Pathophysiology Of T2DM Research Articles

The Associations between Asprosine, Clusterin, Zinc Alpha-2-Glycoprotein, Nuclear Factor Kappa B, and Peroxisome Proliferator-Activated Receptor Gamma in the Development of Complications in Type 2 Diabetes Mellitus.

Objectives: The aim of this study was to investigate the circulating levels of asprosin, clusterin, zinc-alpha-2-glycoprotein (ZAG), nuclear factor-kappa B (NF-κB), and peroxisome proliferator-activated receptor-gamma (PPAR-γ) in patients with T2DM in relation to microvascular and macrovascular complications. Measuring these biomarkers may provide insight into the pathophysiology of T2DM and indicate novel targets for the therapy of diabetes-related complications. Methods: A total of 260 subjects consisting of four groups: healthy controls (Group-1), T2DM patients without complications (Group-2), T2DM patients with microvascular complications (Group-3), and T2DM patients with macrovascular complications (Group-4). Results: The mean age of all subjects was 52.96 ± 6.4, 127 of whom were male. Asprosin, clusterin, and NF-κB levels were significantly higher, while ZAG and PPAR-γ levels were significantly lower in diabetic patients than healthy subjects (p < 0.01, for all). Asprosin (p < 0.01), clusterin (p < 0.01), and NF-κB (p: 0.002) levels were significantly higher and PPAR-γ (p < 0.01) level was significantly lower (p < 0.001) in Group-3 than Group-2. Asprosin (p < 0.01) and NF-κB (p: 0.011) levels were significantly higher while ZAG (p < 0.01) level was significantly lower in Group-4 than Group-2. Serum ZAG level was found lower in Group-4 than in Group-3 (p = 0.037). Further, the biomarkers presented significant correlation with biomarkers like HbA1c and HOMA-IR. It was observed that increasing serum asprosin, clusterin, and NF-κB levels and decreasing serum PPAR-γ levels were effective in the development of microvascular complications while the increased asprosin levels and decreased ZAG levels had a significant effect on the development of macrovascular complications in the binary logistic regression analysis. Conclusions: This study confirms that altered levels of asprosin, clusterin, ZAG, NF-κB, and PPAR-γ are associated with T2DM and its complications. These biomarkers reflect the pathophysiological processes of metabolic disturbance and inflammation in T2DM and, therefore, have the potential for use in targeted interventions to prevent and manage diabetes-related complications.

Serum ferritin level and associated factors among uncontrolled adult type II diabetic follow-up patients: comparative based cross-sectional study

BackgroundUncontrolled type 2 diabetes mellitus (UT2DM) and its associated consequences nowadays have been a global health crisis, especially for adults. Iron has the property to oxidize and reduce reversibly, which is necessary for metabolic processes and excess accumulation of iron indicated by serum ferritin levels could have a significant impact on the pathophysiology of T2DM via generation of reactive oxygen species (ROS). However, no conclusive evidence existed about the association of serum ferritin with the state of glycemic control status. Therefore, this study aimed to evaluate serum ferritin levels and associated factors in uncontrolled T2DM patients and compare them with those of controlled T2DM and non-diabetic control groups.MethodsA hospital-based comparative cross-sectional study was conducted among conveniently selected 156 study participants, who were categorized into three equal groups of uncontrolled T2DM, controlled T2DM, and non-diabetic control groups from October 2 to December 29, 2023 at St. Paul’s Hospital Millennium Medical College. A pre-tested structured questionnaire was used to collect socio-demographic and diabetes-related information. The laboratory tests were done using an automated chemistry analyzer and IBM-SPSS statistical software (version-27) was utilized for data entry and analysis with a significance level of p < 0.05.ResultThe mean serum ferritin level was noticeably higher in uncontrolled T2DM patients as compared to controlled T2DM and control groups (p < 0.001). It was significantly correlated with HbA1c [r = 0.457, p < 0.001], fasting blood sugar (FBs) [r = 0.386, p < 0.001], serum iron [r = 0.430, p < 0.001], and systolic blood pressure (SBP) [r = 0.195, p = 0.047] in T2DM patients. A multivariate logistic regression model revealed that a rise in HbA1c (AOR = 3.67, 95% CI(1.50–8.98), serum iron (AOR = 1.02, 95% CI(1.01–1.04), male gender (AOR = 0.16, 95% CI(0.05–0.57) and being on oral hypoglycemic agent (OHA) monotherapy (AOR = 0.26, 95% CI(0.07–0.95) were key associated factors for the elevated serum ferritin among T2DM patients.ConclusionThe present study demonstrated that T2DM patients had elevated serum ferritin levels which might be related to the existence of long-term hyperglycaemia and that serum ferritin had a significant positive association with HbA1c and FBs, implying that it could be used as an additional biomarker to predict uncontrolled T2DM patients.

