Cause Of Type 2 Diabetes Mellitus Research Articles

Trajectory, Perceived Causes and Efforts in Diabetes Self-management: A Qualitative Study Among Young People With Type 2 Diabetes Mellitus and Caregivers

Introduction: Previous studies have suggested that young individuals with type 2 diabetes mellitus (T2DM) face challenges in achieving optimal diabetes self-management, leading to difficulties in attaining the recommended glycaemic target. The reasons behind these suboptimal practices remain unclear due to the limited number of studies conducted in Malaysia that focused on diabetes self-management among young people. This qualitative study aimed to understand the lived experience of young people with T2DM on self-management in Malaysia. Methods: Young people at the age of 10 to 24 years, who had been diagnosed with T2DM and the caregivers who managing young people with T2DM were interviewed. Data were thematically analysed with the aid of QSR NVivo version 12. Results: Sixteen young informants and eleven caregivers participated in this study. Three major themes conceptualised the lived experience of diabetes self-management: (1) the trajectory to T2DM diagnosis; (2) perceived causes of T2DM; (3) the efforts in diabetes self-management. The route of diagnosis and experiential knowledge about T2DM might determine their efforts in the self-management among the young people. Healthy eating, medication taking and physical activity were perceived as important tasks in diabetes self-management. The involvement of the caregivers in diabetes self-management evolved over time. Conclusion: The study highlighted the experience of young people and caregivers since the beginning of the diagnosis and their strategies in diabetes self-management. More understanding of the lived experiences of patients and caregivers in disease management within the socio-ecological context could help to improve health-care services and intervention for this population.

Shared Genetics between Age at Menarche and Type 2 Diabetes Mellitus: Genome-Wide Genetic Correlation Study.

Background: Age at menarche (AAM) has been associated with type 2 diabetes mellitus (T2DM). However, little is known about their shared heritability. Methods: Our data comes from the Taiwan Biobank. Genome-wide association studies (GWASs) were conducted to identify single-nucleotide polymorphisms (SNPs) related to AAM-, T2DM-, and T2DM-related phenotypes, such as body fat percentage (BFP), fasting blood glucose (FBG), and hemoglobin A1C (HbA1C). Further, the conditional false discovery rate (cFDR) method was applied to examine the shared genetic signals. Results: Conditioning on AAM, Quantile-quantile plots showed an earlier departure from the diagonal line among SNPs associated with BFP and FBG, indicating pleiotropic enrichments among AAM and these traits. Further, the cFDR analysis found 39 independent pleiotropic loci that may underlie the AAM-T2DM association. Among them, FN3KRP rs1046896 (cFDR = 6.84 × 10-49), CDKAL1 rs2206734 (cFDR = 6.48 × 10-10), B3GNTL1 rs58431774 (cFDR = 2.95 × 10-10), G6PC2 rs1402837 (cFDR = 1.82 × 10-8), and KCNQ1 rs60808706 (cFDR = 9.49 × 10-8) were highlighted for their significant genetic enrichment. The protein-protein interaction analysis revealed a significantly enriched network among novel discovered genes that were mostly found to be involved in the insulin and glucagon signaling pathways. Conclusions: Our study highlights potential pleiotropic effects across AAM and T2DM. This may shed light on identifying the genetic causes of T2DM.

25-hydroxy vitamin D concentrations negatively correlated with HbA1c in type 2 diabetes mellitus patients: a cross-sectional study in Mampang, South Jakarta


 
 
 INTRODUCTION: Insulin resistance plays a central role in type 2 diabetes mellitus (T2DM). Another possible cause of T2DM is a deficiency o f 25-hydroxy vitamin D [ 25(OH)D], although the underlying mechanism is not yet clearly understood. The most frequently used laboratory parameters for monitoring T2DM are fasting blood glucose (FBG) and HbA1c. Determining any association of vitamin D with HbA1c and FBG in T2DM.
 METHODS: A cross-sectional study involving 100 T2DM patients with the following characteristics: 18-year and older persons of both genders, not having kidney and liver disease, not on insulin therapy, not pregnant or lactating, a nd n ot consuming vitamin D i n t he last three months. Spearman’s correlation coefficient was use d to test any association of 25(OH)D with HbA1 c and fasting blood glucose (FBG) (p<0.05).
 RESULTS: Subjects comprised 74 females and 26 males with a median age of 56 years. Median HbA1c, 25(OH)D, and FBG were 8.05%, 11.2 ng/mL, and 127 mg/dL, respectively. The Spearman correlation coefficient for vitamin D and HbA1c was r=-0.217 (p=0.03), and for vitamin D and FBG,it was r =-0.153 (p=0.128).
 CONCLUSION: There was a significant negative correlation of vitamin D with HbA1c but not with FBG. Administration of vitamin D should be considered for additional treatment of T2DM.
 
