Diabesity is a modern epidemic that indicates a strong association between obesity and diabetes. Key enzymes have been identified in the development and progression of both diseases, DPP-IV in glucose uptake and FAS in fatty acid synthesis. In both cases, the molecular mechanisms of how each one acts separately have been described, and which are the key inhibitory drugs and molecules for each one. However, although it is known that there is an association between both clinically and molecularly, the mechanism has not been elucidated; therefore, this review focuses on proposing a mechanism of convergence of DPP-IV and FAS in diabesity, and the possible mode of action in which bioactive peptides obtained from plant and animal sources can inhibit these two enzymes in a similar way as drugs do.

Continuous glucose monitoring (CGM) technology has grown rapidly to track real-time blood glucose levels and trends with improved sensor accuracy. The ease of use and wide availability of CGM will facilitate safe and effective decision making for diabetes management. Here, we developed an attention-based deep learning model, CGMformer, pretrained on a well-controlled and diverse corpus of CGM data to represent individual's intrinsic metabolic state and enable clinical applications. During pretraining, CGMformer encodes glucose dynamics including glucose level, fluctuation, hyperglycemia, and hypoglycemia into latent space with self-supervised learning. It shows generalizability in imputing glucose value across five external datasets with different populations and metabolic states (MAE = 3.7 mg/dL). We then fine-tuned CGMformer towards a diverse panel of downstream tasks in the screening of diabetes and its complications using task-specific data, which demonstrated a consistently boosted predictive accuracy over direct fine-tuning on a single task (AUROC = 0.914 for type 2 diabetes (T2D) screening and 0.741 for complication screening). By learning an intrinsic representation of an individual's glucose dynamics, CGMformer classifies non-diabetic individuals into six clusters with elevated T2D risks, and identifies a specific cluster with lean body-shape but high risk of glucose metabolism disorders, which is overlooked by traditional glucose measurements. Furthermore, CGMformer achieves high accuracy in predicting an individual's postprandial glucose response with dietary modelling (Pearson correlation coefficient = 0.763) and helps personalized dietary recommendations. Overall, CGMformer pretrains a transformer neural network architecture to learn an intrinsic representation by borrowing information from a large amount of daily glucose profiles, and demonstrates predictive capabilities fine-tuned towards a broad range of downstream applications, holding promise for the early warning of T2D and recommendations for lifestyle modification in diabetes management.

Prior studies have demonstrated glycemic and cardiometabolic risk in the prediabetic state.

This work aims to examine if insulin resistance (IR) is associated with markers of glycemic, cardiometabolic, and atherosclerotic risk in nonobese, nonprediabetic individuals compared to insulin-sensitive (IS) individuals matched for body mass index (BMI), sex, and age.

Of 1860 patients from the STOP DIABETES study, 624 had normal fasting plasma glucose, BMI less than 30, and glycated hemoglobin A1c (HbA1c) less than 5.7%. All received an oral glucose tolerance test. Insulin sensitivity was quantitated using the Matsuda index: less than the 25th percentile equals IR (n = 151) and 25th percentile or greater equals IS (n = 473). Measures of dysglycemia and cardiometabolic risk were compared between IR individuals (n = 151) and a subset of IS individuals who were matched for BMI, sex, and age (n = 151). Carotid intima media thickness and carotid plaque were measured in 65 IR and 76 IS individuals.

Compared to matched IS patients, IR nonobese individuals demonstrated increased indicators of glycemic and cardiometabolic risk, including increased 60-minute plasma glucose and percentage of patients with 60-minute plasma glucose greater than 155 mg/dL; increased 120-minute plasma glucose; unrecognized impaired glucose tolerance and type 2 diabetes, decreased disposition index; increased systolic and diastolic blood pressure; elevated plasma triglycerides (TGs); reduced high-density lipoprotein (HDL) cholesterol; increased TGs/HDL ratio, and high-sensitivity C-reactive protein. The presence, size, and number of carotid plaques was greater in the IR group.

Approximately 1 in 4 nonobese patients in this population with normal fasting glucose and HbA1c were IR. In these nonobese participants, IR was associated with multiple indicators of dysglycemia and cardiometabolic risk.

Dietary advanced glycation end products (AGEs) have been implicated in promoting insulin resistance. However, their impact on insulin resistance in a mixed population made up of males and females remains controversial. The aim of this study was to evaluate whether the relationship between dietary AGEs and insulin resistance may be sex-dependent.

195 males and 239 females were included in this cross-sectional study. Study participants underwent anthropometric and metabolic assessments. AGE intake was estimated using food frequency questionnaires and databases reporting AGE content in individual food items. The relationship between AGE intake and insulin resistance, estimated using HOMA-IR, was assessed using Pearson correlation test. The predictive power of dietary AGEs towards HOMA-IR was investigated using stepwise linear regression.

AGE intake correlated positively with HOMA-IR in females (p < 0.01) but not in male study participants (p > 0.05). Moreover, AGE intake was able to increase the predictive power of BMI towards insulin resistance in females but not males. Instead, anthropometric variables were the only discriminants able to predict insulin resistance in males.

Dietary AGEs exert a sex-dependent effect on insulin resistance as their intake is associated with and able to predict HOMA-IR in females but not males. This suggests that females may be more susceptible to the deleterious impact of these glycotoxins on insulin sensitivity. Nevertheless, considering this study not involving a nutritional intervention to directly elucidate whether the effect of AGEs on insulin resistance is sex-dependent, further studies are warranted to confirm the present findings.

Coronary atherosclerosis in patients with diabetes mellitus is the most significant pathophysiological mechanism responsible for ischemic heart disease. Atherosclerosis in diabetes is premature, more diffuse, and more progressive, and it affects more coronary blood vessels compared to non-diabetics. Atherosclerosis begins with endothelial dysfunction, continues with the formation of fatty streaks in the intima of coronary arteries, and ends with the appearance of an atherosclerotic plaque that expands centrifugally and remodels the coronary artery. If the atherosclerotic plaque is injured, a thrombus forms at the site of the damage, which can lead to vessel occlusion and potentially fatal consequences. Diabetes mellitus and atherosclerosis are connected through several pathological pathways. Among the most significant factors that lead to atherosclerosis in diabetics are hyperglycemia, insulin resistance, oxidative stress, dyslipidemia, and chronic inflammation. Chronic inflammation is currently considered one of the most important factors in the development of atherosclerosis. However, to date, no adequate anti-inflammatory therapeutic measures have been found to prevent the progression of the atherosclerotic process, and they remain a subject of ongoing research. In this review, we summarize the most significant pathophysiological mechanisms that link atherosclerosis and diabetes mellitus.

Insulin resistance (IR) is an important pathologic component in the occurrence and development of cardiovascular disease (CVD). The estimated glucose disposal rate (eGDR) is a measure of glucose handling capacity, that has demonstrated utility as a reliable marker of IR. The study aimed to determine the predictive utility of IR assessed by eGDR for CVD risk.

