There is an urgent need for effective treatments targeting comorbidities of type 2 diabetes (T2DM) and obesity. Developing dual agonists of glucagon-like peptide 1 receptor (GLP-1R) and neuropeptide Y receptor type 2 (NPY2R) with combined PYY3-36 and GLP-1 bioactivity is promising. However, designing such dual agonists that effectively control glycemia and reduce weight while minimizing gastrointestinal side effects is challenging. In this study, we systematically evaluated the side effects induced by co-administering various GLP-1R agonists and PYY3-36 analogue. Our findings revealed that different GLP-1R agonist-PYY analogue combinations elicited gastrointestinal side effects of varying intensities. Among these, the co-administration of bullfrog GLP-1 analogue (bGLP-1) with PYY3-36 analogue resulted in lower gastrointestinal side effects. Thus, bGLP-1 was selected as the preferred candidate for designing dual GLP-1R/NPY2R agonists. Through stepwise structural design, optimization of linker arms, and durability enhancements, coupled with in vitro receptor screening, the novel peptide bGLP/PYY-19 emerged as the lead candidate. Notably, experimental results in mice and rats showed a significant reduction in emesis with bGLP/PYY-19 compared to semaglutide and bGLP-1 long-acting analogue (LAbGLP-1). Furthermore, bGLP/PYY-19 significantly outperformed semaglutide and LAbGLP-1 in reducing body weight in diet-induced obese (DIO) mice, without inducing nausea-associated behavior. These findings underscore the potential of dual-targeting single peptide conjugates as a promising strategy for developing glucoregulatory treatments that offer superior weight loss benefits and are better tolerated compared to treatments targeting GLP-1R alone.

Obesity is associated with a higher risk of severe diseases such as atherosclerotic cardiovascular disease, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD). Polyunsaturated fatty acids, of the omega-3 family (n-3 PUFA), have been shown to reduce adipose tissue inflammation in obesity, as well as to have lipid-lowering effects and improve insulin sensitivity. However, direct effects on liver transcriptome in humans have not been described. Our aim was to understand the impact of n-3 PUFA on gene expression in obese human liver.

Patients with obesity (BMI ≥ 40 kg/m2) were treated for eight weeks with 3.36 g n-3 PUFAs (1.84 g eicosapentaenoic acid (EPA) and 1.53 g docosahexaenoic acid (DHA)), or with 5 g of butter as a control (n = 15 per group) before undergoing bariatric surgery where liver biopsies were taken. Liver samples were used for mRNA microarray analyses and subsequently Gene Set Enrichment Analysis (GSEA) was performed. This bioinformatic approach led us to identify 80 significantly dysregulated pathways that were divided into 9 different clusters including insulin and lipid metabolism, and immunity. N-3 PUFA treatment significantly affected pathways related to immunity, metabolism, and inflammation. Specifically, it upregulated pathways involved in T-cell and B-cell functions and lipid metabolism, while downregulating glucagon signalling. These findings highlight the impact of n-3 PUFAs on key metabolic and immune processes in the liver of patients with obesity.

This study provides further insights into the impact on n-3 PUFA on human liver gene expression, particularly in pathways associated with immunity, lipid metabolism, and inflammation, setting basis for further clinical research.

Obesity increases the risk of diseases like atherosclerotic- cardiovascular disease, type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease (MASLD). Omega-3 polyunsaturated fatty acids (n-3 PUFA) are known for their anti-inflammatory and metabolic benefits, but their direct impact on liver gene expression in people with obesity, remains unclear. In this study, patients with obesity (BMI ≥ 40 kg/m2) were administered either n-3 PUFAs or butter before bariatric surgery. Liver biopsies were analysed for gene expression via Gene Set Enrichment Analysis (GSEA). The results revealed 80 dysregulated pathways across 9 clusters, including those related to insulin and lipid metabolism, and immunity. This sheds light on how n-3 PUFAs influence gene expression in the liver of patients with obesity, setting the groundwork for further clinical exploration.

Weight loss can improve glycaemic management in individuals with type 2 diabetes, but its long-term effects on remission, cardiovascular risk factors and complications remain unclear. We investigated clinical outcomes following non-interventional ≥10% body weight loss in people with newly diagnosed type 2 diabetes in a routine care setting.

We retrospectively analysed two cohorts of people with newly diagnosed type 2 diabetes. After exclusions, cohort 1 included 1934 individuals followed for up to 25 years; cohort 2 comprised 13,277 individuals followed for up to 10 years. Participants were categorised into two groups based on whether or not they lost at least 10% body weight. In a sensitivity analysis, a group of participants with intermediate weight loss (5% to <10%) was also considered. Outcomes included HbA1c, diabetes remission, cardiovascular parameters and chronic complications.

Participants (58% male) had a mean age of 62 years and a mean diabetes duration of <2 years at inclusion; mean baseline HbA1c was 57-64 mmol/mol (7.4-8.0%) and mean BMI was ~30 kg/m2. Weight loss ≥10% was obtained in 15.9% (n=308) of participants in cohort 1 and in 8.8% (n=1167) in cohort 2. In cohort 1, weight loss ≥10% was associated with a sustained reduction in HbA1c (mean difference 2.1 mmol/mol; 0.19%) and a higher remission rate than in the <10% weight loss group (20.2% vs 5.5%; HR 4.2). These findings were confirmed in cohort 2, with remission rates of 13.2% and 4.1% (HR 2.6) in the ≥10% and <10% weight loss groups, respectively. Weight loss ≥10% improved systolic BP and HDL-cholesterol and triglyceride levels. Participants with weight loss of 5% to <10% (28.2% in cohort 1 and 17.4% in cohort 2) had marginal improvements in HbA1c, lipids and remission rates compared with participants with weight loss <5%, and such results were inferior to those achieved with weight loss ≥10%. In cohort 1, compared with weight loss <5% (reference), the HR for remission was 5.2 with weight loss ≥10% vs 1.7 with weight loss 5% to <10%. Weight loss ≥10% was not associated with a reduced incidence of complications. On the other hand, remission was independently associated with a significantly lower rate of new-onset microangiopathy (adjusted HR 0.84; 95% CI 0.73, 0.97; p=0.019).

Early weight loss of ≥10% in type 2 diabetes was associated with sustained glycaemic improvements, increasing by three to four times the rates of diabetes remission. Remission, in turn, more than weight loss was associated with a reduced risk of complications.

Despite numerous meta-analyses showing an association between air pollutants and diabetes, there is considerable heterogeneity between studies.

This study aims to evaluate the cumulative evidence regarding the association between air pollution and type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM) through systematic reviews and meta-analyses.

Following the PRISMA 2020 guidance, a comprehensive review across three databases, including Web of Science, Embase, and PubMed, from inception to September 30, 2024. The quality of the included systematic reviews was assessed using the AMSTAR 2 tool. The research protocol has been registered in PROSPERO (CRD42024594953).

