Research of Glucagon-Like Peptide 1(GLP-1) in The Treatment of Type 2 Diabetes(T2D)

1. Introduction-T2D

Type 2 diabetes (T2D), the major type of diabetes mellitus (DM), is a long term metabolic disorder primarily occurs as a result of obesity and not enough exercise.^[1]T2D is characterized by high blood sugar, insulin resistance, and relative lack of insulin. It is reported that T2D could lead to a ten-year-shorter life expectancy. Globally, near to 400 million people are suffering from T2D and the rate is still rising. ^[2]

2. Introduction-Insulin, GLP1, GLP1R

Insulin is a peptide hormone which plays a crytical role in the progresses of T2D disease.^[3] The human insulin gene primarily encodes preproinsulin which is a peptide containing 110 amino acids. Preproinsulin is further processed into proinsulin by removal of the N-terminal signal peptide. Afeter that, three peptides (B chain, A chain and C-peptide) are released by post-translational modification. The human insulin protein is a dimer of the A-chain and B-chain linked by disulfide bonds.

Glucagon-like peptide-1 (GLP-1) is a peptide hormone and an incretin derived from preproglucagon protein which in human is encoded by the GCG gene. GLP-1 can increase insulin secretion and decrease glucagon secretion from the pancreas in a glucose-dependent manner. The human glucagon-like peptide 1 receptor (GLP1R) is G protein-coupled receptor encoded by the GLP1R gene. GLP1R binds GLP-1 and glucagon as its natural endogenous agonists.

The GLP1R system has become an important target for T2D treatment.

3. T2D Therapies-DPP4 Inhibitors, GLP1R Agonists

There are mainly two classes of glucose-lowering therapeutics: dipeptidyl peptidase 4 (DPP-4) inhibitors and GLP1R agonists. Both GLP1R agonists and DPP-4 inhibitors affect glucose control via multiple mechanisms, including increase of glucose-dependent insulin secretion, slowed gastric emptying, and reduction of postprandial glucagon and of food intake. These agents have a lower risk of causing hypoglycemia.

3.1) DPP-4 enzyme inhibitors

DPP-4 protein, also known as adenosine deaminase complexing protein 2 or CD26, is encoded by human DPP4 gene. DPP-4 plays a key role in glucose metabolism. ^[4]It is associated with the rapid degradation of incretins including GLP-1, which renders GLP-1 a short half-life, namely less than two minutes.

To circumvent the half-life constraint of GLP-1, multiple DPP-4 inhibitors have been developed, such as Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Gemigliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Omarigliptin (MK-3102), Evogliptin, Dutogliptin etc. These DPP-4 inhibitors prolong and enhance the activity of incretins including GLP-1 through inhibiting the DPP-4 enzyme, which in turn increases glucose-dependent insulin secretion and suppresses inappropriately elevated glucagon secretion.

3.2) GLP1R agonists

GLP-1R agonists mimic the activities of GLP-1. These agents exhibit increased resistance to DPP-4 degradation by virtue of their amino acid sequence and/or through chemical modification, and thus provide pharmacological levels of GLP-1.

There are several approved GLP-1 agonists, such as exenatide, liraglutide, lixisenatide, albiglutide and dulaglutide etc., with more being developed. These agents work in the same pathway as DPP-4 inhibitors but are generally considered more potent.

Stable cells expressing the GLP-1 receptor are a powerful and indispensable tool during the process of screening novel GLP1R agonists.

4. Our Capabilities

We can offer several agents related to research of GLP1-based T2D treatment, including but not limited to the following products. Please contact us for special requirements, we are always happay to provide custom services to assist your research.

cDNA	Human INS ORF clone
	Human GCG ORF clone
	Human DPP4 cDNA clone
	Human GLP1R ORF Clone
shRNA	shRNA set against human INS
	shRNA set against human GCG
	shRNA set against human DPP4
	shRNA set against Human GLP1R
3’UTR	Human INS miRNA 3'UTR clone
	Human GCG miRNA 3'UTR clone
	Human DPP4 miRNA 3'UTR clone
	Human GLP1R miRNA 3'UTR clone
Virus particles	Human INS lentiviral particles
	Human GCG lentivirus particles
	Human GCG adenoviral particles
	Human DPP4 lentivirus particles
	Human DPP4 adenoviral particles
	Human GLP1R lentivirus particles
	Human GLP1R adenoviral particles
Stable cell lines	Human INS stable cell line
	Human GCG stable cell line
	Human DPP4 stable cell line
	Human GLP1R stable cell lines

References:

"Causes of Diabetes". National Institute of Diabetes and Digestive and Kidney Diseases. June 2014. Archived from the original on 2 February 2016. Retrieved 10 February 2016.
Shi, Yuankai; Hu, Frank B (7 June 2014). "The global implications of diabetes and cancer". The Lancet. 383 (9933): 1947–8.doi:10.1016/S0140-6736(14)60886-2. PMID 24910221
Zaccardi F, Webb DR, Yates T, Davies MJ (February 2016). "Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective.". Postgraduate Medical Journal. 92 (1084): 63–9.doi:10.1136/postgradmedj-2015-133281. PMID 26621825
Barnett A (Nov 2006). "DPP-4 inhibitors and their potential role in the management of type 2 diabetes".International Journal of Clinical Practice. 60 (11): 1454–70. doi:10.1111/j.1742-1241.2006.01178.x.PMID 17073841

* For research use only. Not intended for any clinical use.

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