This nationwide prospective cohort study utilized data of 6416 participants from the China Health and Retirement Longitudinal Study (CHARLS) who were free of CVD but had complete data on eGDR at baseline. The Boruta algorithm was performed for feature selection. Multivariate Cox proportional hazards regression models and restricted cubic spline (RCS) analysis were conducted to examine the associations between eGDR and CVD, and the results were expressed with hazard ratio (HR) and 95% confidence interval (CI) values. The area under the receiver operating characteristic (ROC) curve (AUC), calibration curve, Hosmer-Lemeshow test, net reclassification improvement (NRI), and decision curve analysis (DCA) were employed to evaluate the clinical efficacy of eGDR in identifying CVD. Subgroup analysis was performed to explore the potential association of with CVD in different populations.

During a median follow-up of 106.5 months, 1339 (20.87%) incident CVD cases, including 1025 (15.96%) heart disease and 439 (6.84%) stroke, were recorded from CHARLS. The RCS curves demonstrated a significant and linear relationship between eGDR and all endpoints (all P for nonlinear > 0.05). After multivariate adjustment, the lower eGDR levels were found to be significantly associated with a greater prevalence of CVD. Compared to the lowest quartile, the highest eGDR quartile was associated with a decreased risk of CVD (HR 0.686, 95% CI 0.545-0.862). When assessed as a continuous variable, individuals with a unit increasement in eGDR was related to a 21.2% (HR 0.788, 95% CI 0.669-0.929) lower risk of CVD, a 18.3% (HR 0.817, 95% CI 0.678-0.985) decreased risk of heart disease, and 39.5% (HR 0.705, 95% CI 0.539-0.923) lower risk of stroke. The eGDR had an excellent predictive performance according to the results of ROC (AUC = 0.712) and χ2 likelihood ratio test (χ2 = 4.876, P = 0.771). NRI and DCA analysis also suggested the improvement from eGDR to identify prevalent CVD and the favorable clinical efficacy of the multivariate model. Subgroup analysis revealed that the trend in incident CVD risk were broadly consistent with the main results across subgroups.

A lower level of eGDR was found to be associated with increased risk of incident CVD, suggesting that eGDR may serve as a promising and preferable predictor for CVD.

To evaluate the efficacy of sodium butyrate (NaB) in ameliorating nonalcoholic fatty liver disease (NAFLD) in animals.

Chinese and English databases (including PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wangfang Data, CQVIP, and SinoMed) were searched for literature related to NaB to improve the animal model of NAFLD from the establishment of each database to 2023-02. 2 researchers independently screened the literature and extracted the data. The SYRCLE tool was used to assess risk of bias. The extracted data were analyzed using Revman 5.3 and Stata 17.0.

A total of 1008 relevant references were reviewed, and 12 animal experiments involving 192 animals were included in the analysis: 96 in the NaB group and 96 in the model group. The results showed that animals in the NaB group had significantly lower levels of alanine aminotransferase (standardized mean difference (SMD) = -1.29, 95% confidence interval (CI) (-2.08, -0.49), P = .002], aspartate aminotransferase [SMD = -1.13, 95% CI (-1.75, -0.50), P = .0004], NAFLD activity scores [SMD = -3.19, 95%CI(-4.80, -1.58), P = .0001], triglyceride [SMD = -1.28, 95%CI(-1.66, -0.90), P < .00001] and total cholesterol levels [SMD = -1.39, 95%CI(-2.11, -0.67), P = .0002], interleukin-1β [SMD = -1.40, 95%CI (-1.87, -0.92), P < .00001], interleukin-6 [SMD = -1.38, 95%CI (-1.87, -0.90), P < .00001], tumor necrosis factor-alpha [SMD = -1.69, 95% CI (-2.10, -1.28), P < .00001], and other pro-inflammatory factors, and significantly higher tight junction protein-1 expression [SMD = 1.06, 95% CI (0.43,1.69), P = .0009].

NaB treatment improves liver function in animals with NAFLD, protected the liver tissue, reduced triglyceride and total cholesterol levels, inhibited inflammation, and protected intestinal barrier function.

Obesity and type 2 diabetes mellitus (T2D) are widespread diseases that significantly impact cardiovascular and renal morbidity and mortality. In the recent years, intensive research has been performed to assess the role of adipose tissue and body fat distribution in the development of metabolic and non-metabolic complications in individuals with obesity. In addition to lifestyle modifications, glucagon-like peptide-1 receptor agonists (GLP-1-RA) have become a meaningful treatment expansion for the management of both disorders. In addition to improving metabolic control and reducing body weight, treatment with GLP-1-RAs reduces cardiovascular and renal events in individuals with obesity with and without diabetes. These important benefits of GLP-1-RAs have triggered new interest in other enteroendocrine and enteropancreatic peptides for treating obesity and its metabolic and non-metabolic consequences. The first peptide dual-agonist targeting glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors has been approved for the treatment of T2D and obesity. GIP/GLP-1 dual-agonism appear to provide better metabolic control and greater weight reduction compared with GLP-1-R mono-agonism. Other peptide and non-peptide co-agonists are in clinical development for obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD) and other metabolic disorders. This narrative review aims to summarize the available data on approved and emerging enteroendocrine and enteropancreatic based treatment approaches for obesity and metabolic disorders. In addition to available clinical efficacy measures, side effects, limitations and open challenges will also be addressed.

C-reactive protein-triglyceride-glucose index (CTI) has been proposed as a novel biomarker for insulin resistance and inflammation. However, the association between CTI and the risk of stroke, particularly in individuals with different glycemic status, remains unclear.

A total of 10,443 middle-aged and elderly participants were enrolled from the China Health and Retirement Longitudinal Study (CHARLS). The primary endpoint was the occurrence of stroke events. The CTI was calculated using the formula 0.412* Ln (CRP [mg/L]) + Ln (TG [mg/dl] × FPG [mg/dl])/2. The Kaplan-Meier curves, Cox proportional hazard models, and restricted cubic spline analysis were applied to explore the association between CTI and the risk of stroke according to gender, age and glycemic status.

During a median follow-up of 9 years, 960 (9.2%) participants experienced a stroke. Our findings revealed a significant positive linear relationship between CTI and the occurrence of stroke. The association was similar between male and female, despite the HR tended to be higher in females (HR 1.22, 95% CI 1.09, 1.36) than males (HR 1.15, 95% CI 1.02, 1.29), and similar in middle-aged (HR 1.25, 95% CI 1.11, 1.41) and elderly participants (HR 1.12, 95% CI 1.00, 1.26). In different glycemic status, high levels of CTI were found to be linked to an increased risk of stroke in individuals with normal glucose regulation (NGR) (HR 1.33, 95% CI 1.11, 1.59) and prediabetes mellitus (Pre-DM) (HR 1.20, 95% CI 1.04, 1.39). However, this association was not observed in individuals with diabetes mellitus (DM).

Our findings revealed a significant positive linear relationship between CTI and the occurrence of stroke. The association between CTI and stroke was similar between male and female, and similar in middle-aged and elderly participants. In different glycemic status, the association was significant in individuals with NGR and Pre-DM.

We previously reported that a high level of small dense low-density lipoprotein cholesterol (sdLDL-C) calculated by the Sampson equation was independently associated with the development of ischemic heart disease (IHD), but it remains unclear whether the effect depends on the level of low-density lipoprotein cholesterol (LDL-C).

