Insulin Resistance In Type Research Articles

LncRNA UCA1 inhibits mitochondrial dysfunction of skeletal muscle in type 2 diabetes mellitus by sequestering miR-143-3p to release FGF21.

Increasing evidence suggests that insulin resistance in type 2 diabetes mellitus (T2DM) is associated with mitochondrial dysfunction in skeletal muscle, while the underlying molecular mechanisms remain elusive. This study aims to construct a ceRNA regulatory network that is involved in mitochondrial dysfunction of skeletal muscle in T2DM. Based on GEO database analysis, differentially expressed lncRNA and mRNA profiles were identified in skeletal muscle tissues of T2DM. Next, LASSO regression analysis was conducted to predict the key lncRNAs related to T2DM, which was validated by receiver operating characteristic (ROC) analysis. Moreover, the miRNAs related to skeletal muscle in T2DM were identified by WGCNA, followed by construction of gene-gene interaction network and GO and KEGG enrichment analyses. It was found that 12 lncRNAs and 6 miRNAs were related to skeletal muscle in T2DM. Moreover, the lncRNA-miRNA-mRNA ceRNA network involving UCA1, miR-143-3p, and FGF21 was constructed. UCA1, and FGF21 were downregulated, while miR-143-3p was upregulated in skeletal muscle cells (SkMCs) exposed to palmitic acid. Additionally, ectopic expression experiments were performed in SkMCs to confirm the effects of UCA1/miR-143-3p/FGF21 on mitochondrial dysfunction by determining mitochondrial ROS, oxygen consumption rate (OCR), membrane potential, and ATP level. Overexpression of miR-143-3p increased ROS accumulation and reduced the OCR, fluorescence ratio of JC-1, and ATP level, which were reversed by upregulation of UCA1 or FGF21. Collectively, lncRNA UCA1 inhibited mitochondrial dysfunction of skeletal muscle in T2DM by sequestering miR-143-3p away from FGF21, therefore providing a potential therapeutic target for alleviating mitochondrial dysfunction of skeletal muscle in T2DM.

The Profile of Type 2 DM Patients with Insulin Resistance at Citra Husada Hospital

Type 2 DM is a complex chronic multifactorial disease involving many organs. Insulin resistance in type 2 DM patients that occurs due to insulin deficiency or insulin defects can also occur due to metabolic syndrome. This study aims to determine the profile of type 2 DM patients with insulin resistance based on the characteristics of HbA1c levels, leukocyte levels, and hypertension status at Citra Husada Jember Hospital in 2022. This study used a descriptive method with a case series design. The population study consisted of 40 type 2 DM patients who underwent outpatient care in May 2022 using a total sampling technique. The results of the study showed the characteristics of type 2 DM patients with HbA1c levels > 6.5 (25%), 30% leukocytosis, and 45% hypertension. This condition continues even though blood glucose is controlled due to the phenomenon of metabolic memory. The addition of natural bioactive compounds in type 2 DM patients receiving metformin therapy can overcome metabolic memory. Keywords: Type 2 DM, metabolic memory, HbA1c, leukocyte, hypertension

Metabolic remodeling of glycerophospholipids acts as a signature of dulaglutide and liraglutide treatment in recent-onset type 2 diabetes mellitus.