Immunometabolism mRNA expression phenotypes and reprogramming of CD14 in T2DM with or without CVD

Background/AimType 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) have a significant impact on the expression of genes in peripheral blood mononuclear cells (PBMCs). The primary objective of this study was to investigate the role of two signaling pathways, STAT1/6, and two important modulators of immunometabolism, leptin and PPARs, in the development of T2DM with and without CVD. Furthermore, the study aimed to assess the correlation between these factors and the dynamics of CD14 in PBMCs. This research was conducted within the context of a growing body of literature on the complex pathophysiology of T2DM and its association with CVD. Prior studies have indicated that T2DM is characterized by an imbalance in immunometabolism and the involvement of various signaling pathways. Materials and methodsBlood samples were collected from a total of 47 subjects, including 7 healthy volunteers, 20 individuals diagnosed with diabetes and cardiovascular disease (D.CVD) and another 20 individuals diagnosed with diabetes only (D). PBMCs were isolated from these samples, and the expression levels of leptin, PPARγ, PPARα, and CD14 genes were measured using Real-Time PCR. ResultsThe most relevant result showed that diabetic patients with CVD had significantly higher levels of leptin expression, which was positively correlated with STAT1 (r = 0.7497, p = 0.0001). On the other hand, diabetic patients without CVD had elevated PPARγ expression, which was strongly correlated with STAT6 (r = 0.8437, p = 0.0001). Interestingly, we found a significant increase in the PPARγ/ PPARα ratio in the D.CVD group compared to the D group (4.273 ± 0.9531; 7.52 ± 3.556, p = 0.0479). Moreover, CD14 expression was significantly reduced in this group compared to diabetic patients without CVD. ConclusionThese findings suggested that the immunometabolic imbalance in T2DM was driven by a STAT1/Leptin phenotype in diabetic patients with CVD and by a STAT6/PPARγ phenotype in diabetic patients without CVD. Taking into account STAT1/Leptin and STAT6/PPARγ profiling could help clinicians identify novel therapeutic targets for T2DM and other related diseases.

Assessment of serum zinc and its correlation with atherogenic index of plasma in type 2 diabetes

Introduction and Aim: Diabetes, a global health concern, is often compounded by nutritional perturbations. Micronutrients seem to play a regulatory role in the pathogenesis and progression of type 2 diabetes and recent evidence implicates a pivotal role of zinc in diabetes. The study aims to evaluate serum levels of zinc in diabetic patients and assess the correlation of zinc with lipid profile and ASCVD perturbations. Methodology: The present study was carried out in the Department of Biochemistry and Medicine of a tertiary care centre. 30 voluntarily consenting patients diagnosed with diabetes were recruited as cases while 30 non diabetic participants were recruited as controls. Blood samples from the participants were analysed for blood glucose, lipid profile, and serum zinc in Clinical Biochemistry Lab. Mann Whitney U test and Spearman’s rank correlation were performed to obtain statistical evidence. Results: Serum Zinc levels were significantly decreased in diabetics when compared to healthy controls. However, no statistical significance was observed among the two groups in lipid parameters, derived lipid ratios, and AIP. Serum zinc did not show a significant correlation with lipid profile, derived lipid risk assessment ratios, and AIP. Conclusion: Serum zinc levels are significantly lower in diabetics when compared to healthy subjects thus indicating the mechanistic role of zinc in the pathophysiology of T2DM. However, large cohort studies are required to clearly explain the extent of zinc deficiency and the therapeutic role/effect of zinc correction in patients with T2DM.

