Insulin-resistant Diabetes Mellitus Research Articles

Liver ChREBP deficiency inhibits fructose-induced insulin resistance in pregnant mice and female offspring

High fructose intake during pregnancy increases insulin resistance (IR) and gestational diabetes mellitus (GDM) risk. IR during pregnancy primarily results from elevated hormone levels. We aim to determine the role of liver carbohydrate response element binding protein (ChREBP) in insulin sensitivity and lipid metabolism in pregnant mice and their offspring. Pregnant C57BL/6J wild-type mice and hepatocyte-specific ChREBP-deficient mice were fed with a high-fructose diet (HFrD) or normal chow diet (NC) pre-delivery. We found that the combination of HFrD with pregnancy excessively activates hepatic ChREBP, stimulating progesterone synthesis by increasing MTTP expression, which exacerbates IR. Increased progesterone levels upregulated hepatic ChREBP via the progesterone-PPARγ axis. Placental progesterone activated the progesterone-ChREBP loop in female offspring, contributing to IR and lipid accumulation. In normal dietary conditions, hepatic ChREBP modestly affected progesterone production and influenced IR during pregnancy. Our findings reveal the role of hepatic ChREBP in regulating insulin sensitivity and lipid homeostasis in both pregnant mice consuming an HFrD and female offspring, and suggest it as a potential target for managing gestational metabolic disorders, including GDM.

Obesity and Acanthosis Nigricans as the Clinical Markers of Insulin Resistance and Type-2 Diabetes Mellitus in Young Patients; A Case Report of Two Cases

Two young girls, aged 11 and 12 years, presented with obesity and Acanthosis Nigricans. They were found to have severe insulin resistance and type-2 diabetes mellitus. Anti-glutamic acid decarboxylase and anti-islet cell antibodies were negative. Tests for hypothyroidism and Cushing’s syndrome were negative. They were managed with lifestyle modification and metformin.

Bioinformatics analysis of the diversity of gut microbiota and different microbiota on insulin resistance in diabetes mellitus patients

IntroductionIt aimed to explore the diversity of gut microbiota (GM) and the effect of different microbiota on insulin resistance in diabetes mellitus (DM) patients through bioinformatics analysis. Material and Method: Microarray data were obtained from GEO database. GM samples from DM patients and healthy controls were collected, and 16S rRNA gene sequencing was carried out adopting high-throughput sequencing technology. The differential expression genes were screened using the Qlucore Omics Explorer 3.0 software. Subsequently, online tools such as STRING and DAVID were utilized for bioinformatics analysis of the differential expression genes. The differences in bacterial diversity between DM patients and healthy controls were evaluated by analyzing the diversity indicators of the microbiota, such as Shannon and Chao1 indexes. Differential abundance and functional prediction analysis were adopted to explore the different microbiota and its possible metabolic pathways between DM patients and controls. And differences in insulin resistance in specific bacterial taxa were analyzed. Result: GM diversity between DM patients and controls had significant differences. GM diversity was lower in DM patients compared with controls, as indicated by a decrease in Shannon and Chao1 indexes. The differential abundance analysis showed that there were multiple different bacterial communities between DM patients and controls, including some bacterial communities at the genus-level. Functional prediction analysis also revealed potential metabolic pathways related to GM and insulin resistance in DM patients. HEXB, ZC3H12A, CCR, CXCR3, GBR10, CDK9, TXN, IGFBP3, PDHA1, and NDUFB3 genes may be potential targets for treatment. Conclusion: There are differences in GM diversity between DM patients and healthy controls, and the different microbiota may be related to the occurrence and development of insulin resistance.

Tartary buckwheat root polysaccharides ameliorate non-alcoholic fatty liver disease via the IL6-SOCS3-SREBP1c pathway.