As metabolic remodeling is a pathological characteristic in type 2 diabetes (T2D), we investigate the roles of newly developed long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as dulaglutide and liraglutide on metabolic remodeling in patients with recent-onset T2D. We recruited 52 cases of T2D and 28 control cases in this study. In the patient with T2D, 39 cases received treatment with dulaglutide and 13 cases received treatment with liraglutide. Using untargeted metabolomics analysis with broad-spectrum LC-MS, we tracked serum metabolic changes of the patients from the beginning to the end of follow-up (12th week). We identified 198 metabolites that were differentially expressed in the patients with T2D, compared to the control group, in which 23 metabolites were significantly associated with fasting plasma glucose. Compared to pre-treatment, a total of 46 and 45 differentially regulated metabolites were identified after treatments with dulaglutide and liraglutide, respectively, in which the most differentially regulated metabolites belong to glycerophospholipids. Furthermore, a longitudinal integration analysis concurrent with diabetes case-control status revealed that metabolic pathways, such as the insulin resistance pathway and type 2 diabetes mellitus, were enriched after dulaglutide and liraglutide treatments. Proteins such as GLP-1R, GNAS, and GCG were speculated as potential targets of dulaglutide and liraglutide. In total, a metabolic change in lipids existed in the early stage of T2D was ameliorated after the treatments of GLP-1RAs. In addition to similar effects on improving glycemic control, remodeling of glycerophospholipid metabolism was identified as a signature of dulaglutide and liraglutide treatments.

Study of Association of Serum Prolactin Levels with Insulin Resistance in Type 2 Diabetes Mellitus Patients.

Prolactin (PRL) regulates glucose metabolism and insulin sensitivity. The study aimed to evaluate the role of PRL in glucose homeostasis and its association with insulin resistance in patients with diabetes mellitus (DM). This cross-sectional, observational study included 100 patients (25-60 years) with T2DM. Primary information including demographics, anthropometric measurements, and biochemical measures (complete blood count, glucose parameters, liver and kidney function test, lipid profile, thyroid function test, serum fasting insulin levels, serum PRL levels) was collected. A total of 100 patients, 50 men and 50 women (25 premenopausal and 25 postmenopausal), were enrolled in this study. The correlation between serum cholesterol and PRL was found to be statistically non-significant (P = 0.129) in men and significant (P = 0.041) in women. There was an inverse relationship between fasting plasma glucose and serum PRL levels in both men (r = -0.88; P < 0.0001) and women patients (r = -0.768; P < 0.0001). Negative correlation between postprandial plasma glucose and PRL was found to be statistically significant (r = -0.398; P = 0.048) in postmenopausal women. The comparison in both men and women indicated an inverse correlation between serum PRL and glycated haemoglobin levels. There was a significant negative correlation between homeostasis model assessment-estimated insulin resistance (HOMA-IR) and PRL levels in both men (r = -0.362; P = 0.039) and women patients (r = -0.362; P = 0.003). Homeostasis model assessment of β cell function (HOMA-β), which directly correlates with residual pancreatic beta cell function, was positively correlated with prolactin levels, irrespective of gender and menopausal status of female subjects. Serum PRL levels correlate with improved glycaemic control.

Association of Lipid Accumulation Product with Insulin Resistance in Type 2 Diabetes Mellitus: A Cross-sectional Study

Introduction: The increased incidence of diabetes and Cardiovascular Disease (CVD) is attributed to the rising obesity rates, which is one of the major factors contributing to Insulin Resistance (IR). Although there is a close relationship between obesity and IR, not all cases of obesity lead to cardiometabolic complications. Visceral fat is considered to be the primary cause of IR. Lipid Accumulation Product (LAP) is postulated as a new continuous biomarker of visceral adiposity. Aim: To determine the association between LAP and IR in T2DM. Materials and Methods: This institution-based cross-sectional study was conducted over a period of three months at the Department of Biochemistry, Rajarajeswari Medical College and Hospital in Bengaluru, Karnataka, India. A total of 60 Type 2 diabetic patients (including newly diagnosed and known cases) were recruited as cases, along with 30 healthy controls. Height, weight, and Waist Circumference (WC) were measured. Fasting blood samples were collected for laboratory biochemical estimation of glucose, Total Cholesterol (TC), Triglycerides (TG), High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), and fasting insulin. Statistical analysis for continuous variables was performed using unpaired Student’s t-test, and Analysis of Variance (ANOVA) test was used for group comparisons. Results: Fasting serum insulin (p-value=0.007), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (p-value=0.001), and LAP index (p-value&lt;0.001) were significantly higher in the case group. LAP index was divided into quartiles, Insulin and HOMA-IR showed statistical significance across the quartiles (p-value=0.005). The lipid profile analysis across LAP quartiles revealed a progressive increase in TG levels (p&lt;0.001) and a decrease in HDL levels from Q1 to Q4 quartiles. Conclusion: The study concludes that increased LAP levels are associated with IR in T2DM. LAP can serve as a useful marker for cardiometabolic risk in early-stage T2DM, enabling better disease stratification for improved prognosis.

