Insulin resistance in adipose tissue causes dysregulation of various adipokine levels and ectopic fat accumulation in other organs, such as the liver. This study investigated the effects of insulin resistance in adipose tissue and concomitant fatty liver on each stage of impaired glucose metabolism compared with visceral fat mass.

This observational study included 3644 individuals who underwent two 75-g oral glucose tolerance tests at baseline and follow-up. Adipose insulin resistance index (Adipo-IR), lipid accumulation product (LAP) and fatty liver index (FLI) were used as indicators of insulin resistance in the adipose tissue, visceral fat mass and fatty liver, respectively.

Over a mean 2.9-year follow-up period, 463 (32.4%) individuals progressed from normoglycaemia to prediabetes, and 198 (10.6%) developed type 2 diabetes from prediabetes. Comparing the highest-to-lowest quartiles, baseline levels and changes in Adipo-IR were associated with an increased odds of progression from normoglycaemia to prediabetes (odds ratio [OR], 2.22; 95% CI, 1.36-3.65, OR, 2.70; 95% CI, 1.83-3.98, respectively) and from prediabetes to the onset of type 2 diabetes (OR, 2.02; 95% CI, 1.04-3.92, OR, 3.09; 95% CI, 1.84-4.19, respectively), after adjusting for possible confounders. Changes in FLI were associated with progression from prediabetes to type 2 diabetes. LAP did not affect the progression of impaired glucose metabolism.

Adipose tissue insulin resistance, rather than fat mass, is crucial in all stages of deterioration of glycaemic status. Fatty liver plays a decisive role in the eventual development of type 2 diabetes.

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.

Obesity and cardiometabolic diseases are leading causes of morbidity and mortality among adults worldwide. These conditions significantly contribute to and exacerbate other major causes of illness and death, including cancer, neurodegenerative diseases, and chronic kidney disease. The growing burden of these diseases has increased the interest of modern medicine in understanding metabolic processes and health, with diet emerging as a pivotal modifiable factor, alongside physical inactivity and smoking. In this review, we discuss the pathophysiological and evolutionary foundations of metabolic processes that may link "unhealthy" nutrition to obesity and cardiometabolic diseases and review the current literature to assess the effects of various diet interventions and patterns on cardiometabolic parameters. Special emphasis is placed on summarizing the latest, albeit partially contradictory, evidence to offer balanced dietary recommendations with the ultimate aim to improve cardiometabolic health.

Trigonella foenum-graecum L. (HLB), a widely recognized traditional Chinese medicine, has been historically used for the treatment of diabetes mellitus and its complications. However, the efficacy and mechanism of HLB in the treatment of type 2 diabetes mellitus (T2DM) combined with metabolic-associated fatty liver disease (MAFLD) remain poorly understood.

To investigate the therapeutic effects of HLB on T2DM combined with MAFLD in mice and elucidate its underlying mechanisms.

The indices of glucose and lipid metabolism, along with oxidative stress markers, were measured using commercially available assay kits. Histopathological analyses of liver and colon tissues were conducted. Additionally, the mRNA expression levels of genes related to fatty acid metabolism, inflammatory factors, and intestinal tight junction proteins were quantified using reverse transcription polymerase chain reaction (RT-PCR). Microbiome, metabolomic, and transcriptomic analyses were employed to evaluate gut microbiota composition, metabolic profiles, and liver differential genes, respectively.

After a 4-week treatment period, HLB effectively ameliorated abnormalities of glucose-lipid metabolism, hepatic oxidative stress, and inflammatory responses. Furthermore, HLB modulated hepatic function and intestinal damage. Through comprehensive multi-omics analysis, the observed improvements were attributed to the remodeling of the gut microbiota and its metabolic alterations, including an increased abundance of beneficial bacteria, regulation of bile acid metabolism.

These findings not only provide a theoretical foundation for the broader application of HLB in traditional Chinese medicine but also offer novel insights into the potential pharmacological mechanisms underlying HLB's efficacy in T2DM and MAFLD treatment.

Type 2 diabetes mellitus (T2DM) is estimated to impact 693 million individuals globally by 2045. Diabetes remission has the potential to slow disease progression, alleviate psychological burdens, minimize complications, and improve quality of life. We aimed to perform a bibliometric analysis of research on T2DM remission. We searched the Web of Science (WoS) database to identify relevant publications on T2DM remission during 2002 to 2022. Research trends and hotspots in T2DM remission were analyzed using Bibliometrix R and CiteSpace. The analysis considered various factors such as publication year, authors, journal, institution, country/region, themes, thematic evolution, keywords, and keyword bursts. The WoS search yielded 2254 articles. The annual scientific output has consistently increased. Lee was the most prolific author (48 papers). Obesity surgery was the leading journal (296 publications), while diabetes care had the highest h_index (43). The University of Copenhagen was the most active institution (116 papers). The most productive countries were the US (476), China (347), the UK (180), Italy (121), and Japan (90). The top 3 keywords were "bariatric surgery," "weight loss," and "remission." From 2013 to 2015, the usage of the term "medical therapy" significantly surged, lasting for 3 years. The term "GLP-I receptor agonists" also had a lasting burst. In the past 5 years, "weight loss" and "low-calorie diets" have emerged as prominent areas of research. This study analyzed the research trends and key factors in the field of type 2 diabetes mitigation through bibliometrics, providing important data support and a basis for decision-making for future research and public health policies.

