The role of maternal gut hormones in normal pregnancy: fasting plasma active glucagon-like peptide 1 level is a negative predictor of fetal abdomen circumference and maternal weight change

AbstractObjectiveMaternal weight in pregnancy contributes to a glycemic environment that affects fetal growth. Gut peptides (glucagon-like peptide 1 (GLP1), glucose-dependent insulinotropic peptide (GIP), ghrelin, and peptide YY (PYY)) have been related to insulin sensitivity and secretion, weight control, and adipose tissue metabolism. This study aimed at examining the associations of gut hormones during pregnancy with maternal glucose homeostasis, maternal weight, and fetal growth.MethodsA total of 55 pregnant nonobese, nondiabetic Caucasian women were examined during the three trimesters of pregnancy, and anthropometric measurements, evaluation of fasting maternal plasma GLP1 (active), ghrelin (active), total PYY, total GIP, and a 75-g oral glucose tolerance test were done in them. Homeostasis model assessment (HOMA-R), insulin sensitivity index (ISI), and indices of insulin secretion were calculated. Fetal growth was estimated by ultrasound.ResultsFasting GLP1 increased significantly from the second to the third trimester (P<0.05). Fasting GLP1 correlated positively with high-density lipoprotein cholesterol (r=0.52,P=0.04). At the second trimester, fasting GLP1 levels correlated negatively with fetal abdomen circumference (r=−0.55,P=0.034), birth weight (r=−0.50,P=0.040), HOMA-R (r=−0.65,P=0.001), insulin secretion, and triglycerides. At the first trimester, fasting ghrelin levels correlated negatively with HOMA-R and insulin secretion, and positively with ISI. In backward multiple regression analysis, the first trimester GLP1 levels were the best negative predictors of the second trimester fetal abdomen circumference (β=−0.96,P=0.009). In longitudinal regression model, maternal fat and HOMA-R were the positive predictors of maternal weight change during pregnancy, and fasting GLP1 levels were the negative predictors of maternal weight change during pregnancy.ConclusionsDuring pregnancy, maternal GLP1 might be involved in mechanisms that compensate for the pregnancy-related increase in glycemia and insulin resistance, suggesting a role of this peptide in maternal metabolism and weight and fetal growth.

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Postprandial Insulin Secretion After Gastric Bypass Surgery: The Role of Glucagon-Like Peptide 1

Diabetes ◽

10.2337/db11-0798 ◽

2011 ◽

Vol 60 (9) ◽

pp. 2203-2205 ◽

Cited By ~ 20

Author(s):

J. J. Holst

Keyword(s):

Gastric Bypass ◽

Insulin Secretion ◽

Bypass Surgery ◽

Gastric Bypass Surgery ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Postprandial Insulin

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TNF signaling impacts glucagon-like peptide-1 expression and secretion

Journal of Molecular Endocrinology ◽

10.1530/jme-18-0129 ◽

2018 ◽

Vol 61 (4) ◽

pp. 153-161 ◽

Cited By ~ 2

Author(s):

Sufang Chen ◽

Wei Wei ◽

Minjie Chen ◽

Xiaobo Qin ◽

Lianglin Qiu ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Oral Glucose ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Deficient Mice