Type 2 diabetes mellitus-associated cognitive impairment and management

Diabetes mellitus (DM) is a complex metabolic condition characterized by persistent hyperglycemia and poor metabolism due to insulin production irregularities and/or insulin resistance type 2 DM (T2DM) and dementia are linked through a variety of methods. Thus, in terms of the long-term repercussions of diabetes, the current idea focuses on cognitive damage, the exact pathophysiology of which is unknown. A new term, “diabetes-associated cognitive decline,” has recently been proposed to aid study in this field. This review discusses how different variables contribute to the development of T2DM. Furthermore, we investigated an expanding body of literature on insulin signaling in diabetics, as well as various factors such as insulin resistance, hyperglycemia, neuroinflammation, and Aβ (amyloid beta) plaques that may act alone or in combination to link T2DM with cognitive impairments. Finally, we looked at how physical activity and a balanced diet might help fight the condition.

Acute Toxicity Assay and Anti-diabetic Activities of Shemmeco Extract in Drosophila melanogaster

In this study the acute toxicity assay and anti- diabetic properties of Shemmeco extract were examined. The LC50 in this study was conducted using the concentrations: 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, 2500 mg and 5000 mg of extract, each per 10g fly diet. For ten days, Drosophila melanogaster was fed a high diet of sucrose (2.5 g/10 g diet) to elicit insulin resistance type 2 diabetes. The diabetic flies were treated with 5mg, 10mg, 25mg, 50mg and 250 mg per 10 g diet each of Shemmeco extract being safe concentrations from result of acute toxicity and 16mg of metformin/10g diet as standard drug. Glucose content significantly elevated (p&lt;0.05) in diabetes untreated compared to control group. Metformin significantly declined (p&lt;0.05) the glucose content of fruit flies treated with 5 mg (S1) of Shemmeco extract compared to diabetic untreated and metformin treated. The slight decline of glucose content of fruit flies treated with 5mg (S1) of Shemmeco extract therefore indicates that the extract is promising in the treatment of diabetes type 2 if developed further.

THE RELATIONSHIP BETWEEN APOB AND APOA1 WITH INSULINEMIC STATUS IN PREDIABETIC SUBJECTS

The present study was mainly aimed at exploring the causal association of the atherogenic (ApoB) and antiatherogenic apolipoproteins (ApoA1) and their ratio in the basic defects of pancreatic β cell dysfunction and insulin resistance in type 2 Diabetes Mellitus (T2DM). An intermediate stage towards diabetes, the prediabetic stage, was chosen to explore the association. Following a standardized selection process, 131 subjects were purposefully recruited for the study, including 18 with impaired fasting glucose (IFG), 56 with impaired glucose tolerance (IGT), and 57 with type 2 diabetes (T2DM). Fifty-nine healthy subjects served as controls. Glucose, lipid and insulin were estimated by glucose-oxidase, enzymatic colorimetric assay and enzyme linked immunosorbent assay (ELISA) respectively. Serum ApoB and ApoA1 were estimated by immuno-nephelometric method. Appropriate statistical tools were used to calculate statistical differences using Statistical Package for Social studies (SPSS) for Windows V12. Absolute insulin (mIU) levels were significantly higher in the IGT and T2DM groups compared to controls (p 0.001 and p = 0.001, respectively). HOMA%B (meanSD) was significantly lower in T2DM groups (p=&lt;0.001) and higher in IGT compared to the controls although it is significantly lower in IFG compared to the controls but mean value is about 90%. HOMA%S was significantly lower in IGT and T2DM group (p=0.001 and 0.002 respectively). ApoA1 levels were significantly higher only in the T2DM group (p = 0.027), whereas ApoB levels were higher in both the IGT and T2DM groups (p = 0.026-0.001).. Neither ApoB nor ApoA1 showed any significant difference in the IFG group as compared to control. ApoB-ApoA1 ratio did not show significant difference among the groups. ApoB showed significant positive correlation with both fasting and postprandial glucose (p=0.006 and 0.040 respectively). In IGT group ApoB was positively correlated with absolute insulin (p=0.025) and HOMA%B (p=0.049) and negatively with HOMA%S (p=0.026). ApoB, but not ApoA1 or the ApoB and ApoA1 ratio, seem to have a causal association with insulin resistance, and elevation of ApoB is also modulated by obesity and atherogenic lipids. Bioresearch Commu. 9(1): 1170-1176, 2023 (January)

