Glucagon-Like Peptide 1 Analogs and their Effects on Pancreatic Islets

doi:10.1016/j.tem.2016.03.004

Trends in Endocrinology & Metabolism

Volume 27, Issue 5, May 2016, Pages 304-318

https://doi.org/10.1016/j.tem.2016.03.004 Get rights and content

Trends

Although GLP-1-based drugs have been improved to have long-term effects, there are still issues surrounding their oral administration.

GLP-1 analogs stimulate insulin synthesis and secretion and inhibit β cell apoptosis in rodent models.

Most preclinical studies show increased β cell proliferation and mass after GLP-1 analog treatment; however, whether these effects are also seen in humans remains unclear.

GLP-1 analogs reduce plasma glucagon levels, but this effect might not be exerted by a direct action on α cells.

Glucagon-like peptide 1 (GLP-1) exerts many actions that improve glycemic control. GLP-1 stimulates glucose-stimulated insulin secretion and protects β cells, while its extrapancreatic effects include cardioprotection, reduction of hepatic glucose production, and regulation of satiety. Although an appealing antidiabetic drug candidate, the rapid degradation of GLP-1 by dipeptidyl peptidase 4 (DPP-4) means that its therapeutic use is unfeasible, and this prompted the development of two main GLP-1 therapies: long-acting GLP-1 analogs and DPP-4 inhibitors. In this review, we focus on the pancreatic effects exerted by current GLP-1 derivatives used to treat diabetes. Based on the results from in vitro and in vivo studies in humans and animal models, we describe the specific actions of GLP-1 analogs on the synthesis, processing, and secretion of insulin, islet morphology, and β cell proliferation and apoptosis.

Section snippets

Targeting the Incretin System to Treat Diabetes

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The incidence of diabetes is increasing worldwide, mainly due to the rise in obesity; approximately 80% of humans with T2DM are either overweight or obese [1]. Although a proportion of those patients control their glycemic levels by following controlled diets and exercise, many others require specific treatments, including exogenous insulin, sulfonylureas,

Current GLP-1 Analogs Used for the Treatment of T2DM

Efficacy and long-lasting effects are the two main properties of GLP-1 analogs. In 2005, the FDA approved the first GLP-1 receptor (GLP-1R) agonist, exenatide (Byetta), for adjunctive glycemic control in patients with T2DM. Exenatide is bio-identical to exendin-4 (Ex-4), a 39-amino acid peptide isolated from the saliva of the Gila monster (Heloderma suspectum). Exenatide shares 53% homology with GLP-1 [10] and has proven efficacy when given alone, in combination with metformin and

Effects of GLP-1 Analogs on Insulin Synthesis and Secretion

Insulin is synthesized and released from β cells The synthesis of insulin results from the sequential cleavage of two precursor molecules: first, preproinsulin is translocated across the rough endoplasmic reticulum (ER) membrane into the lumen, where the initial amino-terminal segment of the protein is removed to yield proinsulin. Following transportation to the Golgi, proinsulin enters immature secretory granules where, by the action of carboxypeptidase E and the prohormone convertases PC1/3

Effects of GLP-1 Analogs on β Cell Mass and Proliferation

A hallmark of T2DM is a deficit in functional β cell mass and the inability to compensate for insulin resistance. Hence, there has been growing interest in better understanding β cell proliferation and regeneration, in an effort to increase β cell mass. Even though the ability of rat and mouse β cells to proliferate has been extensively reported, studies of human β cell proliferation have been inconclusive. In animal models, GLP-1 increases β cell mass by promoting proliferation 29, 55, 56 and

Effects of GLP-1 Analogs on β Cell Apoptosis

Obesity and HFD are closely associated with high blood glucose and free fatty acid (FFA) levels. The chronic exposure of islets to hyperglycemia is known as glucotoxicity, and to high levels of FFA as lipotoxicity. These environments cause β cell apoptosis and exert deleterious effects on insulin secretion and insulin action; glucotoxicity induces oxidative stress by means of the increased generation of reactive oxygen species, whereas lipotoxicity causes FA-induced apoptosis and activation of

Effects of GLP-1 Analogs on Glucagon and Somatostatin Secretion

Hyperglucagonemia has been described in some humans with diabetes [79] and in diabetic animal models [80]. This pathological condition leads to increased HGP and, therefore, worsens hyperglycemia. Hence, the glucagonostatic (i.e., ability to inhibit glucagon secretion) effect of GLP-1 analogs for the treatment of T2DM is just as important as their insulinotropic action and may contribute to their ability to improve glycemic control.

