Diabetes Insulin Resistance Research Articles

Polygenic scores of diabetes-related traits in subgroups of type 2 diabetes in India: a cohort study.

A machine-learning approach identified five subgroups of diabetes in Europeans which included severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD) with partially distinct genetic aetiologies. We previously validated four of the non-autoimmune subgroups in people with young-onset type 2 diabetes (T2D) from the Indian WellGen study. Here, we aimed to apply European-derived centroids and genetic risk scores (GRSs) to the unselected (for age) WellGen to test their applicability and investigate the genetic aetiology of the Indian T2D subgroups. We applied European derived centroids and GRSs to T2D participants of Indian ancestry (WellGen, n=2217, 821 genotyped) and compared them with normal glucose tolerant controls (Pune Maternal Nutrition Study, n=461). SIDD was the predominant subgroup followed by MOD, whereas SIRD and MARD were less frequent. Weighted-GRS for T2D, obesity and lipid-related traits associated with T2D. We replicated some of the previous associations of GRS for T2D, insulin secretion, and BMI with SIDD and MOD. Unique to Indian subgroups was the association of GRS for (a) proinsulin with MOD and MARD, (b) liver-lipids with SIDD, SIRD and MOD, and (c) opposite effect of beta-cell GRS with SIDD and MARD, obesity GRS with MARD compared to Europeans. Genetic variants of fucosyltransferases were associated with T2D and MOD in Indians but not Europeans. The similarities emphasise the applicability of some of the European-derived GRSs to T2D and its subgroups in India while the differences highlight the need for large-scale studies to identify aetiologies in diverse ancestries. The data provide robust evidence for genetically distinct aetiologies for the T2D subgroups and at least partly mirror those seen in Europeans. Vetenskapsrådet, Diabetes Wellness, and Hjärt-Lungfonden (Sweden), DST (India), Wellcome Trust, Crafoord Foundation and Albert Påhlsson Foundation.

Lower skeletal muscle mass is associated with diabetes and insulin resistance: A cross-sectional study.

The association between skeletal muscle mass and diabetes incidence/insulin resistance/glycated hemoglobin (HbA1C) is unknown. The aim of this study was to investigate such association in clinically apparently healthy males and females. A cross-sectional study of 372,399 Korean males and females who completed bioelectrical impedance analysis (BIA) in a health-screening programme was performed. Skeletal muscle index was used as an indicator of skeletal muscle mass. Skeletal muscle index (%) [appendicular skeletal muscle mass (kg)/body weight (kg)X100] was estimated using BIA. The study outcomes were diabetes incidence, homoeostasis model assessment of insulin resistance (HOMA-IR), and HbA1C. The mean age of study participants was 38.92±8.54years. Multiple logistic regression analysis revealed a significant negative association between Skeletal muscle index and diabetes incidence/HOMA-IR/HbA1C after adjusting for various confounding factors. Odds ratios (95% confidence interval (CI)) of diabetes incidence in Q2, Q3, and Q4 compared to the lowest quantile (Q1) were 0.95 (0.85-1.05), 0.88 (0.78-0.99), and 0.79 (0.69-0.9), respectively. Beta coefficients (95% CI) of HOMA-IR in Q2, Q3, and Q3 with Q1 were 0.05 (0.03-0.07), -0.06 (-0.09∼-0.04), and -0.19 (-0.22∼-0.16), respectively. Beta coefficients (95% CI) of HbA1C in Q2, Q3, and Q4 with Q1 were 0.02 (0.01-0.03), -0.001 (-0.01∼0.01), and -0.02 (-0.03∼-0.01), respectively. This study demonstrated negative associations of skeletal muscle mass with diabetes incidence, insulin resistance, and HbA1C levels in healthy adults.