Sugar substitutes that maintain the homeostasis of glucose, lipid, and protein metabolism are important for nutritional intervention in type 2 diabetes mellitus (T2DM). However, the specific metabolic effects remain unclear. The aim of this study was to systematically compare the effects of four common sugar substitutes on a high-fat diet (HFD) combined with a streptozotocin (STZ)-induced T2DM mouse model from the perspective of hepatic glucose, lipid, and protein metabolism. In this study, based on the establishment of a T2DM mouse model induced by an HFD combined with STZ and nontargeted metabolomics, the effects of four sugar substitutes on regulating and improving sugar, lipid, and protein metabolism were systematically evaluated. The results showed that mogroside V (MOG), stevioside (ST), and erythritol (ERT) enhanced protein synthesis via the mammalian target of the rapamycin/p-P70S6K pathway. MOG and ST also improved glucose and lipid metabolism by activating the phosphor-AMP-activated protein kinase (p-AMPK) pathway and upregulating peroxisome proliferator-activated receptor alpha/carnitine palmitoyltransferase 1. Sucralose primarily improves lipid metabolism by downregulating sterol regulatory element-binding protein 1, whereas ERT increases lipid droplet accumulation in the liver. These findings provide a foundation for the application of sugar substitutes in T2DM nutritional interventions.

Improving β-cell function can lead to remission in some patients with type 2 diabetes mellitus (T2DM). However, research on pharmacotherapy-induced remission in youth-onset T2DM remains scarce. Our study aimed to identify the clinical characteristics of pediatric patients who experience remission.

We retrospectively reviewed 88 pediatric patients with T2DM followed for at least 1 year at Seoul National University Bundang Hospital between 2013 and 2023. Remission was defined as a glycosylated hemoglobin (HbA1c) level less than 6.5% for at least 3 months after ceasing glucose-lowering pharmacotherapy.

Among 88 patients (60 males, 68.2%) diagnosed at an average age of 14.4±2.1 years, 19 patients (21.6%) achieved remission after a median duration of 1.4 years. The remission group had a larger proportion of males (89.5% vs. 62.3%, P=0.024) and a lower urinary albumin-to-creatinine ratio (ACR) at diagnosis (P=0.011). They also showed lower HbA1c levels at 1 year and more significant changes in HbA1c and body mass index (all P<0.05). Higher urinary ACR levels correlated with a longer duration to achieve remission (hazard ratio, 0.928; P=0.013). In three of the 19 remission patients (15.8%), recurrence occurred after a median of 1.5 years.

Among Korean youth with T2DM, 21.6% achieved remission after a median duration of 1.4 years. Those who experienced remission were predominantly male, had lower ACR at diagnosis, and had significant weight loss within the first year. Further investigation into the factors influencing remission and long-term outcomes is essential.

Most epidemiological studies ignore long-term burden, gain and variability in body weight in assessing cardiometabolic disease risk. We investigated the associations of body mass index (BMI) trajectories measured by general practitioners with incident type 2 diabetes (T2D) and coronary artery disease (CAD).

We used electronic healthcare data from 111,615 European-ancestry participants from UK Biobank (57.1 (SD 7.8) years, 59.6 % women) with at least three BMI measurements (median trajectory period: 14.9 [interquartile range 9.5, 20.1] years). We calculated six variables capturing different long-term aspects, including i.e. burden (long-term average, area under the curve), gain (slope) and variability (standard deviation, average of the [absolute] consecutive BMI differences). The variables were used in principal component (PC) analyses and k-means clustering. Newly-derived dimensions and subgroups were used as exposures in cox-proportional hazard models.

The BMI-trajectory indices were captured in two PCs reflecting BMI burden and BMI gain. The BMI-burden PC associated with higher T2D (hazard ratio [95 % confidence interval] per SD higher PC: 1.57 [1.55,1.60]) and CAD (1.17 [1.15,1.19]) risks, while weak or no associations were observed with the BMI-gain PC (T2D: 1.03 [1.01,1.05]; CAD: 1.01 [0.98,1.03]). Participants with the highest BMI burden, compared to those with lowest BMI burden without significant gain, had highest T2D (6.96 [6.41,7.55]) and CAD (1.57 [1.45,1.69]) risks. Both methods to capture BMI burden, gain and variability showed superior model fit compared to a single baseline BMI assessment.

Long-term high BMI burden, irrespective of BMI gain, was a risk factor for cardiometabolic disease.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by pathophysiological mechanisms such as insulin resistance and β-cell dysfunction. Recent advancements in T2DM research have unveiled intricate multi-level regulatory networks and contributing factors underlying this disease. The emergence of precision medicine has introduced new perspectives and methodologies for understanding T2DM pathophysiology. A recent study found that personalized treatment based on genetic, metabolic, and microbiome data can improve the management of T2DM by more than 30%. This perspective aims to summarize the progress in T2DM pathophysiological research from the past 5 years and to outline potential directions for future studies within the framework of precision medicine. T2DM develops through the interplay of factors such as gut microbiota, genetic and epigenetic modifications, metabolic processes, mitophagy, NK cell activity, and environmental influences. Future research should focus on understanding insulin resistance, β-cell dysfunction, interactions between gut microbiota and their metabolites, and the regulatory roles of miRNA and genes. By leveraging artificial intelligence and integrating data from genomics, epigenomics, metabolomics, and microbiomics, researchers can gain deeper insights into the pathophysiological mechanisms and heterogeneity of T2DM. Additionally, exploring the combined effects and interactions of these factors may pave the way for more effective prevention strategies and personalized treatments for T2DM.

To investigate the causal relationship between various lipid-modifying drugs and new-onset diabetes, as well as the mediators contributing to this relationship.

