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peptide science.

Tirzepatide in type 1 diabetes: beyond mere weight loss.

Expert Rev Clin Pharmacol

Theodoros Panou, Evanthia Gouveri, Djordje S Popovic +1 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized treatment for type 2 diabetes mellitus (T2DM), obesity and beyond. Current research focuses on the use of the dual agonist of glucagon-like peptide-1 receptor (GLP-1 R) and glucose-dependent insulinotropic polypeptide receptor (GIPR), tirzepatide.

Effects of Tirzepatide on Metabolic Parameters in Patients with Psoriasis and Obesity: 24-Week Real-World Study.

Dermatol Ther (Heidelb)

Paolo Gisondi, Giampiero Girolomoni

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GIP/GLP-1) receptor agonist, has provided substantial efficacy in improving weight and cardiometabolic parameters in individuals with obesity. However, data on its metabolic effects in patients with psoriasis remain limited. The objective if the study was to investigate the effects of tirzepatide on selected metabolic parameters, in adults with psoriasis and obesity.

Measured and Estimated Glomerular Filtration Rates and Risk of Adverse Health Outcomes.

JAMA

Edouard L Fu, Antoine Créon, Morgan E Grams +9 more

Lower estimated glomerular filtration rate (eGFR) is associated with increased rates of death and kidney and cardiovascular events. Associations of measured GFR (mGFR) with outcomes remain unclear.

Modelling G protein-biased agonism using GLP-1 receptor C-terminal mutations.

Mol Metab

Hanh Duyen Tran, Yiming Zuo, Carissa Wong +3 more

The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target for type 2 diabetes and obesity. Agonists showing bias in favour of G protein signalling over β-arrestin recruitment and GLP-1R internalisation, e.g. tirzepatide and orforglipron, have favourable clinical efficacy profiles. However, understanding of the effects of biased agonism has been hampered by differences in ligand properties such as affinity, efficacy, stability and pharmacokinetics. Here we used GLP-1R C-tail mutations that inhibit phosphorylation to mimic G protein-biased GLP-1R agonism without the need for ligand modifications.

Magnitude and Determinants of Weight Loss Response to GLP-1/GIP Receptor Agonists in India: A Real-World Time-to-Event Analysis.

Indian J Endocrinol Metab

Godana Jarso, Shama Mahendru, Aditya Dutta +3 more

Obesity and type 2 diabetes (T2D) are rapidly increasing in India. Although newer glucagon-like peptide/glucose-dependent insulinotropic polypeptide (GLP-1/GIP) receptor agonists have demonstrated considerable efficacy in weight loss, real-world evidence from the Indian population is lacking. This study evaluated the response to semaglutide and tirzepatide in overweight/obese individuals in routine clinical practice.

Impact of BMI on basal LH in premenarcheal girls with idiopathic central precocious puberty.

Front Endocrinol (Lausanne)

Xin Yuan, Ying Zhang, Jing Zhang +2 more

To examined whether body mass index (BMI) affects basal gonadotropin secretion in premenarcheal girls with idiopathic central precocious puberty (ICPP).

Mild autonomous cortisol secretion: Diagnosis.

Vitam Horm

Leonor Pinto, Sara Donato

Mild autonomous cortisol secretion (MACS) is the most frequent hormonal alteration identified in patients with adrenal incidentalomas and is characterized by adrenocorticotropic hormone (ACTH)-independent cortisol hypersecretion in the absence of specific clinical features of Cushing syndrome. Growing evidence indicates that even mild degrees of cortisol excess are associated with increased cardiometabolic morbidity, including hypertension, type 2 diabetes mellitus, dyslipidemia, and obesity, as well as skeletal fragility, frailty and excess mortality. Diagnosis relies primarily on biochemical evaluation, with the 1-mg dexamethasone suppression test as the cornerstone, complemented by confirmation of ACTH independence. However, hormonal testing is subject to important limitations. Management strategies include individualized consideration of adrenalectomy, conservative treatment with target treatment of associated comorbidities, or selected use of medical therapies targeting cortisol secretion or action. Despite increasing recognition of the clinical relevance of MACS, optimal risk stratification and identification of patients most likely to benefit from surgery remain challenging, highlighting the need for validated biomarkers and well-designed prospective randomized trials. This chapter reviews current concepts in the pathophysiology and genetic background of MACS, its clinical consequences, diagnostic challenges and evolving therapeutic strategies.

