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The article discusses a post hoc analysis of a phase 2 clinical trial on survodutide, a dual agonist for glucagon and GLP-1 receptors, in adults with obesity. The study showed significant weight loss and reductions in blood pressure with survodutide treatment compared to placebo. The results suggest that survodutide may help alleviate cardiovascular risk, regardless of hypertension status at baseline. The study was supported by Boehringer Ingelheim, and the authors disclosed potential conflicts of interest related to the research. [Extracted from the article]

Aims: Pharmacotherapeutic options for obesity treatment include glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, for example, liraglutide. However, an unmet need remains, particularly in patients with a high body mass index (BMI), as GLP‐1R agonists are associated with gastrointestinal adverse events (AEs) and some patients do not respond to treatment. Neuropeptide Y (NPY) and peptide YY bind G‐protein‐coupled Y receptors and represent attractive targets for modulating bodyweight. Materials and Methods: This first‐in‐human, three‐part, partially blinded phase I study (NCT04903509) investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of the peptidic NPY2R agonist BI 1820237, with/without low‐dose liraglutide: part 1 (participants randomized to receive BI 1820237: 0.075–2.4 mg or placebo), part 2 (BI 1820237: 1.2 mg or placebo) and part 3 (BI 1820237: 0.025–1.2 mg + liraglutide 0.6 mg or placebo + liraglutide 0.6 mg). Primary endpoint is the proportion of participants with drug‐related AEs. Secondary endpoints are tolerability, PK and PD. Results: In total, 95 otherwise healthy men with increased BMI (25.0–34.9 kg/m2) were randomized. Drug‐related AEs, mainly gastrointestinal events, were reported by 39.0% of participants (n = 23) in parts 1 + 2 and 30.6% of participants (n = 11) in part 3; one drug‐related AE (11.1%, part 3) was reported in a participant receiving placebo with liraglutide. Post‐dose paracetamol PK suggested that BI 1820237 and low‐dose liraglutide exhibited additive effects on gastric emptying. Conclusions: BI 1820237 treatment was associated with transient nausea and vomiting at higher doses. No differences in tolerability were observed when combined with liraglutide; effects on gastric emptying appeared additive. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this study was to assess the dose–response effects of the subcutaneous glucagon receptor/glucagon-like peptide-1 receptor dual agonist survodutide (BI 456906) on HbA1c levels and bodyweight reduction. Methods: This Phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, conducted in clinical research centres, assessed survodutide in participants aged 18–75 years with type 2 diabetes, an HbA1c level of 53–86 mmol/mol (7.0–10.0%) and a BMI of 25–50 kg/m2 on a background of metformin therapy. Participants were randomised via interactive response technology to receive survodutide (up to 0.3, 0.9, 1.8 or 2.7 mg once weekly [qw; dose group (DG) 1–4, respectively] or 1.2 or 1.8 mg twice weekly [DG 5 and 6, respectively]), placebo or semaglutide (up to 1.0 mg qw). Participants and all those involved in the trial conduct/analysis were blinded; the semaglutide arm was open-label. The primary endpoint was absolute change from baseline in HbA1c after 16 weeks' treatment. The key secondary endpoint was relative change from baseline in bodyweight after 16 weeks' treatment. Results: A total of 413 participants were randomised (DG1, n=50; DG2, n=50; DG3, n=52; DG4, n=50; DG5, n=51; DG6, n=50; semaglutide, n=50; placebo, n=60). The full analysis set comprised 411 treated participants (DG6, n=49; placebo, n=59). Adjusted mean (95% CI) HbA1c decreased from baseline (mean ± SD 64.7±9.2 mmol/mol [8.07±0.84%] after 16 weeks' treatment: DG1 (n=41), −9.92 mmol/mol (−12.27, −7.56; −0.91% [−1.12, −0.69]); DG2 (n=46), −15.95 mmol/mol (−18.27, −13.63; −1.46% [−1.67, −1.25]); DG3 (n=36), −18.72 mmol/mol (−21.15, −16.29; −1.71% [−1.94, −1.49]); DG4 (n=33), −17.01 mmol/mol (−19.59, −14.43; −1.56% [−1.79, −1.32]); DG5 (n=44), −17.84 mmol/mol (−20.18, −15.51; −1.63% [−1.85, −1.42]); DG6 (n=36), −18.38 mmol/mol (−20.90, −15.87; −1.68% [−1.91, −1.45]). The mean reduction in HbA1c was similar with low-dose survodutide (DG2: −15.95 mmol/mol [−1.46%]; n=46) and semaglutide (−16.07 mmol/mol [−1.47%]; n=45). Mean (95% CI) bodyweight decreased dose-dependently up to −8.7% (−10.1, −7.3; DG6, n=37); survodutide ≥1.8 mg qw produced greater bodyweight reductions than semaglutide (−5.3% [−6.6, −4.1]; n=45). Adverse events (AEs) were reported for 77.8% of survodutide-treated participants (mainly gastrointestinal), 52.5% receiving placebo and 52.0% receiving semaglutide. Conclusions/interpretation: Survodutide reduced HbA1c levels and bodyweight after 16 weeks' treatment in participants with type 2 diabetes. Dose-related gastrointestinal AEs could be mitigated with slower dose escalations. Trial registration: ClinicalTrials.gov NCT04153929 and EudraCT 2019-002390-60. Funding: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. [ABSTRACT FROM AUTHOR]