A total of 19 meta-analyses were identified in this review, including two articles investigating the impact of air pollution on T1DM, nine on T2DM, and ten on GDM. Due to limited data, no significant relationship between air pollution and T1DM was found. There is evidence that exposure to particulate matter (PM2.5 and PM10) may significantly increase the risk of T2DM. However, meta-analyses concerning GDM exhibit a less consistent association between air pollution and GDM risk, which varies by pollutant and duration of exposure.

Results suggest that exposure to air pollution may increase diabetes risk to some extent, particularly for T2DM. However, due to limited available studies, further prospective cohort studies are warranted to elucidate the role of air pollutants in diabetes, particularly for T1DM. Additionally, understanding potential mechanisms by which air pollution affects diabetes is crucial for future investigations.

People with clinically diagnosed type 2 diabetes (T2D) but positive antiglutamic acid decarboxylase autoantibodies (GADA), referred to here as latent autoimmune diabetes in adults (LADA), may experience more rapid glycemic deterioration than those with T2D and may benefit from effective diabetes treatment with additional metabolic benefits.

This work aimed to assess glycated hemoglobin A1c (HbA1c) and body weight (BW) changes associated with tirzepatide in GADA-positive vs GADA-negative participants with a clinical T2D diagnosis.

Post hoc analyses based on pooled data from SURPASS 2-5, using mixed-model repeated measures from the efficacy analysis set, adjusting for study and baseline covariates including age, sex, baseline values, body mass index (BMI), and GADA status, were conducted on 3791 individuals. Intervention included tirzepatide (5, 10, 15 mg). Main outcome measure included change from baseline in HbA1c at weeks 40 (SURPASS-2, -3, -5) and 42 (SURPASS-4) by GADA status.

In participants with confirmed GADA status, 3671 (96.8%) were GADA negative and 120 (3.2%) were GADA positive (76 [63.3%] with low and 44 [36.7%] with high GADA levels). Baseline characteristics were similar between groups, except for slightly lower BMI in GADA-positive vs GADA-negative participants (mean [SD] BMI 32.2 [6.1] vs 33.6 [6.3]). At week 40/42, both groups achieved robust reductions in HbA1c (-2.11% vs -2.32%) and BW (-9.2 kg vs -9.6 kg) (P < .001, both groups). HbA1c reductions were greater in GADA-negative participants (estimated difference [95% CI]: 0.21% [0.03, 0.39]; P = .024) and BW reductions did not differ between groups (0.38 kg [-0.99, 1.75]; P = .588).

In this post hoc analysis, tirzepatide was associated with substantial reductions in HbA1c and BW irrespective of GADA status in adults diagnosed with T2D, suggesting that tirzepatide may improve glycemic control in individuals with LADA.

Uncertainties still exist about the effect of vegetarian or vegan diets on glycemic and cardiometabolic risk factors in individuals with type 2 diabetes mellitus (T2DM), although plant-based diets are thought to be beneficial for cardiometabolic health.

The aim was to investigate whether vegetarian or vegan diets can improve blood glucose and cardiometabolic health in patients with T2DM compared with omnivorous diets.

Five databases (PubMed, Web of Science, Cochrane Library, Scopus, and Embase) were searched for eligible randomized controlled trials (RCTs) up to May 24, 2024.

Two authors independently performed the data extraction and quality assessment.

Nine RCTs (681 participants) were included in this meta-analysis. The results indicated that vegetarian or vegan diets could reduce glycosylated hemoglobin, type A1C (HbA1c) (weighted mean difference [WMD] = -0.36%; 95% CI: -0.54, -0.19; P < .001), low-density-lipoprotein cholesterol (WMD = -0.16 mmol/L; 95% CI: -0.26, -0.07; P = .001, and body mass index (WMD = -0.94 kg/m2; 95% CI: -1.43, -0.45; P = .0002) in a population with T2DM; however, they resulted in no significant improvement in systolic blood pressure and fasting plasma glucose. In subgroup analyses, the positive effects of a vegan diet were superior to a vegetarian diet for cardiometabolic health. HbA1c was reduced when vegetarian or vegan intake was more than 12 weeks.

In conclusion, vegetarian or vegan diets could be utilized as a synergistic intervention in the T2DM population, contributing to cardiovascular disease prevention. In the future, the proportion of components that make up a plant-based diet should be explored.

PROSPERO registration no. CRD42024578613.

To estimate the incidence and identify risk factors for diagnosed type 2 diabetes (T2D) among young U.S. adults.

We analyzed 142,884 adults aged 18-79 years with self-reported diabetes type from the cross-sectional National Health Interview Survey in 2016-2022, representing the noninstitutionalized U.S. civilian population. Incidence of diagnosed T2D was calculated for three age groups: young-adult onset (18-44 years), middle-age onset (45-64 years), and older-adult onset (65-79 years); the latter two groups were included to highlight the distinct risk factor profile of young-adult-onset T2D. Multivariable logistic regressions were used to identify risk factors for young-adult-onset T2D.

The estimated incidence of diagnosed young-adult-onset T2D was 3.0 per 1,000 adults (95% CI 2.6-3.5). Minority groups, socioeconomically disadvantaged individuals, and people with cardiometabolic diseases or psychological conditions had a higher incidence of diagnosed young-adult-onset T2D compared with their counterparts. Lipid-lowering medication use (adjusted odds ratio [aOR] 13.15, 95% CI 8.85-19.55), antihypertensive medication use (aOR 11.89, 95% CI 7.97-17.73), and obesity (BMI ≥30 vs. <25 kg/m2, aOR 10.89, 95% CI 6.69-17.7) were the strongest risk factors for young-adult-onset T2D; these risk factors, along with hypertension, hyperlipidemia, and coronary heart disease, were more strongly associated with young-adult-onset T2D compared with later-onset T2D, with up to 4.5 times higher aORs.

This study quantified the incidence of diagnosed young-adult-onset T2D in U.S. adults and identified its distinct risk factor profile. Targeted prevention strategies for young-adult-onset T2D are needed for minority and socioeconomically disadvantaged people and those with cardiometabolic diseases.

The correlations between body mass index (BMI) and risk of all-cause and cardiovascular disease (CVD) mortality in patients with type 2 diabetes mellitus (T2DM) are still controversial.

To explore the correlation between BMI and the risk of all-cause and CVD mortality in patients with T2DM.

The data sources China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, PubMed, Web of Science, Embase, and The Cochrane Library were searched up until May 25, 2024. After adjusting for confounding factors, the original study on the association between BMI and all-cause and CVD mortality in patients with T2DM was analyzed. Number of all-cause and CVD mortality events, BMI, and basic characteristics were extracted.