Our previous study demonstrated that Tartary buckwheat root polysaccharides (TBRP) could reduce insulin resistance in diabetes mellitus by inhibiting SOCS3-stimulated IRS1 protein degradation. However, whether TBRP has the efficiency to treat non-alcoholic fatty liver disease (NAFLD) is still undetermined. This investigation aimed to examine the effects of TBRP on a high-fat diet (HFD)-triggered NAFLD, and elucidate the underlying molecular mechanisms. Briefly, TBRP toxicity in hepatoma (BEL7404) and pancreatic cancer (BxPC3) cells and zebrafish embryos developmental models, were evaluated in-vitro and in-vivo, respectively. TBRP inhibited cellular lipid accumulation by suppressing fat synthesis, furthermore, it improved body weight gain, liver weight, liver-to-body weight ratio, serum lipids triglyceride, total cholesterol, ALT, LDL-C, HDL-C, and AST levels in the NAFLD mice model. Additionally, TBRP treatment also lowered the nitric oxide content. The qPCR assay revealed that mRNA expression of TNF, IL1β, and IL6 was also markedly reduced in TBRP-treated NAFLD mice. The expression of SOCS3, SREBP1c, and STAT3 was elucidated by western blot analysis, which indicated that TBRP markedly decreased the gene expression for de novo fat synthesis by the SOCS3-SREBP1c pathway. These findings reveal that TBRP ameliorates NAFLD via the IL6-SOCS3-SREBP1c signaling pathway and therefore, may represent a promising approach for NAFLD treatment.

Gremlin-1 in pregnancy and postpartum: relation to the fatty liver index, markers of bone health, glucose metabolism and gestational diabetes mellitus status

IntroductionGremlin-1 is a peptide that functions as an antagonist to bone morphogenic proteins and is overexpressed in obesity and type 2 diabetes mellitus. Gremlin-1 has not yet been investigated in pregnancy, pregnancy-related insulin resistance or gestational diabetes mellitus (GDM).Patients and methodsGremlin-1 levels were measured throughout the pregnancy of 58 women at high risk for GDM at the Medical University of Vienna. Furthermore, an oral glucose tolerance test, fasting insulin, fasting glucose, sex hormones, blood lipids, liver and renal parameters, and markers of bone development were evaluated at two points during pregnancy (< 20 weeks of gestation (GW), GW 24–28) and 12–14 weeks postpartum.ResultsGremlin-1 levels decreased from < 20 GW (mean = 9.2 pg/ml, SD = 8.4 pg/ml) to GW 24–28 (mean = 6.7 pg/ml, SD = 5.7 pg/ml, p = 0.033) and increased again postpartum, albeit not significantly (mean = 10.7 pg/ml, SD = 13.1 pg/ml, p = 0.339). During pregnancy, Gremlin-1 levels correlated negatively with osteocalcin and procollagen type I aminoterminal propeptide (P1NP), markers of bone health. Concerning glucose metabolism, Gremlin-1 levels were inversely related to the Insulinogenic Index at GW < 20. However, Gremlin-1 levels were not significantly different between women with normal glucose tolerance and GDM during pregnancy. Postpartum, Gremlin-1 was associated with the fatty liver index, osteocalcin levels, diastolic blood pressure and weight.ConclusionGremlin-1 levels decreased significantly during pregnancy. The biomarker is not related to GDM status, but correlates negatively with the Insulinogenic Index, an index related to beta cell function.Trial Registry Number ACTRN12616000924459.

Maternal obesity-related placental dysfunction: From peri-conception to late gestation

Obesity is a global epidemic with alarmingly high prevalence rates worldwide. The increasing incidence of obesity among reproductive age women, which progresses to obesity in pregnancy is of particular concern. A successful pregnancy is dependent on the balanced interaction between maternal cardiometabolic function, genetic predisposition, and optimal placental development. Maternal obesity, both pre-pregnancy and gestational, has been associated with adverse outcomes including poor fetal development, stillbirth, preterm birth, and metabolic complications later in life. To gain a more comprehensive understanding of the mechanistic interplay of key mediators of obesity-associated placental dysfunction and adverse pregnancy outcomes, we conducted a review of 24 studies that investigated placental dysfunction and maternal obesity retrieved from MEDLINE, LILACS and EMBASE. The findings demonstrate that maternal obesity is a well-established risk factor for poor placental function. Pre-pregnancy obesity alters the placental transcriptome. Maternal obesity during gestation induces changes in placental morphology, dysregulated placental metabolism, inflammation and oxidative state, as well as endothelial dysfunction. There is also clear evidence that maternal obesity is associated with altered placental angiogenesis/vascularisation which increases the risk of early-onset preeclampsia. Studies show a link between maternal obesity and increased placental vascular disorders, placental weight, placental volume and birth weight. These obesity-related placental disorders are often associated with insulin resistance and gestational diabetes mellitus.