Mediation Mendelian randomization was performed to investigate the causal effect of lipid-modifying drug targets on type 2 diabetes (T2D) outcomes and the proportion of this association that is mediated through ectopic fat accumulation traits. Specific sets of variants in or near genes that encode 11 lipid-modifying drug targets (LDLR, HMGCR, NPC1L1, PCSK9, APOB, ABCG5/ABCG8, LPL, PPARA, ANGPTL3, APOC3, and CETP; for expansion of gene symbols, use search tool at www.genenames.org) were extracted. Random effects inverse variance weighted were performed to evaluate the causal effects among outcomes. Mediation analyses were performed to identify the mediators of the association between lipid-modifying drugs and T2D. The study was conducted from November 10, 2023, to April 2, 2024 RESULTS: The genetic mimicry of HMGCR and APOB inhibition was associated with an increased T2D risk, whereas the genetic mimicry of LPL enhancement was linked to a lower T2D risk. Gluteofemoral adipose tissue volume was a mediator for explaining 9.52% (P=.002), 16.90% (P=.03), and 10.50% (P=.003) of the total effect of HMGCR, APOB, and LPL on T2D susceptibility, respectively. Liver fat was a mediator for explaining 21.12% (P=.005), 12.28% (P=.03), and 9.84% (P=.005) of the total effect of HMGCR, APOB, and LPL on T2D susceptibility, respectively.

Our findings support the hypothesis that liver fat and gluteofemoral adipose tissue play a mediating role in the prodiabetic effects of HMGCR and APOB inhibition, as well as in the antidiabetic effects of LPL enhancement.

Ectopic fat is reduced by effective weight management, but difficult to assess clinically.

We evaluated paired data on 42 participants in the intervention group of the Diabetes Remission Clinical Trial (DiRECT) at baseline, 12 and 24 months after weight loss as indicators of liver fat content measured by 3-point Dixon MRI.

Baseline liver fat was elevated at 13.0 [7.8-23.3]% with fasting plasma glucose 7.9 [7.1-10.1] mmol/L. Prevalence of baseline MASLD was 86.4%. After weight loss of 11.9 ± 1.2 kg (0-37 kg) at 12 months, remission of MASLD occurred in 74% and liver fat normalised for many (1.8 [1.2-5.2]%; p < 0.0001) as did fasting glucose (5.9 [5.5-7.2] mmol/L; p < 0.0001). Alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) decreased at 12 months by 38 [19-60]% (p < 0·0001) and 38 [16-53]% (p < 0.0001) respectively. The positive predictive value for decrease in liver fat, with baseline values of >40 IU/L, was 100% for ALT and 87.5% for GGT. As expected, change in liver fat correlated with change in ALT (r = 0.64; p < 0.0001), GGT (r = 0.38; p = 0.013), AST (r = 0.36; p = 0.018), fatty liver index (r = 0.50; p < 0.0001) and hepatic steatosis index (r = 0.44; p < 0.0001).

Metabolic dysfunction-associated steatotic liver disease, an important marker of ill-health is improved by intentional weight loss. If enzyme levels are raised at baseline, following weight loss, changes in ALT and GGT usefully reflect change in liver fat content, with high positive predictive value. Monitoring liver enzymes can provide a simple way to assess change in liver fat following weight loss in day-to-day clinical practice.

Prediabetes is a highly prevalent and increasingly common condition affecting a significant proportion of the global population. The heterogeneous nature of prediabetes presents a challenge in identifying individuals who particularly benefit from lifestyle or other therapeutic interventions aiming at preventing type 2 diabetes (T2D) and associated comorbidities. The phenotypic characteristics of individuals at risk for diabetes are associated with both specific risk profiles for progression and a differential potential to facilitate prediabetes remission and reduce the risk of future T2D. This review examines the current definition and global prevalence of prediabetes and evaluates the potential of prediabetes remission to reduce the alarming increase in the global burden of T2D.

The development of magnetic resonance methods for quantifying intra-organ metabolites has permitted advances in the understanding of fasting and post-prandial carbohydrate and lipid handling in people with and without type 2 diabetes. Insulin resistance in the liver was shown to be related to excess intra-organ fat and was able to be returned to normal by weight loss. The practical effect of having muscle insulin sensitivity in the lower part of the wide normal range resulted in the obligatory shunting of carbohydrates via de novo lipogenesis into saturated fat. These observations provided the basis for the Twin Cycle Hypothesis of the aetiology of type 2 diabetes. Subsequent studies on people with type 2 diabetes confirmed the postulated pathophysiological abnormalities and demonstrated their reversibility by dietary weight loss of 10-15 kg. Overall, the fundamental understanding of the mechanisms causing type 2 diabetes has bridged physiological and clinical perspectives. Large population-based randomised controlled trials confirmed the practical clinical application of the method of achieving substantial weight loss, and an NHS programme is now in place offering potential remission to people within 6 years of diagnosis.

To assess the effect of dapagliflozin plus calorie restriction on remission of type 2 diabetes.

Multicentre, double blind, randomised, placebo controlled trial.

16 centres in mainland China from 12 June 2020 to 31 January 2023.

328 patients with type 2 diabetes aged 20-70 years, with body mass index >25 and diabetes duration of <6 years.

Calorie restriction with dapagliflozin 10 mg/day or placebo.

Primary outcome: incidence of diabetes remission (defined as glycated haemoglobin <6.5% and fasting plasma glucose <126 mg/dL in the absence of all antidiabetic drugs for at least 2 months); secondary outcomes: changes in body weight, waist circumference, body fat, blood pressure, glucose homoeostasis parameters, and serum lipids over 12 months.