Effect of Canagliflozin Alone and in Combination with Metformin on Ovarian Histology of a Polycystic Ovary Syndrome Rat Model

<p><strong>Background and Objective:</strong> Canagliflozin reduces insulin resistance in diabetics and is hypothesized to produce a beneficial effect in polycystic ovarian syndrome (PCOS). Therefore, this study is planned to compare the effects of canagliflozin and metformin alone and in combination on ovarian histology of rat models with letrozole-induced PCOS.</p>
 <p><strong>Methods:</strong> It was a randomized experimental study on Sprague Dawley rats. A total of N = 40 female rats were divided randomly into six groups (A-F). With the exception of normal control group A, rats were given letrozole 1 mg/kg daily for 21 days till PCOS was induced. Group B was disease control, while rats in groups C-F were administered canagliflozin (10 mg/kg), metformin (100 mg/kg), a combination of canagliflozin (10 mg/kg) with metformin (100 mg/kg), and combination of canagliflozin (5 mg/kg) with metformin (50 mg/kg), respectively. Animals were sacrificed on the 48th day. Ovaries and uterus were removed, weighed, and processed for further histopathological analysis.</p>
 <p><strong>Results:</strong> All treatment groups showed significant improvement in ovarian histology. The number of primary and secondary follicles and cystic follicles was significantly lower (p < 0.001) in all treatment groups as compared to the disease control group.</p>
 <p><strong>Conclusion:</strong> Canagliflozin is effective for the treatment of PCOS and augments the effect of metformin in a rat model.</p>

346-OR: IL-10–Treated Adipose Stromal Vascular Fractions Reverse Insulin Resistance in a Type 2 Diabetes Mellitus Mouse Model

Low IL-10 production capacity is associated with type 2 diabetes. Targeting IL-10 in diabetes patients has resulted in inconsistent results. To test if IL-10-treated adipose stromal vascular fraction could be used to reverse diabetes-induced gluconeogenesis and insulin resistance, we purified stromal vascular fractions (SVFs) from adipose tissue from diabetic (Lepdb/db ) and nondiabetic (Lep+/+) mice, treated them with IL-10, and injected them into adipose tissue of diabetic mice. Injection of IL-10 into adipose tissue of diabetic mice decreased mRNA expression of IL-6 and IL-1β of adipose SVFs but did not change G6PC and PCK1 expression in liver. Injection of IL-10-treated SVFs into adipose tissue of diabetic mice significantly decreased CCL2 and IL-1β expression and increased IL-10 and Foxp3 expression of SVFs of Lepdb/db mice. Moreover, injection of IL-10-treated SVFs significantly increased IL-10 levels of adipose tissue and decreased G6PC and PCK1 and insulin resistance of liver in diabetic mice. Altogether, our data suggest that IL-10-treated adipose SVFs could be used to reverse diabetes-induced gluconeogenesis gene expression and insulin resistance in diabetes. These data suggest that modified-adipose stromal vascular fractions could be used as a promising cell therapy tool in alleviating insulin resistance in diabetes mellitus. Disclosure L. Chen: None. Funding National Science and Technology Council, Taiwan (110-2314-B-A49A-540-MY3)

432-P: Role of Patatin-Like Phospholipase Domain–Containing 3 Gene for Kidney Dysfunction in Diabetes Endotypes

Recent studies identified distinct endotypes of diabetes with differences in metabolic features and in risk for diabetes-related comorbidities. Of note, persons allocated to the severe insulin resistant diabetes (SIRD) endotype, who show increased prevalence of nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD), are more frequently carriers of the G-allele in the single-nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase domain containing 3 (PNPLA3) gene. This SNP associates with increased risk of NAFLD yet the association between the presence of the PNPLA3 SNP and CKD remains controversial. The present study examined whether this SNP differently associates with CKD in endotypes of recent-onset diabetes. Participants with newly diagnosed diabetes (n=707) from the prospective German Diabetes Study underwent k-means clustering, genotyping, magnetic resonance spectroscopy to determine hepatocellular lipid content (HCL) and laboratory analyses to calculate the glomerular filtration rates (eGFR). SIRD had the lowest eGFR and highest HCL compared to severe insulin deficient, moderate obesity-related, moderate age-related and severe autoimmune diabetes clusters (all p<0.05). HCL was negatively associated with eGFR (r=-0.287, p<0.01) across all groups. Further stratification by PNPLA3 G-allele carrier status did not reveal any association between HCL and eGFR in any of the diabetes types, irrespective of G-allele carrier status. However, with declining eGFR the proportion of G-allele carriers increased from 44% for eGFR >60 ml/min to 52% for eGFR <60 ml/min (p<0.05). In conclusion, increased hepatic lipid content is associated with reduced kidney function across all diabetes endotypes. This association is independent of the presence of the PNPLA3 polymorphism in newly diagnosed diabetes, but there might be role for PNPLA3 for the severity of CKD. Disclosure O.P. Zaharia: None. K. Strassburger: None. B. Knebel: None. Y. Kupriyanova: None. J. Kotzka: None. K. Bódis: None. M. Schön: None. M. Bombrich: None. C. Möser: None. K. Prystupa: Other Relationship; Berlin-Chemie AG. H. Al-Hasani: None. V. Schrauwen-Hinderling: None. K. Jandeleit-Dahm: None. R. Wagner: Speaker's Bureau; Novo Nordisk, Sanofi. Advisory Panel; Daiichi Sankyo. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis. Consultant; TARGET PharmaSolutions, Inc. Research Support; Sanofi. Funding German Research Foundation; European Foundation for the Study of Diabetes; German Diabetes Association; German Federal Ministry of Education and Research; Heinrich Heine University