Indirect Treatment Comparison of Riociguat Replacement Therapy and Selexipag Add-on Therapy in Patients With Pulmonary Arterial Hypertension: Results From a Systematic Review.

Rev Cardiovasc Med

Ji-Eun An, Jahyun Cho, Min Ju Kim +8 more

Despite standard combination therapy with endothelin receptor antagonists (ERAs) and phosphodiesterase-5 inhibitors (PDE5is), many patients with pulmonary arterial hypertension (PAH) show inadequate therapeutic responses. Riociguat (a soluble guanylate cyclase stimulator) and selexipag (a prostacyclin receptor agonist) are both approved as next-step therapies; however, their comparative effectiveness and safety remain unknown due to the lack of head-to-head trials. We aimed to compare the therapeutic effects of riociguat replacement and selexipag add-on therapy through an indirect treatment comparison.

Centromeric footprints preserve telomere integrity in ALT cancers.

Nature

Ragini Bhargava, Megan A Mahlke, Tobias T Schmidt +18 more

Alternative lengthening of telomeres (ALT) is a specialized telomere extension mechanism associated with 5-10% of all cancers1. Although ALT has been linked to epigenetic dysregulation and genome instability, specific genomic and epigenetic rearrangements generated after ALT activation have not been identified. Here we report the insertion of centromeric α-satellite repeats and CENP-B boxes at telomeric locations specifically in ALT cancer cell lines and primary ALT paediatric neuroblastomas, indicating a pathological link for this alteration. Analysis using directed methylation with long-read sequencing (DiMeLo-seq) revealed discrete footprints of CENP-A chromatin assembled at telomeric locations on subsets of chromosomes. By modelling ALT activation, we show that epigenetic dysregulation due to ATRX loss and DNA hypomethylation facilitates the acquisition of these centromeric chromatin signatures. Functionally, interfering with HJURP-mediated CENP-A deposition compromises telomere integrity and ALT, leading to aberrant telomeric mitotic DNA synthesis (MiDAS). We propose that, while originally generated by illegitimate recombination, these centromeric signatures became integral by maintaining telomeric chromatin integrity in the unique context of ALT cancer cells.

Semaglutide in Adolescents Living With Obesity: A Real-World Data Study Exploring Predictors of Treatment Response.

Diabetes Obes Metab

Valeria Cimador, Sophie Robertson, Christine Desmond +4 more

Real-world use of submaximal doses of long-acting GLP-1 receptor agonist semaglutide in patients with obesity: a prospective observational study.

Sci Rep

Zuzana Miertová, Patrik Lecký, Boris Focko +7 more

Obesity is a global health problem with numerous metabolic and mechanical complications. In previous studies, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide has been identified as one of the most promising medications for treating obesity. We carried out a prospective observational study investigating the effect of submaximal doses of semaglutide in 56 adult patients with obesity (mean age 49 ± 12 years, 42 female and 14 male). We evaluated the effects on body weight, waist circumference, height/waist ratio, and BMI during 3-month follow-up. 30 patients in our group also reached a 6-month follow-up. Our patients achieved a weight loss of 6.45 ± 0.31% (p < 0.01) in 3 months of semaglutide therapy, and in the subgroup of 30 patients where semaglutide was administered for 6 months, weight loss was 11.35 ± 0.47% (p < 0.01). Regarding waist circumference, patients achieved a 7 cm decrease in waist circumference in 3 months, and an additional 6 cm at 6 months, respectively (p < 0.01). The mean height/waist ratio decreased from 0.71 ± 0.08 to 0.67 ± 0.09 after 3 months of treatment (p < 0.01) and to 0.63 ± 0.09 (p < 0.01) after 6-month of semaglutide treatment. Mean BMI decreased from 40.3 ± 6.7 to 37.5 ± 6.83 kg/m2 (p < 0.01) after 3 months of treatment and to 35.5 ± 7.73 kg/m2 in the subgroup with 6 months of therapy (p < 0.01). Our study showed a significant decrease in body weight, waist circumference, height/waist ratio, and BMI in patients with obesity treated with submaximal doses of semaglutide.