 

Association of genetic and epigenetic changes of insulin like growth factor binding protein-1 in Egyptian patients with type 2 diabetes mellitus

BackgroundDiabetes is one of the global health threat. Type 2 Diabetes mellitus (T2DM) is associated with life-threatening complications. This work, aimed to study the association between T2DM and IGFBP-1 gene methylation, gene polymorphism and serum levels of IGFBP-1. MethodWe included 100 subjects with T2DM and 100 control. DNA methylation of IGFBP-1 was analyzed using pyrosequencing, IGFBP-1 gene polymorphism was analyzed using real time polymerase chain reaction and serum level of IGFBP-1 was measured by ELISA. ResultsThere was DNA hyper methylation levels of IGFBP1 gene at each of the six CpG sites in T2DM patients than control (P < 0.001). IGFBP-1 gene polymorphism (rs 2854843) CC pattern was significantly associated with DM, P = 0.002. Also, there was decrease in serum IGFBP-1 in patients with T2DM than control group (P < 0.001). ConclusionWe concluded that DNA hyper methylation of IGFBP-1 gene and CC polymorphism (rs 2854843) of IGFBP-1 gene are associated with T2DM in Egyptian patients, also, decrease serum level of IGFBP-1. Further cohort study is recommended with large sample size to detect which one, epigenetic changes or polymorphism of IGFBP-1 gene, is the cause of T2DM or even both.

Hispidin Inhibits Ferroptosis Induced by High Glucose via the miR-15b-5p/GLS2 Axis in Pancreatic Beta Cells.

Type 2 diabetes mellitus (T2DM) is a global health issue that lacks effective treatments. Dysfunction and/or death of pancreatic β-cells (PBCs) are considered a major cause of T2DM. Therefore, elucidating the mechanisms underlying the death of PBCs might be helpful to develop novel strategies to treat T2DM. Ferroptosis is a newly identified form of cell death that has distinct features. However, knowledge regarding the role of ferroptosis in the death of PBCs remains limited. In the current study, we used high glucose (10 mM) (HG) levels to induce ferroptosis in PBC. We also observed that hispidin, a polyphenol compound that can be isolated from Phellinus linteus, could attenuate ferroptosis induced by HG in PBCs. Mechanistic investigations showed that hispidin led to the upregulation of miR-15b-5p, which directly inhibits the expression of glutaminase (GLS2) which plays an essential role in the glutamine metabolism. In addition, we found that overexpression of GLS2 could abrogate the protective effect of hispidin against ferroptosis caused by HG in PBCs. Therefore, our study provides novel insights into the mechanisms that regulate the death of PBCs.

Identification of Potential Biomarkers of Type 2 Diabetes Mellitus-Related Immune Infiltration Using Weighted Gene Coexpression Network Analysis.