1418-P: Identification and Follow-up of T2D by Subtypes and Their Cardiovascular Risk in Mexican Population—The Experience of the MIDO State Registry in Guanajuato

Type 2 diabetes (T2D) is a complex and heterogeneous disease that has been categorized based on its underlying physiological mechanisms to inform treatment strategies. However, patients with T2D often exhibit a wide range of phenotypic and metabolic profiles, and the subclassification of this disease has only recently been developed, enabling the possibility of personalized management and improved outcomes. The aim of this research was to identify and follow-up T2D subtypes and their cardiovascular risk (CVR) in the Mexican population. In this study, 14,124 patients with incident T2D were assessed to characterize their phenotypic and metabolic profiles and to identify their CVR as part of the MIDO State Registry in Guanajuato, Mexico between April 2014, and April 2022. Of the 14,124 patients with incident T2D, when clustered into subtypes according to their phenotypic and metabolic profile, 3,530 (24.9%) belonged to the mild age-related diabetes (MARD) subtype, 4,304 (30.5%) to the mild obesity-related diabetes (MOD), 3,180 (22.1%) to the severe autoimmune diabetes (SIRD), and 3,111 (11.5%) to the severe insulin-resistant diabetes (SIDD). When the CVR was assessed, 1,767 (50.1%) individuals had a medium CVR and 1,763 (49.9%) had a high CVR in the MARD, 3,313 (76.9%) had a medium CVR and 990 (23.1%) had a high CVR in the MOD, 1,699 (54.6%) had a medium CVR and 1,733 (45.4%) had a high CVR in the SIRD, and 2,290 (72.0%) had a medium CVR and 890 (27.9%) had a high CVR in the SIDD. Of the 13,192 patients that were followed for 6 months, up to 61.0% of the MARD, 61.4% of the MOD, 61.2% of the SIRD, and 40.9% of the SIDD achieved metabolic control (HbA1c <7%). Classifying the subtypes of T2D allows for the design of personalized treatment strategies aiming to delay the progression of the disease and prevent cardiovascular complications. In Mexico, this is a novel approach that seeks to improve the overall outcomes of patients with incident T2D. Disclosure H.Gallardo-rincón: None. R.Tapia-conyer: None. A.Montoya: None. L.Morales-juarez: None. M.J.Rios-blancas: None. D.Álvarez-hernández: None. L.Martinez-juarez: None. D.Diaz-martínez: None. F.Magos-vazquez: None. E.Vargas: None.

Four-Stage Evolution of Diabetes or Whole-Body Insulin Resistance (WBIR): Debunking of The Lipid-Induced Insulin Resistance (LIIR) and Proposing of the Glycation-Induced Insulin Resistance (GIIR)