Comparison of longitudinal changes in four surrogate insulin resistance indexes for incident T2DM in middle-aged and elderly Chinese.

Previous studies suggested a significant relationship between four surrogate indexes of insulin resistance and subsequent type 2 diabetes mellitus (T2DM). But the association of longitudinal changes (denoted as -D) in CVAI (Chinese visceral adiposity index), LAP (lipid accumulation product), TyG (triglyceride-glucose), and TG/HDL-C (triglyceride/ high-density lipoprotein cholesterol) indexes with the risk of T2DM remained uncertain. We aimed to compare the changes in those four surrogate indexes for predicting T2DM in middle-aged and elderly Chinese. We extracted data from the China Health and Retirement Longitudinal Study (CHARLS). Multivariate logistic regression models were used to estimate odds ratio (OR) with 95% confidence interval (CI) of incident T2DM with four surrogate indexes. The restricted cubic spline analysis was used to examine potential non-linear correlation and visualize the dose-response relationship between four indexes and T2DM. The receiver operator characteristic curve was used to compare the performance of the four indexes to predict T2DM. We enrolled 4,596 participants in total, including 504 (10.97%) with T2DM. Analysis results showed that four surrogate indexes were associated with T2DM, and the multivariate-adjusted ORs (95% CIs) of T2DM were 1.08 (1.00-1.16), 1.47 (1.32-1.63), 1.12 (1.00-1.25), and 2.45 (2.12-2.83) for each IQR (interquartile range) increment in CVAI-D, LAP-D, TG/HDLC-D, and TyG-D, respectively. Restricted cubic spline regression showed a non-linear correlation between four surrogate indexes and the risk of T2DM (p for non-linear < 0.001). From the ROC (receiver operating characteristic) curve, TyG-D had the highest AUC (area under curve), and its AUC values were significantly different from other three indexes both in male and female (all P < 0.001). Compared with other indexes, TyG-D was a better predictor in the clinical setting for identifying middle-aged and elderly Chinese with T2DM. Monitoring long-term changes in TyG might help in the early identification of individuals at high risk of T2DM.

Relationship between obesity-related colorectal tumors and the intestinal microbiome: an animal-based trial.

Obesity is a risk factor for colorectal cancer (CRC), and the intestinal microbiome is considered to contribute to CRC and obesity. Nonetheless, the role of the intestinal microbiome in obesity-related CRC is unclear. This study aimed to clarify the relationship between obesity-related CRC and the intestinal microbiome using a mouse model. We compared an obese and insulin-resistant type 2 diabetes mouse model [KKAy] to wild-type mice (WT) [C57BL/6J]. Azoxymethane was intraperitoneally injected to develop a mouse model CRC. At 26weeks, we compared the number of tumors and the intestinal microbiome. We also compared them across two models, namely, antibiotic cocktail and co-housing. In all models, KKAy mice had a significantly greater number of tumors than WT mice. Analysis showed that the distribution of the intestinal microbiome changed in both models; however, no difference in tumor development was observed. Tumor expression was suppressed only in the antibiotic cocktail model of WT, whereas KKAy mice bore tumors (C57Bl/6J: KKAy, 0/9:8/8; p < 0.001). KKAy mice remained predominantly tumor-bearing in all treatments. Based on the results, the intestinal microbiome may not be associated with tumorigenesis in obesity-related CRC. It may be necessary to think of other facts linked to obesity-related CRC.