We investigated the associations of new onset of IHD with categorized groups of high (H-) and low (L-) levels of estimated sdLDL-C and LDL-C using 25thpercentile levels of sdLDL-C level (25.2 mg/dL) and LDL-C (100 mg/dL) as cutoff values in 17,963 Japanese individuals (men/women: 11,508/6,455, mean age: 48 years) who underwent annual health checkups. During a 10-year follow-up period, 570 subjects (men/women: 449/121) had new development of IHD. Multivariable Cox proportional hazard analyses after adjustment of age, sex, smoking habit, hypertension and diabetes mellitus at baseline showed that the hazard ratio (HR) [95% confidence interval (CI)] for new onset of IHD was significantly higher in subjects with H-sdLDL-C/H-LDL-C (1.49 [1.06-2.08]) and subjects with H-sdLDL-C/L-LDL-C (1.49 [1.00-2.22]) than in subjects with L-sdLDL-C/L-LDL-C as the reference.

A high level of sdLDL-C estimated by the Sampson equation was a predominant predictor for the development of IHD, regardless of the level of LDL-C, in a general Japanese population.

There is sufficient proof that static magnetic fields (SMFs) of different parameters have a significant effect on the cardiovascular system. The sometimes contradictory, opposite-directional nature of SMF's hemodynamic effect generates uncertainty; therefore, an explanation of the underlying mechanisms is required. Following SMF selective carotid baroreceptors or microvascular net exposure, both high and low blood pressure (BP)/vascular tone starting conditions showed a return to normal. Beyond the previous descriptions of SMF's simple hemodynamic results, the current study aims to clarify the physiology of the SMF BP/vascular tone normalizing effects. The examination of available literature and hemodynamic tracings provided strong evidence that mechanoreceptor magnetic activation is concealed behind SMF vascular tone adjustment (increasing or decreasing as needed), filling in the knowledge gap regarding SMF opposite directional vascular tone normalizing outcomes. It has been proposed that cytoskeletal actin filament rearrangement, mechanically-gated Ca2+ influx, and nitric oxide (NO) activity may strengthen SMF's vascular mechanoreceptor sensing/regulation ability, modifying BP and vascular tone features in a hemodynamic normalizing pattern. It is suggested that baro/mechanoreceptor magnetic activation physiology is a unique mechanism of the magneto-cardiovascular interaction with substantial potential for cardiovascular protection.

Cardiac allograft vasculopathy (CAV) is a progressive disease with limited options for secondary prevention. Ways to manage lipid parameters and dyslipidemia patterns in care after transplantation remain unclear. In this longitudinal study, we included 32 patients with long-term heart transplantations (median interval after transplant 13.8 years) with angiographic manifest CAV. In 299 matched nonstented segments at 3 distinct time points ([TPs] 0 to 2, with median intervals of 2 years, respectively), progress of diameter stenosis (Δ%DS) defined CAV progress. Values above the median of maximal Δ%DS defined substantial CAV progress. Category of left ventricular ejection fraction was evaluated at TP0 and TP3 (2 years after TP2). Findings were correlated with dyslipidemia patterns at TP0, and lipid variations at follow-up (TP1 to TP3). Analyses included routine lipid assessment, and triglycerides/high-density lipoprotein-cholesterol ratio (TG/HDL-c) and atherogenic index of plasma (AIP). At TP1 and TP2, patients with increase of TG/HDL-c ≥0.1 (p = 0.02, respectively) and with increase of AIP (p = 0.01 and p = 0.049, respectively) presented a greater maximal Δ%DS. Dyslipidemia patterns at TP0 did not show a relevant association with CAV progress. At TP2, increase of TGs, TG/HDL-c, and AIP were associated with substantial CAV progress (odds ratio [OR] 5.0, p = 0.046, and OR 9.2, p = 0.01, OR 6.6, p = 0.02, respectively). At TP3, patients with CAV-related worsening of left ventricular ejection fraction category presented with a greater increase of TG/HDL-c (p = 0.03). Although findings at TP0 did not affect CAV progress, an increase of TG/HDL-c could define patients at greater risk of CAV progress and CAV-related deterioration of graft function.

Estimated glucose disposal rate (eGDR) is considered as a reliable alternative indicator of insulin resistance. However, the relationship between eGDR levels and mortality among individuals with cardiometabolic syndrome (CMS), as well as within different glucose metabolic states in this population, remains unclear.

We conducted a cohort study on 9928 CMS participants from the National Health and Nutrition Examination Survey (NHANES) database from 1999 to 2018. The relationship between eGDR levels and mortality in the CMS population was evaluated using multivariable Cox proportional hazards regression models and restricted cubic splines (RCS). Finally, stratified analysis was performed to determine the relationship between eGDR levels and mortality in different subgroups.

Cox regression analysis showed a significant correlation between eGDR levels and both all-cause and cause-specific mortality in the entire CMS population (all p < 0.05). RCS analysis revealed a non-linear relationship between eGDR levels and both all-cause (p for overall < 0.001, p for non-linear < 0.001) and diabetes specific mortality (p for overall < 0.001, p for non-linear = 0.004) in CMS population, while a linear relationship with cardiovascular specific mortality (p for overall < 0.001, p for non-linear = 0.091). In participants with baseline diabetes mellitus (DM), eGDR levels were significantly correlated with all-cause mortality, cardiovascular specific mortality, and diabetes specific mortality (all p < 0.05). In CMS participants with baseline pre-diabetes mellitus (Pre-DM), eGDR levels were significantly correlated with cardiovascular-specific and diabetes-specific mortality (all p < 0.05). In CMS participants with baseline normal glucose regulation (NGR), eGDR levels were only significantly related to diabetes specific mortality (p < 0.05).

There is a significant correlation between eGDR levels and both all-cause and cause-specific mortality in the entire CMS population. Furthermore, the protective effect of high eGDR levels on mortality persists across various glucose metabolic states.

Electrolyte imbalances are a frequently overlooked yet critical component of obesity-related metabolic dysfunction, contributing to an increased risk of cardiovascular disease, kidney impairment, and metabolic emergencies such as diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and acute kidney injury (AKI). These disturbances arise from insulin resistance, chronic inflammation, hormonal dysregulation, and renal dysfunction, leading to sodium retention, potassium depletion, and deficiencies in calcium and magnesium homeostasis. Managing electrolyte imbalances is essential in obesity management, as imbalances exacerbate hypertension, metabolic acidosis, neuromuscular complications, and insulin resistance. This review explores the pathophysiology of electrolyte disturbances in obesity and their impact on fluid balance, acid-base status, and metabolic health. Effective management strategies include individualized electrolyte monitoring, dietary sodium restriction, potassium supplementation, vitamin D and magnesium correction, and pharmacologic interventions targeting renin-angiotensin-aldosterone system (RAAS) activity and insulin resistance. Additionally, lifestyle interventions, including dietary modification, weight loss strategies, and hydration optimization, play a key role in preventing metabolic complications. Future research should investigate the long-term impact of electrolyte imbalances in obesity, the role of emerging therapies, and how lifestyle interventions can optimize electrolyte homeostasis and metabolic outcomes. A personalized, multidisciplinary approach integrating endocrinology, nephrology, and clinical nutrition is essential to improving the prevention and management of electrolyte imbalances in obese individuals.