Insulin resistance (IR) would develop first preferentially in the muscle tissue with a relatively low cell turnover and then progress in sequence to the subcutaneous adipose tissue, then to the visceral adipose tissue, and then to the liver with higher cell turnovers. Moreover, metabolic disruptions due to IR would vary widely from tissue to tissue, contrary to the widespread notion that IR impairs merely glucose uptake in tissues. This warrants that IR be divided better into four distinct tissue-specific IRs: muscle insulin resistance (MIR), subcutaneous adipose insulin resistance (s-AIR), visceral adipose insulin resistance (v-AIR), and hepatic insulin resistance (HIR). Tissue-specific IRs developing in the order of MIR, s-AIR, v-AIR, and HIR with uniquely tissue-specific metabolic disruptions would amount to nothing but the whole-body insulin resistance (WBIR) evolving in four distinctively insulin-resistant stages, IR-I to IR-IV stage. The four-staged metabolic evolution from rapid weight gain (IR-I stage) to visceral obesity (IR-II stage), then to rapid weight loss (IR-III stage), and then to full-blown diabetes (IR-IV stage) not only complies well with the natural development history of diabetes but also resolves many controversies regarding obesity or diabetes, including visceral obesity, obesity paradox, and dawn phenomenon that have long remained metabolic puzzles. In addition, the entrenched notion of the lipid-induced insulin resistance (LIIR), which is refuted by four-stage WBIR evolution and believed to be the main culprit for the current epidemic of obesity and diabetes around the world, was debunked thoroughly. Then, in order to replace the LIIR, the glycation-induced insulin resistance (GIIR) was proposed and verified to be compatible to the fourstage WBIR evolution.

Prediabetes as atherapeutic challenge in internal medicine

The term prediabetes describes afasting blood glucose level that is elevated but not yet in the diabetic range, ablood glucose level that is elevated after 120 min in astandard 75‑g oral glucose tolerance test, or both. The American Diabetes Association definition also includes glycated hemoglobinA (HbA1c). The incidence of prediabetes is rapidly increasing. Progression from normal glucose tolerance to diabetes is acontinuous process. Insulin resistance and insulin secretory dysfunction, the simultaneous presence of which characterizes manifest diabetes, are already present in the prediabetic stage. Prediabetes is associated with an increased risk of diabetes; however, by no means all people with prediabetes go on to develop diabetes. Nevertheless, the identification of an increased risk of diabetes is still relevant insofar as it requires the adoption of diabetes prevention measures. Structured lifestyle intervention has been shown to be the most effective strategy for treating prediabetes. To increase its efficiency, it should, as far as possible, be made exclusively available to those people on whom it is most likely to confer abenefit. This would make it necessary to stratify people with prediabetes according to their risk profile. In apopulation of people at increased risk of diabetes (Tübingen Diabetes Family Study), acluster analysis was performed, resulting in six clusters/subgroups. Within these, three high-risk subgroups were identified: Two of these risk groupsshow predominant insulin secretory dysfunction or predominant insulin resistance and high diabetes and cardiovascular risk. The third group shows ahigh risk of nephropathy and high mortality, but acomparatively lower diabetes risk. In general, prediabetes cannot yet be treated in atargeted pathophysiologically oriented manner. The new classification of prediabetes-based on pathophysiology-is now opening up new avenues for diabetes prevention. Current and future studies should confirm the assumption that the effectiveness of established, or not yet established, preventive measures depends on the respective subgroup.

A polysaccharide NAP-3 from Naematelia aurantialba: Structural characterization and adjunctive hypoglycemic activity

A novel polysaccharide (NAP-3) was isolated and purified from Naematelia aurantialba after water extraction. The structure of NAP-3, which was determined by FT-IR, HPLC, GC–MS, and NMR, indicated that NAP-3 was a homogeneous polysaccharide with the molecular weight of 428 kDa, mainly consisted of β-1, 3-D-Manp, β-1, 2, 3-D-Manp, β-D-Xylp, β-1, 4-D-Glcp, β-1, 4-D-Rhap in a molar ratio of 6.49: 1.11: 2.4: 0.13: 0.83. In vitro α-glucosidase and α-amylase inhibitory assay showed that NAP-3 had a low IC50 value, which exhibited similar enzyme inhibitory activity as acarbose. NAP-3 was evaluated as an adjuvant with metformin for antidiabetic therapy in HFD/STZ-induced diabetic mice and insulin resistance HepG2 cells. The combination of NAP-3 and metformin in diabetic mice exhibited significant hypoglycemic activity, reducing body weight, serum insulin levels, glucose tolerance, insulin tolerance, and increasing antioxidant levels compared to metformin alone. The combination of NAP-3 and metformin improved oxidative stress by increasing ROS clearance, thereby enhancing glucose uptake in HepG2 cells. This study provided new data for the study of Naematelia aurantialba polysaccharides and offers a new adjuvant therapy for the treatment of diabetes.

Nutritional Modulation of Dietary Sugars as a Strategy to Improve Insulin Resistance and Energy Balance in Diabetes

Lifestyle changes and less healthy behaviours include dietary changes toward increased consumption of Westernised diets and processed food [...]