Remission of diabetes was achieved in 44% (73/165) of patients in the dapagliflozin group and 28% (46/163) of patients in the placebo group (risk ratio 1.56, 95% confidence interval (CI) 1.17 to 2.09; P=0.002) over 12 months, meeting the predefined primary endpoint. Changes in body weight (difference -1.3 (95% CI -1.9 to -0.7) kg) and homoeostasis model assessment of insulin resistance (difference -0.8, -1.1 to -0.4) were significantly greater in the dapagliflozin group than in the placebo group. Likewise, body fat, systolic blood pressure, and metabolic risk factors were significantly more improved in the dapagliflozin group than in the placebo group. In addition, no significant differences were seen between the two groups in the occurrence of adverse events.

The regimen of dapagliflozin plus regular calorie restriction achieved a much higher rate of remission of diabetes compared with calorie restriction alone in overweight or obese patients with type 2 diabetes.

ClinicalTrials.gov NCT04004793.

With the elevated level of NAFLD prevalence, the incidence of diabetes, hypertension, metabolic syndrome and other diseases is also significantly elevated. GLP-1RA can exert weight loss, glucose-lowering effects and various nonglycaemic effects. However, the relationship between quantitative reduction in hepatic fat content and improvement of pancreatic islet function by GLP-1RA is unclear.

This trial was a single-arm open cohort study. A total of 38 patients with T2DM and NAFLD were enrolled in the GLP-1RA treatment group. The included patients were tested for biochemical and blood glucose levels, adiponectin and FGF21 levels, and liver fat content was measured using MRI. Measure the above indicators again after at least 3 months of GLP-1RA treatment. Divided into Q1 (average decrease of 0.37%) and Q2 (average decrease of 8.6%) groups based on the degree of reduction in liver fat content.

Q2 group showed an average reduction in liver fat content of 8.6%, a decrease in glycated haemoglobin of 18.17%, a weight loss of 7.29% and an increase in fasting c-peptide release by 1.03%, 1-h and 2-h postprandial c-peptide release by 28.86% and 18.28% respectively. In contrast, Q1 group had an average reduction in liver fat content of 0.37%, a decrease in glycated haemoglobin of only 6.53%, a weight loss of 3.41%, a decrease in fasting c-peptide release by 1.91% and an increase in 1-h and 2-h postprandial c-peptide release by 19.18% and 11.66% respectively.

Reduction in liver fat content effectively improves pancreatic islet function secretion, particularly postprandial c-peptide secretion, especially in the first hour after a meal. This improvement leads to a decrease in glycated haemoglobin levels and promotes better compliance with blood glucose control.

The objectives of the study were to (1) describe characteristics and lifestyle factors of individuals who have achieved type 2 diabetes (T2D) remission (sub-diabetes glucose levels without glucose-lowering medications for ≥3 months) through changes to diet and exercise behaviour in real-world settings; (2) investigate continuous glucose monitoring (CGM) profiles of these individuals and explore how dietary pattern may influence glucose regulation metrics. This cross-sectional study recruited individuals living with T2D who achieved remission via changes to diet or exercise behaviours. Various questionnaires were used to assess overall health and participants wore a blinded CGM for 14 days to assess glucose profiles and filled out 3-day food records. A total of 21 adults (57 ± 8 years of age) who were recently diagnosed with T2D (4 ± 3 years) with a A1c of 5.7 ± 0.4% volunteered to participate. Participants achieved remission through various means (e.g., combination of diet and exercxise/physical activity) and self-reported following different diets, including 52% following a low-carbohydrate or very low carbohydrate diet, 14% following a "ketovore/carnivore" diet, 10% using a meal replacement diet, 5% following Weight Watcher's diet, and 19% no defined dietary pattern. The 24 h average CGM glucose value was 5.0 [4.8-5.6] mmol/L (median [IQR]) with 92 [85-97]% of time spent in range (between 4.0 and 9.9 mmol/L). The 24 h average CGM glucose (r = 0.692; P = 0.001) and A1c (r = 0.470; P = 0.049) were correlated with the daily percentage of energy intake from carbohydrate. Remission of T2D appears achievable through various means, including adoption of different dietary approaches and a more active lifestyle underpinning the importance of a patient-centred care.

Previous studies have investigated the association between hepatic fat and intrapancreatic fat deposition (IPFD); however, results have been inconclusive. The presence of cardiometabolic factors in certain subpopulations could explain this discrepancy. The aim of the present study was to use moderation analyses to determine the conditions under which hepatic fat is associated with IPFD.

All participants underwent 3T abdominal magnetic resonance imaging (MRI) and spectroscopy. Hepatic fat and IPFD were manually quantified by independent raters. Moderation analyses were performed with adjustment for sex and ethnicity.

There were 367 participants included. Adjusted analyses of the overall cohort revealed that age, glycated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides were significant moderators (p < 0.05) of the association between hepatic fat and IPFD. Ranges of significance included age < 61 years, HbA1c < 45 mmol/mol, LDL-C < 157 mg/dL, HDL-C > 36 mg/dL, and triglycerides < 203 mg/dL.

The association between hepatic fat and IPFD is generally present in young and middle-aged adults with good cardiometabolic health, whereas the link between the two fat depots becomes uncoupled in older adults or individuals with cardiometabolic risk factors.

Pediatric non-alcoholic fatty liver disease (NAFLD) is a chronic steatosis of the liver associated with energy metabolism in children and adolescents, failure to intervene promptly can elevate the risk of developing hepatocellular carcinoma. Therefore, this study aimed to understand the underlying mechanism of pediatric NAFLD and investigate potential biomarkers and therapeutic targets.

We investigated genes using the GSE185051 data set related to energy metabolism from the GeneCards database, constructed protein-protein interaction network, identified hub genes and established networks representing interactions between these hub genes and miRNA, RNA-binding proteins, transcription factors, and drugs. Subsequently, we performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis, Gene Set Enrichment Analysis (GSEA), and immune infiltration analysis.