Insights on the role of anti-inflammatory and immunosuppressive agents in the amelioration of diabetes.

Diabetes is a major health problem worldwide. It is a chronic metabolic disorder that produces overt hyperglycemic condition that occurs either when the pancreas does not produce enough insulin due to excessive destruction of pancreatic β-cells (type 1 diabetes) or due to development of insulin resistance (type 2 diabetes). An autoimmune condition known as type 1 diabetes (T1D) results in the targeted immune death of β-cells that produce insulin. The only available treatment for T1D at the moment is the lifelong use of insulin. Multiple islet autoantibody positivity is used to diagnose T1D. There are four standard autoantibodies observed whose presence shows the development of T1D: antibodies against insulin, glutamic acid decarboxylase (GAD65), zinc T8 transporter (ZnT8), and tyrosine phosphatase-like protein (ICA512). In type 2 diabetes (T2D), an inflammatory response precipitates as a consequence of the immune response to high blood glucose level along with the presence of inflammation mediators produced by macrophages and adipocytes in fat tissue. The slow and chronic inflammatory condition of adipose tissue produces insulin resistance leading to increased stress on pancreatic β-cells to produce more insulin to compensate for the insulin resistance. Thus, this stress condition exacerbates the apoptosis of β-cells leading to insufficient production of insulin, resulting in hyperglycemia which signifies late stage T2D. Therefore, the therapeutic utilization of immunosuppressive agents may be a better alternative over the use of insulin and oral hypoglycemic agents for the treatment of T1D and T2D, respectively. This review enlightens the immune intervention for the prevention and amelioration of T1D and T2D in humans with main focus on the antigen-specific immune suppressive therapy.

Effect of quercetin and Abelmoschus esculentus (L.) Moench on lipids metabolism and blood glucose through AMPK-α in diabetic rats (HFD/STZ).

Phosphoenolpyruvate carboxykinase (PEPCK) is a key enzyme in the glyconeogenesis pathway. The AMP-activated protein kinase alpha (AMPK-α) pathway regulates PEPCK, which itself is activated by the AMP/ATP ratio and liver kinase B1 (KB1). The Abelmoschus esculentus (L.) Moench (okra) plant contains a large amount of quercetin that can function as an agonist or an antagonist. The aim of this study was to examine the effects of quercetin flavonoid and A. esculentus extract on the level of AMPK-α expression and associated metabolic pathways. The findings demonstrate that metformin, quercetin, and okra extract may significantly raise AMPK-α levels while significantly lowering PEPCK and hormone-sensitive lipase (HSL) levels, in addition to improving glucose and lipid profiles. By stimulating KB1, these substances increased AMPK-α activation. Additionally, AMPK-α activation improved insulin resistance and Glucose transporter type 4 (GLUT4) gene expression levels. Since AMPK-α maintains energy balance and its activity has not been reported to be inhibited so far, it could be a potent therapeutic target. PRACTICAL APPLICATIONS: The development of effective AMPK-α agonists and antagonists holds promise for the treatment of metabolic disorders like diabetes. Dietary polyphenols are a valuable source for developing new drugs. However, due to the lack of understanding of the underlying mechanisms of their effect on cells, their use in the treatment of diabetes is controversial. In addition to chemicals that have medicinal benefits, chemists are searching for less harmful substances. Using plants containing bioactive chemicals for this purpose can be a good alternative to chemical drugs.

Diabetic cardiomyopathy: a brief summary on lipid toxicity.