The existence of GLP-1R in non-β cells is still controversial

Concluding Remarks

Current GLP-1-based therapies are at the forefront of managing glycemic control in T2DM and have advantages over several other antidiabetic medications. Several goals defined by the American Diabetes Association (ADA) are achieved by GLP-1 analogs, including HbA1c below 7% without hypoglycemia, no weight gain (or weight loss in the case of obese subjects), and systolic blood pressure <130 mmHg. In addition, at the pancreatic islet level, GLP-1R agonists exert multiple favorable effects,

Glossary

AC: adenylate cyclase
ADA: American Diabetes Association
Akt: serine/threonine protein kinase
AMP: adenosine monophosphate
ATF4: activating transcription factor 4
ATF6: activating transcription factor 6
BAX: BCL2-associated X Protein
BCL-2: B-cell lymphoma 2
CAD: caspase-activated DNase
cAMP: cyclic adenosine monophosphate
CASP3: caspase 3
CASP8: caspase 8
CAT: catalase
CHOP: C/EBP homologous protein
CIDEA: cell death-inducing DNA fragmentation factor A
CYCD: cyclin D
CYLD: cylindromatosis (turban tumor syndrome)
DPP-4: dipeptidyl peptidase 4
EGFR

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Apart from its glucose-lowering effect, GLP-1 also has multi-target effects on various tissues, organs, and systems, such as alleviating nonalcoholic metabolic associated fatty liver disease [7], protecting neuronal function [8], and providing cardiovascular benefits [9]. So far, several GLP-1 receptor agonists, which are mainly analogs or derivatives of the endogenous peptide, have been approved for T2DM and obesity treatment [10,11]. They are highly effective at glycemic control and weight loss with little risk of hypoglycemia.
Glucagon-like peptide-1 (GLP-1) receptor-based therapies have been developed and extensively applied in clinical practice. GLP-1 plays an important role in improving glycemic homeostasis by stimulating insulin biosynthesis and secretion, suppressing glucagon activity, delaying gastric emptying, and reducing appetite and food ingestion. Furthermore, GLP-1 has positive effects on β-cell function by promoting β-cell proliferation and neogenesis while simultaneously reducing apoptosis. Here, we summarize possible mechanisms of action of GLP-1 upon pancreatic islets as well as describe phytochemicals that modulate pancreatic islet β cell function through glucagon-like peptide-1-related mechanisms. Together, this information provides potential lead compound candidates against diabetes that function as GLP-1 receptor-based pharmacotherapy.
Cucurbitane-type triterpenoids from the vines of Momordica charantia and their anti-inflammatory, cytotoxic, and antidiabetic activity
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Phytochemical investigation of the ethanol extract from wild Momordica charantia vines has resulted in isolation of seven cucurbitane-type triterpenoids, including six undescribed compounds, kuguaovins H‒M, and the known compound, momordicoside K. The structures of the isolated compounds were elucidated on the basis of spectroscopic analyses, including 1D and 2D NMR, and MS experiments. The chemical structure of momordicoside K was determined for the first time by X-ray crystallographic analysis and its absolute configuration assigned. The cytotoxicity against four human tumor cell lines and anti-inflammatory activities on LPS-stimulated RAW264.7 macrophages were evaluated. Of the isolates, kaguaovin L exhibited potential cytotoxicity against MCF-7, HEp-2, Hep-G2, and WiDr cancer cell lines and showed moderate anti-NO production activity. In addition, kuguaovins H and J also showed the stimulatory effect of GLP-1 secretion on the murine intestinal secretin tumor cell line (STC-1).
Metformin and exenatide upregulate hepatocyte nuclear factor-4α, sex hormone binding globulin levels and improve hepatic triglyceride deposition in polycystic ovary syndrome with insulin resistance rats
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Intervention with metformin improves insulin sensitivity as well as menstrual irregularity, ameliorates ovulation rates, and may also improve hyperandrogenemia in women with PCOS [6]. Over the past decade, glucagon-like peptide 1 (GLP-1) analogs have emerged as novel anti-diabetic drugs with excellent therapeutic profiles, improving glycemic control and IR and leading to weight loss [7,8]. Meanwhile, our previous meta-analysis provided evidence that both metformin and GLP-1 receptor agonists may improve total testosterone (TT), free testosterone (FT), and sex hormone binding globulin (SHBG) to relieve hyperandrogenemia in obese women with PCOS [9].