Our analysis identified 9 hub genes through the PPI network. The target molecules were identified through the interaction network between hub genes and miRNAs, RNA-binding proteins, transcription factors, and drugs. GO analysis revealed that hub genes were associated with oxidative stress responses and other pathways. KEGG analysis highlighted their involvement in pathways such as insulin resistance, among others. GSEA revealed that hub genes were highly enriched in pathways related to Omega-9 fatty acid synthesis, among others. Immune infiltration analysis suggested that mast cells and T follicular helper cells play significant roles in the pathogenesis of NAFLD.

We identified the hub genes in pediatric NAFLD closely related to energy metabolism. These findings offer the potential for identifying potential novel diagnostic biomarkers, and establishing therapeutic targets for pediatric NAFLD.

Numerous studies have suggested potential associations between maternal subclinical hypothyroidism (SCH) and adverse metabolic outcomes in offspring, however, the underlying mechanism remains unclear. In this study, we generated a maternal SCH mouse model by administering 50 ppm 6-propyl-2-thiouracil (PTU) in the drinking water of pregnant mice until delivery. This model was used to investigate the mechanisms influencing glucose metabolism in offspring. RNA sequencing (RNA-seq) revealed a substantial increase in ARRDC3 expression in the livers of the offspring of the SCH model mice, which may contribute to insulin resistance. Additionally, the phosphorylation levels of key proteins in the insulin signalling pathway, such as protein kinase B (Akt), glycogen synthase kinase 3 beta (GSK-3β), and Forkhead box protein O1 (FoxO1), were correspondingly reduced in the SCH offspring. Moreover, overexpression of ARRDC3 in Hepa1‒6 cells suppressed the Akt/GSK-3β/FoxO1 signalling pathway and increased the expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), which was consistent with the molecular changes observed in SCH offspring. Our results also indicated that the upregulation of ARRDC3 in SCH offspring may result from increased H3K27 acetylation of the ARRDC3 promoter region, driven by elevated expression of P300. Importantly, adequate L-T4 supplementation during pregnancy improved insulin sensitivity and reversed the molecular alterations in the insulin signalling pathway observed in SCH offspring. In conclusion, exposure to intrauterine SCH resulted in altering the P300-ARRDC3 axis in offspring and impaired insulin sensitivity by disrupting the Akt/GSK-3β/FoxO1 signalling pathway. Timely L-T4 supplementation during pregnancy is an effective strategy to prevent insulin resistance in offspring of SCH mothers. This study elucidates potential molecular mechanisms behind insulin resistance in SCH offspring and suggests novel therapeutic targets for treating metabolic disorders related to maternal SCH.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder associated with insulin resistance and ensuing dysglycemia, dyslipidemia, and inflammation. Owing to the putative metabolic benefits of curcumin-piperine combination, we explored the efficacy of this combination in improving cardiometabolic indices of patients with T2DM and hypertriglyceridemia. In this double-blind clinical trial, 72 patients with T2DM and hypertriglyceridemia were randomized to receive either a tablet containing 500 mg of curcuminoids plus 5 mg of piperine, or a matched placebo for 12 weeks. Anthropometric indices, blood pressure, glycemic indices, lipid profile, C-reactive protein (CRP), quality of life, and mood were evaluated at baseline and end of the study. After 12 weeks of intervention, the levels of triglycerides (p-value = 0.001) and fasting blood glucose (p-value = 0.004) were significantly reduced in the curcumin-piperine compared with the placebo group. CRP levels were marginally reduced in the curcumin-piperine compared with the placebo group (p-value = 0.081). In addition, energy/fatigue significantly increased in the curcumin-piperine group compared to the control group (p-value = 0.024). However, between-group comparisons showed no significant change in other parameters, including anthropometric indices (waist circumference and body mass index (BMI)), biochemical parameters (low-density lipoprotein (LDL-c), high-density lipoprotein (HDL-c), and insulin), HOMA-IR, blood pressure, quality of life, and DASS-21 items between the studied groups (p-value >0.05). The current study showed that curcumin-piperine supplementation can improve serum CRP, triglycerides, and glucose concentrations in patients with T2DM and hypertriglyceridemia.

Aggressive weight management in patients with type 2 diabetes mellitus has demonstrated numerous metabolic advantages, however, existing therapies for weight control have not reached satisfactory results. This study aimed to evaluate the efficacy and safety of acupuncture in the weight management of type 2 diabetes mellitus (T2DM) patients by using a randomized, sham-controlled clinical trial design.

In this single-blind randomized clinical trial, 102 overweight adult T2DM patients were randomized into two groups. The control group receives diet, exercise, and sham acupuncture intervention, whereas the acupuncture group receives diet and exercise and acupuncture intervention, both for 1 month. Body weight and other anthropometric and laboratory indices were assessed at baseline and endpoint, meanwhile, the body fat content and spontaneous brain activity were measured by functional magnetic resonance imaging(fMRI)as the exploratory outcomes.

No significant difference was observed between the studied parameters at the baseline. The body weight and BMI were significantly reduced both in the control and acupuncture groups after intervention, without statistical difference between the two groups. What's interesting is that compared to the control, the acupuncture group displayed a greater improvement in central fat tissue. It notes that the acupuncture group achieved significant liver fat content reduction than the sham acupuncture group. At the same time, the spontaneous brain activity in the occipital lobe and parietal lobe significantly increased in the acupuncture group.

One month of acupuncture treatment preferentially improved ectopic fat deposition and was accompanied by changes in brain activity compared with the control group, even before significant changes in total body weight had occurred. further studies of longer duration are necessary for validation.

