To evaluate the effects of tirzepatide on body composition, appetite, and energy intake to address the potential mechanisms involved in body weight loss with tirzepatide.
In a secondary analysis of a ...randomized, double-blind, parallel-arm study, the effects of tirzepatide 15 mg (N = 45), semaglutide 1 mg (N = 44), and placebo (N = 28) on body weight and composition, appetite, and energy intake were assessed at baseline and week 28.
Tirzepatide treatment demonstrated significant reductions in body weight compared with placebo and semaglutide, resulting in greater fat mass reduction. Tirzepatide and semaglutide significantly reduced appetite versus placebo. Appetite scores and energy intake reductions did not differ between tirzepatide and semaglutide.
Differences in energy intake during ad libitum lunch were not sufficient to explain the different weight outcomes. Further evaluation is needed to assess mechanistic differences related to tirzepatide actions on 24-h energy intake, substrate utilization, and energy expenditure.
Considerable progress has been made in the understanding of the sequential activation of signal transduction pathways and the expression of transcription factors during pancreas development. Much of ...this understanding has been obtained by analyses of the phenotypes of mice in which the expression of key genes has been disrupted (knockout mice). Knockout of the genes for Pdx1, Hlxb9, Isl1, or Hex results in an arrest of pancreas development at a very early stage (embryonic d 8–9). Disruption of genes encoding components of the Notch signaling pathway, e.g. Hes1 or neurogenin-3, abrogates development of the endocrine pancreas (islets of Langerhans). Disruption of transcription factor genes expressed more downstream in the developmental cascade (Beta2/NeuroD, Pax4, NKx2.2, and Nkx6.1) curtails the formation of insulin-producing β-cells. An understanding of the importance of transcription factor genes during pancreas development has provided insights into the pathogenesis of diabetes, in which the mass of insulin-producing β-cells is reduced.
Aims/hypothesis
Obesity is characterised by lipid accumulation in skeletal muscle, which increases the risk of developing insulin resistance and type 2 diabetes. AMP-activated protein kinase (AMPK) ...is a sensor of cellular energy status and is activated in skeletal muscle by exercise, hormones (leptin, adiponectin, IL-6) and pharmacological agents (5-amino-4-imidazolecarboxamide ribonucleoside AICAR and metformin). Phosphorylation of acetyl-CoA carboxylase 2 (ACC2) at S221 (S212 in mice) by AMPK reduces ACC activity and malonyl-CoA content but the importance of the AMPK–ACC2–malonyl-CoA pathway in controlling fatty acid metabolism and insulin sensitivity is not understood; therefore, we characterised
Acc2
S212A knock-in (ACC2 KI) mice.
Methods
Whole-body and skeletal muscle fatty acid oxidation and insulin sensitivity were assessed in ACC2 KI mice and wild-type littermates.
Results
ACC2 KI mice were resistant to increases in skeletal muscle fatty acid oxidation elicited by AICAR. These mice had normal adiposity and liver lipids but elevated contents of triacylglycerol and ceramide in skeletal muscle, which were associated with hyperinsulinaemia, glucose intolerance and skeletal muscle insulin resistance.
Conclusions/interpretation
These findings indicate that the phosphorylation of ACC2 S212 is required for the maintenance of skeletal muscle lipid and glucose homeostasis.
Breast cancer is the most common cancer diagnosis for women in the USA and ranks second in cancer-related deaths. Disproportionately higher breast cancer rates can be found in rural and Appalachian ...regions due to several social drivers of health, including poverty, access to healthcare, and lack of culturally sensitive health education. Amish and Mennonite communities, religious groups with distinct cultural practices and beliefs, experience lower mammography screening and higher breast cancer mortality rates (among Amish women). This study focuses on knowledge about breast cancer and causes of cancer among Amish and Mennonite women. A total of 473 women participated in the study at 26 separate women's health clinics throughout Ohio, consisting of 348 Amish and 121 Mennonite women, the largest study conducted on breast cancer knowledge spanning dozens of communities. Statistically significant differences were found in total knowledge scores between Amish and Mennonite women (r
= .178, n = 466, p = .007), with Amish women having lower scores and stronger beliefs in myths associated with breast cancer cause and symptoms (χ(1) = 7.558, p = .006). Both groups often provided scientifically accurate descriptions of cancer etiology. The majority of participants underestimated breast cancer risk, highlighting the need for culturally appropriate health education programs that consider numeracy and health literacy. By implementing targeted interventions and fostering partnerships with community stakeholders using a multifaceted approach that incorporates cultural sensitivity, community engagement, and collaboration, significant progress can be made towards reducing breast cancer disparities and improving health outcomes.