The Triglyceride Glucose (TyG) Index as a Sensible Marker for Identifying Insulin Resistance and Predicting Diabetic Kidney Disease.

BACKGROUND Patients with insulin-resistant diabetes have the highest risk of kidney disease. The triglyceride glucose (TyG) index is considered a reliable and simple marker of insulin resistance. We studied the relationship between the TyG index, diabetic kidney disease (DKD), and related metabolic disorders in patients with type 2 diabetes. MATERIAL AND METHODS This retrospective study included a consecutive case series from January 2021 to October 2022 in the Department of Endocrinology at Hebei Yiling Hospital. In total, 673 patients with type 2 diabetes met the inclusion criteria. The TyG index was calculated by napierian logarithmic (ln) (fasting triglyceride×fasting glucose /2). Patient demographic and clinical indicators were obtained from medical records, and statistical analysis was conducted using SPSS version 23. RESULTS The TyG index was significantly related to metabolic indicators (low-density lipoprotein, high-density lipoprotein, alanine aminotransferase, plasma albumin, serum uric acid, triglyceride, and fasting glucose) and urine albumin (P<0.01) but not with serum creatinine and estimated glomerular filtration rate. In multiple regression analysis, an increase in the TyG index was revealed to be an independent risk factor for DKD (OR: 1.699, P<0.001). CONCLUSIONS The TyG index was independently related to DKD and related metabolic disorders; therefore, the TyG index can be used as an early sensitive target for clinical guidance in the treatment of DKD with insulin resistance.

Regulation and mechanism of action of miRNAs on insulin resistance in skeletal muscles.

The term "insulin resistance" is commonly understood as a decrease in the response of insulin-sensitive tissues to insulin at its sufficient concentration, leading to chronic compensatory hyperinsulinemia. Type 2 diabetes mellitus is based on mechanisms consisting in the development of resistance to insulin in target cells (hepatocytes, adipocytes, skeletal muscle cells), resulting in the termination of an adequate response of these tissues to interaction with insulin. Since in healthy people 75-80% of glucose is utilized by skeletal muscle, it is more likely that the main cause of insulin resistance is impaired insulin-stimulated glucose utilization by skeletal muscle. With insulin resistance, skeletal muscles do not respond to insulin at its normal concentration, thereby determining an increase in glucose levels and a compensatory increase in insulin production in response to this. Despite many years of studying diabetes mellitus (DM) and insulin resistance, the molecular genetic basis for the development of these pathological conditions is still the subject of numerous studies. Recent studies point to the involvement of microRNAs (miRNAs) as dynamic modifiers in the pathogenesis of various diseases. MiRNAs are a separate class of RNA molecules that play a key role in the post-transcriptional regulation of gene expression. Recent studies have shown that miRNAs dysregulation in DM is closely related to miRNAs regulatory abilities in skeletal muscle insulin resistance. This gave grounds to consider an increase or decrease in the expression of individual microRNAs in muscle tissue and consider them as new biomarkers for diagnosing and monitoring insulin resistance and promising directions for targeted therapy. This review presents the results of scientific studies examining the role of miRNAs in skeletal muscle insulin resistance.

Non-Alcoholic Fatty Liver Disease: Current Concepts of a Silent, but Potentially Reversible Disorder

Non-alcoholic fatty liver disease (NAFLD) is a chronic condition characterized by the accumulation of triglycerides in the liver of individuals who consume little to no alcohol. NAFLD is akin to metabolic syndrome, obesity, type 2 diabetes mellitus, insulin resistance, and dyslipidemia, which contribute as crucial risk factors for the appearance and further progression of the disease. NAFLD is also the most common etiology of chronic liver disease worldwide. The high prevalence of this liver complication is estimated to be driven by obesity and diabetes. A recent meta-analysis found the global prevalence of NAFLD in type 2 diabetes as high as 55.5%. NAFLD is a complex disorder with multifactorial etiology and pathophysiology. The progression of NAFLD can lead to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis or liver cancer. The exact cause of NAFLD is not fully understood, but it is believed to result from the interaction between genetic, environmental, and metabolic factors. The clinical presentation, including symptoms and signs associated with NAFLD, varies depending on the stage or progression of liver damage. In non-alcoholic fatty liver, the clinical presentation is often asymptomatic in its early stages. They may also present with nonspecific symptoms such as fatigue, malaise, or mild right upper abdominal discomfort. The diagnosis is made with a combination of clinical history, laboratory tests, and imaging studies tailored to the liver. The cornerstone of treatment involves implementing lifestyle changes. These include adopting a healthy diet, engaging in regular physical activity, losing weight, and quitting smoking. A small percentage of patients with NAFLD will develop Non-alcoholic steatohepatitis (NASH), associated with faster liver disease progression. Fibrosis development seems to occur more often in patients with NASH and is an essential histological feature associated with its mortality. Mortality rates vary among different subgroups of patients, with variables such as age, comorbidities, and severity of liver disease playing an important role. This narrative review comprehensively overviews this silent but potentially harmful condition.