The protocol of this clinical trial is registered at the Acupuncture-Moxibustion Clinical Trial Registry (AMCTR, http://www.acmctr.org/ , No. AMCTR-IOR-20000341).

To evaluate whether the intense simplified strategy, which comprises short term intensive insulin therapy (SIIT) followed by subsequent oral antihyperglycaemic regimens, could improve long term glycaemic outcomes in patients with newly diagnosed type 2 diabetes mellitus and severe hyperglycaemia.

Multicentre, open label, randomised trial.

15 hospitals in China between December 2017 and December 2020.

412 patients with newly diagnosed type 2 diabetes and significant hyperglycaemia (HbA1c ≥8.5%).

All randomised participants initially received SIIT for 2-3 weeks, followed by linagliptin 5 mg/day, metformin 1000 mg/day, combination linagliptin plus metformin, or lifestyle modification alone (control) for 48 weeks.

The primary outcome was the percentage of participants achieving HbA1c <7.0% at week 48 after SIIT. Secondary outcomes included glycaemic control, β cell function, and variations in insulin sensitivity.

412 participants were randomised. At baseline, the mean age was 46.8 (standard deviation 11.2) years, mean body mass index was 25.8 (2.9), and mean HbA1c was 11.0% (1.9%). At week 48, 80% (78/97), 72% (63/88), and 73% (69/95) of patients in the linagliptin plus metformin, linagliptin, and metformin groups, respectively, achieved HbA1c <7.0%, compared with 60% (56/93) in the control group (P=0.02 overall; P=0.003 for linagliptin plus metformin versus control; P=0.12 for linagliptin versus control; P=0.09 for metformin versus control). Additionally, 70% (68/97), 68% (60/88), and 68% (65/95) of patients in the linagliptin plus metformin, linagliptin, and metformin group, respectively, achieved HbA1c <6.5% compared with 48% (45/93) in the control group (P=0.005 overall; P=0.005 for linagliptin plus metformin versus control; P=0.01 for linagliptin versus control; P=0.008 for metformin versus control; all were significant after adjustment for multiple comparisons). Thus, compared with the control group, participants in the linagliptin plus metformin group were more likely to achieve HbA1c <7.0% at week 48 (odds ratio 2.78, 95% confidence interval 1.37 to 5.65; P=0.005). Moreover, the linagliptin plus metformin group showed the most significant improvement in fasting plasma glucose and β cell function indices. All treatments were well tolerated.

The intense simplified strategy using subsequent oral therapies post-SIIT, especially the linagliptin plus metformin combination, sustainably improved glycaemic control and β cell function in patients with newly diagnosed type 2 diabetes mellitus and severe hyperglycaemia. This approach offers a promising direction for decision making in the clinical management of type 2 diabetes mellitus.

ClinicalTrials.gov NCT03194945.

Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet β cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and β cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet β cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. There is currently no cure for T2D, but it can be prevented or in remission by lifestyle intervention and/or some medication. If prevention fails, holistic and personalized management should be taken as soon as possible through timely detection and diagnosis, considering target organ protection, comorbidities, treatment goals, and other factors in reality. T2D is often accompanied by other components of MDS, such as preobesity/obesity, metabolic dysfunction associated steatotic liver disease, dyslipidemia, which usually occurs before it, and they are considered as the upstream diseases of T2D. It is more appropriate to call "diabetic complications" as "MDS-related target organ damage (TOD)", since their development involves not only hyperglycemia but also other metabolic disorders of MDS, promoting an up-to-date management philosophy. In this review, we aim to summarize the underlying mechanism, screening, diagnosis, prevention, and treatment of T2D, especially regarding the personalized selection of hypoglycemic agents and holistic management based on the concept of "MDS-related TOD".

People with obesity and type 2 diabetes (T2D) have reduced life expectancy, partly explained by increased risk of cardiovascular diseases and cancer. Here, we examined whether 2-year diabetes remission after bariatric surgery or usual care is associated with long-term mortality.

This report includes 586 participants with obesity and concomitant T2D from the prospective Swedish Obese Subjects (SOS) cohort study; 338 underwent bariatric surgery and 248 received usual obesity care. At inclusion, age was 37-60 years and BMI ≥34 kg/m 2 in men and ≥38 kg/m 2 in women. Median follow-up was 26.2 years (interquartile range 22.7-28.7). Diabetes status was determined using self-reported data on diabetes medication and in-study measures of blood glucose and HbA1c. The study was cross-linked to Swedish national registers for data on morbidity, death, and emigration.

Overall, 284 participants, 71.9% of surgery and 16.5% of usual care patients were in remission at the 2-year examination. During follow-up, mortality rates were 16.6 deaths per 1000 person-years (95% CI: 13.7-20.1) in the remission subgroup and 26.0 deaths per 1000 person-years (95% CI:22.2-30.4) in the non-remission subgroup (adjusted hazard ratio (HR adj )=0.71, 95% CI:0.54-0.95, P =0.019). The adjusted median life expectancy in the remission subgroup was 2.5 years (95% CI:0.3-4.7) longer than in the non-remission subgroup. Specifically, remission was associated with decreased cardiovascular mortality (sub-HR adj =0.54, 95% CI: 0.35-0.85, P =0.008), but no detectable association with cancer mortality was found (sub-HR adj =1.06, 95% CI:0.60-1.86), P =0.841).

In this post-hoc analysis of data from the SOS study, patients who achieved short-term diabetes remission had increased life expectancy and decreased cardiovascular death over up to 32 years of follow-up. Future studies should confirm these findings.

