Distribution and function of glucagon-like peptide 1 (GLP-1) in the digestive tract of mammals and the clinical use of its analogues

Recently, interest in glucagon-like peptide-1 (GLP-1) and other peptides derived from preproglucagon has increased significantly. GLP-1 is a 30-amino acid peptide hormone produced in L-type enteroendocrine cells as a response to food intake. GLP-1 is rapidly metabolized and inactivated by the dipeptidyl peptidase IV enzyme before the hormone leaves the intestine, which increases the likelihood that GLP-1 action is transmitted through sensory neurons in the intestine and liver through the GLP-1 receptor. The main actions of GLP-1 are to stimulate insulin secretion (i.e. act as incretin hormone) and inhibit glucagon secretion, thus contributing to the reduction of postprandial glucose spikes. GLP-1 also inhibits motility and gastrointestinal secretion, and therefore acts as part of the „small bowel brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these effects, GLP-1 or GLP-1 receptor agonists are now increasingly used to treat type 2 diabetes. Reduced GLP-1 secretion may contribute to the development of obesity, and excessive secretion may be responsible for postprandial reactive hypoglycemia. The use of GLP-1 agonists opens up new possibilities for the treatment of type 2 diabetes and other metabolic diseases. In the last two decades, many interesting studies covering both the physiological and pathophysiological role of GLP-1 have been published, and our understanding of GLP-1 has broadened significantly. In this review article, we have tried to describe our current understanding of how GLP-1 works as both a peripheral hormone and as a central neurotransmitter in health and disease. We focused on its biological effects on the body and the potential clinical application in relation to current research.

Adherence and persistence rates of major antidiabetic medications: a review

The objective of this paper was to review the adherence and persistence rates of major antidiabetic medication classes (i.e., metformin, sulfonylureas, sodium glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, insulin, glucagon-like peptide-1 receptor agonists, and thiazolidinediones) by summarizing the major findings of the studies published since 2017. In addition, we reported the potential causes for low adherence and persistence of antidiabetic medications. Based on the literature, the highest rate of adherence and persistence was consistently observed in metformin users. Second to metformin were sodium glucose cotransporter-2 inhibitors. Injectable therapies such as insulin and glucagon-like peptide-1 receptor agonists trailed low on the adherence and persistence rates. To the best of our knowledge, no studies published since the year 2017 analyzed the adherence and persistence of thiazolidinediones independently. The most frequently cited cause for low adherence and persistence was the severity of adverse events. Baseline characteristics (e.g., baseline HbA1c level), demographic information (e.g., age, gender, or ethnicity), and comorbidity profiles also had significant impacts on adherence and persistence in patients with type 2 diabetes mellitus.

Limosilactobacillus fermentum MG4295 Improves Hyperglycemia in High-Fat Diet-Induced Mice

Hyperglycemia due to uncontrolled glucose regulation is widely known as cause of diabetes, non-alcoholic fatty liver disease (NAFLD), and other complications. NAFLD refers to a condition in which fat is excessively accumulated, whether inflamed or not, and has caused serious medical problems in recent years. The aim of this study was to explore the antihyperglycemia effects of Limosilactobacillus fermentum MG4295 (L. fermentum MG4295) in high-fat diet (HFD)-induced in vivo. We demonstrated the suitability of L. fermentum MG4295 as a probiotic by observing its stability, survivability, and proliferation under simulated gastrointestinal conditions, and safety, antibiotic susceptibility, hemolysis, and enzyme activity. The potential antihyperglycemic activity of L. fermentum MG4295 was investigated in an HFD and sugar-water-induced mouse model. Administration of this strain for 12 weeks showed an improved trend in glucose tolerance, insulin, alanine amino transferase, total cholesterol, low-density lipoprotein cholesterol, and glucagon-like peptide-1. Histopathological analysis revealed that L. fermentum MG4295 significantly reduced the histopathological scores of hepatic steatosis, inflammation, and hepatocellular hypertrophy in liver tissues and lipid content in adipose tissues. Administration of L. fermentum MG4295 upregulated IRS-1, AKT, and GLUT4 and downregulated G6Pc and PEPCK expression in liver and/or muscle tissues. Our results suggest that L. fermentum MG4295 can improve hyperglycemia. Furthermore, it can be used as a dietary functional supplement to manage blood glucose.