Epigenetic and transcriptomic alterations in the ClC-3-deficient mice consuming a normal diet.

Introduction: Metabolic disorders are an important health concern that threatens life and burdens society severely. ClC-3 is a member of the chloride voltage-gated channel family, and ClC-3 deletion improved the phenotypes of dysglycemic metabolism and the impairment of insulin sensitivity. However, the effects of a healthy diet on transcriptome and epigenetics in ClC-3-/- mice were not explained in detail. Methods: Here, we performed transcriptome sequencing and Reduced Representation Bisulfite Sequencing for the liver of 3 weeks old WT and ClC-3-/- mice consuming a normal diet to insight into the epigenetic and transcriptomic alterations of ClC-3 deficient mice. Results: In the present study, we found that ClC-3-/- mice that were younger than 8 weeks old had smaller bodies compared to ClC-3+/+ mice with ad libitum self-feeding normal diet, and ClC-3-/- mice that were older than 10 weeks old had a similar body weight. Except for the spleen, lung, and kidney, the average weight of the heart, liver, and brain in ClC-3-/- mice was lower than that in ClC-3+/+ mice. TG, TC, HDL, and LDL in fasting ClC-3-/- mice were not significantly different from those in ClC-3+/+ mice. Fasting blood glucose in ClC-3-/- mice was lower than that in ClC-3+/+ mice; the glucose tolerance test indicated the response to blood glucose increasing for ClC-3-/- mice was torpid, but the efficiency of lowering blood glucose was much higher once started. Transcriptomic sequencing and reduced representation bisulfite sequencing for the liver of unweaned mice indicated that ClC-3 deletion significantly changed transcriptional expression and DNA methylation levels of glucose metabolism-related genes. A total of 92 genes were intersected between DEGs and DMRs-targeted genes, of which Nos3, Pik3r1, Socs1, and Acly were gathered in type II diabetes mellitus, insulin resistance, and metabolic pathways. Moreover, Pik3r1 and Acly expressions were obviously correlated with DNA methylation levels, not Nos3 and Socs1. However, the transcriptional levels of these four genes were not different between ClC-3-/- and ClC-3+/+ mice at the age of 12 weeks. Discussion: ClC-3 influenced the methylated modification to regulate glucose metabolism, of which the gene expressions could be driven to change again by a personalized diet-style intervention.

A machine learning-based classification of adult-onset diabetes identifies patients at risk of liver-related complications

Diabetes mellitus is a major risk factor for fatty liver disease development and progression. A novel machine learning method identified five clusters of patients with diabetes, with different characteristics and risk of diabetic complications using six clinical and biological variables. We evaluated whether this new classification could identify individuals with an increased risk of liver-related complications. We used a prospective cohort of patients with a diagnosis of type 1 or type 2 diabetes without evidence of advanced fibrosis at baseline recruited between 2000 and 2020. We assessed the risk of each diabetic cluster of developing liver-related complications (i.e. ascites, encephalopathy, variceal haemorrhage, hepatocellular carcinoma), using competing risk analyses. We included 1,068 patients, of whom 162 (15.2%) were determined to be in the severe autoimmune diabetes subgroup, 266 (24.9%) had severe insulin-deficient diabetes, 95 (8.9%) had severe insulin-resistant diabetes (SIRD), 359 (33.6%) had mild obesity-related diabetes, and 186 (17.4%) were in the mild age-related diabetes subgroup. In multivariable analysis, patients in the SIRD cluster and those with excessive alcohol consumption at baseline had the highest risk for liver-related events. The SIRD cluster, excessive alcohol consumption, and hypertension were independently associated with clinically significant fibrosis, evaluated by liver biopsy or transient elastography. Using a simplified classification, patients assigned to the severe and mild insulin-resistant groups had a three- and twofold greater risk, respectively, of developing significant fibrosis compared with those in the insulin-deficient group. A novel clustering classification adequately stratifies the risk of liver-related events in a population with diabetes. Our results also underline the impact of the severity of insulin resistance and alcohol consumption as key prognostic risk factors for liver-related complications. Diabetes represents a major risk factor for NAFLD development and progression. This study examined the ability of a novel machine-learning approach to identify at-risk diabetes subtypes for liver-related complications. Our results suggest that patients that had severe insulin resistance had the highest risk of liver-related outcomes and fibrosis progression. Moreover, excessive alcohol consumption at the diagnosis of diabetes was the strongest risk factor for developing liver-related events.