The prevalence of overweight and obesity, and, consequently, associated comorbidities, is increasing significantly worldwide. The guidelines recommend a percentage of weight loss> 5% to achieve beneficial effects on metabolic comorbidities associated with obesity. Furthermore, greater weight losses (> 10%) produce more significant improvements, and may even produce remission of some of these comorbidities. In this chapter, we review the evidence of the effect of weight loss through different strategies (lifestyle intervention, pharmacological treatment, or bariatric surgery) on the main cardiometabolic pathologies associated with excess adipose tissue (type 2 diabetes, high blood pressure, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, inflammation, cardiovascular diseases, and mortality).

This study explored the mediating effect of diabetes on the relationship between nonalcoholic fatty liver disease (NAFLD) and atherosclerotic cardiovascular disease (ASCVD).

In this prospective community cohort study, 82 975 participants were enrolled, with the primary outcome being the incidence of new-onset ASCVD. Using the Cox proportional hazards model, the hazard ratio (HR) and 95% confidence interval (CI) for ASCVD occurrence were computed between NAFLD and non-NAFLD groups. The correlation between NAFLD and diabetes was assessed using a binary logistic regression model, and that between NAFLD, diabetes and ASCVD using a mediation model.

During follow-up, 9471 ASCVD cases were observed. Compared with individuals without NAFLD, those with NAFLD showed an increased ASCVD risk (HR: 1.424; 95% CI: 1.363-1.488; P < 0.001). Stratifying NAFLD based on metabolic subphenotypes revealed a higher ASCVD risk in the NAFLD combined with diabetes subgroup than in the non-NAFLD subgroup (HR: 1.960; 95% CI: 1.817-2.115; P < 0.001). NAFLD was positively associated with baseline diabetes (odds ratio: 2.983; 95% CI: 2.813-3.163; P < 0.001). Furthermore, NAFLD severity was positively correlated with diabetes risk. Mediation analysis indicated that diabetes partially mediated the effect of NAFLD on ASCVD incidence, accounting for 20.33% of the total effect.

NAFLD is an independent predictor of increased ASCVD risk, which may be slightly mediated by diabetes in patients with NAFLD. Evaluating NAFLD and diabetes may be crucial in the early screening and prevention of ASCVD.

Type 2 diabetes has long been thought to have heterogenous causes, even though epidemiological studies uniformly show a tight relationship with overnutrition. The twin cycle hypothesis postulated that interaction of self-reinforcing cycles of fat accumulation inside the liver and pancreas, driven by modest but chronic positive calorie balance, could explain the development of type 2 diabetes. This hypothesis predicted that substantial weight loss would bring about a return to the non-diabetic state, permitting observation of the pathophysiology determining the transition. These changes were postulated to reflect the basic mechanisms of causation in reverse. A series of studies over the past 15 years has elucidated these underlying mechanisms. Together with other research, the interaction of environmental and genetic factors has been clarified. This knowledge has led to successful implementation of a national programme for remission of type 2 diabetes. This Review discusses the paucity of evidence for heterogeneity in causes of type 2 diabetes and summarises the in vivo pathophysiological changes, which cause this disease of overnutrition. Type 2 diabetes has a homogenous cause expressed in genetically heterogenous individuals.

The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3-/- (Shn3-/-) mice with augmented osteoblast activity, we show Shn3-/-mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3-/-mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.

In recent years, there has been a gradual increase in the prevalence of obesity and type 2 diabetes mellitus (T2DM), with bariatric surgery remaining the most effective treatment strategy for these conditions. Vertical sleeve gastrectomy (VSG) has emerged as the most popular surgical procedure for bariatric/metabolic surgeries, effectively promoting weight loss and improving or curing T2DM. The alterations in the gastrointestinal tract following VSG may improve insulin secretion and resistance by increasing incretin secretion (especially GLP-1), modifying the gut microbiota composition, and through mechanisms dependent on weight loss. This review focuses on the potential mechanisms through which the enhanced action of incretin and metabolic changes in the digestive system after VSG may contribute to the remission of T2DM.

In diabetes mellitus, disordered glucose and lipid metabolisms precipitate diverse complications, including nonalcoholic fatty liver disease, contributing to a rising global mortality rate. Theaflavins (TFs) can improve disorders of glycolipid metabolism in diabetic patients and reduce various types of damage, including glucotoxicity, lipotoxicity, and other associated secondary adverse effects. TFs exert effects to lower blood glucose and lipids levels, partly by regulating digestive enzyme activities, activation of OATP-MCT pathway and increasing secretion of incretins such as GIP. By the Ca2+-CaMKK ꞵ-AMPK and PI3K-AKT pathway, TFs promote glucose utilization and inhibit endogenous glucose production. Along with the regulation of energy metabolism by AMPK-SIRT1 pathway, TFs enhance fatty acids oxidation and reduce de novo lipogenesis. As such, the administration of TFs holds significant promise for both the prevention and amelioration of diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is one of the most common diseases, and epigenetic modification N6-methyladenosine (m6A) is essential for transcriptional modulation involved in its development. However, the precise role and landscape of transcriptome-wide m6A alterations in molecular adaptations after physical exercise have yet to be fully elucidated.

Four-week-old male C57BL/6J mice received a high-fat diet (HFD) for 12 weeks to establish a diabetic state, and HFD mice were simultaneously subjected to physical exercise (HFD + EX). The hepatic RNA m6A methylome was examined, the conjoint MeRIP-seq and RNA-seq was performed, and the exercise-modulated genes were confirmed.

Physical exercise significantly ameliorates liver metabolic disorder and triggers a dynamic change in hepatic RNA m6A. By analyzing the distribution of m6A in transcriptomes, an abundance of m6A throughout mRNA transcripts and a pattern of conserved m6A after physical exercise was identified. It is noteworthy that conjoint MeRIP-seq and RNA-seq data revealed that both differentially methylated genes and differentially expressed genes were enriched in all stages of the PI3K-Akt signaling pathway, in particular the upstream nodes of this pathway, which are considered a valuable therapeutic target for T2DM. Moreover, in vivo and in vitro analyses showed that exercise-mediated methyltransferase Rbm15 positively regulated the expression of two upstream genes (Itga3 and Fgf21) in an m6A-dependent manner.