Diabetes mellitus (DM) is a serious epidemic around the globe, and cardiovascular diseases account for the majority of deaths in patients with DM. Diabetic cardiomyopathy (DCM) is defined as a cardiac dysfunction derived from DM without the presence of coronary artery diseases and hypertension. Patients with either type 1 or type 2 DM are at high risk of developing DCM and even heart failure. Metabolic disorders of obesity and insulin resistance in type 2 diabetic environments result in dyslipidaemia and subsequent lipid-induced toxicity (lipotoxicity) in organs including the heart. Although various mechanisms have been proposed underlying DCM, it remains incompletely understood how lipotoxicity alters cardiac function and how DM induces clinical heart syndrome. With recent progress, we here summarize the latest discoveries on lipid-induced cardiac toxicity in diabetic hearts and discuss the underlying therapies and controversies in clinical DCM.

Hepatoprotective effect of Carica pubescens juice and rutin through improving the Adenosine Monophosphate-activated Protein Kinase (AMPK) pathway in type 2 diabetes Mellitus Wistar Rats

Insulin resistance in type 2 diabetes mellitus (type 2 DM) results in disturbing glucose transport into the cells and increases glucose production in the liver and exacerbates hyperglycemia. It is also correlated with a decrease of adenosine monophosphateactivated protein kinase (AMPK) expression that has effects on insulin resistance aggravation, antioxidant capacity impairment, and glucose-lipid homeostasis disturbance indicates AMPK as a significant target for type 2 DM prevention and treatment. The flavonoid content of Carica pubescens (CP) fruit contains anti-hyperglycemic and antihyperlipidemic properties, however, there is no study about its effect on AMPK expression. This study aimed to investigate the effect of CP fruit juice and rutin on preventing liver damage in type 2 DM through the pathway of AMPK, superoxide dismutase (SOD), high-density lipoprotein (HDL), and triglyceride (TG). The experimental design was a post-test only control group. The immunohistochemical method was used to examine AMPK expression in 25 liver paraffin blocks from five groups of male Wistar rats: C1 = negative control; C2 = type 2 DM; C3 and C4 = type 2 DM given fruit juice at a dosage of 4 g CP/200 g BW/day and 8 g CP/200 g BW/day, respectively; and C5 = type 2 DM given rutin 10 mg/200 g BW/day, for 30 days treatment. AMPK expression in the liver significantly increased in the C3, C4, and C5 compared to the C2 group (p&lt;0.05). There was no significant variation in AMPK expression among C3, C4, or C5, showing that C1 possesses the same capabilities as C4 and C5 groups. The increase in AMPK expression was followed by SOD and HDL levels and lower TG levels. However, a significant correlation was shown in the TG level only. This indicates CP fruit juice and rutin can act as a hepatoprotective to prevent liver damage through the AMPK pathway due to type 2 DM conditions.

Guidelines for cellular and animal models of insulin resistance in type 2 diabetes

AbstractAs a lifelong chronic metabolic disease, there is no effective method to completely eradicate diabetes. In the search for effective treatments, disease models are important as a means of revealing pathogenesis and screening for potentially useful drugs. Insulin resistance (IR) is closely linked to type 2 diabetes (T2D), and is not only the basis for the pathogenesis of T2D but also the main thread running through the disease. It is the key to preventing T2D for improving insulin sensitivity and improving IR. Therefore, the construction of IR models is an important technique in T2D research. Most studies have constructed models by actively manipulating cells or animals to simulate disease phenotypes that are similar to human pathogenesis. This guideline provides experimental details for the construction of IR cells and animal models, which is currently the most common, efficient, and stable models used in laboratories for most cells and animals. The guideline for constructing models can help reveal the pathogenesis of T2D and provide a basis for drug screening and development studies for IR‐related diseases.