Response to insulin glargine 100 U/mL treatment in newly-defined subgroups of type 2 diabetes: Post hoc pooled analysis of insulin-naïve participants from nine randomised clinical trials

AimsTo assess insulin glargine 100 U/mL (IGlar-100) treatment outcomes according to newly-defined subgroups of type 2 diabetes mellitus (T2DM). MethodsInsulin-naïve T2DM participants (n = 2684) from nine randomised clinical trials initiating IGlar-100 were pooled and assigned to subgroups “Mild Age-Related Diabetes (MARD)”, “Mild Obesity Diabetes (MOD)”, “Severe Insulin Resistant Diabetes (SIRD)”, and “Severe Insulin Deficient Diabetes (SIDD)”, according to age at onset of diabetes, baseline HbA1c, BMI, and fasting C-peptide using sex-specific nearest centroid approach. HbA1c, FPG, hypoglycemia, insulin dose, and body weight were analysed at baseline and 24 weeks. ResultsSubgroup distribution was MARD 15.3 % (n = 411), MOD 39.8 % (n = 1067), SIRD 10.5 % (n = 283), SIDD 34.4 % (n = 923). From baseline HbA1c 8.0–9.6% adjusted least square mean reductions after 24 weeks were similar between subgroups (1.4–1.5 %). SIDD was less likely to achieve HbA1c < 7.0 % (OR: 0.40 [0.29, 0.55]) than MARD. While the final IGlar-100 dose (0.36 U/kg) in MARD was lower than in other subgroups (0.46–0.50 U/kg), it had the highest hypoglycemia risk. SIRD had lowest hypoglycemia risk and SIDD exhibited greatest body weight gain. ConclusionsIGlar-100 lowered hyperglycemia similarly in all T2DM subgroups, but level of glycemic control, insulin dose, and hypoglycemia risk differed between subgroups.

The catabolism of bilirubin to urobilin might be a leading factor in obesity-induced insulin resistance: New findings in human studies

For unknown reasons, plasma bilirubin levels are lower in obese humans and rodents. One possible explanation is that the hepatic expression of enzymes that regulate its half-life, such as the UGT1A1 UDP-glucuronosyltransferase, is higher in the obese compared to lean persons. Bilirubin is marked for excretion within the liver by the conjugation of two glucuronyl groups by UGT1A1, where it is then transported to the intestines by the biliary system. Once in the intestines, the gut microbiota containing bilirubin reductase remove the glucornyl groups and modify the structure to produce urobilin which can be absorbed via the hepatic portal vein and enter the systemic circulation. Previous correlation studies indicate that urobilin might be a factor that induces visceral obesity and cardiovascular disease. However, the physiological function of urobilin is unknown. The purpose of our study was to determine if there is a correlation between bilirubin and urobilin compared to adiposity and insulin resistance in lean and obese women and men. We hypothesized that bilirubin would be lower and urobilin higher in the plasma of obese humans compared to lean. We found that the plasma levels of urobilin and bilirubin are inversely correlated in women and men. Urobilin levels were positively associated with adiposity (BMI R 2 =0.29 and body fat percentage R 2 =0.25) and insulin resistance (blood glucose R 2 =0.05, insulin R 2 =0.22, and HOMA IR R 2 =0.18) in obese women. Urobilin was only correlated with adiposity in males (BMI R 2 =0.025 and body fat percentage R 2 =0.03). However, the males were not insulin resistant and had no significant difference in HOMA IR compared to lean men. In both women (BMI R 2 =0.065 and body fat percentage R 2 =0.05) and men (BMI R 2 =0.24 and body fat percentage R 2 =0.13), plasma bilirubin levels were negatively associated with adiposity. We observed that plasma bilirubin levels are negatively associated with adiposity, which has been previously reported. The new findings in our study indicate that urobilin is positively associated with adiposity and insulin resistance. Based on these data, we propose that bilirubin and urobilin are maintained at inverse levels in humans via the UGT1A1 axis and that activity is higher in the obese, reducing plasma bilirubin and providing more substrates to produce urobilin in the gut. These events cause an elevation in plasma urobilin levels that commence obesity-associated comorbidities. Future work to determine the role of urobilin in obesity-associated comorbidities such as insulin-resistant diabetes is warranted and may provide a biomarker for the early This work was supported by the National Institutes of Health R01DK121797 (T.D.H.J.). The sample collection was supported by the Center for Clinical and Translational Science (CCTS) grant UL1TR001998 at the University of Kentucky. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Metabolic Syndrome Puzzles; Possible Pathogenesis and Management.