Numerous studies have implicated tumor necrosis factor α (TNFα) in the pathogenesis of type 2 diabetes. However, the role of its primary receptor, TNF receptor 1 (TNFR1), in homeostatic regulation of glucose metabolism is still controversial. In addition to TNFα, lymphotoxin α (LTα) binds to and activates TNFR1. Thus, TNFα and LTα together are known as TNF. To delineate the role of TNF signaling in glucose homeostasis, the present study ascertained how TNF signaling deficiency affects major regulatory components of glucose homeostasis. To this end, normal diet-fed male TNFR1-deficient mice (TNFR1−/−), TNFα/LTα/LTβ triple-deficient mice (TNF/LT∆3) and their littermate controls were subjected to intraperitoneal glucose tolerance test, insulin tolerance test and oral glucose tolerance test. The present results showed that TNFR1−/− and TNF/LT∆3 mice vs their controls had comparable body weight, tolerance to intraperitoneal glucose and sensitivity to insulin. However, their tolerance to oral glucose was significantly increased. Additionally, glucose-induced insulin secretion assessments revealed that TNFR1 or TNF/LT deficiency significantly increased oral but not intraperitoneal glucose-induced insulin secretion. Consistently, qPCR and immunohistochemistry analyses showed that TNFR1−/− and TNF/LT∆3 mice vs their controls had significantly increased ileal expression of glucagon-like peptide-1 (GLP-1), one of the primary incretins. Their oral glucose-induced secretion of GLP-1 was also significantly increased. These data collectively suggest that physiological TNF signaling regulates glucose metabolism primarily through effects on GLP-1 expression and secretion and subsequently insulin secretion.

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Fructose induces glucose‐dependent insulinotropic polypeptide, glucagon‐like peptide‐1 and insulin secretion: Role of adenosine triphosphate‐sensitive K + channels

Journal of Diabetes Investigation ◽

10.1111/jdi.12356 ◽

2015 ◽

Vol 6 (5) ◽

pp. 522-526 ◽

Cited By ~ 12

Author(s):

Yusuke Seino ◽

Hidetada Ogata ◽

Ryuya Maekawa ◽

Takako Izumoto ◽

Atsushi Iida ◽

...

Keyword(s):

Insulin Secretion ◽

Adenosine Triphosphate ◽

K Channels ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Glucagon-like peptide-1 induces a cAMP-dependent increase of [Na+]i associated with insulin secretion in pancreatic β-cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00005.2003 ◽

2003 ◽

Vol 285 (5) ◽

pp. E1001-E1009 ◽

Cited By ~ 19

Author(s):

Yoshikazu Miura ◽

Hisao Matsui

Keyword(s):

Insulin Secretion ◽

Adenylate Cyclase ◽

Islet Cells ◽

Free Calcium ◽

Dependent Manner ◽

Intracellular Free Calcium Concentration ◽

Free Calcium Concentration ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) elevates the intracellular free calcium concentration ([Ca2+]i) and insulin secretion in a Na+-dependent manner. To investigate a possible role of Na ion in the action of GLP-1 on pancreatic islet cells, we measured the glucose-and GLP-1-induced intracellular Na+ concentration ([Na+]i), [Ca2+]i, and insulin secretion in hamster islet cells in various concentrations of Na+. The [Na+]i and [Ca2+]i were monitored in islet cells loaded with sodium-binding benzofuran isophthalate and fura 2, respectively. In the presence of 135 mM Na+ and 8 mM glucose, GLP-1 (10 nM) strongly increased the [Na+]i, [Ca2+]i, and insulin secretion. In the presence of 13.5 mM Na+, both glucose and GLP-1 increased neither the [Na+]i nor the [Ca2+]i. In a Na+-free medium, GLP-1 and glucose did not increase the [Na+]i. SQ-22536, an inhibitor of adenylate cyclase, and H-89, an inhibitor of PKA, incompletely inhibited the response. In the presence of both 8 mM glucose and H-89, 8-pCPT-2′-O-Me-cAMP, a PKA-independent cAMP analog, increased the insulin secretion and the [Na+]i. Therefore, we conclude that GLP-1 increases the cAMP level via activation of adenylate cyclase, which augments the membrane Na+ permeability through PKA-dependent and PKA-independent mechanisms, thereby increasing the [Ca2+]i and promoting insulin secretion from hamster islet cells.