Background Type 2 diabetes mellitus (T2DM) is characterized by chronic low-grade inflammation, showing an increasing trend. The infiltration of immune cells into adipose tissue has been shown to be an important pathogenic cause of T2DM. The purpose of this study is to use the relevant database to identify some abnormally expressed or dysfunctional genes related to diabetes from the perspective of immune infiltration. Methods Weighted gene coexpression network analysis (WGCNA) was employed to systematically identify the coexpressed gene modules and hub genes associated with T2DM development based on a microarray dataset (GSE23561) from the Gene Expression Omnibus (GEO) database. The key genes in modules highly related to clinical features were calculated and screened by using R software, and their participation in T2DM was determined by gene enrichment analysis. The mRNA levels of CSF1R, H2AFV, LCK, and TLR9 in pre-T2DM mice and normal wild-type mice were detected by WGCNA screening and real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Results We constructed 14 coexpressed gene modules, and the brown module was shown to be significantly related to T2DM. Through verification of the protein-protein interaction (PPI) network, four upregulated hub genes, CSF1R, H2AFV, LCK, and TLR9, were screened from the brown module and successfully distinguishedT2DM patients from healthy people. These hub genes may be used as biomarkers and important indicators for patient diagnosis. Enrichment analysis showed that these hub genes were highly associated with IL-6-related inflammatory metabolism, immune regulation, and immune cell infiltration. Finally, we verified the hub genes CSF1R, LCK, and TLR9 in a T2DM animal model and found that their mRNA levels were significantly higher in animals with T2DM than in control group mice (NC). Conclusions In summary, our results suggest that these hub genes (CSF1R, LCK, and TLR9) can serve as biomarkers and immunotherapeutic targets for T2DM.

Role of Mitochondrial Dynamics in Type 2 Diabetes Mellitus Dysfunction

Type 2 Diabetes Mellitus (T2DM) is influenced by the action of both hereditary and environmental factors. These factors are comprehended in the disease interaction with β cells and insulin sensitivity to the receptors.The main cause of T2DM development is ageing, obesity, and oxidative stress. The dysfunction of the β cells of the pancreas leads to insulin insensitivity in the liver, muscle and fat metabolism. These occur due to the result of oxidative stress. Lipid peroxidation is a key initiating factor in the development of oxidative stress, which results in T2DM and its related micro-and macro-vascular problems. These are initially compensated for the generation of excess insulin synthesis, thus ensuring normal glucose tolerance. When these compensatory processes are disrupted, the majority of persons develop T2DM. Although the gene is the primary cause of T2DM, the environment also plays an important role in the disease's progression. Particularly, a sedentary lifestyle characterised by excessive food consumption and physical inactivity is a known risk factor for obesity and type 2 diabetes. This review has briefly discussed the significance of numerous causal factors, and genomic and biochemical pathways which are responsible for increasing the production of oxidative stress, a crucial component for the etiology and development of T2DM. The conclusion drawn was that the analysis of oxidative stress markers may be one of the potential methods for the diagnosis and prognosis of T2DM. Furthermore, this review will be helpful to establish the broaden conceptual framework for future studies on oxidative stress with relation to etiology of type 2 diabetes and therapeutic development.

Inflammatory Markers Associated With Diabetes Mellitus - Old and New Players.

Diabetes mellitus (DM) is a chronic and complex metabolic disorder, and also an important cause of cardiovascular (CV) diseases (CVDs). Subclinical inflammation, observed in patients with type 2 DM (T2DM), cannot be considered the sole or primary cause of T2DM in the absence of classical risk factors, but it represents an important mechanism that serves as a bridge between primary causes of T2DM and its manifestation. Progress has been made in the identification of effective strategies to prevent or delay the onset of T2DM. It is important to identify those at increased risk for DM by using specific biomarkers. Inflammatory markers correlate with insulin resistance (IR) and glycoregulation in patients with DM. Also, several inflammatory markers have been shown to be useful in assessing the risk of developing DM and its complications. However, the intertwining of pathophysiological processes and the not-quite-specificity of inflammatory markers for certain clinical entities limits their practical use. In this review we consider the advantages and disadvantages of various inflammatory biomarkers of DM that have been investigated to date as well as possible future directions. Key features of such biomarkers should be high specificity, non-invasiveness and cost-effectiveness.

MiR-344-5p Modulates Cholesterol-Induced β-Cell Apoptosis and Dysfunction Through Regulating Caveolin-1 Expression.