Twenty-eight papers with a total of 728 321 participants were finally included. Compared to normal-weight patients with T2DM, the risk of all-cause (HR = 1.61; 95% CI [1.51, 1.72]; P = .000) and CVD (HR = 1.31; 95% CI [1.10, 1.54]; P = .002) mortality were increased in underweight patients; however, they were reduced (HR = 0.85; 95% CI [0.81, 0.89]; P = .000) and (HR = 0.86; 95% CI [0.78, 0.96]; P = .007), respectively in patients with overweight. Also, there were significant reductions in the risk of all-cause (HR = 0.85; 95% CI [0.78, 0.92]; P = .000) and CVD (HR = 0.81; 95% CI [0.74, 0.89]; P = .000] mortality in patients with mild obesity. The difference in the risk of all-cause mortality (HR = 0.98; 95% CI [0.80, 1.21]; P = .881) in patients with moderate obesity was not statistically significant.

We found that there were correlations between BMI and the risk of all-cause and CVD mortality in patients with T2DM. The obesity paradox remains.

Diabetes mellitus is a global health burden, with factors contributing to its prevalence and costs. Educating people with diabetes improves outcomes and affects the economic burden on the individual and health systems.

We included recent diabetes data from the Centers for Disease Control and Prevention and articles from PubMed and Ovid MEDLINE.

Diabetes prevalence in the United States increased from 10.3% in 2001 to 14.7% in 2021. Factors contributing are an aging population, increased obesity, and social determinants of health. Total costs for diabetes in 2022 reached $412.9 billion, consisting of 74% direct medical and around 26% indirect costs. The highest medical expenses were hospital inpatient services ($96.2 billion), and indirect costs were decreased productivity while at work ($35.8 billion). The effect on the health economy in the United States and globally is only increasing. Interventions to improve disease outcomes such as diabetes education programs that teach self-management skills, healthy lifestyle behaviors, and coping strategies have improved glycated hemoglobin A1c and other outcomes. The economic effect of education is not well studied. However, the Diabetes Prevention Program demonstrated the benefits of lifestyle-based education in preventing or delaying the development of type 2 diabetes in high-risk people and in being cost-effective long term.

High direct and indirect costs and the prevalence of diabetes require urgent global awareness and interventions from many angles. We encourage clinicians and agencies to prioritize the education of people living with diabetes to prevent and treat diabetes and its complications.

Diabetes represents a global health crisis that necessitates advancements in prevention, treatment, and management. Beyond glucose regulation, addressing weight management and associated complications is imperative. This study introduces an oral nanoparticle formulation designed to simultaneously control blood glucose, obesity, and metabolic dysfunction. These nanoparticles, based on poly (zwitterion-cholic acid), incorporate a polyzwitterion component to enhance permeation through the mucus layer and prolong drug residence. Furthermore, bile acid polymers not only regulate lipid metabolism but also ameliorate obesity-associated inflammation in adipose and liver tissues. In vivo experiments demonstrated significant hypoglycemic effects in healthy, type I diabetic, and type II diabetic mice. Notably, the nanocarriers significantly reduced body weight gain, ameliorated inflammation in adipose and liver tissues, and modulated lipid metabolism in the liver of db/db mice. Our study elucidates a comprehensive strategy for addressing glycemic control and diabetes-related complications, offering a promising approach for diabetes prevention and treatment.

In this article the authors review recent advances in the treatment of chronic kidney disease (CKD) with diabetes, and summarize evidence supporting combination therapy approaches to improve patient outcomes. Driven by the global rise in diabetes, the worldwide burden of CKD has nearly doubled since the 1990s. People with CKD have notably increased risks for premature cardiovascular disease (heart and blood vessels disease), kidney failure and death. CKD, diabetes, obesity and cardiovascular disease are closely interrelated and share common risk factors. These health conditions therefore comprise what is now known as cardiovascular-kidney-metabolic (CKM) syndrome. Recently approved medications, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and the non-steroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone, represent agents capable of reducing metabolic, kidney and cardiovascular risk through complementary mechanisms of action. Current evidence supports use of these therapies in combination. Besides providing additive protective effects, combination therapy may also help reduce side effects. For instance, using an SGLT2 inhibitor in combination with finerenone helps decrease the risk for high potassium levels. Through the multipronged approach, combination therapy allows tailoring treatment for the individual patient characteristics and needs. Several planned and ongoing clinical trials continue to study the benefits of combination therapy in people with CKM syndrome. With building evidence supporting the use of combination therapy, it is crucial to raise awareness of the importance of this treatment approach and develop processes to incorporate new therapies into every day practice to support optimal care and improved outcomes.

The global burden of chronic kidney disease (CKD) increased by nearly 90% in the period spanning 1990 to 2016, mostly attributed to an increase in the prevalence of CKD in diabetes. People living with CKD have an elevated lifetime risk for cardiovascular disease (CVD) when compared with the general population, with risk increasing in parallel with albuminuria and kidney function decline. Metabolic disease, CKD and CVD share common risk factors including neurohumoral activation, systemic inflammation and oxidative stress, thus prompting the introduction of a broader construct of cardiovascular-kidney-metabolic (CKM) syndrome. An important rationale for the introduction of this concept are recent and ongoing therapeutic advancements fundamentally changing CKM management. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and the non-steroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone have shifted the therapeutic paradigm for patients with CKD and have emerged in rapid succession as cornerstones of guideline-directed medical therapy (GDMT). Recently completed clinical trials of aldosterone synthase inhibitors and endothelin receptor antagonists have additionally reported additive antiproteinuric effects on the background of renin-angiotensin system and SGLT2 inhibition, with acceptable safety profiles. The sum of current evidence from both preclinical and clinical studies support combination therapy in the setting of CKD to achieve additive and potentially synergistic kidney and heart protection by addressing metabolic, hemodynamic, and pro-inflammatory and pro-fibrotic mechanistic pathways. This narrative review will discuss available evidence supporting combination GDMT in CKD with diabetes and additionally discuss ongoing and future trials evaluating the efficacy and safety of combination therapies for CKD with or without diabetes.

In the SURPASS J-mono trial, tirzepatide demonstrated significant improvements in bodyweight and several metabolic parameters in Japanese participants with type 2 diabetes. This post hoc analysis evaluated the potential relationships between weight loss and metabolic improvements in SURPASS J-mono.

Metabolic parameter data from tirzepatide-treated participants were analyzed by weight loss subgroups and compared to dulaglutide 0.75 mg. Correlations between changes from baseline to week 52 in weight loss and each metabolic parameter were assessed; Pearson correlation coefficients were derived. Mediation analyses were conducted to evaluate weight loss-associated and -unassociated effects of tirzepatide vs dulaglutide 0.75 mg.

This analysis included 548 participants (tirzepatide: n = 411, dulaglutide: n = 137). Weight loss subgroups showed greater improvement in metabolic parameters with greater bodyweight loss. Significant (P < 0.05) but weak correlations between changes in bodyweight and triglycerides (r = 0.18-0.25), high-density lipoprotein cholesterol (r = -0.37 to -0.29), and systolic blood pressure (r = 0.19-0.41) were observed across treatment groups; in diastolic blood pressure in the tirzepatide 5-mg (r = 0.28), pooled tirzepatide (r = 0.20), and dulaglutide 0.75-mg (r = 0.23) groups; and in fasting serum glucose in the dulaglutide 0.75-mg (r = 0.18) and pooled tirzepatide (r = 0.13) groups. Weight loss was associated with treatment differences between tirzepatide and dulaglutide 0.75 mg to varying degrees across metabolic parameters, with improvements in fasting serum glucose having the lowest association with weight loss (36.6%-43.5%).

