I. Introduction II. History of the Incretin Concept: Discovery of Gastric Inhibitory Polypeptide III. Discovery of GLP-1 IV. Structures of GLPs and Family of Glucagon-Related Peptides V. Tissue Distribution of the Expression of GLPs A. Pancreatic α-cells B. Intestinal L cells C. Central nervous system VI. Proglucagon Biosynthesis A. Organization/structure of the proglucagon gene B. Regulation of glucagon gene expression C. Posttranslational processing of proglucagon VII. Regulation of GLP Secretion A. Overview B. Intracellular signals C. Carbohydrates D. Fats E. Proteins F. Endocrine G. Neural H. GLP-2 VIII. Metabolism of GLPs A. GLP-1 B. GLP-2 IX. Physiological Actions of GLPs A. Overview B. Pancreatic islets C. Counterregulatory actions of GLP-1 and leptin on β-cells D. Stomach E. Lung F. Brain G. Liver, skeletal muscle, and fat H. Pituitary, hypothalamus, and thyroid I. Cardiovascular system J. GLP-2 X. GLP Receptors A. Structure B. Signaling C. Distribution D. Regulation E. GLP-2 XI. Pathophysiology o...

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The glucagon-like peptides.

I. Introduction THE presence of intestinal factors regulating the function of endocrine secretion from the pancreas was first described in 1906 by Moore and colleagues (1). The idea that humoral factors secreted from the gut might act in this way arose after the recognition of “secretin” as a regulator of pancreatic secretion. Later it became evident that the hypoglycemic intestinal factor(s) is/are not “secretin” and the names “incretin” and “duodenin” were introduced in the 1920s and 1930s to describe these putative mediators (2–4). For several decades the nature of this/these factor(s) remained largely unknown (5–8) and before the first incretin hormone was chemically characterized, several other hormones produced in the gastrointestinal tract were discovered. The connection between the gastrointestinal tract and the endocrine pancreas was shown in the 1960s when insulin became measurable in plasma. In these classic studies, the insulin response to oral glucose and intravenous glucose, resulting in nea...

Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide

Exendin-4 is a 39 amino acid peptide isolated from the salivary secretions of the Gila monster (Heloderma suspectum). It shows 53% sequence similarity to glucagon-like peptide (GLP)-1. Unlike GLP-1, exendin-4 has a prolonged glucose-lowering action in vivo. We compared the potency and duration of glucose-lowering effects of exendin-4 and GLP-1 in hyperglycemic db/db and ob/ob mice. Whereas reductions in plasma glucose of up to 35% vanished within 1 h with most doses of GLP-1, the same doses of exendin-4 resulted in a similar glucose-lowering effect that persisted for >4 h. Exendin-4 was 5,530-fold more potent than GLP-1 in db/db mice (effective doses, 50% [ED50s] of 0.059 microg/kg +/-0.15 log and 329 microg/kg+/-0.22 log, respectively) and was 5,480-fold more potent in ob/ob mice (ED50s of 0.136 microg/kg+/-0.10 log and 744 microg/kg+/-0.21 log, respectively) when the percentage fall in plasma glucose at 1 h was used as the indicator response. Exendin-4 dose-dependently accelerated glucose lowering in diabetic rhesus monkeys by up to 37% with an ED50 of 0.25 microg/kg +/-0.09 log. In two experiments in which diabetic fatty Zucker rats were injected subcutaneously twice daily for 5-6 weeks with doses of exendin-4 up to 100 microg x rat(-1) x day(-1) (approximately 250 microg/kg), HbA1c was reduced relative to saline-injected control rats. Exendin-4 treatment was also associated in each of these experiments with weight loss and improved insulin sensitivity, as demonstrated by increases of up to 32 and 49%, respectively, in the glucose infusion rate (GIR) in the hyperinsulinemic euglycemic clamp. ED50s for weight loss and the increase in clamp GIR were 1.0 microg/kg+/-0.15 log and 2.4 microg/kg+/-0.41 log, respectively. In conclusion, acute and chronic administration of exendin-4 has demonstrated an antidiabetic effect in several animal models of type 2 diabetes.

Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).

Our knowledge of the physiological systems controlling energy homeostasis has increased dramatically over the last decade. The roles of peripheral signals from adipose tissue, pancreas, and the gastrointestinal tract reflecting short- and long-term nutritional status are now being described. Such signals influence central circuits in the hypothalamus, brain stem, and limbic system to modulate neuropeptide release and hence food intake and energy expenditure. This review discusses the peripheral hormones and central neuronal pathways that contribute to control of appetite.

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Hormonal Regulation of Food Intake

The increasing prevalence of obesity worldwide has imparted renewed impetus to the study of the mechanisms of appetite regulation. Digestion and nutrient absorption take place in the gastrointestinal (GI) tract, whereas food intake is controlled by neuronal circuits in the central nervous system. The need for gut-brain cross talk is therefore clear. It is now recognized that hormones released into the circulation from the GI tract in response to nutritional stimuli form a key component of this gut-brain axis. Peptides such as glucagon-like peptide-1, oxyntomodulin, pancreatic polypeptide, and peptide YY3-36 reduce food intake in both animal models and in humans. Physiologically, such peptides are thought to act as satiety signals and meal terminators. Here, we review the current state of the field of the effects of gut hormone action on appetite control.

Gastrointestinal satiety signals.

Stable expression of the rat GLP-I receptor in CHO cells: Activation and binding characteristics utilizing GLP-I(7–36)-amide, oxyntomodulin, exendin-4, and exendin(9–39)

125I-glucagon-like peptide l(7-36)amide was covalently cross-linked to a specific binding protein in human insulinoma cell membranes. A single radiolabeled band at Mr 63,000 was identified by SDS-PAGE after solubilization of the ligand-binding protein complex. The molecular weight of this apparent GLP-1 receptor in human endocrine pancreatic tissue was of identical size as the GLP-1 receptor on rat insulinoma-derived RINm5F cell membranes. The radiolabeled band was undetectable when 1 µM of unlabeled GLP-l(7-36)am-ide or of the GLP-1 antagonist exendin(9-39)amide was included in the binding assay. Utilizing isolated poly-A+ RNA from the human insulinoma and a 1,500 bp Eco-RI fragment of the cDNA coding for the rat GLP-1(7-36)amide receptor for Northern blot analysis, a main hybridization signal at about 7 kb was found by Nothern blotting. Our data provide the first direct evidence of the existence of GLP-1 receptors in human endocrine pancreatic tissue.

Detection of the Human Glucagon-Like Peptide 1(7-36) Amide Receptor on Insulinoma-Derived Cell Membranes

Glucagon-like peptide-I (GLP-I) is a potent incretin hormone and mediates its actions via the cyclic AMP (cAMP) pathway. The GLP-I receptor belongs to the family of seven-transmembrane domain receptors coupled to G proteins. We have analyzed the regulation of GLP-I receptor function and expression by its own ligand and the cAMP-dependent pathway in rat insulinoma-derived beta cells (RINm5F). The GLP-I receptor underwent rapid homologous desensitization, which occurred at the receptor level. This was characterized by a reduced binding capacity not mediated by protein kinase A (PKA). GLP-I receptor mRNA levels were down-regulated during incubation of cells by agents increasing cAMP levels including GLP-I itself. This effect was dependent upon time and concentration. Forskolin, the PKA activator 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole-3, 5-monophosphorothiotate, and GLP-I stabilized the GLP-I receptor mRNA. All induced down-regulation of the GLP-I receptor number within 3 h, a time point at which GLP-I receptor mRNA levels were not decreased. This effect was not influenced by cycloheximide. Therefore, in addition to transcriptional effects, posttranslational mechanisms exist to regulate GLP-I receptor numbers in insulin-secreting cells.

