William Geoffrey Haynes

Aims/hypothesis: The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling. Methods: Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability >0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome. Results: Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units −0.16, 95% CI −0.30, −0.02), C-reactive protein (−0.13, 95% CI −0.19, −0.08) and triacylglycerol levels (−0.17, 95% CI −0.22, −0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome. Conclusions/interpretation: This study provides genetic evidence to support a beneficial role of sustained GIP signalling on cardiometabolic health greater than that expected from improved glycaemic control alone. Further clinical investigation is warranted. Data availability: All data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP. Graphical

BACKGROUND: There is an unmet need for a safer and more effective treatment for obesity. This study assessed the effects of licogliflozin, a dual inhibitor of sodium‐glucose co‐transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity. METHODS: Patients with obesity (BMI, 35‐50 kg/m ² ) were enrolled into a 12‐week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two‐part study, comprising a single‐dose cross‐over study (N = 12; 2.5 − 300 mg) and a 14‐day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE ₂₄ ) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP‐1, PYY _3‐36 , and GIP), insulin and glucagon. RESULTS: Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo ( P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% ( P < 0.001; incremental AUC _0‐4h ) and suppressed insulin by 90% ( P < 0.01; incremental AUC _0‐4h ). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24‐hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE ₂₄ to 100 g ( P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP‐1 by 54% ( P < 0.001) and PYY _3‐36 by 67% ( P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% ( P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12‐week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%‐43% with licogliflozin vs 9%‐11% with placebo in the 12‐week study) were among the other gastrointestinal events reported. CONCLUSION: Licogliflozin treatment (1‐84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes.

Human in vitro physiological models studying disease and drug treatment effects are urgently needed as more relevant tools to identify new drug targets and therapies. We have developed a human microfluidic two-organ-chip model to study pancreatic islet–liver cross-talk based on insulin and glucose regulation. We have established a robust co-culture of human pancreatic islet microtissues and liver spheroids maintaining functional responses up to 15 days in an insulin-free medium. Functional coupling, demonstrated by insulin released from the islet microtissues in response to a glucose load applied in glucose tolerance tests on different days, promoted glucose uptake by the liver spheroids. Co-cultures maintained postprandial glucose concentrations in the circulation whereas glucose levels remained elevated in both single cultures. Thus, insulin secreted into the circulation stimulated glucose uptake by the liver spheroids, while the latter, in the absence of insulin, did not consume glucose as efficiently. As the glucose concentration fell, insulin secretion subsided, demonstrating a functional feedback loop between the liver and the insulin-secreting islet microtissues. Finally, inter-laboratory validation verified robustness and reproducibility. Further development of this model using tools inducing impaired glucose regulation should provide a unique in vitro system emulating human type 2 diabetes mellitus.

Objective: Obesity is a major risk factor for chronic daily headaches, including migraine and tension‐type headache (TTH). Although migraine is associated with increased risk of cardiovascular diseases (CVD), a relation between TTH and CVD risk has not been established. It was hypothesized that higher carotid‐femoral pulse wave velocity (CFPWV) and augmentation index (AI), measures of aortic stiffness and pressure wave reflection, respectively, and biomarkers of CVD risk, would be higher among adults with obesity and migraine or TTH compared with those with no headache.Methods: Adults with obesity (n = 93; body mass index ≥30 kg/m²) who were between 40 and 75 years old with at least one additional CVD risk factor were enrolled. Subjects had CFPWV and AI assessed and a complete neurological exam for diagnosis of headache in the past 12 months.Results: Adults with obesity and TTH (P = 0.018), but not migraine (P = 0.29), had significantly higher AI compared with those with no headache. When both CFPWV and AI were considered in a logistic regression model with migraine or TTH, only AI was associated with TTH (P = 0.008) and migraine (P = 0.032) but could not distinguish between the two headache phenotypes.Conclusions: Increased aortic AI but not stiffness is associated with TTH and migraine among middle‐aged/older adults with obesity and high CVD risk.

We sought to determine whether heart rate variability (HRV), blood pressure (BP) variability, and baroreceptor-heart rate reflex sensitivity can be reliably assessed using finger volume pulse waveforms obtained from the commercially available EndoPAT device. Non-invasive BP (Finometer Pro as a non-invasive standard) and finger volume (EndoPAT) waveforms were recorded in 65 adults (37 ± 14 years; 60% female) and systolic BP and heart rate (HR) time series were derived after calibrating the EndoPAT signal based on systolic and diastolic BP values obtained by a sphygomomanometer. Transfer function analyses were performed to test for coherence between systolic BP and HR time series derived from the Finometer and EndoPAT devices. Time-domain HRV parameters, frequency domain HR and systolic BP variability parameters, and baroreflex sensitivity (sequence technique) were computed from Finometer- and EndoPAT-derived time series and intraclass correlation coefficients (ICC) were calculated. Squared coherence between systolic BP time series derived from the Finometer and EndoPAT devices was low, suggesting poor correlation. In contrast, squared coherence between HR time series derived from the two devices was excellent [High Frequency (HF) = 0.80, Low Frequency (LF) = 0.81], with gain values close to 1.0. ICC values for time- and frequency-domain HRV parameters were excellent (>0.9 except for relative HF HRV, which was 0.77), while ICC values for frequency-domain BP variability parameters and baroreceptor-HR reflex sensitivity were low. Finger volume pulse waveforms can be used to reliably assess both time-domain and frequency-domain HR variability. However, frequency domain BP variability parameters cannot be reliably assessed from finger volume pulse waveforms using the simple calibration technique used in this study.