In this post hoc analysis, non-glycemic and glycemic parameter improvements appeared differentially associated with weight loss, suggesting both weight loss-associated and -unassociated effects of tirzepatide.

Previous studies, using clinical trial data, demonstrated that once-weekly (OW) semaglutide is dominant versus other glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in China. This study aims to evaluate the long-term clinical and economic effects of switching to OW semaglutide from other GLP-1 RAs among patients with type 2 diabetes mellitus (T2DM) in China.

The Institute of Health Economics Diabetes Cohort Model (IHE-DCM) was used to project life expectancy, quality-adjusted life years (QALYs), and total direct medical cost over 40 years from a Chinese healthcare system perspective. Baseline characteristics, clinical effectiveness, and the treatment dose of OW semaglutide were derived from previously real-world studies. Patients were assumed to switch to semaglutide or continue previous GLP-1 RAs for 3 years and change to intensive therapy. Drug prices were based on the median bidding price in January 2024 in China. Costs of other GLP-1 RAs were calculated on the basis of their market share in China. All costs were accounted as 2023 Chinese yuan (CNY). A discount of 5% was applied. One-way sensitivity analyses and probabilistic sensitivity analyses were used to test the robustness of the base-case result.

The results show that switching to OW semaglutide from other GLP-1 RAs among patients with T2DM in China can improve life expectancy by 0.02 years and afford an additional 0.12 QALYs per patient. Meanwhile, switching to OW semaglutide is associated with decreased total lifetime direct medical costs of 4204 CNY per patient, mainly resulting from savings in microvascular costs (2214 CNY) and macrovascular costs (1228 CNY). Sensitivity analyses show the robustness of modeling projection findings.

Based on real-world data from China, this modeling projection study demonstrates that switching to OW semaglutide from other GLP-1 RAs can have better clinical and economic effects for patients with T2DM in China, indicating it as a dominant treatment choice.

The effectiveness of calorie restriction (CR) for weight loss in type 2 diabetes mellitus (T2DM) has not been thoroughly studied. This review aims to evaluate CR's short- and long-term effectiveness for weight loss and its impact on cardiometabolic parameters in T2DM. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, Medline Complete, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane Library databases were searched to identify studies up to June 7, 2024. Furthermore, a reference search was conducted. Randomized controlled trials involving adults with T2DM examining CR and reporting weight changes were included. The revised Cochrane risk-of-bias tool was used to assess the study's quality. A narrative synthesis was used to analyze the findings. Eleven studies, with 1,554 participants, were included; all had a low risk of bias. The intervention group participants' mean baseline weight and Body Mass Index were 93.3 kg and 32.7 kg/m², respectively. Interventions used included total diet replacement (TDR) and very low- and low-calorie diets lasting 12 weeks to two years. CR with TDR resulted in >12% weight loss. Additionally, CR improved cardiometabolic parameters; glycated hemoglobin (HbA1c) decreased to ≤6.5%; diabetes remission was achieved in 19% to 83%; high-density lipoprotein significantly increased; and triglyceride, systolic, and diastolic blood pressure significantly decreased. In conclusion, CR effectively reduces weight and improves cardiometabolic markers in T2DM. However, large long-term studies addressing CR in T2DM are lacking, which challenges drawing firm conclusions. This highlights the need for further research to address this gap. This review is registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42024573505.

Obesity and its complications are associated with high morbidity/mortality and a significant healthcare cost burden in Spain. It is therefore essential to know the potential clinical and economic benefits of reducing obesity. The objective of this study is to predict the decrease in rates of onset of potential complications associated with obesity and the cost savings after a weight loss of 15% over 10 years in Spain.

Data were combined in an adapted version of a weight loss benefit simulation model. Sources with demographic information on the Spanish population and the distribution of obesity and type 2 diabetes mellitus (T2DM) were used to obtain the data for the model. In addition, use was made of prevalence data on obesity-associated complications from a cohort of patients with obesity in the United Kingdom (UK). These data were combined by age and sex to create a Spanish synthetic cohort.

The simulation showed that, for a cohort of 100,000 individuals with a body mass index (BMI) of 30-50 kg/m2, a weight loss of 15% is estimated to lead to relevant relative risk reductions in obstructive sleep apnoea (OSA) (- 56.4%), T2DM (- 39.2%), asthma (- 20.2%) and arterial hypertension (- 18.7%). The estimated overall savings were €105 million for a cohort of 100,000 individuals, mainly resulting from the decrease in T2DM and arterial hypertension (23% and 22% of the total savings at year 10, respectively), as well as osteoarthritis and chronic kidney disease (CKD) (16% and 13%, respectively).

Sustained weight loss could significantly reduce the burden derived from future complications associated to obesity in Spain, as well as the excess economic cost associated with its treatment.

The study objective was to describe characteristics and utilization patterns of tirzepatide users with type 2 diabetes (T2D) using the Healthcare Integrated Research Database in the USA.

Adults (≥18 years) included had T2D diagnosis; ≥1 tirzepatide claim (May 2022-January 2023; first claim date = index date); and continuous medical and pharmacy enrollment during the 6-month baseline and follow-up periods from the index date. Baseline demographics, clinical characteristics, and 6-month follow-up dosing and treatment patterns were summarized descriptively.

The study included 15,665 patients with T2D initiating tirzepatide (mean age: 53.2 years; 58.5% women; 76.7% non-Hispanic white). During the 6-month baseline period, hypertension (69.2%), dyslipidemia (69.2%), overweight/obesity (58.4%), and obstructive sleep apnea (22.8%) were commonly reported comorbidities. Over half of the patients (51.2%) had used glucagon-like peptide-1 (GLP-1) receptor agonist (RA) before initiating tirzepatide. The mean glycated hemoglobin (HbA1c) was 7.6% (n = 5175), and 58.4% of these patients had HbA1c ≥7%. The mean body mass index (BMI) was 38.7 kg/m2 (n = 3459), and 87.8% of these patients either had Class 1, 2, or 3 obesity. Among patients with a single prescription on each fill date (N = 14,986), 84.1% initiated tirzepatide at ≤5 mg dose. During sixth prescription refill (n = 7304), 56.5% were receiving tirzepatide doses of <10 mg. During the 6-month follow-up period, 69.6% of patients had ≥1 dose escalation and 17.2% had ≥1 dose de-escalation. The mean time to first dose escalation was 59.1 days and first dose de-escalation was 104.8 days. Tirzepatide adherence (proportion of days covered [PDC] ≥80%) was 57.5% and persistence (45-day gap) was 73.3% at 6 months. Of patients who discontinued tirzepatide (n = 4177; 26.7%), 29.1% re-initiated tirzepatide (45-day gap).