To explore the efficacy and underlying mechanisms of metformin and exenatide in reversing reproductive and metabolic disturbances in letrozole combined with high-fat diet-induced polycystic ovary syndrome (PCOS) rats.
Rats with PCOS and insulin resistance (IR) were induced by intra-gastric instillation of letrozole combined with a high-fat diet and verified by histological screening of vaginal exfoliated cells. After metformin and exenatide supplementation, body weight, chow intake and ovarian morphology were observed. Serum biochemical profiles were analyzed using ELISA, while the levels of key anabolism-related proteins, including sex hormone binding globulin (SHBG), hepatocyte nuclear factor-4α (HNF-4α), PI3K, and AKT, were determined using western blotting.
The estrus cycle and ovarian morphology of rats with PCOS and IR were significantly recovered following metformin and exenatide treatment, with decreased body weight and chow intake. Furthermore, PCOS-induced changes in metabolic disorders including IR and hepatic triglyceride (TG) deposition, and hyperandrogenemia were reversed by treatment with both drugs. Specifically, the levels of HNF-4α and SHBG in liver tissue of rats with PCOS and IR were upregulated significantly.
Both metformin and exenatide could recover the estrous cycle and ovarian morphology, reduce body weight and high-fat chow intake, and improve glycolipid metabolism disorders and hyperandrogenemia in PCOS with IR rat models. Interestingly, our findings also highlight the potential of both therapeutic agents for improving IR by regulating the liver PI3K/AKT pathway, reducing the deposition of hepatic TG, as well as upregulating the levels of SHBG and HNF-4α in PCOS with IR rat liver tissue.
Dietary supplementation of rutin and rutin-rich buckwheat elevates endogenous glucagon-like peptide 1 levels to facilitate glycemic control in type 2 diabetic mice
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GLP-1 is an incretin hormone secreted from intestinal L cells. It is an important antidiabetes hormone and its actions are involved in stimulating insulin secretion, enhancing β-cell function, and suppressing glucagon secretion and hepatic glucose production (Edwards, 2005; Tuduri, Lopez, Dieguez, Nadal, & Nogueiras, 2016). Our results clearly suggest that improved β-cell function plays a crucial role in the hypoglycemic effects of TBW and rutin consumption.
Rutin and rutin-rich buckwheat are commonly used as alternative medicines due to their wide range of health benefits. The present study aims to investigate their anti-diabetes effects and the association with glucagon-like peptide 1 (GLP-1) levels. A murine model of type 2 diabetes (T2D), induced by a high-fat diet combined with streptozocin injection, was utilized. T2D mice were fed 3% buckwheat, 10% buckwheat, or 0.1% rutin as part of their diet for 4 weeks. Dipeptidyl peptidase-4 assays, secretin tumor cell line (STC-1) cells, and GLP-1 receptor-knockout mice were employed for mechanistic studies. Dietary consumption of 10% buckwheat and 0.1% rutin provided beneficial outcomes including lowering blood glucose levels and HbA1c, enhancing HOMA-B%, improving glucose tolerance and pyruvate tolerance. Serum GLP-1, ghrelin, leptin, and adiponectin levels were also increased at the end of the treatment. Increased GLP-1 levels and the improvement of β-cell function were closely associated with the blood glucose-lowering effects observed. Hypoglycemic effects of buckwheat and rutin supplement were abolished in diabetic GLP-1 receptor knockout mice. In conclusion, rutin and related herbal materials are expected to provide health benefits due to their ability to modulate endogenous GLP-1 levels in T2D mice.
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To develop a dual-functional medicine for hypoglycemic and anti-thrombus.
The long-acting glucagon like peptide-1 (5×GLP-1) and nattokinase (NK) were cloned by SOE PCR and gained the GLP-1 and NK fusion polypeptide after transformed into E. coli. Use of mice models for the hypoglycemic and anti-thrombus activity of the fusion polypeptide. Balb/C mice were given the carrageenan by intraperitoneal injection to induce tail thrombus models. Type 2 diabetes mellitus mice model was used to research the hypoglycemic function of the fusion polypeptide.
Results showed that the fusion polypeptide could significantly prevent thrombus formation after oral administration. Continuous administration for 15 days, fasting blood glucose levels of the experimental group decreased to nearly normal levels.
The present study investigated the expression, purification and functional activity of the rolGLP-1 and NK fusion polypeptide, which provided a foundation for further studying the detailed pharmaceutical mechanism and drug development.

