Greater improvement in insulin sensitivity per unit weight loss associated with tirzepatide versus semaglutide: An exploratory analysis.

Aims: To explore the relationship between weight loss and insulin sensitivity in response to tirzepatide or semaglutide.

Materials And Methods: We conducted a post hoc exploratory analysis of a 28-week, double-blind, randomized trial in people with type 2 diabetes treated with metformin, randomized to tirzepatide 15 mg, semaglutide 1 mg or placebo. We evaluated the relationship between change in body weight and change in insulin sensitivity determined from hyperinsulinemic euglycemic clamp (M value), or from mixed-meal tolerance testing (Matsuda index).

Brainstem BDNF neurons are downstream of GFRAL/GLP1R signalling.

Growth differentiation factor 15, GDF15, and glucagon-like peptide-1 (GLP-1) analogues act through brainstem neurons that co-localise their receptors, GDNF-family receptor α-like (GFRAL) and GLP1R, to reduce food intake and body weight. However, their use as clinical treatments is partially hampered since both can also induce sickness-like behaviours, including aversion, that are mediated through a well-characterised pathway via the exterolateral parabrachial nucleus. Here, in mice, we describe a separate pathway downstream of GFRAL/GLP1R neurons that involves a distinct population of brain-derived neurotrophic factor (BDNF) cells in the medial nucleus of the tractus solitarius.

The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron.

Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs.

High prevalence of low bone mineral density in young adults with phenylketonuria.

Background: It has been reported that phenylalanine (Phe)-restricted diets may have negative effects on bone health in patients with classical phenylketonuria (cPKU). We aimed to evaluate bone mineral density (BMD) in adults with cPKU and determine the risk factors associated with low BMD.

Methods: Eighty adult patients with cPKU were examined, including 41 women and 39 men.