As the development of clinically efficacious glucagon receptor (GCGR) agonists for the treatment of metabolic diseases evolves, the challenge to identify physiologically relevant preclinical models ...that predict glucagon receptor actions in humans becomes ever more important. While many hepatocyte models are available, most fail to recapitulate fundamental metabolic regulatory responses to key physiologic stimuli including integration of glucagon and insulin actions that govern hepatic carbohydrate or lipid metabolism. We developed and optimized a human induced pluripotent stem cell (iPSC)-derived hepatocyte model to mimic physiologic insulin and glucagon signaling and counter-regulation of metabolic pathways. We leveraged the model to evaluate functional responses of different glucagon receptor agonist molecules to regulate carbohydrate and lipid metabolism. Unlike assays conducted in several other cell line and primary isolated hepatocyte systems, hepatic glucose output assays in the human IPSC hepatocyte model demonstrated substantial potency differences between two novel soluble glucagon analog agonists. These findings predicted differential dose-dependent blood glucose excursions in response to these agonists when administered in a single ascending dose study in healthy human volunteers. Modeling physiologic integration of insulin and glucagon signaling in a clinically translatable human iPSC hepatocyte model can advance understanding of the regulation of nutrient metabolism by glucagon receptor agonists in humans and support the development of novel therapeutic approaches to address metabolic disorders, including type 2 diabetes, obesity, and nonalcoholic fatty liver disease.
Disclosure
W.Roell: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Regmi: Employee; Eli Lilly and Company. C.T.Benson: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. T.Coskun: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.S.Moyers: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.Alsina-fernandez: Employee; Eli Lilly and Company. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.
Invasive species can lead to community-level damage to the invaded ecosystem and extinction of native species. Most surveillance systems for the detection of invasive species are developed based on ...expert assessment, inherently coming with a level of uncertainty. In this research, info-gap decision theory (IGDT) is applied to model and manage such uncertainty. Surveillance of the Asian House Gecko, Hemidactylus frenatus Duméril and Bibron, 1836 on Barrow Island, is used as a case study. Our research provides a novel method for applying IGDT to determine the population threshold (Formula: see text) so that the decision can be robust to the deep uncertainty present in model parameters. We further robust-optimize surveillance costs rather than minimize surveillance costs. We demonstrate that increasing the population threshold for detection increases both robustness to the errors in the model parameter estimates, and opportuneness to lower surveillance costs than the accepted maximum budget. This paper provides guidance for decision makers to balance robustness and required surveillance expenditure. IGDT offers a novel method to model and manage the uncertainty prevalent in biodiversity conservation practices and modelling. The method outlined here can be used to design robust surveillance systems for invasive species in a wider context, and to better tackle uncertainty in protection of biodiversity and native species in a cost-effective manner.
CD95 is a member of the TNF receptor superfamily that is ubiquitously expressed in healthy and pathological tissues. Stimulation of CD95 by its physiological ligand CD95L induces its oligomerization ...leading in turn to the transduction of either apoptotic or nonapoptotic signals. CD95L can exist as both membrane‐anchored and soluble forms (sCD95L), the latter resulting from the proteolytic cleavage of the former. Candidate proteases able to achieve CD95L cleavage were identified as matrix metalloproteases (MMP) due to their demonstrated ability to cleave other TNF superfamily ligands. The main goal of this study was to systematically identify the MMP family members capable of cleaving CD95L and subsequently determine the corresponding cleavage sites. By using different orthogonal biochemical approaches and combining them with molecular modelling, we confirmed data from the literature regarding CD95L cleavage by MMP‐3 and MMP‐7. Moreover, we found that MMP‐2 and MMP‐12 can cleave CD95L and characterized their resulting cleavage sites. This study provides a systematic approach to analyse the cleavage of CD95L, which until now had only been poorly described.
CD95 and its ligand CD95L were first described for their implication in extrinsic apoptotic signal transmission. The extracellular domain of CD95L can be proteolytically cleaved through the action of metalloproteases. Releasing a trimeric soluble CD95L can trigger non‐apoptotic signalling cascades. High serum levels of sCD95L have been detected in patients with various pathologies. This study aimed to systematically identify the proteases capable of cleaving CD95L and subsequently determine the corresponding cleavage sites.