Type 2 diabetes (T2D) and metabolic (dysfunction)-associated steatotic liver disease (MASLD) affect a growing number of individuals worldwide. T2D and MASLD often coexist and substantially elevate the risk of adverse hepatic and cardiovascular clinical outcomes. Several common pathogenetic mechanisms are responsible for T2D and MASLD onset and progression, including insulin resistance, oxidative stress, and low-grade inflammation, among others. The latter can also be induced by gut microbiota and its derived metabolites. Natural bioactive compounds (NBCs) have been reported for their therapeutic potential in both T2D and MASLD. A large amount of evidence obtained from clinical trials suggests that compounds like berberine, curcumin, soluble fibers, and omega-3 fatty acids exhibit significant hypoglycemic, hypolipidemic, and hepatoprotective activity in humans and may be employed as adjunct therapy in T2D and MASLD management. In this review, the role of the most studied NBCs in the management of T2D and MASLD is discussed, emphasizing recent clinical evidence supporting these compounds' efficacy and safety. Also, prebiotics that act against metabolic dysfunction by modulating gut microbiota are evaluated.

Cardiometabolic multimorbidity (CMM) has emerged as a global health challenge with a high mortality risk. This study aimed to explore the association between the metabolic score for insulin resistance (METS-IR) and the incidence of CMM.

This study included 6,977 individuals in the CHARLS database. We used multiple cox proportional hazards regression and restricted cubic splines (RCS) analysis to evaluate the association between METS-IR and CMM. Subgroup analyses and interaction tests were also performed.

During a median 109 (108-109) months of follow-up, 745 (10.7%) participants were diagnosed with new-onset CMM. The incidences of CMM among participants in quartiles (Q) 1-4 of METS-IR were 4.99, 7.51, 10.67, and 19.54%, respectively. METS-IR was significantly higher in individuals with CMM compared to those without CMM (p < 0.001). After multivariate adjustment, a higher METS-IR was significantly associated with an increased risk of CMM. Compared to participants in Q1 of METS-IR, the hazard ratios (HRs) (95% confidence intervals [CIs]) using cox proportional hazards regression analysis for those in Q2-4 were 1.52 (1.15-2.00), 2.02 (1.56-2.63), and 3.61 (2.80-4.64), respectively. RCS analysis revealed a significant nonlinear association between METS-IR and CMM (nonlinear p < 0.05). The association between METS-IR and the incidence of CMM was present in almost all the subgroups. Furthermore, the predictive ability of METS-IR for CMM was 0.669, which surpassed that of both the triglyceride to high-density lipoprotein cholesterol ratio and the triglyceride glucose index.

A higher METS-IR was closely associated with an increased risk of CMM. Further studies on METS-IR could be beneficial for preventing and treating CMM.

Developing effective drug screening methods for type 2 diabetes requires physiologically relevant models. Traditional 2D cell cultures have limitations in replicating in vivo conditions, leading to challenges in assessing drug efficacy. To overcome these issues, we developed a 3D artificial muscle model that induces insulin resistance, a hallmark of type 2 diabetes. Using C2C12 myoblasts cultured in a scaffold of 1% alginate and 1 mg/mL collagen type 1, we optimized conditions for differentiation and structural stability. Insulin resistance was induced using palmitic acid (PA), and glucose uptake was assessed using the fluorescent glucose analog 2-NBDG. The 3D model demonstrated superior glucose uptake responses compared with 2D cultures, with a threefold increase in insulin-stimulated glucose uptake on days 4 and 8 of differentiation. Induced insulin resistance was observed with 0.1 mM PA, which maintained cell viability and differentiation capacity. The model was validated through comparative drug screening using rosiglitazone and metformin, as well as 165 candidate compounds provided by Korea Chemical Bank. Drug screening revealed that three out of five hit compounds identified in both 2D and 3D models exhibited greater efficacy in 3D cultures, with results consistent with ex vivo assays using mouse soleus muscle. This model closely mimics in vivo conditions, offering a robust platform for type 2 diabetes drug discovery while supporting ethical research practices.

Cardiometabolic multi-morbidity (CMM) has emerged as a global healthcare challenge with a high mortality risk. This study aimed to explore the association between serum uric acid to high-density lipoprotein cholesterol ratio (UHR) and the incidence of CMM.

We enrolled 8188 individuals in the CHARLS database. Multivariable cox proportional hazards regression, logistic regression, and restricted cubic splines (RCS) analysis were conducted to evaluate the association between UHR and CMM. During a median 109 months of follow-up, 858 (10.5 %) participants were identified with new-onset CMM. The incidences of CMM among participants in quartiles (Q) 1-4 of UHR were 7.57 %, 9.18 %, 10.75 %, and 14.41 %, respectively. A fully adjusted Cox model showed a higher UHR was significantly associated with an increased risk of CMM. Compared to participants in Q1 of UHR, the hazard ratios (HRs) (95 % confidence intervals [CIs]) using cox proportional hazards regression analysis for those in Q2-4 were 1.33 (1.05-1.68), 1.62 (1.29-2.04), and 2.14 (1.71-2.68), respectively. Additionally, the odds ratios (ORs) (95 % CIs) using multivariate logistic regression analysis for participants in quartiles 2 to 4 were 1.38 (1.07-1.78), 1.69 (1.32-2.16), and 2.34 (1.82-3.00), respectively, when compared to participants in Q1 of UHR. RCS analysis revealed a significant nonlinear association between UHR and CMM (nonlinear P < 0.05).

A higher UHR was closely associated with an increased risk of CMM. Further studies on UHR could be beneficial for preventing and treating CMM.

Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of beta cell function. Here, we show that an lncRNA-transcribed antisense to Pax6, annotated as Pax6os1/PAX6-AS1, was upregulated by high glucose concentrations in human as well as murine beta cell lines and islets. Elevated expression was also observed in islets from mice on a high-fat diet and patients with type 2 diabetes. Silencing Pax6os1/PAX6-AS1 in MIN6 or EndoC-βH1 cells increased several beta cell signature genes' expression. Pax6os1/PAX6-AS1 was shown to bind to EIF3D, indicating a role in translation of specific mRNAs, as well as histones H3 and H4, suggesting a role in histone modifications. Important interspecies differences were found, with a stronger phenotype in humans. Only female Pax6os1 null mice fed a high-fat diet showed slightly enhanced glucose clearance. In contrast, silencing PAX6-AS1 in human islets enhanced glucose-stimulated insulin secretion and increased calcium dynamics, whereas overexpression of the lncRNA resulted in the opposite phenotype.

The history of antiobesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the prevailing conviction that excess body weight signifies a lack of willpower. However, categories of emerging pharmacotherapies generate hope to reduce obesity rates. This systematic review of phase 2 and phase 3 trials in adults with overweight/obesity investigates the effect of novel weight loss pharmacotherapies, compared to placebo/control or US Food and Drug Administration-approved weight loss medication, through searching Medline, Embase, and ClinicalTrials.gov (2012-2024). We identified 53 phase 3 and phase 2 trials, with 36 emerging antiobesity drugs or combinations thereof and 4 withdrawn or terminated trials. Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, and TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide and survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate. Completed phase 2 trials on incretin-based therapies showed a mean percent weight loss of 7.4% to 24.2%. Almost half of the drugs undergoing phase 2 trials are incretin analogs. The obesity drug pipeline is expanding rapidly, with the most promising results reported with incretin analogs. Data on mortality and obesity-related complications, such as cardio-renal-metabolic events, are needed. Moreover, long-term follow-up data on the safety and efficacy of weight maintenance with novel obesity pharmacotherapies, along with studies focused on underrepresented populations, cost-effectiveness assessments, and drug availability, are needed to bridge the care gap for patients with obesity. SIGNIFICANCE STATEMENT: Obesity is the epidemic of the 21st century. Except for the newer injectable medications, drugs with suboptimal efficacy have been available in the clinician's armamentarium for weight management. However, emerging alternatives of novel agents and combinations populate the current obesity therapeutic pipeline. This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives.