Identification of G protein-coupled receptor 55 (GPR55) as a target of curcumin

The identification of molecular targets of bioactive food components is important to understand the mechanistic aspect of their physiological functions. Here, we have developed a screening system that enables us to determine the activation of G protein-coupled receptors (GPCRs) by food components and have identified GPR55 as a target for curcumin. Curcumin activated GPR55 and induced serum-response element- and serum-response factor-mediated transcription, which were inhibited by Rho kinase and GPR55 antagonists. Both the methoxy group and the heptadienone moiety of curcumin were required for GPR55 activation. The F1905.47 residue of GPR55 was important for the interaction with curcumin. The curcumin-induced secretion of glucagon-like peptide-1 in GLUTag cells was inhibited by a GPR55 antagonist. These results indicate that expression screening is a useful system to identify GPCRs as targets of food components and strongly suggest that curcumin activates GPR55 as an agonist, which is involved in the physiological function of curcumin.

Glucose-Lowering Medications and Post-Dementia Survival in Patients with Diabetes and Dementia

Background: The effectiveness of glucose-lowering drugs (GLDs) is unknown among patients with dementia. Objective: To analyze all-cause mortality among users of six GLDs in dementia and dementia-free subjects, respectively. Methods: This was a longitudinal open-cohort registry-based study using data from the Swedish Dementia Registry, Total Population Register, and four supplemental registers providing data on dementia status, drug usage, confounders, and mortality. The cohort comprised 132,402 subjects with diabetes at baseline, of which 11,401 (8.6%) had dementia and 121,001 (91.4%) were dementia-free. Subsequently, comparable dementia – dementia-free pairs were sampled. Then, as-treated and intention-to-treat exposures to metformin, insulin, sulfonylurea, dipeptidyl-peptidase-4 inhibitors, glucagon-like peptide-1 analogues (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) were analyzed in the parallel dementia and dementia-free cohorts. Confounding was addressed using inverse-probability weighting and propensity-score matching, and flexible parametric survival models were used to produce hazard ratios (HR) and 95% confidence intervals (CI) of the association between GLDs and all-cause mortality. Results: In the as-treated models, increased mortality was observed among insulin users with dementia (HR 1.34 [95%CI 1.24–1.45]) as well as in dementia-free subjects (1.54 [1.10–1.55]). Conversely, sulfonylurea was associated with higher mortality only in dementia subjects (1.19 [1.01–1.42]). GLP-1a (0.44 [0.25–0.78]) and SGLT-2i users with dementia (0.43 [0.23–0.80]) experienced lower mortality compared to non-users. Conclusion: Insulin and sulfonylurea carried higher mortality risk among dementia patients, while GLP-1a and SGLT-2i were associated with lower risk. GLD-associated mortality varied between dementia and comparable dementia-free subjects. Further studies are needed to optimize GLD use in dementia patients.

Therapeutic Advances in Diabetic Nephropathy

Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD) in the United States. Risk factor modification, such as tight control of blood glucose, management of hypertension and hyperlipidemia, and the use of renin–angiotensin–aldosterone system (RAAS) blockade have been proven to help delay the progression of DKD. In recent years, new therapeutics including sodium-glucose transport protein 2 (SGLT2) inhibitors, endothelin antagonists, glucagon like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRA), have provided additional treatment options for patients with DKD. This review discusses the various treatment options available to treat patients with diabetic kidney disease.

Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation

The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists.

GLP-1a: Going Beyond Traditional Use

Glucagon-like peptide-1 (GLP-1) is a human incretin hormone derived from the proglucagon molecule. GLP-1 receptor agonists are frequently used to treat type 2 diabetes mellitus and obesity. However, the hormone affects the liver, pancreas, brain, fat cells, heart, and gastrointestinal tract. The objective of this study was to perform a systematic review on the use of GLP-1 other than in treating diabetes. PubMed, Cochrane, and Embase were searched, and the PRISMA guidelines were followed. Nineteen clinical studies were selected. The results showed that GLP-1 agonists can benefit defined off-medication motor scores in Parkinson’s Disease and improve emotional well-being. In Alzheimer’s disease, GLP-1 analogs can improve the brain’s glucose metabolism by improving glucose transport across the blood–brain barrier. In depression, the analogs can improve quality of life and depression scales. GLP-1 analogs can also have a role in treating chemical dependency, inhibiting dopaminergic release in the brain’s reward centers, decreasing withdrawal effects and relapses. These medications can also improve lipotoxicity by reducing visceral adiposity and decreasing liver fat deposition, reducing insulin resistance and the development of non-alcoholic fatty liver diseases. The adverse effects are primarily gastrointestinal. Therefore, GLP-1 analogs can benefit other conditions besides traditional diabetes and obesity uses.

