Glucagon-like peptide-1 (7-36) amide

The mammalian precursor gene proglucagon, which contains the glucagon sequence together

with two structurally related glucagon-like peptides, glucagonlike peptides-1 and -2 (GLP-1

and GLP-2), is found in both gut and pancreas. In the pancreas, glucagon is the major

biologically active hormone to be cleaved from proglucagon, but in the gut the cleavage site

differs and glucagon-like peptide-1 (7-36) amide (GLP-1 (7-36) amide), a truncated form of

GLP-1, is produced as a major active peptide. GLP-1 (7-36) amide is also the predominant

form found circulating post-prandially in man.

Degradation of GLP-1

There are four forms of GLP-1 secreted in vivo: the inactive form of GLP-1 (1-37) and GLP-1

(1-36)-NH2, and the biologically active form of GLP-1 (7-37) and GLP-1 (7-36)-NH2. Both GLP-

1 (7-37) and GLP-1 (7-36)-NH2 are produced from their full-length precursors by the action of

PC enzyme and show the equipotent ability to stimulate glucose-dependently insulin

secretion. It was found that GLP-1 (7-36)-NH2 is the major form of GLP-1 in the circulation in

humans. It was also reported that addition of the amide group (NH3) to GLP-1 (1-36) is

associated with prolonged survival of GLP-1 (7-36) in plasma. The concentration of total GLP-

1 (including GLP-1(7-36)-NH2 and GLP-1(9-36)-NH2) levels in fasting plasma is 10-20 pM in

healthy Caucasians, while it peaks at 30-60 pM 30 min after 75-g glucose or mixed meals

loading.
In vivo, biologically active forms of GLP-1 [GLP-1 (7-37) and GLP-1 (7-36)-NH2] are rapidly

degraded to the respective inactive forms [GLP-1 (9-37) and GLP-1 (9-36)-NH2] through

dipeptidyl peptidase-4 (DPP-4)-mediated cleavage of the alanine residue at position 2, with a

half life of less than 2 minutes. Hansen et al. examined the GLP-1 newly secreted from the

porcine ileum and found that about 75% of the GLP-1 leaving the gastrointestinal tract has

already been degraded by DPP-4. Study in the anesthetized pig showed that GLP-1 is further

degraded in liver, eventually resulting in only 10% to 15% of newly secreted GLP-1 in

circulation system. It was also reported that less than 5% of intact GLP-1 reaches systemic

circulation in Japanese.

CAT# 10-101-46 10-101-85

Product Name GLP-1 (7-37) Acetate GLP-1 (7-36) amide Acetate

CAS No. 106612-94-6 (net) 107444-51-9 (net)

M.W/Mr. 3355.71 3297.68

Introduction of GLP-1 (7-36) amide

GLP-1 (7-36) amide is a 30 amino acid peptide with the sequence

HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2. It is an incretin hormone that can potentiate

glucose-induced insulin secretion, stimulate insulin biosynthesis and inhibit glucagon

secretion. Accordingly, it is a potential drug for the treatment of non-insulin-dependent

diabetes mellitus (NIDDM or type II diabetes). However, GLP-1 suffers from physical instability.

Thus it has been found that the conformation, aggregation and solubility of GLP-1 depend on

the purification procedure and the in-process storage and handling. Efforts have been made

to characterize the structural properties of GLP-1 in greater detail, including its aggregation

behaviour in solution, but so far only limited structural information about GLP-1 has been

reported. However, the α-helix seems to be an important structural motif of GLP-1 in solution.

Thus it was found that GLP-1 can form oligomers with a high helical content, and that it is

mainly helical in membrane-like environments (dodecylphosphocholine micelle). However, β-

sheet formation also seems significant and can lead to less soluble GLP-1 aggregates.

GLP-1 (7-36) amide is a potent stimulator of insulin secretion. Together with the

gastrointestinal hormone glucosedependent insulinotropic polypeptide (GIP), it is capable of

acting as an 'incretin’, making an important contribution to insulin secretion via the entero-

insular axis. In addition to stimulating insulin secretion, GLP-1 (7-36) amide has, in common

with GIP, a direct anabolic insulin-like action on adipose tissue, stimulating de novo

lipogenesis, and can also act as an enterogastrone, inhibiting pentagastrin-stimulated gastric

acid secretion.

The nutritional stimuli for GIP secretion have been well documented. In contrast,

comparatively little is known about the circulating levels of GLP-1 (7-36) amide and the effects

of different nutrients on its secretion. There are discrepancies between the reported results

from the small number of groups able to measure GLP-1 (7-36) amide by immunoassay, with

mean fasting levels of immunoreactive GLP-1 ranging between 15 pmol/1 and 236 pmol/1.

Several groups have found a small rise in circulating plasma immunoreactive GLP-1 following

oral glucose or a mixed meal. In contrast, Hirota et al. observed a reduction in total

immunoreactive GLP-1 in normal subjects following an oral glucose load. These discrepancies

are largely due to varying cross-reactivity with extended forms of GLP-1 secreted from the

pancreas and problems associated with different plasma extraction techniques. It is therefore

difficult to assign a physiological endocrine role to GLP-1 (7-36) amide with any confidence.

The present study describes a radioimmunoassay to measure circulating levels of GLP-1 (7-36)

amide in man. It compares the acute effects of ingestion of different macronutrients on GIP

and GLP-1 (7-36) amide secretion, with particular emphasis on carbohydrate. In addition,

circulating levels of GIP and GLP-1 (7-36 )amide have been investigated over a 24-h period in
healthy subjects consuming a typical Western diet, to assess secretion of the hormone under

more normal dietary circumstances.

References:

Kang, Z. (2012). Impaired Incretin Effects in Type 2 Diabetes: Mechanism and Therapeutic

Implication (Doctoral dissertation, Chinese University of Hong Kong).

Elliott, R. M., Morgan, L. M., Tredger, J. A., Deacon, S., Wright, J., & Marks, V. (1993). Glucagon-

like peptide-1 (7-36) amide and glucose-dependent insulinotropic polypeptide secretion in

response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns.

Journal of Endocrinology, 138(1), 159-166.

Chang, X., Keller, D., Bjørn, S., & Led, J. J. (2001). Structure and folding of glucagon-like

peptide-1-(7-36)-amide in aqueous trifluoroethanol studied by NMR spectroscopy. Magnetic

Resonance in Chemistry, 39(8), 477-483.