The correlation of vitamin D with HOMA-IR and glycated hemoglobin in type 2 diabetes mellitus patients

Background and objective: Diabetes mellitus, the most common endocrine condition, is characterised by an elevated level of plasma glucose. Vitamin D's primary functions are homeostasis of calcium and metabolism of bone, but it also has a significant role in homeostasis of plasma glucose. This study sought to examine the relationship between vitamin D and glycated haemoglobin and insulin resistance in type 2 diabetes mellitus (T2DM) subjects by analysing vitamin D, homeostasis model assessment of insulin resistance (HOMA-IR), and haemoglobin A1c (HbA1c) levels. Methods: 150 patients with newly diagnosed T2DM participated in this case-control research. Additionally, 150 controls of the same age and gender were also recruited. Serum vitamin D and fasting insulin levels were estimated by the electrochemiluminescence immunoassay (ECLIA) method. High-performance liquid chromatography (HPLC) was used to analyse HbA1c. Pearson's correlation coefficient was used to determine the relationship of vitamin D with HbA1c and HOMA-IR. Results: Around 70.7% of diabetes subjects had low vitamin D levels, compared to 31.3% in the control group. Vitamin D-deficient T2DM subjects had significantly higher HOMA-IR and HbA1c levels. Both vitamin D and HOMA-IR (r = -0.75) and vitamin D and HbA1c (r = -0.73) showed a strong inverse connection in T2DM patients. Conclusions: Vitamin D deficiency is correlated with ineffective glycemic control, and the reason might be its potential role in the secretion and sensitivity of insulin. Therefore, vitamin D screening must be incorporated as a routine check-up for T2DM patients.

Abstract 10408: Insulin Resistance in Type 2 Diabetes is Moderated by Saturated Fatty Acids

Background: Increased intramyocellular lipid storage occurs in skeletal muscle of both athletes and type 2 diabetes patients (T2D) but their metabolic phenotypes are at opposite ends of insulin sensitivity and cardiometabolic risk. Hypothesis: Intramyocellular lipid saturation and flux are determinants of insulin resistance. Methods: Age-matched athletes (n=28) and T2D (n=27) underwent 1 H-magnetic resonance spectroscopy for analysis of saturated (fSL) and unsaturated lipid (fUL) fractions of vastus lateralis, blood lipids, glucose and insulin sensitivity, skeletal muscle biopsy for lipidomics/insulin signalling, cardiopulmonary exercise peak VO 2 and intravenous administration of stable isotopes of [U- 13 C]-palmitate and -linoleate for skeletal muscle saturated/unsaturated fatty acid fluxes (fractional synthesis rate, FSR). Tests were performed at baseline and after controlled insulin sensitivity changes (4-week athletes deconditioning and endurance exercise training at ≥65% of baseline peakVO 2, 5 hours/week x 8 weeks in T2D). Results: We demonstrate higher intramyocellular fSL and lower fUL in athletes compared to T2D (p=0.0004). Trained athletes have a 4-fold (palmitate) and 2.2-fold (linoleate) higher FSR compared to T2D (p=0.005 and 0.006, respectively). Athletes’ deconditioning results in reductions in skeletal muscle lipid saturation, palmitate and linoleate FSR. Conversely, 8-week endurance training of T2D results in intramyocellular lipid saturation increase (p&lt;0.0001) as well as a relatively larger (2.2-fold) palmitate FSR increase (p=0.04) than the 1.8-fold linoleate FSR increase (p=0.03), re-aligning the T2D skeletal muscle phenotype to that of deconditioned athletes. These adaptations were synchronous with significant insulin sensitivity improvement (p&lt;0.05), decrease in serum cholesterol (p=0.02) and triglycerides (p=0.0005), improved glycaemic control (HBA1c, p=0.0003), increased peak VO 2 (p&lt;0.0001) and upregulation of skeletal muscle phosphorylated AKT (p=0.01) and AMPK (p=0.005) in T2D. Conclusions: Maladapted intramyocellular lipid storage and fluxes in T2D patients show reversibility after endurance training through increased contributions of the saturated fatty acids pools.

New insights into mechanisms of endothelial insulin resistance in type 2 diabetes.