Insulin resistance describes the lack of activity of a known quantity of insulin (exogenous or endogenous) to promote the uptake of glucose and its utilization in an individual, as much as it does in metabolically normal individuals. On the cellular level, it suggests insufficient power of the insulin pathway (from the insulin receptor downstream to its final substrates) that is essential for multiple mitogenic and metabolic aspects of cellular homeostasis. Atherosclerosis is a slow, complex, and multifactorial pathobiological process in medium to large arteries and involves several tissues and cell types (immune, vascular, and metabolic cells). Inflammatory responses and immunoregulation are key players in its development and progression. This paper examines the possible pathophysiological mechanisms that govern the connection of insulin resistance, hyperinsulinemia, and the closely associated cardiometabolic syndrome with atherosclerosis, after exploring thoroughly both in vitro and in vivo (preclinical and clinical) evidence. It also discusses the importance of visualizing and developing novel therapeutic strategies and targets for treatment, to face this metabolic state through its genesis.

In this complex realm of diabetes, hyperinsulinemia is no longer regarded as just a compensatory response to insulin resistance but rather has evolved into an integral feature. This comprehensive review provides a synthesis of the current literature, including various aspects associated with hyperinsulinemia in diabetic complications. Hyperinsulinemia has been shown to be more than just a compensatory mechanism, and the key findings demonstrate how hyperinsulinism affects the development of cardiovascular events as well as microvascular complications. Additionally, recognizing hyperinsulinemia as a modifiable factor, the diabetes management paradigm shifts towards cognitive ones that consider the use of lifestyle modifications in combination with newer pharmacotherapies and precision medicine approaches. These findings have crucial implications for the clinical work, requiring a careful appreciation of hyperinsulinemia's changing aspects as well as incorporation in personalized treatment protocol. In addition, the review focuses on bigger issues related to public health, showing that prevention and early diagnosis will help reduce the burden of complications. Research implications favor longitudinal studies, biomarker discovery, and the study of emerging treatment modalities; clinical practice should adopt global evaluations, patient education, and precision medicine adaptation. Finally, this critical review provides an overview of the underlying processes of hyperinsulinemia in diabetes and its overall health effects.

As a novel oral anti-hyperglycemic agent, sodium-glucose cotransporter 2 inhibitors (SGLT2-i) have been demonstrated to improve cardiovascular outcomes in acute myocardial infarction (AMI) patients with type 2 diabetes mellitus (T2DM). However, the mechanism responsible for the beneficial effects remains unclear. Recently, extensive studies have demonstrated a close relationship between elevated fasting triglyceride-glucose (TyG) index and the risk of AMI. Additionally, research has identified that SGLT2-i can reduce the TyG index in T2DM patients. However, it remains ambiguous whether the benefit of SGLT2-i in patients with AMI and T2DM is due to an improvement in the TyG index. Consequently, we aimed to assess the impact of SGLT2-i on the TyG index in AMI patients with T2DM.

A retrospective and cross-sectional study was conducted on 180 AMI patients with T2DM admitted to the chest pain center of the Second Affiliated Hospital of Anhui Medical University from January 2020 to January 2023. Based on the hypoglycemic regimens administered after admission, the patients were categorized into a control group (79 cases treated with sulfonylureas, α-glycosidase inhibitors, metformin, etc.) and a SGLT2-i group (101 cases administered with dapagliflozin or empagliflozin). Propensity score matching (PSM) was adopted to balance the baseline characteristics of patients and minimize selection bias to confirm the robustness of the results. After PSM, control group remained 32 patients, and SGLT2-i group remained 37 patients. All patients underwent regular follow-up after discharge, and comparisons were made between the two groups in terms of clinical indicators and major adverse cardiovascular events (MACEs) in 1 year. Univariate and Multivariate Cox regression analysis was performed to identify the predictors of MACE.

Significant differences were observed between the two groups in terms of various parameters before PSM, included age, proportion of insulin use, Gensini score, serum creatinine (Cr), total cholesterol (TC), and cardiac troponin I (cTnI). After PSM, there were no statistically significant differences in baseline clinical indicators and laboratory tests. The median follow-up period was 11 months in both cohorts. The comparison of follow-up results between the two groups after matching confirmed statistically significant differences in triglyceride (TG) reduction index reduction, left ventricular end-diastolic diameter (LVDD) reduction, and white blood cell (WBC) reduction in the SGLT2-i group (all P<0.05). Additionally, a higher incidence of MACEs was observed in the control group (P=0.01). Univariate analysis showed that usage of SGLT2-i, Cr, low-density lipoprotein cholesterol (LDL-C), TyG index at baseline, and changes of TyG index (TyG at follow-up minus TyG at baseline) were associated with the risk of MACE. However, multivariate analysis showed only usage of SGLT2-i was associated with the risk of MACE [hazard ratio (HR) =0.077; 95% confidence interval (CI): 0.009-0.682; P=0.02].

In AMI patients with T2DM, the use of SGLT2-i was associated with a lower risk of MACE and an improvement of TyG index during 11 months follow-up. Our findings offer new insights into the cardio-protective mechanisms of SGLT2-i in the context of AMI.

The Triglyceride-glucose (TyG) index represents a simple, cost-effective, and valid proxy for insulin resistance. This surrogate marker has also been proposed as a predictor of metabolic and cardiovascular disease (CVD). In this descriptive review, we aimed to assess the utility of the TyG index as a predictive biomarker of cardiometabolic diseases.

A search was conducted in PubMed, and Web of Science to identify cross-sectional and more importantly prospective studies examining the use of the TyG index as a predictive biomarker. The following terms were utilized in addition to the TyG index: "insulin resistance", "metabolic syndrome", "diabetes"; "cardiovascular diseases".

This descriptive review included thirty prospective studies in addition to cross-sectional studies. Following adjustment for confounding variables, an elevated TyG index was associated with a significantly increased risk for the development of Metabolic Syndrome (MetS), Type 2 Diabetes, hypertension, and CVD. Also in limited studies, the TyG index was associated with endothelial dysfunction, increased oxidative stress and a pro-inflammatory phenotype.

Overall, our findings support the use of the TyG index as a valid biomarker to assess the risk of developing MetS, T2DM, as well as atherosclerotic cardiovascular disease.

Historically, microglial activation has been associated with diseases of a neurodegenerative and neuroinflammatory nature. Some, like Alzheimer's disease, Parkinson's disease, and multiple system atrophy, have been explored extensively, while others pertaining to metabolism not so much. However, emerging evidence points to hypothalamic inflammation mediated by microglia as a driver of metabolic dysregulations, particularly insulin resistance and type 2 diabetes mellitus. Here, we explore this connection further and examine pathways that underlie this relationship, including the IKKβ/NF-κβ, IRS-1/PI3K/Akt, mTOR-S6 Kinase, JAK/STAT, and PPAR-γ signaling pathways. We also investigate the role of non-coding RNAs, namely microRNAs and long non-coding RNAs, in insulin resistance related to neuroinflammation and their diagnostic and therapeutic potential. Finally, we explore therapeutics further, searching for both pharmacological and non-pharmacological interventions that can help mitigate microglial activation.