Low serum creatinine, a surrogate marker of muscle mass, correlates with insulin sensitivity in nonhuman primates.

Decreased serum creatinine levels are associated with increased risk of type 2 diabetes (T2DM) in humans, however, its association with muscle mass and insulin sensitivity have not been studied in NHPs. Retrospective data of 229 adult NHPs were studied for association of serum creatinine levels with muscle mass and onset of T2DM. Serum creatinine levels were positively correlated with lean muscle mass in nondiabetic (non-DM), male and female NHPs. Aged NHPs had significantly reduced lean muscle mass and corresponding creatinine levels compared to young age groups (p < .001). Creatinine was positively correlated with insulin sensitivity in nonDM male NHPs and significant decrease in creatinine was observed in T2DM (p < .001) compared to same age group nonDM NHPs. The pathophysiology of T2DM in NHPs is similar to humans, low creatinine further provides utility of surrogate biomarkers of lower muscle mass and risk factor for T2DM NHPs.

Association of tag single nucleotide polymorphisms (SNPs) at lncRNA MALAT1 with type 2 diabetes mellitus susceptibility in the Chinese Han population: A case-control study

BackgroundType 2 diabetes mellitus (T2DM) is a chronic, lifelong disease. The molecular mechanisms and pathophysiology of T2DM have not yet been fully elucidated. Dysregulation of the long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) is considered one of the main contributing factors of the dysfunction found in many diseases, including those of the endocrine system. The aim of this study was to investigate the association between lncRNA MALAT1 single nucleotide polymorphisms (SNPs) and T2DM in the Chinese Han population. MethodsWe genotyped three SNPs (rs3200401 C > T, rs619586 A > G, rs11227209 C > G) of the MALAT1 gene, including 571 T2DM patients and 526 controls. The association between different genotypes and the risk of T2DM was analyzed using logistic regression, and the results were expressed by odds ratio (OR) and its 95% confidence interval (95%CI), and then stratified by age, sex, and BMI. P < 0.05 on both sides was considered as statistically significant. ResultsWe found that the CT + TT genotypes of the rs3200401 polymorphism were significantly associated with an increased risk of T2DM in Chinese Han population (OR = 1.77; 95% CI:1.35–2.33; Padjusted < 0.001), whereas MALAT1 rs619586 AG + GG genotypes were associated with a reduced risk of T2DM (OR = 0.67; 95% CI:0.48–0.94; Padjusted = 0.021). Subsequent stratified analysis showed that compared with the rs3200401 CC genotype, CT + TT genotypes were associated with an increased risk of T2DM in the male, female, age ≥ 65 years, and BMI ≥ 24 subgroups (OR = 1.68, 95% CI:1.10–2.56, Padjusted = 0.016; OR = 1.83, 95% CI:1.27–2.62, Padjusted = 0.001; OR = 1.86, 95% CI:1.38–2.52, Padjusted < 0.001; OR = 2.13, 95% CI:1.45–3.15, Padjusted < 0.001; respectively). Haplotype analysis showed that T-A-C haplotype had a 1.533-fold increased risk of T2DM (95% CI, 1.208–1.945, P < 0.001) and C-G-G was associated with a decreased risk of T2DM. No significant association was found between rs11227209 and T2DM risk (P > 0.05). ConclusionThe results suggest that MALAT1 rs619586 and rs3200401 confer susceptibility for T2DM in the Chinese Han population and provide new genetic targets for the treatment of diabetes and its complications in the future.

