreting cells distribution along the small intestine and its variation according to diabetes status could provide insights on NT role in mediating type 2 diabetes (T2D) improvement after bariatric surgery. So, our aims were to characterize NT-expressing cell distribution along the human small intestine and to compare the relative density of NT-expressing cells in the small intestine of individuals with and without T2D undergoing bariatric surgery for obesity treatment. Autopsy-derived small intestine fragments (n = 30) were obtained at every 20 cm along the entire intestinal length. Additionally, jejunum biopsies (n = 29) were obtained during elective gastric bypass interventions from patients with (n = 10) or without T2D (n = 18). NT-expressing cells were identified by immunohistochemistry and quantified via computerized morphometric analysis. NT-expressing cell density increased along the human small intestine. NT-expressing cell density was significantly higher from 200 cm distal to the duodenojejunal flexure onward, as well as in subjects with T2D when compared to those without T2D. NT-expressing cell density increases along the human small gut, and a higher density is found in individuals with T2D. This finding suggests a potential role for NT in the mechanisms of disease and T2D improvement observed after bariatric surgery.

Enhanced Endosomal Signaling and Desensitization of GLP-1R vs GIPR in Pancreatic Beta Cells.

The incretin receptors, glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR), are prime therapeutic targets for the treatment of type 2 diabetes (T2D) and obesity. They are expressed in pancreatic beta cells where they potentiate insulin release in response to food intake. Despite GIP being the main incretin in healthy individuals, GLP-1R has been favored as a therapeutic target due to blunted GIPR responses in T2D patients and conflicting effects of GIPR agonists and antagonists in improving glucose tolerance and preventing weight gain. There is, however, a recently renewed interest in GIPR biology, following the realization that GIPR responses can be restored after an initial period of blood glucose normalization and the recent development of dual GLP-1R/GIPR agonists with superior capacity for controlling blood glucose levels and weight. The importance of GLP-1R trafficking and subcellular signaling in the control of receptor outputs is well established, but little is known about the pattern of spatiotemporal signaling from the GIPR in beta cells. Here, we have directly compared surface expression, trafficking, and signaling characteristics of both incretin receptors in pancreatic beta cells to identify potential differences that might underlie distinct pharmacological responses associated with each receptor. Our results indicate increased cell surface levels, internalization, degradation, and endosomal vs plasma membrane activity for the GLP-1R, while the GIPR is instead associated with increased plasma membrane recycling, reduced desensitization, and enhanced downstream signal amplification. These differences might have potential implications for the capacity of each incretin receptor to control beta cell function.

ßHB inhibits glucose-induced GLP-1 secretion in GLUTag and human jejunal enteroids.

Ingestion of nutrients stimulates incretin secretion from enteroendocrine cells (EECs) of the epithelial layer of the gut. Glucagon-like peptide-1 (GLP-1) is one of these incretins that stimulate postprandial insulin release and signal satiety to the brain. Understanding the regulation of incretin secretion might open up new therapeutic options for obesity and type-2 diabetes mellitus. To investigate the inhibitory effect of the ketone body ß-hydroxybutyrate (ßHB) on glucose-induced GLP-1 secretion from EECs, in vitro cultures of murine GLUTag cells and differentiated human jejunal enteroid monolayers were stimulated with glucose to induce GLP-1 secretion. The effect of ßHB on GLP-1 secretion was studied using ELISA and ECLIA methods. GLUTag cells stimulated with glucose and ßHB were analysed using global proteomics focusing on cellular signalling pathways and the results were verified by Western blot. Results demonstrated ßHB had a significant inhibitory effect on glucose-induced GLP-1 secretion at a dose of 100 mM in GLUTag cells. In differentiated human jejunal enteroid monolayers, glucose-induced secretion of GLP-1 was inhibited at a much lower dose of 10 mM ßHB. The addition of ßHB to GLUTag cells resulted in decreased phosphorylation of kinase AKT and transcription factor STAT3 and also influenced the expressions of signalling molecule IRS-2, kinase DGKε and receptor FFAR3. In conclusion, ßHB displays an inhibitory effect on glucose-induced GLP-1 secretion in vitro in GLUTag cells and in differentiated human jejunal enteroid monolayers. This effect may be mediated through multiple downstream mediators of G-protein coupled receptor activation, such as PI3K signalling.

Benefits of GLP-1 Mimetics on Epicardial Adiposity.

The epicardial adipose tissue, which is referred to as fats surrounding the myocardium, is an active organ able to induce cardiovascular problems in pathophysiologic conditions through several pathways, such as inflammation, fibrosis, fat infiltration, and electrophysiologic problems. So, control of its volume and thickness, especially in patients with diabetes, is highly important. Incretin-based pharmacologic agents are newly developed antidiabetics that could provide further cardiovascular benefits through control and modulating epicardial adiposity. They can reduce cardiovascular risks by rapidly reducing epicardial adipose tissues, improving cardiac efficiency. We are at the first steps of a long way, but current evidence demonstrates the sum of possible mechanisms. In this study, we evaluate epicardial adiposity in physiologic and pathologic states and the impact of incretin-based drugs.

Possible Mechanisms and Molecular Signaling of Incretins against the Development of Type 2 Diabetes Mellitus.