As a major noncommunicable disease, stroke poses a major threat to public health. In the context of predictive, preventative, and personalised medicine (PPPM/3PM), early identification of high-risk individuals is crucial for targeted prevention and personalised treatment for stroke. This study aimed to investigate the association between changes in the Metabolic Score for Insulin Resistance Index (METS-IR) and incident stroke. From the perspective of PPPM/3PM, we hypothesised that monitoring dynamic changes of the METs-IR levels and targeting cumulative METs-IR index contribute to risk prediction, targeted prevention, and personalised management of stroke.

All data were obtained from the China Health and Retirement Longitudinal Study (CHARLS), a nationwide prospective cohort study. The individuals were categorised into four subgroups based on the quartiles (Q) of the cumulative METS-IR index as a reflection of changes in the METS-IR values from 2012 to 2015. Logistic regression was employed to examine the association between cumulative METS-IR index and stroke incidence. Additionally, restricted cubic spline regression analysis was used to assess potential linearity.

Among the 4288 participants, 275 (6.4%) experienced a stroke. The risk of stroke events increased with higher cumulative METS-IR index levels. Compared with the lowest quartile (Q1), the OR of having a stroke was 1.20 (0.81, 1.78) for Q2, 1.51 (1.04, 2.21) for Q3 and 2.17 (1.52, 3.10) for the highest quartile (Q4). After adjusting for multiple potential confounders, Q4 (OR: 1.57, 95% CI: 1.04, 2.35) remained significantly associated with stroke. The association between the cumulative METS-IR index and stroke incidence was linear in males, females, and the overall population (all P values for nonlinearity > 0.05).

A higher cumulative METS-IR index was associated with an increased risk of incident stroke among middle-aged and older Chinese individuals. In the context of PPPM/3PM, incorporating metabolic health into stroke risk assessment advances the prediction, prevention and personalised management of stroke.

The online version contains supplementary material available at 10.1007/s13167-024-00388-y.

One measurement of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) is considered to be associated with insulin resistance and cardiovascular disease (CVD) risk. This study aimed to exploring the association between cumulative non-high-density lipoprotein cholesterol/high-density lipoprotein cholesterol (Cum NHHR) exposure levels and the risk of cardiometabolic disease (CMD).

This prospective cohort study included 43,735 participants, who participated in three consecutive health examinations in 2006, 2008, 2010 and had no history of CMD or cancer. The participants were divided into quartiles bases on their cum NHHR. Multivariate Cox proportional hazards model was used to assess the association between cum NHHR and the risk of CMD. Additionally, the direct method of standardized ratios was employed to calculate the absolute risk of CMD attributable to cum NHHR.

Over a median follow-up period of 10.92 years (IQR: 10.22-11.26 years), 7,388 participants were newly diagnosed with CMD. In the multivariate-adjusted model, participants in quartiles Q2, Q3 and Q4 showed a progressively increased relative risk of CMD compared to those in Q1, The fully adjusted hazard ratios (95% confidence intervals) for the risk of CMD in the Q2, Q3, and Q4 groups were 1.11 (1.04-1.20), 1.23 (1.14-1.32), and 1.29 (1.20-1.38), respectively, compared with the Q1 group. This association remained significant even after further adjustment for single measurements of NHHR. Moreover, cum NHHR was positively correlated with the absolute risk of CMD, cardiovascular diseases (CVD), and type 2 diabetes (T2DM).

Higher cum NHHR is significantly associated with an increased risk of CMD, independent of single-point NHHR level. Additionally, there are significant different strengths of correlations between cum NHHR and different diseases.

Type 2 diabetes mellitus (T2DM) is a significant health issue affecting the quality of life including male reproductive functions. Orange peel ethanolic extract (OPEE) has been established to have antioxidant properties and has been shown to alleviate diabetic complications. This study determined to establish OPEE effect and physical exercise (EX) in T2DM-induced testicular dysfunction.

Thirty male Wistar rats were randomly distributed in five groups as follows: control group (received 1 ml/b.w of normal saline), and groups 2-5 were induced with diabetes, with group 2 left untreated, group 3 received 600 mg/kg b.w OPEE, group 4 was subjected to EX while group 5 was treated with OPEE alongside EX.

OPEE + EX ameliorated T2DM-induced decrease in sperm motility, count, and morphology and increased testicular lactate dehydrogenase, alkaline phosphate, gamma-glutamyl transferase, and lactate. T2DM-induced disruption of gonadotropin-releasing hormone, luteinizing hormone, follicle-stimulating hormone and, testosterone was also mitigated by OPEE + EX. In addition, OPEE + EX blunted T2DM-induced increase in oxidative stress, inflammatory, and apoptotic markers and the accompanied decrease in testicular nuclear factor erythroid 2-related factor 2 (Nrf2) and increase in nuclear factor kappa B (NF-κB). Also, OPEE + EX reversed T2DM-induced testicular histology distortion.

The outcome of this study revealed that the combination of OPEE and EX ameliorated T2DM-mediated testicular damage via Nrf2/NF-κB signaling.

Although the hypoglycaemic effect of Andrographis paniculata (Burm.f.) Nees [Acanthaceae] has been documented, reports on its effect in an apparently healthy state are limited.

This study investigated whether or not A. paniculata exerts hypoglycaemic effect in a non-diabetic state. It also explored the impact of A. paniculata on glycolytic enzymes and GLUT 4 protein expression, as a possible mode of action.

Twenty male Wistar rats were randomly assigned into two groups (n = 10 rats/group). The control rats were vehicle-treated (0.5 ml of distilled water), while the A. paniculata-treated rats had 500 mg/kg of A. paniculata per os once daily for 35 days.

A. paniculata treatment led to improved insulin sensitivity evidenced by increased HOMA-β (88.08 ± 2.13 vs. 120.80 ± 1.52, p < 0.0001), HOMA-S (283.60 ± 8.82 vs. 300.50 ± 9.30, p = 0.0189), and reduced TyG index (4.22 ± 0.04 vs. 3.95 ± 0.07, p < 0.0002) and HOMA-IR (0.32 ± 0.01 vs. 0.25 ± 0.01, p < 0.0001) when compared with the control. It also improved glucose regulation as depicted by reduced fasting blood glucose (3.77 ± 0.10 vs. 3.24 ± 0.11, p < 0.0001) and glycated hemoglobin (HbA1c; 7.69 ± 1.15 vs. 5.95 ± 0.82, p = 0.0245), and atherogenic dyslipidaemia, including AIP (-0.12 ± 0.03 vs. -0.26 ± 0.03, p < 0.0001) and CRI-I (2.70 ± 0.29 vs. 1.84 ± 0.27, p < 0.0001). These findings were accompanied by enhanced hepatic and muscular redox state, increased activities of glycolytic enzymes, upregulated GLUT 4 (0.80 ± 0.27 vs. 6.20 ± 0.84, p < 0.0001), and increased circulating nitric oxide (5.45 ± 0.24 vs. 6.79 ± 0.33, p = 0.0002).