Diabetes is a metabolic disorder induced by the modulation of insulin on glucose metabolism, and the dysfunction and decreased number of islets β-cells are the main causes of T2DM (type 2 diabetes mellitus). Among multiple factors that might participate in T2DM pathogenesis, the critical roles of miRNAs in T2DM and β-cell dysfunction have been reported. Through bioinformatics analyses and literature review, we found that miR-344 might play a role in the occurrence and progression of diabetes in rats. The expression levels of miR-344-5p were dramatically decreased within cholesterol-stimulated and palmitic acid (PA)-induced rats’ islet β-cells. In cholesterol-stimulated and PA-induced diabetic β-cell model, cholesterol-caused and PA-caused suppression on cell viability, increase in intracellular cholesterol level, decrease in GSIS, and increase in lip droplet deposition were dramatically attenuated via the overexpression of miR-344-5p, whereas aggravated via the inhibition of miR-344-5p. miR-344-5p also inhibited cholesterol-induced β-cell death via affecting the apoptotic caspase 3/Bax signaling. Insulin receptor downstream MPAK/ERK signaling was involved in the protection of miR-344-5p against cholesterol-induced pancreatic β-cell dysfunction. Moreover, miR-344-5p directly targeted Cav1; Cav1 silencing could partially reverse the functions of miR-344-5p inhibition upon cholesterol-induced β-cell dysfunction, β-cell apoptosis, the apoptotic caspase 3/Bax signaling, and insulin receptor downstream MPAK/ERK signaling. In conclusion, the miR-344-5p/Cav1 axis modulates cholesterol-induced β-cell apoptosis and dysfunction. The apoptotic caspase 3/Bax signaling and MAPK/ERK signaling might be involved.

Normalized Hand Grip and Back Muscle Strength as Risk Factors for Incident Type 2 Diabetes Mellitus: 16 Years of Follow-Up in a Population-Based Cohort Study.

PurposeMuscle strength is associated with type 2 diabetes mellitus (T2DM). However, it is controversial whether muscle strength and normalized muscle strength is a risk factor for T2DM. Moreover, the relationship of back muscle strength (BMS) and incident T2DM has not been reported. In this study, we investigated the relationship between HGS, BMS, normalized HGS and BMS, and incident T2DM.MethodsA total of 2699 non-diabetes subjects aged 40–69 years (1313 women and 1386 men) in the Korean Genome and Epidemiology Study (KoGES) Ansan cohort were followed for 16 years. At the baseline and biennial follow‐up visits, fasting glucose, postprandial 2-h glucose, clinical examinations, HGS, and BMS were measured by trained interviewers and examiners. HGS and BMS were measured at baseline. The relationships between incident T2DM, HGS, BMS, and normalized HGS and BMS were estimated using Cox proportional hazard regression models after adjusting for the confounding factors.ResultsHGS and BMS were not associated with incident T2DM in multivariate analysis. However, the hazard ratio (HR) per one standard deviation (SD) increase in the body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR)-normalized HGS, and BMS was associated with a lower risk for incident T2DM in both women and men after adjusting for the confounding factors (HR = 0.842–0.880-fold for women, p ≤ 0.015; HR = 0.887–0.903-fold for men, p ≤ 0.024). In the sub-analysis of menopause status, the HR per one SD increase in BMI, weight2/3, WC, and WHR-normalized HGS was associated with a lower risk for incident T2DM in both pre- and post-menopausal women after adjusting for the confounding factors (HR = 0.860–0.820-fold for premenopausal, P ≤ 0.006; HR = 0.900–0.867-fold for postmenopausal, p ≤ 0.024). Additionally, we confirmed that the quartile group with higher muscle strength was associated with a lower risk for incident T2DM.ConclusionThe present study suggested that normalized HGS and BMS were associated with a lower risk for the future development of T2DM. Moreover, weak muscle strength in premenopausal women may be the cause of T2DM. Further research is needed to determine whether efforts to improve muscle strength, such as exercise can reduce the risk of T2DM.

Evaluation of galectin-3 levels in patients with type 2 diabetes mellitus and chronic kidney disease