Insulin resistance in the vasculature is a hallmark of type 2 diabetes (T2D), and blunting of insulin-induced vasodilation is its primary consequence. Individuals with T2D exhibit a marked impairment in insulin-induced dilation in resistance arteries across vascular beds. Importantly, reduced insulin-stimulated vasodilation and blood flow to skeletal muscle limits glucose uptake and contributes to impaired glucose control in T2D. The study of mechanisms responsible for the suppressed vasodilatory effects of insulin has been a growing topic of interest for not only its association with glucose control and extension to T2D but also its relationship with cardiovascular disease development and progression. In this mini-review, we integrate findings from recent studies by our group with the existing literature focused on the mechanisms underlying endothelial insulin resistance in T2D.

Liver Fetuin-A at Initiation of Insulin Resistance

Hepatokines (liver secreted proteins with possible distant action) are emerging potential players in insulin resistance in type 2 diabetic patients. Here, we explored the effect of a high-fat diet on the expression of fetuin-A, one of those candidate liver proteins, and its relationship with liver macrophage activation. Mice were fed a normal diet or a high-fat diet for 3 days, known to initiate steatosis and liver insulin resistance. A preventive liver macrophage depletion was obtained by intravenous injection of clodronate-loaded liposomes. The mRNA and protein expression of fetuin-A was evaluated by qPCR, Western blot and immunofluorescence on different insulin-sensitive tissues (liver, adipose tissue, and muscle). Short-term high-fat diet-induced steatosis, liver macrophage activation, and hepatic insulin resistance together with a significantly increased expression of liver AHSG (α2-HS glycoprotein/fetuin-A) mRNA and serum fetuin-A concentration. On immunofluorescence, fetuin-A was mostly expressed in centrilobular hepatocytes. This increase in fetuin-A under high-fat diet was not evidenced in other peripheral insulin-sensitive tissues (skeletal muscle and adipose tissue). The mRNA expression of α2-HS glycoprotein was 800 times higher within the liver compared with the adipose tissue or the muscle. Liver macrophage depletion that significantly ameliorated insulin sensitivity was associated with a significant decrease in α2-HS glycoprotein mRNA expression. In conclusion, this study demonstrated liver fetuin-A overexpression at the initiation of high-fat diet feeding, concurrent with hepatic steatosis and insulin resistance. Targeting liver macrophages in this setting reduced liver α2-HS glycoprotein expression suggesting that fetuin-A acts as an hepatokine with proinsulin resistance effects.

MMPP promotes adipogenesis and glucose uptake via binding to the PPARγ ligand binding domain in 3T3-L1 MBX cells.

Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor involved in adipogenesis, and its transcriptional activity depends on its ligands. Thiazolidinediones (TZDs), well-known PPARγ agonists, are drugs that improve insulin resistance in type 2 diabetes. However, TZDs are associated with severe adverse effects. As current therapies are not well designed, novel PPARγ agonists have been investigated in adipocytes. (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) is known to have anti-arthritic, anti-inflammatory, and anti-cancer effects. In this study, we demonstrated the adipogenic effects of MMPP on the regulation of PPARγ transcriptional activity during adipocyte differentiation in vitro. MMPP treatment increased PPARγ transcriptional activity, and molecular docking studies revealed that MMPP binds directly to the PPARγ ligand binding domain. MMPP and rosiglitazone showed similar binding affinities to the PPARγ. MMPP significantly promoted lipid accumulation in adipocyte cells and increased the expression of C/EBPβ and the levels of p-AKT, p-GSK3, and p-AMPKα at an early stage. MMPP enhanced the expression of adipogenic markers such as PPARγ, C/EBPα, FAS, ACC, GLUT4, FABP4 and adiponectin in the late stage. MMPP also improved insulin sensitivity by increasing glucose uptake. Thus, MMPP, as a PPARγ agonist, may be a potential drug for type 2 diabetes and metabolic disorders, which may help increase adipogenesis and insulin sensitivity.