Patients with T2D initiating tirzepatide had multimorbidity; uncontrolled diabetes; and mean BMI was consistent with Class 2 obesity. Patients showed favorable tirzepatide adherence and persistence profiles, and the majority remained at <10 mg doses during the 6-month follow-up period.

Previous studies demonstrated that diabetes remission can occur during intensive intervention and in real-world settings. However, the impact of diabetes remission in real-world settings on the incidence of cardiovascular disease (CVD) remains unclear.

This retrospective cohort study included 299,967 individuals aged 20-72 years who underwent multiple checkups between 2008 and 2020 and completed ≥ 3 years of follow-up. Patients were divided into four groups according to changes in glycated hemoglobin levels and the use of diabetes medications during the 1-year baseline period: diabetes mellitus (DM)+/no remission, DM+/remission, DM-/no progression, and DM-/progression. The risk of CVD was evaluated using multivariable Cox regression analysis.

The median follow-up period was 5.0 years. The rates of CVD in the DM+/no remission, DM+/remission, DM-/no progression, and DM-/progression groups were 7.96, 4.76, 1.99, and 5.47 per 1000 person-years, respectively. Compared with DM+/no remission, DM+/remission reduced the risk of CVD [hazard ratio (HR) = 0.71, 95% confidence interval (CI) = 0.57-0.89]. Meanwhile, the HR for CVD in the DM+/remission group was 0.75 (95% CI = 0.56-0.99) for change in BMI ≤ 0%, versus 0.66 (95% CI = 0.45-0.96) for change in BMI > 0%.

In a real-world setting without intensive intervention, diabetes remission decreased the risk of CVD by approximately 30% regardless of changes in BMI, suggesting that diabetes remission can prevent CVD without weight loss in routine care and emphasizing the importance of achieving remission.

The global prevalence of obesity and type 2 diabetes mellitus (T2D) has risen in parallel over recent decades. Most individuals diagnosed with T2D exhibit adiposopathy-related diabetes (ARD), a condition characterized by hyperglycemia accompanied by three core features: increased ectopic and visceral fat deposition, dysregulated adipokine secretion favoring a pro-inflammatory state, and insulin resistance. Despite advancements in precision medicine, international guidelines for T2D continue to prioritize individualized therapeutic approaches focused on glycemic control and complications, and many healthcare providers predominantly maintain a glucocentric strategy. This review advocates for an adipocentric treatment paradigm for most individuals with T2D, emphasizing the importance of prioritizing weight loss and visceral fat reduction as key drivers of therapeutic intensification. By combining lifestyle modifications with pharmacological agents that promote weight loss-including SGLT-2 inhibitors, GLP-1 receptor agonists, or dual GLP-1/GIP receptor agonists-and, when appropriate, metabolic surgery, this approach offers the potential for disease remission in patients with shorter disease duration. For others, it enables superior metabolic control compared to traditional glucose-centered strategies while simultaneously delivering cardiovascular and renal benefits. In conclusion, an adipocentric treatment framework for ARD, which represents the majority of T2D cases, effectively integrates glucocentric and cardio-nephrocentric goals. This approach constitutes the optimal strategy for ARD due to its efficacy in achieving disease remission, improving metabolic control, addressing obesity-related comorbidities, and reducing cardiovascular and renal morbidity and mortality.

With increasing prevalence of obesity and cardiovascular diseases, there is a growing interest in the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) as an adjunct therapy in type 1 diabetes (T1D). The GLP-1RAs are currently not approved by the US Food and Drug Administration for the treatment of T1D in the absence of randomized controlled trials documenting efficacy and safety of these agents in this population. The Diabetes Technology Society convened a series of three consensus meetings of clinicians and researchers with expertise in diabetes technology, GLP-1RA therapy, and T1D management. The project was aimed at synthesizing current literature and providing conclusions on the use of GLP-1RA therapy as an adjunct to automated insulin delivery (AID) systems in adults with T1D. The expert panel members met virtually three times on January 17, 2024, and April 24, 2024, and August 14, 2024, to discuss topics ranging from physiology and outcomes of GLP-1RAs in T1D to limitations of current sensors, algorithms, and insulin for AID systems. The panelists also identified research gaps and future directions for research. The panelists voted to in favor of 31 recommendations. This report presents the consensus opinions of the participants that, in adults with T1D using AID systems, GLP-1RAs have the potential to (1) provide effective adjunct therapy and (2) improve glycemic and metabolic outcomes without increasing the risk of severe hypoglycemia or diabetic ketoacidosis.

Obesity and prediabetes affect a substantial part of the general population, but are largely underdiagnosed, underestimated, and undertreated. Prediabetes differs from diabetes only in the degree of hyperglycaemia consequent to the progressive decline in residual beta-cell function. Both prediabetes and diabetes occur as a consequence of insulin resistance that starts several years before the clinical onset of overt diabetes. Macrovascular complications in patients with diabetes are mainly caused by insulin resistance. This is why in prediabetes, the overall cardiovascular risk is, by all means, similar to that in patients with diabetes. It is important, therefore, to identify prediabetes and treat patients not only to prevent or delay the onset of diabetes, but to reduce the cardiovascular risk associated with prediabetes. This review provides an overview of the pathophysiology of prediabetes in patients with obesity and the progression toward overt diabetes. We have reviewed nutritional and pharmacological approaches to the management of obesity and reduced glucose tolerance, and the treatment of the major comorbidities in these patients, including hypertension, dyslipidaemia, and Metabolic dysfunction-associated Steatotic Liver Disease (MASLD), has also been reviewed. In patients with obesity and prediabetes, the nutritional approach is similar to that adopted for patients with obesity and diabetes; treatments of dyslipidaemia and hypertension also have the same targets compared to patients with diabetes. MASLD is a critical issue in these patients; in the prediabetic state, MASLD rarely progresses into fibrosis. This highlights the importance of the early recognition of this pathological condition before patients become diabetic when the risk of fibrosis is much higher. It is necessary to raise awareness of the clinical relevance of this pathological condition in order to prompt early intervention before complications occur. The single most important therapeutic goal is weight loss, which must be early and persistent.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

To investigate the risk of biliary diseases in patients with type 2 diabetes mellitus (T2DM) or obesity treated with tirzepatide.

Literature searches were performed using the PubMed, Web of Science, Cochrane Library, and CNKI databases until 20 May 2024. Randomized controlled studies (RCTs) investigating the safety of tirzepatide vs placebo/other hypoglycemic drugs in patients with T2DM or obesity were included. The safety outcomes mainly included the incidence of cholelithiasis, pancreatitis, cholecystitis, and gallbladder/biliary diseases. Cochrane Collaboration's tool for assessing the risk of bias was used to assess the quality of literature. Heterogeneity was evaluated using I2 statistics.