The increasing number of cases of diabetes mellitus (DM) and related diseases has become a global health concern. In this context, controlling blood glucose levels is critical to prevent and/or slow down the development of diabetes-related complications. Incretins, as gutderived hormones that trigger the post-meal secretion of insulin, are a well-known family of blood glucose modulators. Currently, incretin medications, including glucagon-like peptide-1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors, are extensively used to treat patients with type 2 diabetes mellitus (T2D). Several experimental and clinical studies illustrate that these metabolic hormones exert their antidiabetic effects through multiple molecular mechanisms. Accordingly, the current review aims to investigate key mechanisms and signaling pathways, such as the cAMP/PKA, Nrf2, PI3K/Akt, and AMPK pathways, associated with the antidiabetic effects of incretins. It also summarizes the outcomes of a group of clinical trials evaluating the incretins' antidiabetic potential in diabetic patients.

Metabolic Dysregulation in Adult Survivors of Pediatric Hematopoietic Stem Cell Transplantation: The Role of Incretins.

CONTEXT: Survivors of pediatric hematopoietic stem cell transplantation (HSCT) have increased risk of developing metabolic syndrome (MetS), but the mechanisms are poorly understood. OBJECTIVE: We aimed to test the hypothesis that insufficient secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) plays a pathogenetic role in HSCT survivors with MetS. METHODS: This cross-sectional cohort study, conducted at the Danish national referral center for HSCT, studied 42 male HSCT survivors (median age 28.9 years) for a median 21.2 years from HSCT, along with 15 age- and sex-matched healthy controls. Main outcome measures were glucose metabolism and incretin hormones (by oral glucose tolerance test [OGTT]) and MetS criteria. The hypothesis was formulated before data collection. RESULTS: GLP-1, GIP, and glucagon during an OGTT were similar in patients and controls, with no overall difference between survivors with (24%) and without MetS. However, fasting glucagon was significantly higher in patients with hypertriglyceridemia (mean difference [MD]: 6.1 pmol/L; 95% CI, 1.5-10.8; P = 0.01), and correlated with HDL (MD: 4.7 mmol/L; 95% CI, -0.6 to 9.9; P = 0.08), android-gynoid ratio (correlation coefficient [r] = 0.6, P = 0.0001) and waist-hip ratio (r = 0.5, P = 0.002). A similar pattern was seen for GIP, correlating positively with triglyceride (MD: 60%; 95% CI, 44-82; P = 0.002). GIP levels were significantly increased in patients treated with total body irradiation (TBI) (MD: 165%; 95% CI, 118-230; P = 0.004), which was found to be a significant risk factor for MetS. CONCLUSION: This study demonstrates an altered production of incretin hormones in HSCT survivors previously treated with TBI, developing dyslipidemia and abdominal adiposity.

A review on phytochemical and pharmacological facets of tropical ethnomedicinal plants as reformed DPP-IV inhibitors to regulate incretin activity.

Type 2 diabetes mellitus is a metabolic disorder resulting from impaired insulin secretion and resistance. Dipeptidyl peptidase (DPP)-IV is an enzyme known to trigger the catalysis of insulinotropic hormones, further abating the endogenous insulin levels and elevating the glucose levels in blood plasma. In the field of drug development, DPP-IV inhibitors have opened up numerous opportunities for leveraging this target to generate compounds as hypoglycemic agents by regulating incretin activity and subsequently decreasing blood glucose levels. However, the practice of synthetic drugs is an apparent choice but poses a great pharmacovigilance issue due to their incessant undesirable effects. The ideology was set to inventively look upon different ethnomedicinal plants for their anti-diabetic properties to address these issues. To date, myriads of phytochemicals are characterized, eliciting an anti-diabetic response by targeting various enzymes and augmenting glucose homeostasis. Antioxidants have played a crucial role in alleviating the symptoms of diabetes by scavenging free radicals or treating the underlying causes of metabolic disorders and reducing free radical formation. Plant-based DPP-IV inhibitors, including alkaloids, phenolic acid, flavonoids, quercetin, and coumarin, also possess antioxidant capabilities, providing anti-diabetic and antioxidative protection. This review article provides a new gateway for exploring the ability of plant-based DPP-IV inhibitors to withstand oxidative stress under pathological conditions related to diabetes and for reforming the strategic role of ethnomedicinal plants as potent DPP-IV inhibitors through the development of polyherbal formulations and nanophytomedicines to regulate incretin activity.

SMALL INTESTINAL L CELL DENSITY IN PATIENTS WITH SEVERE OBESITY AFTER ROUX-EN-Y GASTRIC BYPASS.

BACKGROUND: Enteroendocrine L cells can be found in the entire gastrointestinal tract and their incretins act on glycemic control and metabolic homeostasis. Patients with severe obesity and type 2 diabetes mellitus may have lower density of L cells in the proximal intestine. AIMS: This study aimed to analyze the density of L cells in the segments of the small intestine in the late postoperative of Roux-en-Y gastric bypass in diabetic patients with standardization of 60 cm in both loops, alimentary and biliopancreatic. METHODS: Immunohistochemistry analysis assays were made from intestinal biopsies in three segments: gastrointestinal anastomosis (GIA= Point A), enteroenteral anastomosis (EEA= Point B= 60 cm distal to the GIA) and 60 cm distal to the enteroenteral anastomosis (Point C). RESULTS: A higher density of L cells immunostaining the glucagon-1 peptide was observed in the distal portion (Point C) when compared to the more proximal portions (Points A and B). CONCLUSIONS: The concentration of L cells is higher 60 cm distal to enteroenteral anastomosis when comparing to proximal segments and may explain the difference in intestinal lumen sensitization and enterohormonal response after Roux-en-Y gastric bypass.