A. paniculata exerts positive effect on glucose metabolism and utilization by improving insulin sensitivity and upregulating the activities of glycolytic enzymes and GLUT 4 protein expression. This implies that A. paniculata may be beneficial in preventing insulin resistance and incident diabetes. Nonetheless, it should be used with caution to prevent hypoglycaemia in a non-diabetic state.

The metabolic syndrome (MetS) is a multiplex modifiable risk factor for cardiovascular disease, type 2 diabetes mellitus and other health outcomes, and is a major challenge to clinical practice and public health. The rising global prevalence of MetS, driven by urbanization, sedentary lifestyles and dietary changes, underlines the urgency of addressing this syndrome. We explore the complex underlying mechanisms, including genetic predisposition, insulin resistance, accumulation of dysfunctional adipose tissue and ectopic lipids in abdominal obesity, systemic inflammation and dyslipidaemia, and how they contribute to the clinical manifestations of MetS. Diagnostic approaches vary but commonly focus on abdominal obesity (assessed using waist circumference), hyperglycaemia, dyslipidaemia and hypertension, highlighting the need for population-specific and phenotype-specific diagnostic strategies. Management of MetS prioritizes lifestyle modifications, such as healthy dietary patterns, physical activity and management of excess visceral and ectopic adiposity, as foundational interventions. We also discuss emerging therapies, including new pharmacological treatments and surgical options, providing a forward-looking perspective on MetS research and care. This Primer aims to inform clinicians, researchers and policymakers about MetS complexities, advocating for a cohesive, patient-centred management and prevention strategy. Emphasizing the multifactorial nature of MetS, this Primer calls for integrated public health efforts, personalized care and innovative research to address this escalating health issue.

Triglyceride (TG) and its related metabolic indices are recognized as important biomarker gauging cardiovascular diseases. This study aimed to explore the association between multiple TG-derived metabolic indices including the atherogenic index of plasma (AIP), triglyceride-glucose (TyG) index, triglyceride glucose-body mass index (TyG-BMI) and cardiovascular outcomes to identify valuable predictors for cardiovascular prognosis in patients with type 2 diabetes (T2DM) and coronary heart disease (CHD).

Data of 1034 patients with T2DM and CHD from China-Japan Friendship Hospital between January 2019 and March 2022 were collected and analyzed. Multivariate Cox proportional hazards models and restricted cubic spline (RCS) analysis were conducted to examine the associations between AIP, TyG index, TyG-BMI and major adverse cardiac and cerebrovascular events (MACCEs). The area under the receiver operating characteristic (ROC) curve (AUC) was used to screen the most valuable predictor. Kaplan-Meier curve analysis was employed to examine the relationship between the predictor and prognosis. The goodness-of-fit of models was evaluated using the calibration curve and χ2 likelihood ratio test. Subgroup analysis and interaction test were performed to control for confounding factors.

The overall incidence of MACCEs was 31.04% during a median of 13.3 months of follow-up. The results showed that AIP, TyG index and TyG-BMI were all positively correlated with the risk of MACCEs in patients with T2DM and CHD (P < 0.05). Furthermore, ROC (AUC = 0.899) suggested that AIP had the strongest ability to predict the risk of MACCEs, and the highest AIP values enhanced the risk by 83.5% in the population. RCS model demonstrated that AIP was nonlinearly associated with the incident cardiovascular outcomes (P for nonlinear = 0.0118). The Kaplan-Meier analysis for MACCEs grouped by the AIP tertiles indicated that the probability of cumulative incidences of MACCEs was significantly higher in patients with a higher AIP (all Log rank P < 0.001). Meanwhile, the calibration curve demonstrated an excellent goodness-of-fit of the multivariate model (χ2 = 13.210, P = 0.105). Subgroup analysis revealed that the trend of positive association of AIP with cardiovascular risk was similar across subgroups except in non-hypertensive individuals.

Our study, for the first time, may provide valuable information that multiple TG-derived metabolic indices play a crucial role in the risk of MACCEs and it is recommended to monitor the AIP for lipid management in patients with established T2DM and CHD.

To investigate the relationship between estimated glucose disposal rate (eGDR), a surrogate indicator of insulin resistance, and atherosclerotic cardiovascular diseases (ASCVD) incidence risk.

This prospective cohort study utilized data from the 6026 participants from the Multi-Ethnic Study of Atherosclerosis. The eGDR (mg/kg/min) was computed as 21.158 - (0.09 × waist circumference [cm]) - (3.407 × hypertension [yes/no]) - (0.551 × HbA1c [%]). The population was categorized into four subgroups according to the quartiles (Q) of eGDR. Cox proportional hazard models were applied to assess the associations between eGDR and ASCVD incidence, and restricted cubic spine (RCS) was employed to examine the dose-response relationship.

The mean age of participants was 63.6 ± 10.1 years, comprising 3163 (52.5%) women. Over a median follow-up duration of 14.1 years, 565 (9.4%) developed ASCVD, including 256 (4.2%) myocardial infarctions, 234 (3.9%) strokes, and 358 (5.9%) fatal coronary heart disease. Compared to the lowest quartile, the adjusted hazard ratios (95% confidence intervals) for incident ASCVD for Q2-Q4 were 0.87 (0.68-1.10), 0.63 (0.47-0.84), and 0.43 (0.30-0.64), respectively. Per 1 standard deviation increase in eGDR was associated with a 30% (HR: 0.70, 95% CI 0.60-0.80) risk reduction of ASCVD, with the subgroup analyses indicating that age and hypertension modified the association (P for interaction < 0.05). RCS analysis indicated a significant and linear relationship between eGDR and ASCVD incidence risk.

eGDR level was negatively associated with incident ASCVD risk in a linear fashion among the general population. Our findings may contribute to preventive measures by improving ASCVD risk assessment.

Glucagon-like peptide-1 (GLP-1) receptor agonists have gained widespread use in the treatment of individuals with type 2 diabetes because of their potent weight loss promoting effect, ability to augment β-cell function, and cardiovascular protective effects. However, despite causing impressive weight loss, GLP-1 receptor agonists do not normalise insulin sensitivity in people with type 2 diabetes and obesity, and the long-term effects of this class of antidiabetic medication on muscle mass, frailty, and bone density have been poorly studied. Although GLP-1 receptor agonists improve insulin sensitivity secondary to weight loss, the only true direct insulin-sensitising drugs are thiazolidinediones. Because of side-effects associated with type 2 diabetes therapy, these drugs have not gained widespread use. In lieu of the important role of insulin resistance in the cause of type 2 diabetes and in the pathogenesis of atherosclerotic cardiovascular disease in type 2 diabetes, development of potent insulin-sensitising drugs that can be used in combination with GLP-1 receptor agonists remains a large unmet need in the management of individuals with type 2 diabetes.

The purpose of this study was to determine the efficacy and safety profile of pioglitazone compared with placebo (PBO) in patients with type 2 diabetes (T2D) inadequately controlled with metformin and dapagliflozin.

In this prospective, multicenter, randomized, double-blind, PBO-controlled trial, 366 patients with T2D who did not meet glycemic targets (7.0% ≤ glycosylated hemoglobin [HbA1c] ≤ 10.5%), despite treatment with metformin ≥1000 mg and dapagliflozin 10 mg, received either a PBO, 15 mg of pioglitazone daily (PIO15), or 30 mg of pioglitazone daily (PIO30). The primary end point was the mean change in HbA1c from baseline at 24 weeks across the groups.