ABSTRACT INTRODUCTION: Type 2 diabetes mellitus (T2DM) is the most common manifestation of diabetes, accounting for about 90% of diagnosed cases. The causes of T2DM are not fully understood, but its pathogenesis is possibly associated with increased adiposity and a chronic low-grade inflammatory response. The glycoprotein galectin-3 (Gal-3) is known to play an important role in the modulation of blood glucose, adiposity, and inflammation. OBJECTIVES: The aim of this study was to evaluate Gal-3 levels in patients with T2DM and chronic kidney disease (CKD), in addition to relating them with complications and comorbidities present in these patients, comparing them to a control group. MATERIAL AND METHODS: Gal-3 was evaluated in 84 selected individuals, of which 42 had clinical and laboratory diagnosis of T2DM and CKD (treated at Santa Casa Hospital in Belo Horizonte, Minas Gerais, Brazil), and 42 individuals from the local community, with no history of diabetes (control group). RESULTS AND DISCURSION: Gal-3 levels were significantly higher (p = 0.012) in the T2DM group (15.17 ± 5.54 ng/ml) when compared to the control group (12.62 ± 3.2 ng/ml). There was a tendency for higher levels of Gal-3 in diabetic patients with hypertension (15.74 ± 5.61 ng/ml) when compared to patients without this complication (10.96 ± 2.49 ng/ml) (p = 0.069) CONCLUSION: The results suggest that Gal-3 may be involved in the pathophysiology of T2DM and still be a promising biomarker associated with hypertension in this group.

Review of type-2 diabetes mellitus illness perceptions and associations with illness management

Objective: Determine illness perceptions associated most frequently with measures of type-2 diabetes mellitus (T2DM) maintenance. We measured illness perceptions using the Illness Perception Questionnaire (IPQ) and variants (IPQ-Revised and Brief IPQ) Design: Review of literature from publication of IPQ to September 2020. Searched for articles utilizing IPQ but no other models of illness perception and studying T2DM Main Outcome Measures: Glucose control (measured by HbA1c levels), adherence to medications, and adherence to diet, exercise, and other lifestyle recommendations Results: Symptom attribution and fear of consequences are frequently associated with worse T2DM management and sense of control of illness progression and positive emotional valence are frequently associated with better T2DM management. Other subscales have less frequent but generally positive associations with the exceptions of recurring thoughts about T2DM duration, which had a negative association with management, and understanding the causes of T2DM, which had no associations at all. Other reviews found similar associations and highlighted a need for more general T2DM education. Conclusion: Future T2DM management interventions should promote sense of control over illness progression and positive emotional valence and provide education regarding symptoms to expect. Interventions should also consider managing patient fear, which has many associations with worse management.

Type 2 diabetes mellitus: pathogenesis and genetic diagnosis.

Type 2 diabetes mellitus (T2DM) is a heterogeneous condition that is related to both defective insulin secretion and peripheral insulin resistance. Beta cells are the major organ for secreting insulin hence, it is important to maintain an adequate beta-cell mass in response to various changes. Insulin resistance is a major cause of T2DM leads to elevated free fatty acid (FFA) levels which increases beta-cell mass and insulin secretion to compensate for insulin insensitivity. Chronic increase of plasma FFA levels results in disturbances in lipid metabolism, which contributes to decreased beta-cell function and lipotoxicity thus promoting T2DM. In the present review, we have discussed the process of beta-cell destruction, the role of genes in contributing to the fast increase in the progression of T2DM in detail. More than 130 variants in various T2DM susceptibility and candidate genes have been discovered to be associated with T2DM. Still, these variants elucidate only a small amount of total heritability of T2DM. Further, there is also an inventory of presently used therapeutic tools and a review of novel therapeutic approaches like incretin-based therapies or sodium-glucose transporter-2 inhibitors. Additionally, providing a concise but comprehensive update, this review will be essential to every clinician involved in the treatment of diabetes mellitus.

Mechanism study on the abnormal accumulation and deposition of islet amyloid polypeptide by cold-spray ionization mass spectrometry.

The abnormal accumulation and deposition of islet amyloid polypeptide (IAPP) are important causes of type-2 diabetes mellitus (T2DM). The common anti-amyloid strategy employs inhibitors to prevent the formation of oligomers and the cytotoxicity caused by them, thus reducing the production of amyloid fibres. Therefore, the real characterization of the oligomers formed at the early stage of aggregation is crucial to understanding the structure of IAPP and the drug development of T2DM. For the first time, in this study, native cold-spray ionization mass spectrometry (CSI-MS) technology was employed to characterize the oligomers. It was found that CSI was more suitable for the determination of these unstable species compared to traditional ESI-MS. The ionic strengths, organic solvent and pH all had effects on the characterization of oligomers and the stability of protein conformation. The MS/MS experiments showed that odd-charge dimer ions were mainly composed of two monomer products. Moreover, a CSI-MS method for the rapid screening of IAPP-inhibitors was established and two of the most potential inhibitors (rutin and quercitrin) were screened from a series of flavonoids. Then, the structure-activity relationship and the mechanism between flavonoids and IAPP were studied. The results showed that 3-OH and sugar chains play a vital role and hydrogen bonds are the main binding force. We further confirmed that rutin and quercitrin could effectively inhibit the fibre formation of IAPP by fluorescence and TEM experiments. This study provides a new insight for analyzing the structure of IAPP and screening potential drugs for T2DM.