A total of 12 high-quality RCTs (involving 12,351 patients) were included. The results of meta-analysis showed that tirzepatide was associated with gallbladder/biliary diseases (RR = 1.52; 95%CI: 1.17-1.98; I2 = 0%, P = 0.76) and cholelithiasis (RR = 1.67; 95%CI: 1.14-2.44; I2 = 0%, P = 0.95). Subgroup analysis based on the dose of tirzepatide found no dose-response relationship between different doses of tirzepatide and the risk of gallbladder/biliary diseases and cholelithiasis.

Based on the data currently available, tirzepatide is associated with the development of cholelithiasis in patients. However, the findings from RCTs still need to be further investigated in many post-marketing safety surveillance programs.

Steatotic liver disease (SLD) interacts with various comorbidities, impacting outcomes, yet little is known about the duration of comorbidities in SLD occurrence and mortality. We investigated this relationship, focusing on disease predictors and mortality rates.

Analyzing 2010 and 2015 Korea National Health and Nutrition Examination Survey data for patients aged ≥ 20, we categorized ten comorbidities (hypertension [HTN], diabetes mellitus [DM], dyslipidemia, stroke, myocardial infarction [MI], angina pectoris, asthma, chronic obstructive lung disease [COPD], chronic kidney disease [CKD], and depression) by duration. Association rule mining and logistic regression analyzed the association between SLD occurrence and comorbidity duration, while Cox regression assessed survival.

The analysis included 2,757 SLD and 9,505 non-SLD cases. Association rule mining showed that the shorter duration of DM and dyslipidemia and the longer duration of HTN comprised the top-ranked component for presence of SLD. DM with a duration ≤ 1 year showed higher risk of SLD than longer periods (odds ratio, 11.53), while the duration of cardiovascular disease, lung disease, or CKD was not significantly associated with the presence of SLD. In terms of prognosis, multivariate Cox regression showed that longer HTN and DM durations were significantly associated with increased hazard ratio (HR) beyond 10 years (HR, 2.22 and 2.11, respectively). Cardiovascular disease duration ≤ 5 years and lung disease duration > 5 years showed statistical significance (HR 2.49and 2.38, respectively).

Duration of comorbidities should be considered for comprehensive SLD risk stratification, for both the identification of SLD and the assessment of their prognosis after detection.

Tirzepatide is a once-weekly dual agonist, acting on glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. It is approved at the same doses (5, 10 and 15 mg) for both type 2 diabetes (T2D) and chronic weight management.

Following a search in PubMed, clinicaltrials.gov, conference abstracts and Lilly website, we review herein the global phase 3 SURMOUNT program on tirzepatide's safety and efficacy for chronic weight management. Additionally, we discuss findings from the regional SURMOUNT-CN and SURMOUNT-J trials (in East-Asian populations) and the phase 2 SYNERGY-NASH, phase 3 SURMOUNT-OSA and SUMMIT studies on tirzepatide's impact on obesity-related complications. We also explore the clinical implications of SURMOUNT program results, considerations for tirzepatide prescribing for overweight/obesity, ongoing research and evidence gaps.

Tirzepatide marks a new era in overweight/obesity treatment, enabling many to achieve ≥ 20% weight loss. It is well-tolerated with a safety profile similar to GLP-1 receptor agonists. Tirzepatide also results in clinically important improvements in multiple obesity-related complications including sleep apnea, metabolic-dysfunction associated steatohepatitis, heart failure with preserved ejection fraction and diabetes prevention. Ongoing trials will provide further data on tirzepatide's long-term safety, efficacy (including cardiovascular outcomes) and potential cost-effectiveness for managing overweight/obesity and/or T2D.

The objective is to assess the effectiveness and safety of tirzepatide, liraglutide, and SGLT2i in individuals diagnosed with type 2 diabetes.

An inquiry was undertaken within the electronic database spanning from its inception to February 11th, 2024, aimed at identifying randomized controlled trials that assess the efficacy and safety of tirzepatide, liraglutide, canagliflozin, ertugliflozin, empagliflozin, dapagliflozin, and henagliflozin. Perform a network meta-analysis to examine the distinctions among them (PROSPERO registration number: CRD42024537006).

Twenty-eight RCTs were included, involving 8499 participants. Compared with placebo, all treatments improved HbA1c levels: tirzepatide 15 mg reduced HbA1c the most (MD [95% CI], -2.24% [-2.52, -1.96]%), followed by tirzepatide 10 mg (MD [95% CI], -1.99% [-2.29, -1.69]%), tirzepatide 5 mg (MD [95% CI], -1.82% [-2.11, -1.53]%), and liraglutide 1.2 mg (MD [95% CI], -1.23% [-1.41, -1.05]%). Canagliflozin 300 mg also showed a significant reduction in HbA1c (MD [95% CI], -1.00% [-1.18, -0.82]). Tirzepatide was also the most effective in promoting weight loss, with the following results compared with placebo: tirzepatide 15 mg (MD [95% CI], -8.74 kg [-9.83, -7.66] kg), tirzepatide 10 mg (MD [95% CI], -7.13 kg [-8.40, -5.88] kg), tirzepatide 5 mg (MD [95% CI], -5.38 kg [-6.65, -4.11] kg), canagliflozin 300 mg (MD [95% CI], -2.31 kg [-2.79, -1.83] kg), and empagliflozin 10 mg (MD [95% CI], -2.00 kg [-2.44, -1.55] kg). In reducing systolic blood pressure (SBP), canagliflozin 300 mg showed the greatest effect (MD [95% CI], -5.96% [-7.96, -3.96] %). For diastolic blood pressure (DBP), henagliflozin 5 mg demonstrated the most significant reduction compared to placebo (MD [95% CI], -2.46% [-3.82, -1.10] %). Liraglutide 1.8 mg was most likely to cause adverse events (AE) (OR [95% CI], 2.57 [1.78, 3.70]), but there was no significant difference in serious adverse events (SAEs) between the interventions (including placebo).

Out of the seven medications examined in this study, tirzepatide demonstrates the most effective antidiabetic and weight-reducing effects. Furthermore, the dosage of Liraglutide at 1.2 mg and above demonstrates a more pronounced hypoglycemic effect in comparison to SGLT2 inhibitors. SGLT2 inhibitors exhibit a distinct hypotensive effect and are suitable for diabetic individuals experiencing hypertension.

Background: There are now four FDA-approved anti-obesity medications (AOMs) for youth ≥12 years, which can be effective therapies to treat obesity and obesity-related comorbidities. Objectives: This study describes parent/guardian (caregiver) openness to using AOMs for adolescents with obesity and evaluates factors that may contribute to openness. Methods: Caregivers of adolescents aged 12-17 years were surveyed. Self-reported height, weight, demographic information, family, and personal history of obesity or obesity-related comorbidities were collected. Participants rated their openness to starting an AOM for their child for obesity alone or obesity-related comorbidities on a 7-point Likert scale. A Likert rating of less than 4 was considered "less open" versus 4-7 was considered "more open." Results: A total of 344 participants completed the survey. Average openness toward AOM use for obesity as the only indication (as opposed to comorbid conditions) was 3.2 ± 1.74. Caregivers who were knowledgeable that the FDA-approved AOM use in adolescents had greater odds of being open to using these medications compared with caregivers who were not knowledgeable (odds ratio: 2.18; 95% confidence interval: 1.25-2.86). Conclusions: Caregivers reported openness to starting an AOM if they had prior knowledge of these medications, highlighting the need for family education on AOM use and indications.

