RESUMO
Patients with type 2 diabetes vary in their response to currently available therapeutic agents (including GLP-1 receptor agonists) leading to suboptimal glycemic control and increased risk of complications. We show that human carriers of hypomorphic T2D-risk alleles in the gene encoding peptidyl-glycine alpha-amidating monooxygenase (PAM), as well as Pam-knockout mice, display increased resistance to GLP-1 in vivo. Pam inactivation in mice leads to reduced gastric GLP-1R expression and faster gastric emptying: this persists during GLP-1R agonist treatment and is rescued when GLP-1R activity is antagonized, indicating resistance to GLP-1's gastric slowing properties. Meta-analysis of human data from studies examining GLP-1R agonist response (including RCTs) reveals a relative loss of 44% and 20% of glucose lowering (measured by glycated hemoglobin) in individuals with hypomorphic PAM alleles p.S539W and p.D536G treated with GLP-1R agonist. Genetic variation in PAM has effects on incretin signaling that alters response to medication used commonly for treatment of T2D.
RESUMO
PURPOSE: A close relationship between obstructive sleep apnea (OSA) and atherosclerosis has been reported, but it is still discussed controversially whether OSA affects vascular function and structure independently. Therefore, we prospectively investigated the independent impact of OSA and its treatment on arterial stiffness. METHODS: One hundred seventy-two patients with suspected OSA were prospectively enrolled in a non-randomized 6-month study to determine whether effective treatment (respiratory events sufficiently reduced and proven compliance) of OSA with continuous positive airway pressure (CPAP) would affect vascular function as measured by augmentation index (Aix) and pulse wave velocity (PWV). Additionally, using a nested case-control, we matched 45 pairs of patients with and without OSA for gender, age, and hypertension. RESULTS: Overall, OSA (n = 117) was associated with increased Aix (23.6 ± 13.5 vs. 8.9 ± 13.7, p < 0.001) and PWV (9.1 ± 1.6 vs. 7.8 ± 1.6 m/s, p < 0.001) as compared with that in controls without OSA (n = 55). Multivariable analysis and results from the nested case-control cohort showed that OSA was associated with increased Aix and PWV independently from hypertension, age, gender, body mass index, and antihypertensive medications. In 49 effectively treated OSA patients, Aix (baseline 22.0 ± 13.4, follow-up 20.1 ± 12.9, p < 0.01) and PWV (baseline 9.6 ± 1.5, follow-up 8.7 ± 1.4, p < 0.05) had improved. In contrast, ineffectively treated OSA patients (n = 39) showed no change in Aix and PWV. CONCLUSIONS: This prospective controlled study suggests that OSA is independently associated with increased arterial stiffness. Furthermore, treatment with CPAP significantly reduced arterial stiffness. These findings extend our understanding of the recently shown cardiovascular burden in OSA and help to explain why CPAP treatment proved to ameliorate cardiovascular outcome even in patients without preexisting cardiovascular disease.