Citrus flavonoids as a target for the prevention of pancreatic β-cells dysfunction in diabetes.

The number of patients with type 2 diabetes mellitus (T2DM) has rapidly increased, especially in East and Southeast Asia. In these areas, in general, people have especially vulnerable β-cells and insulin secretion deficiency and reduced β-cell mass are the primary cause of T2DM. Therefore, the alleviation of such β-cell dysfunction would provide therapeutic approaches to prevent the development of T2DM. Nobiletin, a polymethoxylated flavonoid found in citrus fruits, has been shown to improve obesity and insulin resistance in T2DM model mice. We focused on β-cells and investigated the effects of nobiletin on insulin secretion and β-cell apoptosis. In β-cell line INS-1, nobiletin increased glucose-induced insulin secretion (GSIS) in a concentration-dependent manner, which was inhibited by an Epac inhibitor. In addition, nobiletin at 10 μM inhibited thapsigargin-induced apoptosis, which was inhibited by a PKA inhibitor. Nobiletin also suppressed thapsigargin-induced increases in cleaved caspase-3 and phosphorylated JNK. Thus, nobiletin is suggested to promote GSIS and prevent ER stress-induced β-cell apoptosis, which are mediated via Epac and PKA-dependent pathways, respectively. In summary, nobiletin is suggested to exhibit insulinotropic and anti-apoptotic effects on β-cells, which are one of the causes of its anti-diabetic effect. Moreover, nobiletin seems to be able to alleviate the development of T2DM by protecting β-cells from apoptosis.

Performance evaluation of naive Bayes and support vector machine in type 2 Diabetes Mellitus gene expression microarray data

Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder that the number of diabetics increases every year. So that prevention is needed by knowing the trigger of T2DM. Gene expression microarray data contains information of gene that can be used to determine the causes of T2DM. It is necessary to use certain techniques to analyze gene expression microarray data because it has a large amount of data and attributes. This study aims to evaluate the performance of algorithms in classifying gene expression microarray data. Algorithms that were used in this study were Naive Bayes, and Support Vector Machine (SVM). SVM used many kernels function such as Linear, Radial Basis Function (RBF), Polynomial, and Sigmoid. Information gain was used to select the features in GSE18732 dataset by choosing top 10, 20, 30, 40, and 50 features. Performance of algorithms was evaluated and compared by using 30% testing set and 20% testing set. The results of the study indicated that SVM using Polynomial kernel had a high performance if it was compared to other algorithms. It achieved 98.15% accuracy using 30% testing set and achieved 100% accuracy using 20% testing set.

The relationship between pancreatic cancer and type 2 diabetes: cause and consequence.

Pancreatic cancer (PC) is a devastating and lethal malignant disease and it is well known that there is a complex bidirectional relationship between PC and type 2 diabetes mellitus (T2DM). In order to more deeply summarize the relationship between them, this article summarizes the epidemiological data on the relationship between PC and T2DM in the past 5 years, and further explains the mechanism of interaction between them. Meanwhile, it also summed up the effects of drug therapy for T2DM on PC and the impact of T2DM on surgical resection of PC. Epidemiological studies clearly indicate that the risk of PC is increased in patients with T2DM. But increasing epidemiological data points out that PC also acts as a cause of T2DM and new-onset T2DM is sign and consequence of PC. Insulin resistance, hyperinsulinemia, hyperglycemia, and chronic inflammation are the mechanisms of T2DM-Associated PC. Metformin decreases the risk of PC, while insulin therapy increases the risk of PC. Besides, studies have shown that T2DM decreases the survival in patients with PC resection.

Restoration of insulin receptor improves diabetic phenotype in T2DM mice.