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Trends in Endocrinology & Metabolism

ReviewGlucagon-Like Peptide 1 Analogs and their Effects on Pancreatic Islets

Trends

Section snippets

Targeting the Incretin System to Treat Diabetes

Current GLP-1 Analogs Used for the Treatment of T2DM

Effects of GLP-1 Analogs on Insulin Synthesis and Secretion

Effects of GLP-1 Analogs on β Cell Mass and Proliferation

Effects of GLP-1 Analogs on β Cell Apoptosis

Effects of GLP-1 Analogs on Glucagon and Somatostatin Secretion

Concluding Remarks

Glossary

Gastroenterology

Regul. Pept.

Prog. Mol. Biol. Transl. Sci.

Toxicon

Regul. Pept.

Metabolism

Mol. Cell Endocrinol.

Pharmacol. Res.

Mol. Cell Endocrinol.

Cell Metab.

Peptides

J. Biol. Chem.

J. Pharmacol. Sci.

Peptides

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Pharmacol. Ther.

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol.

Transplant. Proc.

Lancet

American Diabetes Association Annual Meeting, 1999: diabetes and obesity

Diabetes Care

Gastric emptying and release of incretin hormones after glucose ingestion in humans

J. Clin. Invest.

Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients

Diabetes

Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

Diabetologia

Lixisenatide: evidence for its potential use in the treatment of type 2 diabetes

Core Evid.

A role for glucagon-like peptide-1 in the central regulation of feeding

Nature

Exenatide (Byetta) as a novel treatment option for type 2 diabetes mellitus

Proc. Bayl. Univ. Med. Cent.

Liraglutide in the management of type 2 diabetes

Drug Des. Devel. Ther.

Newer therapies for diabetes management

Diabetes Technol. Ther.

Lixisenatide for type 2 diabetes mellitus

Expert Opin. Invest. Drugs

Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes

Diabetes Care

Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in healthy subjects

Diabetes Obes. Metab.

Once-weekly albiglutide in the management of type 2 diabetes: patient considerations

Patient Prefer. Adherence

Dulaglutide, a long-acting GLP-1 analog fused with an Fc antibody fragment for the potential treatment of type 2 diabetes

Curr. Opin. Mol. Ther.

Dulaglutide: an evidence-based review of its potential in the treatment of type 2 diabetes

Core Evid.

Albiglutide: a review of its use in patients with type 2 diabetes mellitus

Drugs

Expression of the GLP-1 receptor in mouse, rat, and human pancreas

J. Histochem. Cytochem.

GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody

Endocrinology

Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model

Diabetes

Insulinotropic hormone glucagon-like peptide-I(7-37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma beta TC-1 cells

Endocrinology

Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets

Diabetologia

Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line

Proc. Natl. Acad. Sci. U.S.A.

The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion

Diabetes

Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas

Review
Glucagon-Like Peptide 1 Analogs and their Effects on Pancreatic Islets