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)

Association between integrase strand transfer inhibitor use with insulin resistance and incident diabetes mellitus in persons living with HIV: a systematic review and meta-analysis

Whether integrase strand transfer inhibitors (INSTIs) are associated with a higher risk of incident type 2 diabetes mellitus (DM) than other antiretroviral therapies (ART) needs to be established.MEDLINE, Embase, Web...

Correlation between diabetes mellitus insulin resistance and cardiovascular endocrine hormones in the elderly

Correlation between diabetes mellitus insulin resistance and cardiovascular endocrine hormones in the elderly

Correlation between visceral fat, muscles mass, and blood sugar levels in adults

The correlation between visceral fat levels (VF) or muscle mass and insulin resistance or type-2 diabetes mellitus has been studied extensively elsewhere, particularly in the urban-dwelling populations. The current study aimed to evaluate the association of VF or muscle mass with random blood glucose (RBG) among the rural population. A cross-sectional study was conducted in Buleleng Regency. A total of 105 samples were enrolled in the study and obtained through a systematic interview, random blood glucose measurement, anthropometry, and bioelectrical impedance analysis. Spearman’s correlation test was used to determine the correlation between visceral fat levels (VF) or muscle mass with RBG levels. A partial correlation test was used to control confounding variables (age, muscle mass, body mass index, body weight, waist circumference, hip circumference). Most of the samples (61.9%) were female, with a mean age was 53,48 ± 13,03. The statistical analysis results show VF had a significant correlation with RBG (r= 0.363, p&lt;0.001 but neither as role of muscle mass in which the r= -0.073, p=0.461). There was no significant correlation found on the partial correlation test, between VF and RBG. In conclusion, although the correlation between VF levels and RBG was weak, the clinician should aware of the role of VF in the development of insulin resistance or diabetes mellitus type-2.

Abstract #1325336: General Characteristics of a Lebanese Cluster of Patients With Berardinelli-Seip Syndrome

Berardinelli-Seip congenital lipodystrophy (BSCL) syndrome is a rare autosomal recessive disease defined by lipodystrophy and a near-absent adipose tissue. Concomitant features are liver steatosis, hypertriglyceridemia, and insulin-resistant diabetes mellitus (DM). DM associated with BSCL is difficult to treat with lack of studied options. We present the characteristics and disease complications of 6 patients with BSCL from the Lebanese cluster. We also describe their DM treatment and control status

STAMP2 Attenuates Cardiac Dysfunction and Insulin Resistance in Diabetic Cardiomyopathy via NMRAL1-Mediated NF-κB Inhibition in Type 2 Diabetic Rats.

BackgroundPrevious studies have reported that six transmembrane protein of prostate 2 (STAMP2) attenuates metabolic inflammation and insulin resistance in diabetes mellitus. However, the role of STAMP2 in the diabetic heart is still unclear.MethodsA diabetic rat cardiomyopathy model was established via intraperitoneal STZ injection. STAMP2 was overexpressed in the treatment group using adeno-associated virus. Rat heart diastolic function was measured using echocardiography and a left ventricular catheter, and cardiac interstitial fibrosis was detected by immunohistochemistry and histological staining. Insulin sensitivity and NF-κB expression were shown by Western blotting. NMRAL1 distribution was illustrated by immunofluorescence.ResultsSTAMP2 expression in the diabetic rat heart was reduced, and exogenous overexpression of STAMP2 improved glucose tolerance and insulin sensitivity and alleviated diastolic dysfunction and myocardial fibrosis. Furthermore, we found that NF-κB signaling is activated in the diabetic heart and that exogenous overexpression of STAMP2 promotes NMRAL1 translocation from the cytoplasm to the nucleus and inhibits p65 phosphorylation.ConclusionSTAMP2 attenuates cardiac dysfunction and insulin resistance in diabetic cardiomyopathy, likely by promoting NMRAL1 retranslocation and NF-κB signaling inhibition.

Research Progress of Improving Insulin Resistance of Diabetes Mellitus with Chinese Herbal Monomer

In recent years, large-scale clinical trials have confirmed that Traditional Chinese Medicine (TCM) has made progress in controlling blood sugar levels. Studies have found that TCM monomers play a significant role in the regulation of insulin resistance-related signaling pathway proteins. Therefore, Chinese and foreign scholars have conducted a lot of studies on the mechanism of insulin resistance. This paper integrates the studies on insulin receptor resistance of TCM (Rhizoma Alismatis, Scutellaria baicalensis, the root of kudzu vine, berberine, Cortex Moutan), and provides a useful reference for the treatment of metabolic diseases such as type 2 diabetes.