These findings highlight the pivotal role of the exercise-induced m6A epigenetic network and contribute insights into the intricate epigenetic mechanism underlying insulin signaling.

Achieving diabetes remission (HbA1c<48mmol/mol without the use of anti-diabetic medication for 3 months) might not assure restoration of a normal glycemic profile [fasting blood sugar level <5.6 mmol/L and Post-Prandial (PP) blood glucose <7.8mmol/L]. The study investigates the factors associated with OGTT clearance in patients under type 2 diabetes remission. Four hundred participants who achieved remission during a one-year online structured lifestyle modification program, which included a plant-based diet, physical activity, psychological support, and medical management (between January 2021 and June 2022), and appeared for the OGTT were included in the study. OGTT clearance was defined by fasting blood glucose < 5.6 mmol/L and 2-hour post-prandial blood glucose <7.8 mmol/L post-consumption of 75g glucose solution. Of the 400 participants, 207 (52%) cleared OGTT and 175 (44%) had impaired glucose tolerance (IGT). A shorter diabetes duration (<5 years) was significantly associated with OGTT clearance (p<0.05). Pre-intervention use of glucose-lowering drugs showed no association with OGTT clearance (p<0.1). Post-intervention, the OGTT-cleared group showed significantly higher weight loss (p<0.05) and a decrease in HbA1c compared to the IGT group (p<0.05). Improvement in Insulin resistance and β-cell function was also higher in the OGTT-cleared group compared to the IGT group (p<0.05). In conclusion, clearing the OGTT is a possibility for those achieving remission through lifestyle interventions. Higher weight loss, a shorter duration of diabetes, and improvement in insulin resistance were significantly associated with OGTT clearance in participants in remission. Future randomized controlled trials with longer follow-ups may help substantiate our findings.

Type 2 diabetes mellitus is a long-lasting endocrine disorder characterized by persistent hyperglycaemia, which is often triggered by an entire or relative inadequacy of insulin production or insulin resistance. As a result of resistance to insulin (IR) and an overall lack of insulin in the body, type 2 diabetes mellitus (T2DM) is a metabolic illness that is characterized by hyperglycaemia. Notably, the occurrence of vascular complications of diabetes and the advancement of IR in T2DM are accompanied by dysbiosis of the gut microbiota. Due to the difficulties in managing the disease and the dangers of multiple accompanying complications, diabetes is a chronic, progressive immune-mediated condition that plays a significant clinical and health burden on patients. The frequency and incidence of diabetes among young people have been rising worldwide. The relationship between the gut microbiota composition and the physio-pathological characteristics of T2DM proposes a novel way to monitor the condition and enhance the effectiveness of therapies. Our knowledge of the microbiota of the gut and how it affects health and illness has changed over the last 20 years. Species of the genus Eubacterium, which make up a significant portion of the core animal gut microbiome, are some of the recently discovered 'generation' of possibly helpful bacteria. In this article, we have focused on pathogenesis and therapeutic approaches towards T2DM, with a special reference to gut bacteria from ancient times to the present day.

It has long been known that some patients with type 2 diabetes (T2DM) can experience sustained metabolic improvement to near-normal levels of glycemia either spontaneously or after medical intervention. Now recognized as remission of diabetes, this intriguing state is currently more feasible than ever before due to profound advances in metabolic surgery, pharmacologic therapy, and regimens of lifestyle modification. This enhanced capacity to induce remission has revealed new pathophysiologic insights, including the presence of a reversible component of the pancreatic beta-cell dysfunction that otherwise drives the chronic progressive nature of T2DM. In doing so, it has changed the therapeutic landscape by offering new potential management objectives and considerations for patients and providers. However, the excitement around these developments must also be tempered by the sobering realities of our current understanding of remission, including the recognition that this condition may not be permanent (resulting in glycemic relapse over time) and that beta-cell function may not be normalized in the setting of remission. These limitations highlight both the many gaps in our current understanding of remission and the caution with which clinical discussions must be handled for clear patient-directed communication of the pros and cons of targeting this outcome in practice. In this mini-review, we consider this rapidly growing literature, including its implications and its limitations, and thereby seek to provide objective balanced perspectives on targeting remission of T2DM in current clinical care.

Although bariatric surgery is an effective treatment for type 2 diabetes by inducing weight loss and augmenting gut hormone secretion, the immediate effect on beta-cell function itself remains to be elucidated in type 2 diabetes. Therefore, a prospective, randomized trial was performed in 30 patients with insulin-treated type 2 diabetes and a body mass index ≥ 35 kg/m2. Patients were randomly assigned (1:1:1) to Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) in combination with protein-sparing modified fast (PSMF), or to PSMF alone. Eu- and hyperglycemic clamps were performed before and 3 weeks after surgery and/or PSMF initiation. The primary outcome was the evolution of insulin sensitivity and beta-cell function after surgery, calculated using the composite measures of glucose disposal rate, insulin secretion rate, and disposition index (DI). Results revealed that markers of insulin sensitivity increased similarly in all arms (p = 0.43). A higher marker for maximal beta-cell function was observed when comparing SG to PSMF (p = 0.007). The DI showed a clear positive evolution after RYGB and SG, but not after PSMF alone. Altogether, these findings indicate that bariatric surgery results in an immediate beta-cell function recovery in insulin-treated type 2 diabetes.