Metabolic syndrome is a multifactorial pathophysiological process with complicated homeostatic disorders that arise from various systematic metabolic defects. Various theories underlie the development of metabolic syndrome but are fully not understood. Revising PubMed and Scopus literature data on metabolic syndrome pathogenesis and management. The most accepted hypothesis is that a cluster of risk factors combined to obtain a truly metabolic syndrome. The pathophysiology of the metabolic syndrome depends on the underlying development path due to insulin resistance or chronic inflammation and is usually combined with neurohormonal disturbance. Meanwhile, these defects can be inherited via loss of function of certain genes that lead to severe obesity, early diabetes, or severe insulin resistance (with or without lipodystrophy). Chronic inflammation is also a driver of metabolic syndrome. Lifestyle is still the therapy of choice in managing metabolic syndrome, but unfortunately, during the lockdown, most people could not reserve a healthy regime; therefore, it can also be referred to as a pandemic with COVID-19. This powerful illustration shows how defects in specific encoded proteins located predominantly in the brain, pancreatic beta-cell, muscle, or fat give rise to these distinct components of the metabolic syndrome. Primarily, obesity and its sequela are the initiators of metabolic syndrome. The presence of metabolic syndrome increases the risk and severity of other pathologies' emergence, even in non-related metabolic syndrome diseases such as COVID-19. The article provides new insights into the pathogeneses and management of the metabolic syndrome.

Role of obesity related inflammation in pathogenesis of peripheral artery disease in patients of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) has emerged as one of the greatest global health challenges of twenty-first century. Visceral obesity is one of the most important determinant of insulin resistance (IR) as well as T2DM complications. Therefore this review focuses on the molecular mechanism of obesity induced inflammation, signaling pathways contributing to diabetes, as well as role of lifestyle interventionsand medical therapies in the prevention and management of T2DM. Articles were searched on digital data base PubMed, Cochrane Library, and Web of Science. The key words used for search included Type 2 diabetes mellitus, obesity, insulin resistance, vascular inflammation and peripheral arterial disease. Visceral obesity is associated with chronic low grade inflammation and activation of immune systems which are involved in pathogenesis of obesity related IR and T2DM. Metabolic dysregulation of adipose tissue leads to local hypoxia, misfolded/unfolded protein response and increased circulating free fatty acids, which in turn initiate inflammatory signaling cascades in the population of infiltrating cells. Mechanism that relates the role of adipocytokines with insulin sensitivity and glucose homeostasis might throw a light on the development of therapeutic interventions and subsequently might result in the reduction of vascular complications.

The Pathogenesis of Diabetes.

Diabetes is the most common metabolic disorder, with an extremely serious effect on health systems worldwide. It has become a severe, chronic, non-communicable disease after cardio-cerebrovascular diseases. Currently, 90% of diabetic patients suffer from type 2 diabetes. Hyperglycemia is the main hallmark of diabetes. The function of pancreatic cells gradually declines before the onset of clinical hyperglycemia. Understanding the molecular processes involved in the development of diabetes can provide clinical care with much-needed updates. This review provides the current global state of diabetes, the mechanisms involved in glucose homeostasis and diabetic insulin resistance, and the long-chain non-coding RNA (lncRNA) associated with diabetes.