Establishing a Reference Interval for an Estimate of Peripheral Insulin Resistance in a Group of Iraqi People

Background and aims: Insulin resistance (IR) is the cornerstone in pathophysiology of T2DM. Identifying people with IR can slow the progress to diabetes. Triglyceride and glucose index (TyG index) is a simple tool to assess IR without insulin measurement. This study aims at establishing the reference interval for TyG index in apparently healthy Iraqis. Material and method: This study involved (77) apparently healthy adults (41 men and 36 women) in Mosul, Iraq. Fasting Serum lipids, glucose and insulin were measured and BMI was calculated. The modified TyG index was calculated and compared to other surrogate measures of IR and its reference interval was calculated. Results: TyG index values were normally distributed and significantly correlated with HOMA-IR, Mc-Auley index, QUICKI, and triglycerides/ HDL-c index (r= 0.322, p= 0.004; r=-0.68, p&lt;0001; r= -0.29, p=0.01; r=0.84, p&lt;0.0001respectively). ANOVA and PostHoc Duncan’s analyses revealed significant differences in mean TyG between (lean people) and (overweight and obese subjects), (p=0.02). BMI- based TyG reference intervals were calculated as (4.11- 4.91) and (4.25- 5.05) respectively. This is the first study in Iraq to set a reference interval for TyG index. Values should be interpreted according to BMI.&#x0D;

Evaluation of Galectin1 gene, miRNA22 and LncRNA MEG3 in type2 diabetic patients

Abstract Background Diabetes mellitus is considered the ninth major cause of death, biomarkers have been investigated in DM research field to understand the pathophysiology of DM, help in diagnosis and find new therapeutics. This study evaluated the role of Galectin 1, LncRNA MEG3, miR22 in T2DM. Aim of the work we aimed to evaluate the role of galectin 1 expression in type 2 DM and to explore the epigenetic regulatory effect of miRNA22 and LncRNA, MEG3 on gelatin 1 expression in type 2 DM Materials and methods The study included two groups: Fifteen type 2 diabetes mellitus patients and fifteen normal healthy individuals. Blood samples were collected from every participant and serum was separated. Expressions of Gal-1, LncRNA MEG3, miR22 were assessed in each serum sample by quantitative real time polymerase chain reaction (qRT-PCR). Results The study revealed higher levels of gal-1, miR22 and lower levels of MEG3 in serum samples of T2DM Patients compared to normal healthy individuals with statistical significance difference (p &amp;lt; 0.05). Conclusion Gal-1, MEG3, miR22 may play a role in the pathophysiology of T2DM. Studies with larger sample sizes are required to further confirm their role in early detection and diagnosis of T2DM.

Psychosocial stress, sleep deprivation, and its impact on type II diabetes mellitus: Policies, guidelines, and initiatives from Malaysia.

Type II Diabetes Mellitus (T2DM) is a serious public health issue, affecting the global population, particularly those living in low‐ and middle‐income countries. Worldwide, the prevalence of T2DM ranges between 10.4% and 13.5%, depending on the domiciliary. T2DM negatively affects individuals' quality of life and causes high economic burden due to the increasing cost of treatment and management of the disease. Risk factors associated with T2DMs include aging, lifestyle or behavior, genetics, and important biopsychological aspects, which are psychological stress and sleep deprivation. By understanding the associations of psychological stress and sleep deprivation, which contribute to pathophysiology of T2DM, policies, programs, and guidelines were developed in Malaysia to combat the issue among population at large. This narrative review examines 19 national public health policies, programs, and guidelines from the past 20 years in Malaysia that aimed to mitigate the negative health effects of psychological stress, sleep deprivation, and T2DM, both from the government and non‐governmental organizations. Both psychological stress and sleep deprivation works independently or as combined effects in the pathophysiology of T2DM. Besides, in Malaysia, the government, in collaboration with non‐governmental organizations, have been developing and implementing policies, programs, and guidelines to combat mental health and T2DM issues, targeted to population at large. Integration of digital technology, such as usage of social media for health promotion and dissemination of public health messages to the community and good governance from government were deemed important in the effective implementation of health policies and guidelines, resulting in better health outcome.