Contemporary (2019) prevalence of cardiovascular disease in adults with type 2 diabetes in Brazil: the cross-sectional CAPTURE study

Background Type 2 diabetes (T2D) is a known risk factor for cardiovascular disease (CVD), and CVD is a major cause of mortality in patients with T2D. The CAPTURE study investigated the contemporary (2019) prevalence of established CVD in adults with T2D around the world. We report the findings from Brazil. Methods The multinational, non-interventional, cross-sectional CAPTURE study was conducted across 13 countries from five continents. The current manuscript explores data for the CAPTURE study sample in Brazil. Standardized demographic and clinical data were collected from adults with T2D aged ≥ 18 years attending a single routine healthcare visit in primary or specialized care between December 2018 and September 2019. Data were analyzed descriptively. Results Data from 912 adults with T2D were collected in the CAPTURE study in Brazil, with 822 patients from primary care and 90 patients from specialized care. Median (interquartile range [IQR]) patient characteristics were as follows: age 64 years (57; 71), diabetes duration 11 years (6; 19), glycated hemoglobin 7.7% (6.7; 9.1), and body mass index 29.5 kg/m2 (26.4; 33.5); 59% were female. The CVD prevalence and atherosclerotic CVD prevalence in the Brazil sample were 43.9% (95% confidence interval [CI] 40.9; 46.8) and 37.6% (95% CI 34.7; 40.5), respectively. The majority of patients with CVD had atherosclerotic CVD (85.8%). For the specific CVD subtypes, coronary heart disease prevalence was 27.9% (95% CI 25.2; 30.5), heart failure was 12.4% (95% CI 10.4; 14.4), cerebrovascular disease was 8.7% (95% CI 6.8; 10.5), and carotid artery disease was 3.4% (95% CI 2.3; 4.5). Glucagon-like peptide-1 receptor agonists and/or sodium-glucose co-transporter-2 inhibitors with proven cardiovascular benefit were prescribed to 15.5% of patients with CVD, compared with 18.4% of patients without CVD. Conclusions CAPTURE was the first multinational, standardized study to provide contemporary data on CVD prevalence in adults with T2D in Brazil, and it demonstrated that almost one in two adults with T2D had established CVD. Except for carotid artery disease, the prevalence of all CVD subtypes in adults with T2D in Brazil appeared higher than the global CAPTURE prevalence. Trial registration NCT03786406, NCT03811288

Efficacy of L-Arabinose in Lowering Glycemic and Insulinemic Responses: The Modifying Effect of Starch and Fat

L-arabinose is a bio-active compound derived from the side-streams of plant food processing. L-arabinose lowers glycemic and insulinemic responses when added to simple water-based sugary liquids. However, the effect in more complex foods, including fat and starch, is inconsistent. This study assessed the effect of fat or starch in a sugary drink on the efficacy of L-arabinose. Twenty-three healthy volunteers (12 female/11 male; aged 24 ± 3 years; BMI 23 ± 3 kg/m2) participated in a randomised cross-over trial with six drinks: control: 50 g sucrose in water; fat: control + 22 g oil; starch: control + 50 g starch; and all three with and without the addition of 5 g L-arabinose. The addition of L-arabinose to the control drink lowered glucose and insulin peaks by 15% and 52%; for the fat drink by 8% and 45%; and for the starch drink by 7% and 29%. For all three drinks, adding L-arabinose increased glucagon-like peptide 1 (GLP-1) responses and lowered Glucose-dependent insulinotropic polypeptide (GIP) responses. Despite adding large quantities of starch and fat to sugary drinks, L-arabinose significantly lowered postprandial glycemic and insulinemic responses in healthy subjects. These findings suggest that L-arabinose can be functional in more complex foods; however, the factors affecting its efficacy in solid food matrices need to be studied in more detail.