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Effects of somatostatin-28 on circulating concentrations of insulin and gut hormones in sheep

Journal of Endocrinology ◽

10.1677/joe.0.1510107 ◽

1996 ◽

Vol 151 (1) ◽

pp. 107-112 ◽

Cited By ~ 16

Author(s):

P A Martin ◽

A Faulkner

Keyword(s):

Insulin Secretion ◽

Basal Insulin ◽

Gut Hormones ◽

Serum Concentrations ◽

Nutrient Partitioning ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Glucose Stimulated Insulin Secretion

Abstract The effects of intravenous somatostatin-28 (S28) infusion on glucose-stimulated and glucagon-like peptide-1(7–36)amide (GLP-1)-augmented insulin secretion were studied in sheep. S28 was infused via a jugular catheter for 15 min at a rate of 1·1 pmol/kg/min either alone or together with GLP-1 and/or glucose. S28 infusion did not significantly lower circulating basal insulin concentrations in fed sheep. Glucose-stimulated insulin secretion was significantly inhibited by S28 infusion, serum concentrations decreasing from about 200 to 150 pmol/l. GLP-1 significantly augmented glucose-stimulated insulin secretion, serum concentrations increasing from about 230 to 280 pmol/l. S28 completely counteracted this effect of GLP-1. S28 infusion also significantly decreased the circulating concentrations of glucose-dependent insulinotrophic polypeptide (GIP) and GLP-1 in fed sheep (from about 110 to 45 pmol/l for GIP and from about 25 to 15 pmol/l for GLP-1). The physiological implications of these observations are discussed with particular reference to the ruminant. It is concluded that S28 may have an important endocrine role in the control of insulin secretion and regulation of nutrient partitioning. Journal of Endocrinology (1996) 151, 107–112

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The Role of the Bacterial Muramyl Dipeptide in the Regulation of GLP-1 and Glycemia

International Journal of Molecular Sciences ◽

10.3390/ijms21155252 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5252

Author(s):

Laura Williams ◽

Amal Alshehri ◽

Bianca Robichaud ◽

Alison Cudmore ◽

Jeffrey Gagnon

Keyword(s):

Glucose Tolerance ◽

Muramyl Dipeptide ◽

Gut Hormones ◽

Oral Glucose ◽

L Cells ◽

Nucleotide Oligomerization ◽

Mouse Intestine ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The host’s intestinal microbiota contributes to endocrine and metabolic responses, but a dysbiosis in this environment can lead to obesity and insulin resistance. Recent work has demonstrated a role for microbial metabolites in the regulation of gut hormones, including the metabolic hormone, glucagon-like peptide-1 (GLP-1). Muramyl dipeptide (MDP) is a bacterial cell wall component which has been shown to improve insulin sensitivity and glucose tolerance in diet-induced obese mice by acting through the nucleotide oligomerization domain 2 (NOD2) receptor. The purpose of this study was to understand the effects of MDP on GLP-1 secretion and glucose regulation. We hypothesized that MDP enhances glucose tolerance by inducing intestinal GLP-1 secretion through NOD2 activation. First, we observed a significant increase in GLP-1 secretion when murine and human L-cells were treated with a fatty acid MDP derivative (L18-MDP). Importantly, we demonstrated the expression of the NOD2 receptor in mouse intestine and in L-cells. In mice, two intraperitoneal injections of MDP (5 mg/kg body weight) caused a significant increase in fasting total GLP-1 in chow-fed mice, however this did not lead to an improvement in oral glucose tolerance. When mice were exposed to a high-fat diet, they eventually lost this MDP-induced GLP-1 release. Finally, we demonstrated in L-cells that hyperglycemic conditions reduce the mRNA expression of NOD2 and GLP-1. Together these findings suggest MDP may play a role in enhancing GLP-1 during normal glycemic conditions but loses its ability to do so in hyperglycemia.

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Role of a Dual Glucose-Dependent Insulinotropic Peptide (GIP)/Glucagon-like Peptide-1 Receptor Agonist (Twincretin) in Glycemic Control: From Pathophysiology to Treatment

Life ◽

10.3390/life12010029 ◽

2021 ◽

Vol 12 (1) ◽

pp. 29

Author(s):

Maria Chiara Pelle ◽

Michele Provenzano ◽

Isabella Zaffina ◽

Roberta Pujia ◽

Federica Giofrè ◽

...