Perivascular space, brain functional connectivity and sleep: a healthy aging population study.

NPJ Biol Timing Sleep

Nien-Chu Shih, Joey A Contreras, Wendy J Mack +1 more

Perivascular space (PVS) surrounds cortical perforating vessels as part of the brain clearance system. Sleep affects both brain clearance and functional connectivity (FC), but impacts of PVS on FC remains unclear. We utilized T1-W and resting state-fMRI data, Pittsburgh Sleep Quality Index, and NIH cognitive tests from 512 health aging (HCP-Aging). Basal ganglia (BG)-PVS was positively correlated with FC in the right anterior medial temporal gyrus (aMTG) and right temporal regions, while centrum-semiovale (CSO)-PVS was positively correlated with FC in the left hippocampus and right frontal regions. In early middle-aged, increased CSO-PVS showed higher hippocampal FC and better cognition. Individuals with longer time spent in bed had larger BG-PVS linked to higher FC in the right aMTG. Additionally, older adults with better sleep quality had larger BG-PVS linked to higher FC in the right aMTG. This suggests that PVS morphology may reflect changes in neural connections involved in memory-related regions. This study is based on the same cohort as our previous work; however, it extends the investigation by incorporating functional connectivity analyses to provide novel insights beyond regional activity.

Heart Failure Phenotypes and the Prognostic Utility of NT-proBNP in Patients With Chronic Kidney Disease: A Propensity-Score Matched Cohort Study.

Mayo Clin Proc

Chien-Chou Chen, Cai-Mei Zheng, Chih-Chin Kao +4 more

To evaluate the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) across different heart failure phenotypes in patients with chronic kidney disease (CKD).

Differential diagnosis between endogenous Cushing´s syndrome and pseudo-Cushing.

Vitam Horm

Ahmed Alaa Abdul-Aziz

The differentiation between pathological Cushing's syndrome (CS) and pseudo-Cushing's states, also termed non-neoplastic hypercortisolism (NNH), remains one of the biggest challenges in clinical endocrinology. NNH is defined as a reversible condition of clinical and/or biochemical hypercortisolism resulting from persistent activation of the hypothalamic-pituitary-adrenal (HPA) axis by a secondary, non-tumorous etiology. Prevalent conditions such as major depressive disorder, chronic alcoholism, obesity, and eating disorders are frequent causes. Neuropsychiatric disorders drive HPA axis hyperactivity via corticotropin-releasing hormone (CRH) excess and impaired glucocorticoid feedback, while metabolic states often feature tissue-specific amplification of cortisol action via 11β-hydroxysteroid dehydrogenase type 1. Critically, emerging evidence suggests that even functional hypercortisolism may actively contribute to cardiometabolic and neuropsychiatric morbidity, underscoring the importance of accurate discrimination. Clinical evaluation, though essential, is often insufficient, as specific catabolic signs may be absent and metabolic features are common to both entities. Consequently, refined biochemical dynamic tests are pivotal. This review synthesizes evidence on key second-line tests: the combined dexamethasone-CRH test, the desmopressin (DDAVP) test, which exploits aberrant vasopressin receptor expression on corticotroph adenomas and demonstrates high specificity; the combined dexamethasone-DDAVP test, offering a robust and practical alternative; and the 4 mg intravenous dexamethasone suppression test. Radiological studies have no role in this specific differential. A systematic, stepwise diagnostic approach-prioritizing thorough clinical assessment, followed by validated dynamic testing-is imperative to avoid misdiagnosis and ensure appropriate management for both true CS and clinically significant NNH.