Association between integrase strand transfer inhibitor (INSTIs) use with insulin resistance and incident diabetes mellitus in persons living with HIV: A systematic review and meta-analysis protocol.

Poeple living with HIV have higher prevalence of diabetes mellitus and metabolic perturbations compared to non-HIV populations. Diabetes and metabolic syndrome co-morbidities add significant burden to HIV care. Currently, WHO recommends integrase strand transfer inhibitors (INSTIs) as the first or second line therapy in people with HIV due to overall good tolerability and safety profile. However, whether INSTI use increases the risk of incident diabetes (with or without metabolic syndrome) compared to other anti-retroviral therapies (ART) is controversial. In this systematic review and meta-analysis, we aim to examine this risk in HIV-positive populations receiving INSTIs compared to other ART regimens (not containing INSTIs). The study will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement and the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. This protocol adheres to the Standard Protocol Items for reporting systematic reviews and meta-analyses checklist. Eligibility criteria will be original peer-reviewed published articles and conference abstracts with no language or geographical restriction; that report the ocurrence of diabetes mellitus as a discrete outcome or part of metabolic syndrome, in adult PLWHIV receiving INSTIs compared to other ART regimens. PubMed/ Medline, Web of Science, Embase and Cochrane Database of Systematic Reviews will be searched from 1st- January-2000 to 31st-January-2022. Per our a priori, screening, inclusion and data extraction will be conducted separately by two investigators, and a senior researcher will be consulted in case of disagreement. The quality of included studies will be assessed by the Newcastle-Ottawa Scale (NOS) for cohort and case-control studies and the revised Cochrane risk-of-bias tool (ROB2) for randomized controlled trials. The quantitative synthesis of the study outcomes will be explored in different subgroups and sensitivity analyses. Meta regression will also be performed to further test the predictors of the outcome. Ethical approval is waived as the study is a review of published litterature. The analyses will be presented in conferences and published as a scientific article. PROSPERO registration number is; CRD42021273040.

Magnesium Deficiency Associated with Stress, Systemic Inflammation, and Insulin Resistance in Diabetes Mellitus: a review

Magnesium Deficiency Associated with Stress, Systemic Inflammation, and Insulin Resistance in Diabetes Mellitus: a review

Glypican-4 in pregnancy and its relation to glucose metabolism, insulin resistance and gestational diabetes mellitus status

Glypican-4 (GPC-4) is an adipokine that enhances insulin receptor signaling. Plasma concentrations were found to be elevated in patients with prediabetes but reduced in type 2 diabetes mellitus. No study on Glypican-4 in pregnancy and pregnancy-related insulin resistance has been published yet. GPC-4 levels were investigated in 59 overweight women throughout their pregnancy at the Medical University of Vienna. GPC-4 levels, fasting insulin, fasting glucose, estradiol, liver and renal parameters, and markers of bone development were assessed before the < 21st week of gestation (GW), and at GW 35–37. GPC-4 levels increased from < 21 GW (mean = 2.38 pg/ml, SD = 0.68 pg/ml) to GW 35–37 (mean = 2.96 pg/ml, SD = 0.77 pg/ml, p < 0.001). At the same time, GPC-4 levels correlated negatively with estimated glomerular filtration rate (eGFR), serum protein and serum albumin levels and were positively related to creatinine and uric acid levels at GW 35–37. Concerning glucose metabolism, GPC-4 levels were inversely related to ISSI-2, fasting insulin and HOMA-IR, however, not significantly different between women with normal glucose tolerance (NGT) and GDM (p = 0.239). In conclusion, GPC-4 levels rose significantly during pregnancy, correlated negatively with fasting insulin and HOMA-IR but might not be related to gestational diabetes mellitus status.

HOMA-IR as a risk factor of gestational diabetes mellitus and a novel simple surrogate index in early pregnancy.