Multifunctional incretins are in clinical development for several metabolic conditions. Novel LY3437943 has potent agonist activity on glucose-dependent insulinotropic polypeptide (GIP), ...glucagon-like peptide-1 (GLP-1) and glucagon receptors. The primary objective of this randomized, double-blind, placebo (PBO)-controlled, Phase 1, first in human study was to assess safety and tolerability of single-ascending doses of LY3437943. Forty-five healthy subjects were randomized (6:2) to subcutaneous LY3437943 (6 rising dose levels) or PBO. Vital signs, ECGs, laboratory data and adverse events (AEs) were monitored to assess safety and tolerability. LY3437943 pharmacokinetics (PK) as well as change from baseline (BL) in fasting insulin, C-peptide and weight were measured. Appetite was assessed using a visual analog scale (VAS). The most common treatment-emergent AEs were gastrointestinal, including vomiting (with higher doses), abdominal distention and nausea, which were dose-dependent, mostly mild in severity, occurred within 4 days of dosing and resolved within a week of onset. Dose-dependent increases in heart rate and decreases in systolic blood pressure were observed, which returned to near BL by Day 29. Mean terminal half-life of LY3437943 ranged from 134-165 h (∼7 days) across the 6 doses, supporting once-weekly dosing. Dose-dependent increases in mean fasting insulin and C-peptide, with maximum levels observed at 24 and 48 h, returned to near BL by Day 15. Dose-dependent weight loss was statistically significant with the 3 highest doses vs. PBO (up to 3.5 kg at the highest dose). Weight loss was maintained up to Day 43 following single administration of the two highest doses. Overall VAS score significantly increased with higher doses vs. PBO, reflecting decreased appetite. Triple-agonist peptide LY3437943 had a safety and tolerability profile similar to other incretins in Phase 1 trials with PK and pharmacodynamic outcomes that support further clinical evaluation.
Disclosure
S. Urva: Employee; Self; Eli Lilly and Company. Y. Du: None. M. K. Thomas: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. Z. Milicevic: Employee; Self; Eli Lilly and Company. T. Coskun: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. C. Benson: Employee; Self; Eli Lilly and Company. C. Loghin: Employee; Self; Eli Lilly and Company.
Funding
Eli Lilly and Company
LY3305677 (LY) is an acylated single chain peptide analog of mammalian oxyntomodulin designed for once weekly dosing. It has dual pharmacology of GLP-1 and glucagon and has therapeutic potential for ...T2D, obesity and NASH. This randomized, double blind, placebo-controlled phase 1 study assessed safety and tolerability of single ascending doses of LY. Healthy subjects (N=48) were randomized (6:2) and 47 received subcutaneous LY (6 doses: 0.03 mg to 5.0 mg) or placebo. Safety biomarkers, LY pharmacokinetics (PK), and key exploratory pharmacodynamic (PD) biomarkers were assessed including fasting insulin, glucagon, triglyceride levels, and body weight. Most common LY-related AEs were gastrointestinal events. Dose-dependent increase in nausea, decreased appetite, and vomiting were seen. Most of the events were mild and transient. Increase in heart rate was noted, which returned to baseline for most groups at follow-up visit. No injection site reactions were seen. Median time to maximum LY concentration ranged from 18.2 to 72.1 h, and geometric mean half-life ranged from 7.5 to 9.8 days. Generally, mean fasting insulin level increased within 24 h and lasted over 8 days. At Day 8, LY 2.5 mg and 5.0 mg reduced mean fasting glucagon levels by 2.33 pmol/L and 2.67 pmol/L, respectively as compared with placebo. At Day 5, mean fasting triglyceride levels reduced from baseline by 0.5 mmol/L with LY 5.0 mg as compared to 0.1 mmol/L with placebo. Change from baseline in body weight reached a maximum -2.4 kg with the 5 mg dose, versus -0.5 kg for placebo at Day 8 and this effect was sustained through Day 29 at 5 mg.
LY3305677 PK properties are suitable for once-weekly dosing with a safety and tolerability profile similar to other incretins in Phase 1 trials, supporting future clinical evaluation.
Disclosure
L. Tham: Employee; Self; Eli Lilly and Company. M. K. Thomas: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. C. Benson: Employee; Self; Eli Lilly and Company. R. Bray: None. C. Tang: Employee; Self; Eli Lilly and Company, Employee; Spouse/Partner; Novartis AG. C. Loghin: Employee; Self; Eli Lilly and Company.
Funding
Eli Lilly and Company
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