The role of lycopene for the amelioration of glycaemic status and peripheral antioxidant capacity among the Type II diabetes mellitus patients: a case–control study

Background The use of lycopene as a complementary medicine for Type II diabetes mellitus (T2DM) is limited and controversial. This study evaluated the effect of lycopene intake on the changes of glycaemic status and antioxidant capacity among the T2DM patients. Patients and methods This case–control study involved the participation of 87 patients and 122 healthy individuals. Lycopene intake was assessed by using a food frequency questionnaire. The peripheral antioxidant capacity among the T2DM patients was evaluated. Glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) were measured as indications of glycaemic status. Results Peripheral antioxidant capacity was significantly lower in the T2DM group. Direct positive correlations were found between the lycopene intake and peripheral antioxidant level among the T2DM patients. Contrarily, HbA1c and FPG levels decreased significantly with the higher lycopene intake. Conclusions T2DM patients with a higher lycopene intake showed a greater peripheral antioxidant capacity and better glycaemic control. Lycopene may act to ameliorate oxidative stress and improve the pathophysiology of T2DM.

Beta-Cell Mass in Obesity and Type 2 Diabetes, and Its Relation to Pancreas Fat: A Mini-Review.

Type 2 diabetes (T2DM) is characterized by insulin resistance and beta-cell dysfunction. Although insulin resistance is assumed to be a main pathophysiological feature of the development of T2DM, recent studies have revealed that a deficit of functional beta-cell mass is an essential factor for the pathophysiology of T2DM. Pancreatic fat contents increase with obesity and are suggested to cause beta-cell dysfunction. Since the beta-cell dysfunction induced by obesity or progressive decline with disease duration results in a worsening glycemic control, and treatment failure, preserving beta-cell mass is an important treatment strategy for T2DM. In this mini-review, we summarize the current knowledge on beta-cell mass, beta-cell function, and pancreas fat in obesity and T2DM, and we discuss treatment strategies for T2DM in relation to beta-cell preservation.

SGLT2 Inhibitors as Add-On Therapy to Metformin for People with Type 2 Diabetes: A Review of Placebo-Controlled Trials in Asian versus Non-Asian Patients.

Metformin remains the first pharmacological choice for treating hyperglycemia in type 2 diabetes (T2DM) in most international guidelines. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are increasingly used as add-on therapy. T2DM pathophysiology is different in Asian and non-Asian (mainly Caucasian) patients. The aim of this systematic review is to compare the efficacy of SGLT2is vs placebo added to metformin in randomized controlled trials (RCTs: range 12–52 weeks) in Asian versus non-Asian patients with T2DM. The primary endpoint is the reduction in glycated hemoglobin (HbA1c) from baseline and key secondary endpoints are reductions in fasting plasma glucose (FPG), body weight (BW) and systolic blood pressure (SBP). Systematic literature search collected 7 RCTs (3 with 2 doses) in Asian patients (10 analyses, n=1164, iSGLT2: canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, tofogliflozin)) and 10 RCTs (6 with two doses) in non-Asian patients (16 analyses, n=2482, iSGLT2: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin). Baseline values of HbA1c (7.98±0.19 vs 7.89±0.27%), FPG (8.80 ±0.46 vs 9.11±0.49 mmol/l) and SBP (128.4±1.6 vs 130.2±3.1 mmHg) were not significantly different in Asian vs non-Asian patients, but BW was lower in Asian patients (71.6±4.8 vs 88.0±2.5 kg, p<0.001). The placebo-adjusted weighed mean differences (WMD, 95% CI) were similar in Asian versus non-Asian patients regarding the reductions in HbA1c −0.60 (−0.68, −0.53) % versus −0.54 (−0.59, −0.49) % (p=0.568), FPG −1.37 (−1.53, −1.22) mmol/l vs −1.37 (−1.47, −1.27) mmol/l (p=0.627), BW when expressed in percentage of baseline BW −2.23 (−2.55, −1.90) % vs −2.16 (−2.37, −1.96) % (p=0.324), and SBP −4.53 (−5.53, −3.53) mmHg vs −4.06 (−4.83, −3.29) mmHg) (p=0.223). In conclusion, clinical efficacy of SGLT2i, as an add-on treatment to metformin monotherapy in patients with T2DM, is similar in Asian versus non-Asian patients, despite known ethnic differences in phenotype and pathophysiology of T2DM.