This work describes a first attempt of palindromic design for dual compounds that act simultaneously on peroxisome proliferator-activated receptor gamma (PPARγ) and G-protein-coupled receptor 40 (GPR40) for the treatment of type 2 diabetes. The compounds were synthesized by multi-step chemical reactions and the relative mRNA expression levels of PPARγ, GPR40, and GLUT-4 were measured in cultured C2 C12 muscle cells and RIN-m5 f β-pancreatic cells. In addition, insulin secretion and GLUT-4 translocation were measured. Compound 2 displayed a moderate increase in the mRNA expression of PPARγ and GPR40. However, the translocation of the GLUT-4 transporter was 400 % with a similar effect to pioglitazone. The in vivo effect of compound 2 was determined at 25 mg/kg single dose using a normoglycemic and non-insulin dependent diabetes mellitus (NIDDM) rat models. Compound 2 showed basal plasma glucose in diabetic rats with feed intake, which is associated with the moderate release of insulin measured in cells. Surprisingly, the glucose does not decrease in normoglycemic rats. Compound 2 maintained significant interactions with the GPR40 and PPARγ receptors during molecular dynamics. Altogether, the results demonstrate that compound 2, with a palindromic design, simultaneously activates PPARγ and GPR40 receptors without inducing hypoglycemia.

Excessive body weight and obesity elevate the risk of chronic non-communicable diseases. The judicious application of the gut microbiome, encompassing both microorganisms and their derived compounds, holds considerable promise in the treatment of obesity.

In this study, we showed that a cocktail of gut microbiota-derived metabolites, comprising indole 3-propionic acid (IPA), sodium butyrate (SB) and valeric acid (VA), alleviated various symptoms of obesity in both male and female mice subjected to a high-fat diet (HFD). The 16S ribosomal RNA (rRNA) sequencing revealed that administering the cocktail via oral gavage retained the gut microbiota composition in obese mice. Fecal microbiota transplantation using cocktail-treated mice as donors mitigated the obesity phenotype of HFD-fed mice. Transcriptomic sequencing analysis showed that the cocktail preserved the gene expression profile of hepatic tissues in obese mice, especially up-regulated the expression level of leptin receptor. Gene delivery via in vivo fluid dynamics further validated that the anti-obesity efficacy of the cocktail was dependent on leptin signaling at least partly. The cocktail also inhibited the expression of appetite stimulators in hypothalamus. Together, the metabolite cocktail combated adiposity by retaining the gut microbiota configuration and activating the hepatic leptin signaling pathway.

Our findings provide a sophisticated regulatory network between the gut microbiome and host, and highlight a cocktail of gut microbiota-derived metabolites, including IPA, SB, and VA, might be a prospective intervention for anti-obesity in a preclinical setting. © 2024 Society of Chemical Industry.

Brown adipocytes are defined based on a distinct morphology and genetic signature that includes, amongst others, the expression of the Purinergic 2 Receptor X5 (P2RX5). However, the role of P2RX5 in brown adipocyte and brown adipose tissue function is poorly characterized. In the present study, we conducted a metabolic characterization of P2RX5 knockout male mice; next, we characterized this purinergic pathway in a cell-autonomous context in brown adipocytes. We then tested the role of the P2RX5 receptor agonism in metabolic responses in vivo in conditions of minimal adaptive thermogenesis requirements. Our data show that loss of P2RX5 causes reduced brown adipocyte differentiation in vitro, and browning in vivo. Lastly, we unravel a previously unappreciated role for P2RX5 agonism to exert an anti-obesity effect in the presence of enhanced brown adipose tissue recruitment in male mice housed at thermoneutrality. Altogether, our data support a role for P2RX5 in mediating brown adipocyte differentiation and function that could be further targeted for benefits in the context of adipose tissue pathology and metabolic diseases.

Rare ginsenosides (Rg3, Rh2, C-K, etc.) refer to a group of dammarane triterpenoids that exist in low natural abundance, mostly produced by deglycosylation or side chain modification via physicochemical processing or metabolic transformation in gut, and last but not least, exhibited potent biological activity comparing to the primary ginsenosides, which lead to a high concern in both the research and development of ginseng and ginsenoside-related nutraceutical and natural products. Nevertheless, a comprehensive review on these promising compounds is not available yet.

In this review, recent advances of Rare ginsenosides (RGs) were summarized dealing with the structurally diverse characteristics, traditional usage, drug discovery situation, clinical application, pharmacological effects and the underlying mechanisms, structure-activity relationship, toxicity, the stereochemistry properties, and production strategies.

A total of 144 RGs with diverse skeletons and bioactivities were isolated from Panax species. RGs acted as natural ligands on some specific receptors, such as bile acid receptors, steroid hormone receptors, and adenosine diphosphate (ADP) receptors. The RGs showed promising bioactivities including immunoregulatory and adaptogen-like effect, anti-aging effect, anti-tumor effect, as well as their effects on cardiovascular and cerebrovascular system, central nervous system, obesity and diabetes, and interaction with gut microbiota. Clinical trials indicated the potential of RGs, while high quality data remains inadequate, and no obvious side effects was found. The stereochemistry properties induced by deglycosylation at C (20) were also addressed including pharmacodynamics behaviors, together with the state-of-art analytical strategies for the identification of saponin stereoisomers. Finally, the batch preparation of targeted RGs by designated strategies including heating or acid/ alkaline-assisted processes, and enzymatic biotransformation and biosynthesis were discussed. Hopefully, the present review can provide more clues for the extensive understanding and future in-depth research and development of RGs, originated from the worldwide well recognized ginseng plants.

This study explores the extraction of polysaccharides from star anise (Illicium verum Hook. f.) with its anti-obesity, antihypertensive, antidiabetic, and antioxidant properties. The aim is to optimize the extraction conditions of star anise polysaccharides (SAP) utilizing propane alcohols-based deep eutectic solvents and microwave-assisted methods. The optimized conditions resulted in an extraction yield of 5.14%. The characteristics of acidic pectin-like SAP, including high viscosity (44.86 mPa s), high oil-holding capacity (14.39%), a high degree of esterification (72.53%), gel-like properties, highly amorphous, a high galacturonic acid concentration, and a highly branching size polysaccharide structure, significantly contribute to their potent inhibition of pancreatic lipase (86.67%), angiotensin-converting enzyme (73.47%), and α-glucosidase (82.33%) activities as well as to their antioxidant properties of azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS, 34.94%) and ferric ion reducing antioxidant power (FRAP, 0.56 mM FeSO4). Therefore, SAP could be used as a potential therapeutic agent for obesity, hypertension, and diabetes mellitus management.