Type 2 diabetes mellitus (T2DM), also known as adult-onset diabetes, is characterized by ineffective insulin action due to insulin resistance in key metabolic tissues. Insulin receptor (IR) plays an important role in insulin signal transduction, defect of which has been considered the fundamental cause of T2DM. IR content reduction in diabetes is one key contributor to the defective insulin signaling and diabetes progression. Rescuing IR levels by transgenic complementation has not been considered as a treatment option because it is limited by uncontrollable expression level, tissue selectivity, or developmental defects. In the current study, we demonstrated that single-dose adeno-associated virus (AAV) vector delivered expression of human IR (hIR) in the liver of inducible IR-knockout mice and significantly improved the diabetic phenotype caused by IR deletion during adulthood. Such an approach was also applied, for the first time to our knowledge, to treating ob/ob mice, a model of severe T2DM attributed to superfluous calorie intake and insulin resistance. Interestingly, similar treatment with AAV-hIR had no obvious effect in healthy animals, indicative of low hypoglycemic risk as a consequence of potential excessive insulin action. The results described here support restoration of IR expression as a safe and effective T2DM therapeutic with a long-lasting profile.

Association of endothelial nitric oxide synthase (eNOS) and norepinephrine transporter (NET) genes polymorphism with type 2 diabetes mellitus.

Genetic factors in combination with environmental factors play a critical role in the development type 2 diabetes mellitus (T2DM) which is growing as an epidemic globally. In present study we aim to assess the association of eNOS (G894T, rs1799983) and NET (G1287A, rs5569) genes polymorphism with T2DM. A case-control study including a total of 400 North Indian subjects (200 T2DM cases and 200 controls) was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach to analyze genetic polymorphism. Alleles/genotype frequencies between cases and controls were compared using χ2 and Student's t-tests. Odds ratios and 95% confidence intervals were calculated by logistic regression to assess the relative association between disease and genotypes. In case of NET gene, GG (P = 0.002 in T2DM males, 0.053 in overall T2DM cases) genotype and G allele (P = 0.003 in T2DM males, 0.027 in overall T2DM cases) were found to be a positive risk factors and AG genotype (P = 0.012 in T2DM males) and A allele (P = 0.003 in T2DM males, P = 0.027 in overall T2DM cases) as negative risk factor for T2DM. No association of eNOS gene polymorphism was found with T2DM (P values of all genotypes and alleles were greater than 0.05). NET gene polymorphism might be associated with the risk of T2DM whereas; eNOS gene polymorphism do not confer any risk of T2DM in North Indian Ethnic group. It is hoped that understanding genetic causes of T2DM will lead to earlier diagnosis, preventive measures and more effective and specific treatment.

Cardiovascular sexual dimorphism in a diet-induced type 2 diabetes rodent model, the Nile rat (Arvicanthis niloticus).

BackgroundThe Nile rat (Arvicanthis niloticus) is an emerging laboratory model of type 2 diabetes. When fed standard rodent chow, the majority of males progress from hyperinsulinemia by 2 months to hyperglycemia by 6 months, while most females remain at the hyperinsulinemia-only stage (prediabetic) from 2 months onward. Since diabetic cardiomyopathy is the major cause of type-2 diabetes mellitus (T2DM)-related mortality, we examined whether sexual dimorphism might entail cardiac functional changes. Our ultimate goal was to isolate the effect of diet as a modifiable lifestyle factor.Materials and methodsNile rats were fed either standard rodent chow (Chow group) or a high-fiber diet previously established to prevent type 2 diabetes (Fiber group). Cardiac function was determined with echocardiography at 12 months of age. To isolate the effect of diet alone, only the small subset of animals resistant to both hyperinsulinemia and hyperglycemia were included in this study.ResultsIn males, Chow (compared to Fiber) was associated with elevated heart rate and mitral E/A velocity ratio, and with lower e’-wave velocity, isovolumetric relaxation time, and ejection time. Of note, these clinically atypical types of diastolic dysfunction occurred independently of body weight. In contrast, females did not exhibit changes in cardiovascular function between diets.ConclusionsThe higher prevalence of T2DM in males correlates with their susceptibility to develop subtle diastolic cardiac dysfunction when fed a Western style diet (throughout most of their lifespan) despite no systemic evidence of metabolic syndrome, let alone T2DM.