Treat liver to beat diabetes

Management of Type 2 Diabetes (T2DM) with existing strategies of life style and pharmaceutical interventions has gained limited success as evidenced by its uncontrolled progression. Two key organs which are involved in pathophysiology of T2DM are liver and pancreas, both are the derivatives of endoderm with common precursor. In the invertebrates, hepatopancreas performs function of both liver and pancreas. It is known that derangement in glycolysis, neoglucogenesis, and glycogenolysis lead to hyperglycemia in T2DM although insulin levels are high. Several studies have reported implication of abnormal liver function in the development of metabolic syndrome i.e. T2DM. Partial hepatectomy has been shown to improve glycemic status in animal models of diabetes. This could be because liver and pancreas share same regenerating factors. These evidences suggest that abnormal liver status can impair pancreatic beta cell function and survival along with peripheral insulin resistance. We therefore hypothesize that restoring deranged liver functions may aid in the better control and management of T2DM. If found true, it may shift current intervention strategy towards liver rather than pancreas in the treatment of T2DM.

The Role of Obesity-Induced Inflammation in Pancreatic -Cell Dysfunction and Death

Type 2 diabetes (T2DM) is frequently associated with elevated levels of lipids, in particular plasma free fatty acids and toxic lipid metabolites in muscle, liver, adipocytes, pancreatic islets and arterial tissues, contributing to insulin resistance and pancreatic islet β-cell dysfunction. The pathophysiology of T2DM is increasingly being linked with inflammatory mediators such as cytokines and chemokines as well as with changes in the number and activation state of macrophages/monocytes leading to β-cell dysfunction and subsequently to insulin insufficiency. The prevalent product of the cyclooxygenase 2 (COX-2) enzyme PGE2, controls numerous physiological functions through a family of cognate G proteincoupled receptors (EP1-EP4). The EP3 receptor which is selectively upregulated in islets of T2DM individuals, is upregulated under lipotoxic conditions and is involved in β-cell dysfunction and demise. This EP3 target presents a new approach to delay the progression of T2DM disease by preserving the pancreatic β-cells.

Plasma glucagon levels measured by sandwich ELISA are correlated with impaired glucose tolerance in type 2 diabetes.

Glucagon dysfunction as well as insulin dysfunction is associated with the pathogenesis of type 2 diabetes (T2DM). However, it is still unclear whether the measurement of plasma glucagon levels is useful in understanding the pathophysiology of T2DM. We recently reported that sandwich ELISA provides more accurate plasma glucagon values than conventional RIA in healthy subjects. Here we used sandwich ELISA as well as RIA to assess plasma glucagon levels, comparing them in T2DM patients and healthy subjects during oral glucose (OGTT) or meal tolerance tests (MTT). We confirmed that sandwich ELISA was able to detect more significant difference between healthy subjects and T2DM patients in the fasting levels and the response dynamics of plasma glucagon than RIA. We also found significant differences in the following glucagon parameters: (1) fasting glucagon, (2) the area under the curve (AUC) of glucagon in OGTT, and (3) the change in glucagon between 0 and 30 min (ΔGlucagon0-0.5h) in OGTT or MTT. Among these, the most apparent difference was ΔGlucagon0-0.5h in MTT. When we divided T2DM patients into two groups whose ΔGlucagon0-0.5h in MTT was either below or above the maximum value in healthy subjects, the group with higher ΔGlucagon0-0.5h showed more significant impairment of glucose tolerance. These results suggest that the assessment of plasma glucagon levels by sandwich ELISA might enhance our understanding of the pathophysiology of T2DM.