For the 366 participants (PBO, n = 124; PIO15, n = 118; PIO30, n = 124), the mean age was 55.6 years and mean duration of diabetes was 8.7 years, with a baseline HbA1c of 7.9%. After 24 weeks, HbA1c reduced significantly in the PIO15 and PIO30 groups from baseline, with intergroup differences of -0.38% and -0.83%, respectively, compared with the PBO group. The proportion of patients with HbA1c levels <7% was significantly higher in the PIO15 and PIO30 groups than in the PBO group. The adverse event rates did not significantly differ across the groups, indicating favorable safety profiles for triple combination therapy using metformin, dapagliflozin, and pioglitazone.

The addition of pioglitazone as a third oral antidiabetic medication is an appropriate option for patients with T2D inadequately controlled with metformin and dapagliflozin based on the resulting significant efficacy in glycemic control and favorable safety profile.

gov identifier: NCT04885712.

Klotho, an anti-aging protein, is believed to participate in metabolic diseases and play a potential protective role by regulating insulin sensitivity. This study aimed to explore the relationship between the triglyceride-glucose (TyG) index (a simple marker of insulin resistance) and serum soluble Klotho (S-Klotho) levels. The cross-sectional study comprised 5237 adults aged 40-79 years who participated in the National Health and Nutrition Examination Surveys (NHANES) 2007-2016. The TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The serum levels of S-Klotho were measured by enzyme-linked immunosorbent assay. The association between the TyG index and S-Klotho levels was investigated by multiple linear regression models, smoothed curve fitting, segmented linear regression models, subgroup analyses, and interaction tests. The TyG index was inversely associated with serum S-Klotho level after full adjustment (β = - 45.11, 95% CI (- 79.53, - 10.69), P = 0.011). Furthermore, we also found a non-linear correlation and saturation phenomenon between the TyG index and serum S-Klotho levels, with a turning point of 9.56. In addition, a significant interaction effect of sex was found between the two (P for interaction < 0.001), with a more pronounced association observed in females. Further studies are required to explore the mechanisms and verify the correlation.

Mitochondrial dysfunction has long been implicated in the development of insulin resistance, which is a hallmark of type 2 diabetes. However, recent studies reveal ethnicity-related differences in mitochondrial processes, underscoring the need for nuance in studying mitochondrial dysfunction and insulin sensitivity. Furthermore, the higher prevalence of type 2 diabetes among African Americans and individuals of African descent has brought attention to the role of ethnicity in disease susceptibility. In this review, which covers existing literature, genetic studies, and clinical data, we aim to elucidate the complex relationship between mitochondrial alterations and insulin stimulation by considering how mitochondrial dynamics, contact sites, pathways, and metabolomics may be differentially regulated across ethnicities, through mechanisms such as single nucleotide polymorphisms (SNPs). In addition to achieving a better understanding of insulin stimulation, future studies identifying novel regulators of mitochondrial structure and function could provide valuable insights into ethnicity-dependent insulin signaling and personalized care.

One billion people live with obesity. The most promising medications for its treatment are incretin-based therapies, based on enteroendocrine peptides released in response to oral nutrients, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The mechanisms by which GLP-1 receptor agonism cause weight reduction are becoming increasingly understood. However, the mechanisms by which GIP receptor-modulating medications cause weight loss remain to be clarified.

This review describes GLP-1 and GIP physiology and explores the conflicting data regarding GIP and weight management. It details examples of how to reconcile the contradictory findings that both GIP receptor agonism and antagonism cause weight reduction. Specifically, it discusses the concept of 'biased agonism' wherein exogenous peptides cause different post-receptor signaling patterns than native ligands. It discusses how GIP effects in adipose tissue and the central nervous system may cause weight reduction. It describes GIP receptor-modulating compounds and their most current trials regarding weight reduction.

Effects of GIP receptor-modulating compounds on different tissues have implications for both weight reduction and other cardiometabolic diseases. Further study is needed to understand the implications of GIP agonism on not just weight reduction, but also cardiovascular disease, liver disease, bone health and fat storage.

To explore routinely measured markers of systemic inflammation in hypertension (HTN) and type 2 diabetes (T2D) comorbidity, and their association with atherogenicity.

This study included a total of 70 patients with T2D which were categorised into 2 groups, that is with T2D and with HTN comorbidity (T2D + HTN) (n = 35/group). All measured laboratory parameters were determined using standardised methods.

The neutrophil/lymphocyte ratio (NLR) was elevated in patients with T2D + HTN when compared to those with T2D (P = .0494). This was also the case with C-reactive protein (CRP) levels (P < .0001) and systemic immune-inflammation (SII) index (P = .0298). Notably, the majority of patients with T2D + HTN [63% (n = 22)] were classified as having an intermediate or high atherogenic index of plasma (AIP). The correlation analysis of systemic inflammation showed significant associations between CRP and age (r = .24, P = .0477); CRP and red blood cell count (r = -.4, P = .0455), and SII and systolic blood pressure (SBP) (r = .33, P = .0056). However, there was no association between inflammatory profiles and lipograms (P > .05). We further assessed predictors for an elevated AIP using mutivariable regression model adjusted for age, SBP, CRP and SII. Only NLR was a significant predictor of AIP (β = .287, SE: 0.1, P = .0046).

HTN comorbidity in T2D is associated with exacerbated levels of inflammation and atherogenicity. NLR is a significant independent risk factor for increased atherogenicity in patients with T2D. Therefore, the use of therapeutic strategies that target and alleviate inflammation in patients with T2D and HTN comorbidity is imperative in reducing the initiating and progression of cardiovascular events (CVEs).

The prognostic nutritional index (PNI), a simple and comprehensive predictor of nutritional and immunological health, is connected to cancer and cardiovascular disease. The effects of PNI on myocardial infarction (MI) in individuals with diabetes remain unclear. Thus, we aim to investigate the correlation of PNI with predictive outcomes in this specific population group to inform therapeutic decision-making.

This prospective observational study included 417 diabetic patients with MI who underwent coronary angiography intervention at Fujian Medical University Union Hospital from May 2017 to May 2020. We collected follow-up and prognostic data from these patients at 6, 12, 18, and 24 months post-procedure via outpatient visits or phone interviews. The main focus of the study was on major adverse cardiovascular events (MACE) in the two years after surgery. Based on the median PNI, patients were categorized into two groups: high PNI (H-PNI) and low PNI (L-PNI). Data were analyzed using IBM SPSS 25.0. Kalpan-Meier survival curves and Cox proportional hazards regression analysis were utilized to examine the associations between preoperative PNI and the prognosis of diabetic patients with MI.

In the study, 417 participants were observed for two years. Of these patients, 159 (38.1%) had MACE. According to the Kaplan-Meier curves, patients in the L-PNI group had more MACE than those in the H-PNI group (log-rank p < 0.001) and had a heightened susceptibility to all categories of MACE. After adjusting for confounding variables, the corrected hazard ratio for developing unstable angina in the L-PNI group was 2.55 (95% CI 1.57-4.14, p < 0.001).

Low PNI levels are associated with MACE after coronary angiography intervention in diabetic patients with myocardial infarction. This highlights the prognostic value of PNI and broadens its potential use in larger populations.

Not applicable.