242 research outputs found
An update on peptide-based therapies for type 2 diabetes and obesity
Long-acting analogues of the naturally occurring incretin, glucagon-like peptide-1 (GLP-1) and those modified to interact also with receptors for glucose-dependent insulinotropic polypeptide (GIP) have shown high glucose-lowering and weight-lowering efficacy when administered by once-weekly subcutaneous injection. These analogues herald an exciting new era in peptide-based therapy for type 2 diabetes (T2D) and obesity. Of note is the GLP-1R agonist semaglutide, available in oral and injectable formulations and in clinical trials combined with the long-acting amylin analogue, cagrilintide. Particularly high efficacy in both glucose- and weight lowering capacities has also been observed with the GLP-1R/GIP-R unimolecular dual agonist, tirzepatide. In addition, a number of long-acting unimolecular GLP-1R/GCGR dual agonist peptides and GLP-1R/GCGR/GIPR triagonist peptides have entered clinical trials. Other pharmacological approaches to chronic weight management include the human monoclonal antibody, bimagrumab which blocks activin type II receptors and is associated with growth of skeletal muscle, an antibody blocking activation of GIPR to which are conjugated GLP-1R peptide agonists (AMG-133), and the melanocortin-4 receptor agonist, setmelanotide for use in certain inherited obesity conditions. The high global demand for the GLP-1R agonists liraglutide and semaglutide as anti-obesity agents has led to shortage so that their use in T2D therapy is currently being prioritized. [Abstract copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Differential Acute and Long Term Actions of Succinic Acid Monomethyl Ester Exposure on Insulin-Secreting BRIN-BD11 Cells
Esters of succinic acid are potent insulin secretagogues,
and have been proposed as novel antidiabetic
agents for type 2 diabetes. This study
examines the effects of acute and chronic exposure
to succinic acid monomethyl ester (SAM) on insulin
secretion, glucose metabolism and pancreatic beta
cell function using the BRIN-BD11 cell line. SAM
stimulated insulin release in a dose-dependent
manner at both non-stimulatory (1.1mM) and stimulatory
(16.7mM) glucose. The depolarizing actions
of arginine also stimulated a significant increase
in SAM-induced insulin release but 2-ketoisocaproic
acid (KIC) inhibited SAM induced insulin
secretion indicating a possible competition between
the preferential oxidative metabolism of these two
agents. Prolonged (18hour) exposure to SAM revealed
decreases in the insulin-secretory responses
to glucose, KIC, glyceraldehyde and alanine.
Furthermore, SAM diminished the effects of nonmetabolized
secretagogues arginine and 3-isobutyl-1-methylxanthine (IBMX). While the ability of
BRIN-BD11 cells to oxidise glucose was unaffected
by SAM culture, glucose utilization was substantially
reduced. Collectively, these data suggest that
while SAM may enhance the secretory potential of
non-metabolized secretagogues, it may also serve as
a preferential metabolic fuel in preference to other
important physiological nutrients and compromise
pancreatic beta cell function following prolonged
exposure
Incretins play an important role in FFA4/GPR120 regulation of glucose metabolism by GW-9508
Aims: To assess the role of GPR120 in glucose metabolism and incretin regulation from enteroendocrine L- and K-cells with determination of the cellular localisation of GPR120 in intestinal tissue and clonal Glucagon-Like Peptide-1 (GLP-1)/Gastric Inhibitory Polypeptide (GIP) cell lines. Main methods: Anti-hyperglycaemic, insulinotropic and incretin secreting properties of the GPR120 agonist, GW-9508 were explored in combination with oral and intraperitoneal glucose tolerance tests (GTT) in lean, diabetic and incretin receptor knockout mice. Cellular localisation of GPR120 was assessed by double immunofluorescence. Key findings: Compared to intraperitoneal injection, oral administration of GW-9508 (0.1 μmol/kg body weight) together with glucose reduced the glycaemic excursion by 22–31 % (p < 0.05-p < 0.01) and enhanced glucose-induced insulin release by 30 % (p < 0.01) in normal mice. In high fat fed diabetic mice, orally administered GW-9508 lowered plasma glucose by 17–27 % (p < 0.05-p < 0.01) and augmented insulin release by 22–39 % (p < 0.05-p < 0.001). GW-9508 had no effect on the responses of GLP-1 receptor knockout mice and GIP receptor knockout mice. Consistent with this, oral GW-9508 increased circulating total GLP-1 release by 39–44 % (p < 0.01) and total GIP by 37–47 % (p < 0.01-p < 0.001) after 15 and 30 min in lean NIH Swiss mice. Immunocytochemistry demonstrated GPR120 expression on mouse enteroendocrine L- and K-cells, GLUTag cells and pGIP/Neo STC-1 cells. Significance: GPR120 is expressed on intestinal L- and K-cells and stimulates GLP-1/GIP secretory pathways involved in mediating enhanced insulin secretion and improved glucose tolerance, following oral GW-9508. These novel data strongly support the development of potent and selective GPR120 agonists as an effective therapeutic approach for diabetes.</p
Functional Enhancement of Electrofusion-derived BRIN-BD11 Insulin-secreting Cells After Implantation into Diabetic Mice
Electrofusion-derived BRIN-BD11 cells are glucosesensitive
insulin-secreting cells which provide an
archetypal bioengineered surrogate β-cell for
insulin replacement therapy in diabetes mellitus,
5x106 BRIN-BD11 cells were implanted intraperitoneally
into severely hyperglycaemic (>24mmol/l)
streptozotocin-induced insulin-treated diabetic
athymic nude (nu/nu) mice. The implants reduced
hyperglycaemia such that insulin injections were
discontinued by 5–16 days (<17mmol/l) and normoglycaemia
(<9mmol/l) was achieved by 7–20
days. Implanted cells were removed after 28 days
and re-established in culture. After re-culture for 20
days, glucose-stimulated (16.7mmol/l) insulin
release was enhanced by 121% (p<0.001) compared
to non-implanted cells. Insulin responses to
glucagon-like peptide-1 (10−9mol/l), cholecystokinin-8 (10−8 mol/l) and L-alanine (10 mmol/l) were
increased by 32%, 31% and 68% respectively
(p<0.05–0.01). Insulin content of the cells was 148%
greater at 20 days after re-culture than before
implantation (p<0.001), but basal insulin release (at
5.6 mmol/l glucose) was not changed. After re-culture
for 40 days, insulin content declined to 68% of
the content before implantation (p<0.01), although
basal insulin release was unchanged. However, the
insulin secretory responses to glucose, glucagonlike
peptide-1, cholecystokinin-8 and L-alanine
were decreased after 40 days of re-culture to 65%,
72%, 73% and 42% respectively of the values before
implantation (p<0.05–0.01). The functional
enhancement of electrofusion-derived surrogate β-cells that were re-cultured for 20 days after implantation
and restoration of normoglycaemia indicates
that the in vivo environment could greatly assist β-cell engineering approaches to therapy for diabetes
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