A Recent Achievement In the Discovery and Development of Novel Targets for the Treatment of Type-2 Diabetes Mellitus.

Type 2 diabetes (T2DM) is a chronic metabolic disorder. Impaired insulin secretion, enhanced hepatic glucose production, and suppressed peripheral glucose use are the main defects responsible for developing the disease. Besides, the pathophysiology of T2DM also includes enhanced glucagon secretion, decreased incretin secretion, increased renal glucose reabsorption, and adipocyte, and brain insulin resistance. The increasing prevalence of T2DM in the world beseeches an urgent need for better treatment options. The antidiabetic drugs focus on control of blood glucose concentration, but the future treatment goal is to delay disease progression and treatment failure, which causes poorer glycemic regulation. Recent treatment approaches target on several novel pathophysiological defects present in T2DM. Some of the promising novel targets being under clinical development include those that increase insulin sensitization (antagonists of glucocorticoids receptor), decreasing hepatic glucose production (glucagon receptor antagonist, inhibitors of glycogen phosphorylase and fructose-1,6-biphosphatase). This review summarizes studies that are available on novel targets being studied to treat T2DM with an emphasis on the small molecule drug design. The experience gathered from earlier studies and knowledge of T2DM pathways can guide the anti-diabetic drug development toward the discovery of drugs essential to treat T2DM.

4-Phenylbutyric acid and rapamycin improved diabetic status in high fat diet/streptozotocin-induced type 2 diabetes through activation of autophagy

An accumulating body of evidence supports the role of autophagy in the pathophysiology of T2DM. Also, abnormal endoplasmic reticulum (ER) stress response that has been implicated as a cause of insulin resistance (IR) could also be affected by the autophagic status in β-cells. The present study was designed to investigate whether autophagy is regulated in T2DM as well as to investigate the modulatory effect of the ER stress inhibitor 4-phenylbutyric acid (4-PBA) and the autophagy inducer rapamycin (Rapa) on the autophagic and diabetic status using type 2 diabetic animal model with IR. Treatment of diabetic rats with either 4-PBA or Rapa improved significantly the states of hyperglycaemia and dyslipidaemia, increased the antioxidant capacity, reduced the levels of lipid peroxidation and ER stress and increased the autophagic flux. The obtained improvements were attributed mainly to the induction of autophagy with subsequent regulation of ER stress-oxidative activation and prevention of β-cell apoptosis.

Changing the Concept of Type 2 Diabetes: Beta Cell Workload Hypothesis Revisited.

BackgroundDespite a number of innovations in anti-diabetic drugs and substantial improvement in diabetes care, the number of people with diabetes continues to increase, suggesting further need to explore novel approaches to prevent diabetes. Type 2 diabetes (T2DM) is characterized by beta cell dysfunction and insulin resistance. However, insulin resistance, usually a consequence of obesity, is often emphasized and the role of beta cell dysfunction in T2DM is less appreciated.Objective and ResultsThis paper summarizes recent evidence showing the importance of beta cell dysfunction in T2DM and refines the “beta cell workload hypothesis”, emphasizing the importance of beta cell preservation for the prevention and management of T2DM.ConclusionIt is hoped that this novel concept will foster a better understanding of the pathophysiology of T2DM by not only medical staff and patients with diabetes, but also the general population, and encourage more people to adhere to a healthy lifestyle, eventually resulting in “stopping diabetes”.