We characterized the longitudinal serum protein signatures of women 6 and 10 years after having gestational diabetes mellitus (GDM) to identify factors associated with the development of type 2 diabetes mellitus (T2D) and prediabetes in this at-risk post-GDM population, aiming to discover potential biomarkers for early diagnosis and prevention of T2D. Our study identified 75 T2D-associated serum proteins and 23 prediabetes-associated proteins, some of which were validated in an independent T2D cohort. Machine learning (ML) performed on the longitudinal proteomics highlighted protein signatures associated with progression to post-GDM diabetes. We also proposed prognostic biomarker candidates that were differentially regulated in healthy participants at 6 years postpartum who later progressed to having T2D. Our longitudinal study revealed T2D risk factors for post-GDM populations who are relatively young and healthy, providing insights for clinical decisions and early lifestyle interventions.

Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear hormone receptor that is a master regulator of adipocyte differentiation and function. ZBTB9 is a widely expressed but poorly studied transcription factor that was predicted to interact with PPARγ based on large-scale protein-protein interaction experiments. In addition, genome-wide association studies (GWAS) revealed associations between ZBTB9 and BMI, T2D risk, and HbA1c levels. Here we show that Zbtb9 deficiency in mature adipocytes decreased PPARγ activity and protein level, and thus acts as a positive regulator of PPARγ signaling. In contrast, Zbtb9 deficiency in 3T3-L1 and human preadipocytes increased PPARγ levels and enhanced adipogenesis. Transcriptomic and transcription factor binding site analyses of Zbtb9 deficient preadipocytes revealed that the E2F pathway, controlled by the E2F family of transcription factors that are classically associated with cell cycle regulation, was among the most upregulated pathways. E2F1 positively regulates adipogenesis by promoting Pparg expression, independent of its cell cycle role, via direct binding to the Pparg promoter early during adipogenesis. RB phosphorylation (pRB), which regulates E2F activity, was also upregulated in Zbtb9 deficient preadipocytes. Critically, an E2F1 inhibitor blocked the effects of Zbtb9 deficiency on adipogenesis. Collectively, these results demonstrate that Zbtb9 inhibits adipogenesis as a negative regulator of Pparg expression via pRB-E2F signaling. Our findings reveal cell-state dependent roles of ZBTB9 in adipocytes, identifying a new molecule that regulates adipocyte biology as both a positive and negative regulator of PPARγ signaling depending on the cellular context, and thus may be important in the pathogenesis of obesity and T2D.

Postbiotics have recently garnered substantial research attention, especially in obesity research. In this study, upon comparing the proliferative effects of three food-derived media-skim milk, soy milk, and almond milk-on Lactiplantibacillus plantarum J26 (L. plantarum J26), skim milk was found to be the most effective. The metabolomic analysis further unveiled that the metabolites produced by the strain cultured in skim milk influenced the greatest number of lipid metabolism-associated pathways. Additionally, to better preserve heat-sensitive substances, ultrasound and pasteurization were combined and used here for inactivation. L. plantarum J26 postbiotics, prepared through pasteurization combined with 400 W ultrasound treatment for 30 min, exhibited the most effectiveness at inhibiting cellular triglyceride accumulation, reducing its level to 0.99 mg per 104 CFU. The prepared postbiotics significantly reduced the increase in multiple indicators, including body weight, blood lipids, and adipokines in obese mice (p < 0.05). Following treatment, liver tissue damage as well as white and brown adipose tissue damage were also markedly improved in obese mice. According to gut microbiota sequencing, the postbiotic intervention increased Lactobacillus and Bifidobacterium abundances but reduced the abundances of obesity-associated Faecalibacterium and Erysipelotrichaceae. Additionally, the postbiotics elevated the acetate, propionate, and butyrate levels by 14.95%, 23.89%, and 8.31%, respectively. High postbiotic doses significantly upregulated the expression of GPR41/GPR43, short-chain fatty acid (SCFA) receptor genes, in the liver and adipose tissues (p < 0.05), thus correcting the obesity-induced anomalies in the SCFAs-GPR41/GPR43 signaling pathway. This research offers compelling evidence supporting the use of edible postbiotics in targeted obesity regulation.

To investigate the relationship between obesity indices and sarcopenia in postmenopausal patients with type 2 diabetes mellitus (T2DM) at different body mass index (BMI) levels.

This retrospective cross-sectional study included 298 hospitalized postmenopausal women diagnosed with T2DM. We collected demographic, biochemical, and anthropometric data on each subject. Body composition was measured using dual-energy X-ray absorptiometry (DXA), and skeletal muscle mass index (SMI) and body fat percentage (%BF) were calculated. According to BMI stratification, the patients were divided into normal group A (18.5 kg/m2≤BMI < 24 kg/m2), overweight group B (24.0 kg/m2≤BMI < 28 kg/m2), and obesity group C (28.0 kg/m2 ≤BMI < 35 kg/m2).

From group A to group C, SMI (5.21±0.56 vs 5.48±0.56 vs 6.03±0.69) increased gradually (P < 0.05). Logistic regression analysis indicated that for each 1-unit increase in BMI, the risk of sarcopenia decreased by 63.2% (OR=0.368, 95% CI 0.215-0.629, P=0.000) in group A. Age (OR=1.077, 95% CI 1.015-1.144, P=0.015) and %BF (OR=1.094, 95% CI 1.010-1.186, P=0.028) increased the risk of sarcopenia by 1.077 and 1.094 times, respectively, in group B. While every 1-unit increase in BMI, the risk of sarcopenia decreased by 35% (OR=0.650, 95% CI 0.430-0.983, P=0.041) in group B. %BF (OR=1.459, 95% CI 1.093-1.949, P=0.010) increased the risk factors of sarcopenia by 1.459 times in group C.

In postmenopausal patients with T2DM, BMI had a protective effect on the occurrence of sarcopenia within a certain range, and with the increase of BMI, the risk of sarcopenia was increasing by increased %BF levels in overweight and obese patients.

Restriction of lipid uptake and absorption from the diet is regarded as an efficient strategy for the management of obesity, while lipase inhibition could successfully block the digestion of dietary lipids. Mume Fructus (MF) and Schisandrae Chinensis Fructus (SCF) were used as fruits, the biological effect of which on obesity desired more attention. Herein, the extracts of MF and SCF displayed significant efficacy in managing obesity in mice fed with a high-fat diet, via the inhibition of hydrolase activity of lipase in the digestive tract. Using the bioactivity guidance strategy, citric acid and malic acid were identified as the major lipase inhibitors from MF and SCF, respectively, which could prevent body weight gain, along with adipose tissue formation, and alleviate hyperlipidemia and hepatic steatosis in obese mice. Above all, MF and SCF could be used for the management of obesity via the lipase inhibition by citric acid and malic acid, displaying potential applications in healthy foods, nutritional supplements, and pharmaceutical materials.