Keyword(s):

Clinical Trials ◽

Insulin Secretion ◽

Phase 1 ◽

Synergetic Effect ◽

Insulin Response ◽

Gut Hormones ◽

Acute Effect ◽

Oral Glucose ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two gut hormones, defined incretins, responsible for the amplification of insulin secretion after oral glucose intake. Unlike GLP-1, GIP has little acute effect on insulin secretion and no effect on food intake; instead it seems that the GIP may be an obesity-promoting hormone. In patients with type2 diabetes mellitus (T2DM) some studies found a downregulation of GIP receptors on pancreatic β cells caused by hyperglycemic state, but the glucagonotropic effect persisted. Agonists of the receptor for the GLP-1 have proven successful for the treatment of diabetes, since they reduce the risk for cardiovascular and renal events, but the possible application of GIP as therapy for T2DM is discussed. Moreover, the latest evidence showed a synergetic effect when GIP was combined with GLP-1 in monomolecular co-agonists. In fact, compared with the separate infusion of each hormone, the combination increased both insulin response and glucagonostatic response. In accordance with theseconsiderations, a dual GIP/GLP-1receptor agonist, i.e., Tirzepatide, known as a “twincretin” had been developed. In the pre-clinical trials, as well as Phase 1–3 clinical trials, Tirzepatideshowedpotent glucose lowering and weight loss effects within an acceptable safety.

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Signal bias at glucagon family receptors: rationale and downstream impacts

10.1101/2020.04.26.062372 ◽

2020 ◽

Author(s):

Ben Jones ◽

Emma Rose McGlone ◽

Zijian Fang ◽

Phil Pickford ◽

Ivan R Corrêa ◽

...

Keyword(s):

Insulin Secretion ◽

Energy Metabolism ◽

Cyclic Amp ◽

Selective Reduction ◽

Preclinical Studies ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Glucose Output ◽

Downstream Impacts

AbstractReceptors for the peptide hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) are important regulators of insulin secretion and energy metabolism. Recently described GLP-1 receptor agonists showing signal bias in favour of cyclic AMP over β-arrestin-2 recruitment have delivered promising results in preclinical studies. Here we first sought to establish the role of β-arrestins in the control of intracellular signalling and trafficking responses at the closely related GLP-1, GIP and GCG receptors, through studies performed in cells depleted of both β-arrestin isoforms. We also generated analogues of GLP-1, GCG and GIP which in some cases showed selective reduction in β-arrestin-2 recruitment versus cAMP signalling compared to the parent peptide. Despite reduced acute signalling potency and/or efficacy, some biased GLP-1 and GIP analogues increased maximal sustained insulin secretion from INS-1 832/3 clonal beta cells, although only at high agonist concentrations. Biased GCG analogues did not affect maximal insulin release, or glucose output in hepatocytes.

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Exendin-4 as a Versatile Therapeutic Agent for the Amelioration of Diabetic Changes

Advanced Pharmaceutical Bulletin ◽

10.34172/apb.2022.025 ◽

2021 ◽

Author(s):

Hadi Rajabi ◽

Mahdi Ahmadi ◽

Somayeh Aslani ◽

Shirin Saberianpour ◽

Reza Rahbarghazi

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Insulin Secretion ◽

Signaling Pathways ◽

Diabetic Patients ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Type 2 diabetes mellitus is a chronic metabolic abnormality leading to microvascular and macrovascular complications. Non-insulin Incretin mimic synthetic peptide exendin-4 was introduced as an anti-diabetic drug which helped diabetic patients with triggering insulin secretion; further researches have revealed an effective role of exendin-4 in treatment of type 2 diabetes mellitus related diseases. Exendin-4 is approximately similar to Glucagon-like peptide, thus it can bind to the glucagon-like peptide-1 receptor and activated different signaling pathways that are involved in various bioactivities such as apoptosis, insulin secretion and inactivation of microglial. In this review, we investigated the interesting role of exendin-4 in various kinds of type 2 diabetes mellitus related disorders through the activation of different signaling pathways.

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