ACTH independent Cushing's syndrome: Diagnosis and etiology.

Vitam Horm

Andrés E Ortiz-Flores

Cushing´s syndrome (CS) is a heterogeneous disorder characterized by chronic exposure to cortisol excess, leading to significant metabolic and cardiovascular complications. Timely diagnosis is crucial to reduce morbidity and mortality in these patients. Approximately 20 percent of endogenous CS cases are adrenocorticotropic hormone (ACTH)-independent and arise from primary adrenal disease. This review focuses on the diagnostic work-up and etiological spectrum of ACTH-independent CS. ACTH-independent CS most frequently results from unilateral adrenal adenomas, whereas adrenocortical carcinomas represent a less common but aggressive cause. Bilateral forms include primary pigmented nodular adrenocortical disease and primary bilateral macronodular adrenal hyperplasia, which present micronodular or macronodular adrenal enlargement, respectively, often with subtle or cyclic cortisol excess and characteristic imaging patterns. Recognizing these entities and integrating hormonal data with detailed radiological findings is essential for accurate etiological diagnosis and appropriate therapeutic planning in ACTH-independent CS​​. Radiological assessment with adrenal computed tomography, complemented by magnetic resonance imaging when needed, is crucial to distinguish unilateral from bilateral disease, characterize lesion morphology, and suggest specific etiologies, using unenhanced attenuation values in Hounsfield units to differentiate lipid-rich adenomas from non-adenomatous or potentially malignant lesions.

Serum soluble ASGR1 concentration is elevated in patients with metabolic dysfunction-associated steatotic liver disease and is associated with adiponectin.

BMJ Open Diabetes Res Care

Jing-Ming Wang, Li-Yan Jiang, Yu-Ting Deng +4 more

Current studies have shown that the asialoglycoprotein receptor 1 (ASGR1) is involved in glycolipid metabolism and is associated with systemic insulin resistance. This study aims to explore the correlation between serum soluble ASGR1 (sASGR1) levels and metabolic dysfunction-associated steatotic liver disease (MASLD) by assessing the relationship between sASGR1 concentrations and various biomarker levels.

Optimization of nursing strategies for semaglutide treatment in overweight type 2 diabetes based on gene polymorphism.

Front Clin Diabetes Healthc

Xing Chen, Miaoqing Zhou, Liang Guo +1 more

To evaluate the impact of a gene polymorphism-based individualized nursing strategy on the efficacy of semaglutide in overweight type 2 diabetes (T2DM) patients and to assess its role in mitigating genotype-driven outcome disparities.

Kidney and Survival Benefits of Semaglutide in Diabetes With Chronic Kidney Disease: FLOW Trial Cardiovascular Subgroup Analyses.

J Am Coll Cardiol

Katherine R Tuttle, George L Bakris, Florian M M Baeres +16 more

Cardiovascular disease increases risks of chronic kidney disease (CKD) progression and mortality in type 2 diabetes.

The GLP-1 Ceiling and GIP Dividend: Unraveling the Cardio-Metabolic Paradox in SURPASS-CVOT.

J Am Coll Cardiol

Ying Sun, Yingli Lu, Ningjian Wang

Comprehensive Long-Term Changes in Cardiovascular Risk Biomarkers With Tirzepatide: A SURMOUNT-1 Post Hoc Analysis.

J Am Coll Cardiol

Naveed Sattar, Bruno Linetzky, Giacomo Ruotolo +8 more

Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for treatment of type 2 diabetes and obesity. The effect of tirzepatide on cardiovascular risk biomarkers in people with overweight or obesity remains uncertain.