Dynamic transcriptome profile in db/db skeletal muscle reveal critical roles for long noncoding RNA regulator

T2DM is a global health problem that seriously lowers the quality of life and insulin resistance makes a considerable contribution to the pathophysiology of T2DM. Long noncoding RNAs (lncRNAs) have emerged as important regulators in glucose and lipid metabolism. However, comprehensive analysis of lncRNAs in db/db mice skeletal muscle and their potential roles involved in skeletal muscle insulin resistance (IR) remains poorly characterized. Here, we identified 331 lncRNAs, 172 upregulated and 159 downregulated (|fold change|>2, q<0.05), differentially expressed in db/db mice skeletal muscle. Gene Ontology analysis, Pathway analysis and Gene Set Enrichment Analysis of network gene expression revealed the potential functions of dysregulated lncRNAs may involve skeletal muscle function, fatty acid metabolism and the PPAR signaling pathway. In addition, differentially expressed lncRNAs were verified in skeletal muscle from the widely known IR mouse models (db/db and ob/ob mice). Further validation of lncRNAs in C2C12 myotubes exposed with various concentrations of palmitate uncovered that lncRNAs were responsive to palmitate exposure at the high concentrations (0.5mM and 0.75mM). Coexpression analysis revealed the key lncRNA-mRNA interactions and indicated a potential regulatory role of lncRNAs. Moreover, we characterized two candidate lncRNAs Gm15441 and 3110045C21Rik by a comprehensive examination of their genomic context and validated their expression with neighboring genes (Txnip and Ddr2) by the Spearman correlation analysis. Collectively, these findings improve our understanding of lncRNAs that mediate skeletal muscle insulin resistance in diabetes and represent potential molecular therapeutic targets to improve insulin sensitivity and associated metabolic diseases.

Applied Predictive Modeling of Coronary Microvascular Disease using Coronary Doppler and Cardiac Echocardiography

IntroductionType 2 diabetic (T2DM) coronary resistance microvessels (CRMs) show early inward hypertrophic remodeling and reduced wall stiffness, which are associated with decreased blood flow (CBF), coronary flow reserve, and disrupted flow patterns. These data may suggest that coronary microvascular disease (CMD) underlies the early pathophysiology of T2DM. Furthermore, distinct correlations have been identified between the Doppler coronary flow pattern in both normal and T2DM mice, potentially allowing for a predictive relationship between coronary flow patterns and CMD. Currently, CMD is extremely difficult to diagnose due to lack of non‐invasive methods. The goal of this study was to develop an applied predictive model for CMD non‐invasively in early T2DM using CBF combined with functional and structural measurements of the heart.MethodsCBF of the left main coronary artery, aortic flow, E &amp; A wave, left ventricular structural dimensions, and aortic diameter were recorded using high frequency, high resolution non‐invasive Doppler echocardiography (Vevo2100, Visual Sonics, Toronto, Canada) in 37 normal heterozygous Db/db mice and 36 T2DM homozygous db/db mice. Coronary flow patterns were analyzed using a Matlab program developed in our laboratory to identify 13 distinct parameters. All other flow patterns and structural and functional features were manually measured in the Vevo2100 software resulting in 13 additional parameters. All the parameters were feature engineered, and a factor analysis model was created and tested using various machine learning algorithms.ResultsPhysiological data were subjected to a variety of machine learning models, and the “glmnet algorithm” in R software (generalized linear regression via penalized maximum likelihood) best predicted CMD with a cross validation accuracy of 80.19% and test dataset accuracy to date of 84.84%.ConclusionAn applied predictive model for CMD in T2DM was developed using 73 mice, which shows a promising ability to accurately predict CMD in T2DM. Further studies will be undertaken to improve the predictive accuracy of the model to be suitable for clinical diagnostics and/or decision support.Support or Funding InformationSupported by the National Institutes of Health (R00 HL‐116769 to AJT) and Nationwide Children's Hospital (to AJT and CWB).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.