To assess the association between insulin resistance and gestational diabetes mellitus (GDM) in early pregnancy and find a simple surrogate index of the homeostasis model assessment of insulin resistance (HOMA-IR). A total of 700 pregnant women were included in this prospective, double-center, observational cohort study. The glucose and lipid metabolic characterization was performed at 6-12weeks of pregnancy. All participants underwent a 75-g oral glucose tolerance test at 24-28weeks of pregnancy. Linear regression analysis was applied to find a novel surrogate index of HOMA-IR. Binary logistic analysis was applied to estimate possible associations of different indices with GDM and insulin resistance. GDM was diagnosed in 145 of 700 women with singleton pregnancies (20.7%). HOMA-IR was higher in the GDM group than in the normal glucose tolerance (NGT) group and was an individual risk factor for GDM (adjusted risk ratio RR 1.371, 95% confidence interval [CI] 1.129-1.665, P<0.001). TyHGB index as the surrogate index of HOMA-IR was represented as TG/HDL-C+0.7*FBG (mmol/L)+0.1*preBMI (kg/m2 )(where TG/HDL-C is triglyceride/high-density lipoprotein cholesterol; FBG is fasting blood glucose, and preBMI is the pre-pregnancy body mass index [calculated as weight in kilograms divided by the square of height in meters]). The cut-off point of the TyHGB index was 6.0 (area under the curve 0.827, 95% CI 0.794-0.861, P<0.001) for mild insulin resistance. Increased HOMA-IR in early pregnancy was a risk factor of GDM. TyHGB index could be a surrogate index of HOMA-IR and had a predictive value for GDM.

Generalized lipoatrophy syndromes

Generalized lipodystrophy (GL) syndromes are a group of rare heterogenous disorders, characterized by total subcutaneous fat loss. The frequency of GL is currently assessed as approximately 0,23 cases per million of the population, in Europe – as 0,96 cases per million of the population. They can be congenital (CGL) or acquired (AGL) depending on the etiology and the time of the onset of fat loss. Both CGL and AGL are often associated with different metabolic complications, such as hypertriglyceridemia, insulin resistance and lipoatrophic diabetes mellitus, metabolically associated FLD, arterial hypertension, proteinuria, reproductive system disorders. In this review we aimed to summarize the information on all forms of generalized lipodystrophy, especially the ones of genetic etiology, their clinical manifestations and complications, the perspectives for diagnostics, treatment and further research.

What Was Known About Childhood Diabetes Mellitus Before the Discovery of Insulin?

It has been widely reported by historians that physicians were aware of two distinct types of diabetes mellitus by the 1880s, and that these were both similar to and the direct forerunners of type 1, juvenile-onset and type 2, adult-onset diabetes. The writings of prominent specialist physicians practicing just prior to the discovery of insulin in 1921–1922 were reviewed and there is little evidence that experts believed that adult and childhood diabetes were different. In fact, more than a decade passed after the discovery of insulin before diabetes in children and adults even began to be distinguished. Childhood diabetes was exceedingly rare in the early 20th century and diabetes was believed to be primarily a chronic disease of adults. It is interesting to speculate about what might have happened if the first pancreatic extract tests had been performed on adult-onset diabetics with insulin-resistant diabetes mellitus. Clearly, the results would have been disappointing and the discovery of insulin delayed. This essay explores how the test subject decision was made. It is fortuitous that a 14 year old boy with what was unequivocally type 1 diabetes was selected to be the first insulin recipient, and the rest is history.

Risk of Gestational Diabetes Mellitus in relation to Plasma Concentrations of Fatty Acid-Binding Protein 4: A Nested Case-Control Study in China.

Objective The study is aimed at examining the effects of fatty acid-binding protein 4 (FABP4) on insulin resistance and gestational diabetes mellitus (GDM). Methods Based on a prospective birth cohort in Beijing, China, we conducted a nested case-control study and analyzed 135 GDM case-control pairs matched by age and the gestational week when they took the oral glucose tolerance test. We performed linear regression to analyze the association of plasma FABP4 concentrations with insulin resistance. We used logistic regression to estimate odds ratios (ORs) of FABP4 for GDM, controlling for potential confounders, including dietary intake and physical activity. Results Plasma FABP4 levels in the first and second trimesters were positively associated with fasting insulin and homeostasis model assessment for insulin resistance (HOMA-IR) in the second trimester (both P < 0.001). Compared with those in the lowest FABP4 tertile, women in the highest tertile of FABP4 levels in the first and second trimesters had 1.053 times (OR = 2.053, 95% CI 1.091 to 3.863) and 1.447 times (OR = 2.447, 95% CI 1.305 to 4.588) higher risk of developing GDM. Conclusions Elevated FABP4 levels in the first and second trimesters were associated with a higher level of insulin resistance and greater GDM risk, indicating FABP4 might predict women with high risk of developing GDM.