Module 4 - readings

Question 1

GIP agonism vs GIP antagonism effects in FA uptake - Killon et al. 2020

Answer 1

• diet induced mice treated with agonism and antagonism had similar effects on body weight
• GIP antagonism inhibits FA uptake in adipocytes in humans and mice
• chronic GIP agonism also inhibits FA uptake via desensitisation of adipocytes

Question 2

GIP antagonist antibodies conjugated to GLP-1 peptide in mice and monkeys - Lu et al. 2021

Answer 2

• GIPR antagonism and GLP-1 agonism showed increased cAMP in vitro
• mice and monkeys saw significant weight loss with minimal side effects

Question 3

AMG 133 = GIP antagonist bound to GLP-1 agonists - Veniant et al. 2024

Answer 3

• showed significant reduction in body weight and BMI in both animal and human models
• decrease triglycerides and cholesterol in obese monkeys
• increased cAMP responses = promoted internalisation of both receptors

Question 4

LOF variants in Gs and B-arrestin recruitment in GIPR - Kizelkaya et al. 2024

Answer 4

• LOF variants in both Gs signalling and B-arrestin recruitment in GIPR had decreased BMI, BF%, and hip/waist circumference > UK biobank data
• KO B-arrestin mice models saw loss of GIP function but retained GLP-1 function

Question 5

Cagrisema - Fias et al. 2023

Answer 5

• GLP-1 agonist and amylin analogue
• Phase II double blind clinical trial
• Treatment resulted in a significant change in body weight and mean fasting blood glucose
• well tolerated with no fatal AE

Question 6

Comparison of GLP-1 and GIP antagonists in healthy individuals - Gasbjerg et al. 2021

Answer 6

• GLP-1 antagonists caused a significant increase in gastric emptying, glucagon levels and hunger > showed GLP-1 triple effect
• GIP antagonism resulted in a significant increase in blood glucose and reduced insulin signalling > shows its role in glucose tolerance.
• Together they had an additive effect.

Question 7

Leptin responsiveness restored by amylin agonism in diet-induced obesity - Roth et al. 2008

Answer 7

• Amylin restored leptin sensitivity causing a more significant weight loss in both humans and rats when compared to monotherapy
• Sensitivity occurred via increased STAT3 and leptin signalling in the brain.

Question 8

Enhanced weight loss with pramlintide/metreleptin - Ravussin et al. 2009

Answer 8

• Combination of pramlintide (amylin analogue) and metreleptin (modified human leptin) was safe and effective in humans
• showed significant increase in weight loss
• reduction in obese biomarkers = triglycerides, cholesterol and fasting glucose