Introduction: Overweight and obesity lead to numerous complications and their treatment. The associated costs represent a health and sociopolitical burden. Therefore, the development of overweight and obesity is of great importance for health policy. Methods: The Gutenberg Health Study (GHS), a population-based observational study of individuals aged 35–74 years in the city of Mainz and the district of Mainz-Bingen, examined current data on the prevalence and development of overweight and obesity and their association with concomitant diseases and medication use. Results: Among men, 48.1% were overweight and 26.3% had obesity. Among women, these proportions were 32.1% and 24.1%, respectively. Elevated body mass index (BMI) was associated with numerous complications, particularly insulin resistance and type 2 diabetes, arterial hypertension, elevated triglycerides and low HDL cholesterol, and cardiovascular disease. Accordingly, medications to treat these conditions were used significantly more often in individuals with elevated BMI. During the 10-year observation period, mean weight increased in the population. Both men and women had a moderate but significant increase in BMI compared to men and women of the same age at baseline. Individual weight changes over the 10-year observation period, on the other hand, were age-dependent. In the two younger age decades, weight gain was observed, while in the oldest age decade, mean body weight decreased. Conclusion: These current data confirm that overweight and obesity are associated with relevant complications and that these complications lead to significant use of appropriate medications. The study also suggests that there is a significant trend toward increased prevalence of obesity (BMI ≥30) over the 10-year period. [ABSTRACT FROM AUTHOR]

The pore-forming [K.sup.+]-channel [alpha]-subunit KCNQ1 is expressed in a wide variety of tissues including heart, skeletal muscle, fiver, and epithelia. Most recent evidence revealed an association of the KCNQ1 gene with the susceptibility to type 2 diabetes. KCNQ1 participates in the regulation of cell volume, which is, in turn, critically important for the regulation of metabolism by insulin. The present study explored the influence of KCNQ1 on insulin-induced cellular [K.sup.+] uptake and glucose metabolism. Insulin (100 nM)-induced [K.sup.+] uptake was determined in isolated perfused livers from KCNQl-deficient mice ([kcnql.sup.-/-]) and their wild-type littermates ([kcnql.sup.+/+]). Moreover, plasma glucose and insulin levels, intraperitoneal glucose (3 g/kg) tolerance, insulin (0.15 U/kg)-induced hypoglycemia, and peripheral uptake of radiolabeled [sup.3]H-deoxy-glucose were determined in both genotypes. Insulin-stimulated hepatocellular [K.sup.+] uptake was significantly more sustained in isolated perfused livers from [kcnql.sup.-/-] mice than from [kcnql.sup.+/+] mice. The decline of plasma glucose concentration following an intraperitoneal injection of insulin was again significantly more sustained in [kcnql.sup.-/-] than in [kcnql.sup.+/+] mice. Both fasted and nonfasted plasma glucose and insulin concentrations were significantly lower in [kcnql.sup.-/-] than in [kcnql.sup.+/+] mice. Following an intraperitoneal glucose injection, the peak plasma glucose concentration was significantly lower in [kcnql.sup.-/-] than in [kcnql.sup.+/+] mice. Uptake of [sup.3] H-deoxy-glucose into skeletal muscle, liver, kidney and lung tissue was significantly higher in [kcnql.sup.-/-] than in [kcnql.sup.+/+] mice. In conclusion, KCNQ1 counteracts the stimulation of cellular [K.sup.+] uptake by insulin and thereby influences [K.sup.+]-dependent insulin signaling on glucose metabolism. The observations indicate that KCNQ1 is a novel molecule affecting insulin sensitivity of glucose metabolism. [K.sup.+] channels; blood glucose; kidney; liver; skeletal muscle