Ligand-induced regulation of glucagon-like peptide-I receptor function and expression in insulin-secreting β cells

Glucagon-like peptide-I (GLP-I) is an important insulinotropic incretin hormone. The GLP-I receptor belongs to the family of seven transmembrane domain receptors. We studied the regulation of its expression by the protein kinase C (PKC)-dependent pathway in rat insulinoma RINm5F cells. Cells were incubated for 3, 6 and 24 h with an optimal concentration of tissue plasminogen activator (TPA), an activator of PKC. TPA induced significantly lower GLP-I receptor mRNA levels under steady-state conditions after 6 and 24 h. The stability of the GLP-I receptor mRNA was unchanged. The number of GLP-I receptors present on RINm5F cells was reduced after 6 and 24 h. TPA did not influence the affinity of remaining receptors to its specific ligand. These data indicate that PKC activation downregulates the expression of the GLP-I receptor gene, mainly at the transcriptional level.

Regulation of glucagon-like peptide-I receptor expression and transcription by the protein kinase C pathway

In the process of rice straw nutrient bowl tray drying, real-time detection of changes in moisture content to achieve automatic adjustment of drying factors is one of the important means to ensure its drying quality. At present, the main method for measuring the moisture content of rice straw nutrient bowl trays is the drying and weighing method. This method is not only time consuming, labor intensive, and complex to operate, but also has poor real-time performance, which cannot meet the demand for real-time detection of the moisture content in the production process of rice straw nutrient bowl trays. In this regard, a real-time moisture content detection method for rice straw nutrient bowl trays based on hyperspectral imaging technology was studied. In this study we took the rice straw nutrient bowl tray during the drying process as the research object, adopted a single factor experiment, took microwave power, hot air temperature, and hot air speed as the drying factors, and took the moisture content of the rice straw nutrient bowl tray as the drying index. The rice straw nutrient bowl tray was dried according to the designed drying conditions. When drying, we removed the rice straw nutrient bowl tray every 5 min for weighing and collected hyperspectral image data within the wavelength range of 400~1000 nm until its quality remained unchanged. A total of 204 samples were collected. Using the average spectrum of the region of interest as the sample for effective spectral information, spectral preprocessing was performed using multivariate scattering correction (MSC), standardization normal variables (SNV), and Savitzky–Golay convolution smoothing (SG) methods. Principal component analysis (PCA) and competitive adaptive reweighting (CARS) methods were adopted for the dimensionality reduction of the spectral data. Three prediction models of rice straw nutrient bowl tray moisture content, namely random forest regression (RF), particle swarm optimization support vector regression (PSO-SVR), and XGBoost model were constructed using the reduced dimension spectral data. Finally, the performance of the model was compared using the coefficient of determination (R2) and mean square error (RMSE) as evaluation indicators. The research results indicate that the PCA-PSO-SVR model established based on SG method preprocessing has the best predictive performance, with a training set decision coefficient R2C of 0.984, a training set mean square error RMSE-C of 2.775, a testing set decision coefficient R2P of 0.971, and a testing set mean square error RMSE-P of 3.448. The model therefore has a high accuracy. This study achieved rapid detection of water content in rice straw nutrition trays. This method provides a reliable theoretical basis and technical support for the rapid detection of rice straw nutrient bowl tray moisture content, and is of great significance for improving the quality of rice straw nutrient bowl trays; promoting the popularization and application of raising rice straw nutrient bowl tray seedlings and whole process mechanized planting technology system; improving soil structure; and protecting the ecological environment.

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Jiwen Jiang

Papers

Stable expression of the rat GLP-I receptor in CHO cells: Activation and binding characteristics utilizing GLP-I(7–36)-amide, oxyntomodulin, exendin-4, and exendin(9–39)

Detection of the Human Glucagon-Like Peptide 1(7-36) Amide Receptor on Insulinoma-Derived Cell Membranes

Ligand-induced regulation of glucagon-like peptide-I receptor function and expression in insulin-secreting β cells

Regulation of glucagon-like peptide-I receptor expression and transcription by the protein kinase C pathway

Hyperspectral Detection of Moisture Content in Rice Straw Nutrient Bowl Trays Based on PSO-SVR