Homozygous deletion of the gene of the neuronal glucose transporter GLUT3 (S1c2a3) in mice results in embryonic lethality, whereas heterozygotes ([Slc2a3.sup.+/-]) are viable. Here, we describe the characterization of heterozygous mice with regard to neuronal function, glucose homeostasis, and, since GLUT3 might be a component of the neuronal glucose-sensing mechanism, food intake and energy balance. Levels of GLUT3 mRNA and protein in brain were reduced by 50% in [Slc2a3.sup.+/-] mice. Electrographic features examined by electroencephalographic recordings give evidence for slightly but significantly enhanced cerebrocortical activity in [Slc2a3.sup.+/-] mice. In addition, [Slc2a3.sup.+/-] mice were slightly more sensitive to an acoustic startle stimulus (elevated startle amplitude and reduced prepulse inhibition). However, systemic behavioral testing revealed no other functional abnormalities, e.g., in coordination, reflexes, motor abilities, anxiety, learning, and memory. Furthermore, no differences in body weight, blood glucose, and insulin levels were detected between wild-type and [Slc2a3.sup.+/-] littermates. Food intake as monitored randomly or after intracerebroventricular administration of 2-deoxyglucose or D-glucose, or food choice for carbohydrates/fat was not affected in [Slc2a3.sup.+/-] mice. Taken together, our data indicate that, in contrast to Slc2a1, a single allele of Slc2a3 is sufficient for maintenance of neuronal energy supply, motor abilities, learning and memory, and feeding behavior. glucose transporter 3; knockout; glucose sensing; food in take; neurons and astrocytes

Insulin and IGF-I activate antiapoptotic pathways via insulin receptor substrate (IRS) proteins in most mammalian cells, including [beta]-cells. IRS-I knockout (IRS-1KO) mice show growth retardation, hyperinsulinemia, and hyperplastic but dysfunctional islets without developing overt diabetes, whereas IRS-2KOs develop insulin resistance and islet hypoplasia leading to diabetes. Because both models display insulin resistance, it is difficult to differentiate islet response to insulin resistance from islet defects due to loss of proteins in the islets themselves. We used a transplantation approach, as a means of separating host insulin resistance from islet function, to examine alterations in proteins in insulin/IGF-I signaling pathways that may contribute to [beta]-cell proliferation and/or apoptosis in IRS-1KO islets. Islets isolated from wild-type (WT) or IRS-1KO mice were transplanted into WT or insulin-resistant IRS-1KO males under the kidney capsule. The [beta]-cell mitotic rate in transplanted islets in IRS-1KO recipients was increased 1.5-fold compared with WT recipients and was similar to that in endogenous pancreases of IRS-1KOs, whereas [beta]-cell apoptosis was reduced by ~80% in IRS-1KO grafts in IRS-1KO recipients compared with WT recipients. Immunohistochemistry showed a substantial increase in IRS-2 expression in IRS-1KO islets transplanted into IRS-1KO mice as well as in endogenous islets from IRS-1KOs. Furthermore, enhanced cytosolic forkhead transcription factor (FoxO1) staining in IRS-1KO grafts suggests intact Akt/PKB activity. Together, these data indicate that, even in the absence of insulin resistance, [beta]-cells deficient in IRS-1 exhibit a compensatory increase in IRS-2, which is associated with islet growth and is characterized by both proliferative and antiapoptotic effects that likely occur via an insulin/IGF-I/IRS-2 pathway. insulin receptor substrate proteins; islets; transplantation; insulin resistance; [beta]-cell growth

Previous studies showed an insulin-'desensitizing' action of IL-6 on glycogen synthesis in hepatocytes. We recently found no inhibition of the proximal steps of the insulin signal cascade in human skeletal muscle cells. Because these data indicate a possible tissue-specific effect of IL-6, we investigated the influence of IL-6 on insulin-stimulated glycogen synthesis in these cells. At first, we found that incubation of the cells with 20 ng/ml IL-6 alone induced phosphorylation of [Ser.sup.473] of Akt, but not of [Thr.sup.308] time dependently and we observed that IL-6 augments insulin-induced [Ser.sup.473] and [Thr.sup.308] phosphorylation in the low nanomolar range of insulin. Moreover, IL-6 increased insulin-stimulated phosphorylation of glycogen synthase kinase-3. Accordingly, IL-6 enhanced glycogen synthesis in the presence of 3 and 10 nM insulin, whereas IL-6 alone had only a marginal effect. IL-6 treatment of C57B1/6 mice readily stimulated phosphorylation of [Ser.sup.473] in skeletal muscle. Our result that IL-6 did not induce [Ser.sup.473] phosphorylation in the liver of these mice suggests a tissue-specific effect. Together, our data demonstrate a novel insulin-sensitizing function of IL-6 on glycogen synthesis in skeletal muscle cells and indicate that IL-6 exerts cell/tissue-specific effects on insulin action. insulin signaling; signaling; Akt; muscle; liver