Obese Type 2 Diabetes Mellitus Research Articles

Effectiveness comparisons of catgut implantation at acupoint for obese type 2 diabetes: A protocol for systematic review and meta analysis.

Background:With the change of people's life style, many more people are suffering from obese type 2 diabetes mellitus (T2DM). Acupoint catgut embedding is one of the acupuncture treatment principles in traditional Chinese medicine, which is widely used in the treatment of obese T2DM. However, there is no systematic review of the therapeutic effect of acupoint catgut embedding on obesity T2DM. Therefore, this article aims at the meta-analysis of acupoint catgut embedding in the treatment of obese T2DM, to clarify its curative effect.Methods:A structured and systemic literature search was conducted in the following databases up to December 1, 2019: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, EMBASE, CNKI, Wanfang Database. We will use the Review Manager 5.3 software provided by Cochrane collaborative network for statistical analysis. Then we assessed the quality and risk of the included studies and observed the outcome measures.Results:This meta-analysis will further determine the beneficial efficacy of acupoint catgut embedding on obesity T2DM.Conclusion:The purpose of this meta-analysis is to explore the effect of acupoint catgut embedding intervention on obese T2DM patients, and provide more options for clinicians and patients to treat obese T2DM.Ethics and dissemination:This systemic review will evaluate the efficacy and safety of acupoint catgut embedding in the treatment of obesity T2DM. Since all the data included are published, the systematic review does not need ethical approval.Registration number:CRD42020160801.

Gravicentric approach to Type 2 Diabetes therapy. 
 The success prediction. A proof-of-concept

This study is the proof-of-concept of our "Gravicentric" theory. This concept is based on several fundamental points: obesity as the main foe; rapid reversibility of the disease; as well as a new perspective on the roles different pharmacological classes play in general, and the role of insulin and GLP-1 analogs, in particular. The paper presents and discusses our experience of the implementation of insulin and GLP-1 analogs. The possibility of "insulin weaning"; the therapeutic approach for over-treated patients; and physiological dosing of insulin is also discussed therein.
 Objectives
 Primary: To evaluate the long-term efficacy of GLP-1 analogs in insulin-treated Type 2 Diabetes Mellitus (T2DM) patients.
 Secondary: To analyze which patient would most likely benefit from this combined treatment.
 Methods
 In 54 T2DM patients with a mean disease duration of 17.5 years and a mean extent of insulin therapy of 4.5 years, additional GLP-1 analogs therapy was prescribed. Mean duration of GLP-1 treatment was 25.8 months (2.15 years).
 During the intervention, clinical, biochemical, and anthropometric parameters were analyzed. Compliance, Hypoglycemia and Metabolic Index (MI) assessments were implemented.
 Results
 Mean Glycated hemoglobin (HbA1C) decreased from 9.28 1.43 to 8.54 1.4% on GLP-1 analogs, p 0.01. Total Daily dose of Insulin (TDI) showed considerable reduction: 80.6 42.7 U/day before starting GLP-1 vs.41.0 30.7 U/day on GLP-1, p 0.01. These changes were directly linked to weight loss: BMI has dropped from 35.1 4.8 kg/cm2 before, to 32.8 5.0 kg/cm2 on GLP-1 analogs, with patients losing 6.7 kg on average. Moreover, 13 (24%) participants discontinued at least one kind of insulin, while 7 (13%) stopped taking insulin completely, with simultaneous improvement in diabetes control. No clinically significant hypoglycemia was observed.
 Post-hoc, the participants were categorized according to each patients ability to reduce TDI by more than 20 U/day, and then split into two groups. Group A 34 patients (64.2%) who successfully reduced TDI; Group B 19 patients (35.8%) who failed to do so. The comparison of the two groups showed the following:
 
 Significantly larger virtually twice as large baseline TDI in Group A (97.440.4 U/day vs. 52.231.0 U/day), p 0.001.
 Very effective BMI reduction (BMI 3.3 2.4 kg/cm2 0.9 1.2 kg/cm2, p 0.001) and much better compliance (1.4 1.1 vs. 2.2 1.0, p 0.02) in Group A.
 A considerable decline of insulin requirements in group A, on GLP-1 therapy (TDI on GLP-1 was -62.4 31.9 U/day) with no TDI reduction in Group B (TDI on GLP-1 was +0.03 14.1 U/day, p 0.001).
 
 Thus, in spite of the fact that on GLP1 therapy HbA1C has declined to the same levels in both groups, patients from group A became much leaner and metabolically healthier.
 We suggest overtreatment as the critical factor of obesity in Group A.
 Conclusions
 Adding GLP-1 analogs to insulin in poorly controlled, insulin-treated T2DM patients resulted in an impressive weight (BMI) reduction with significant improvements in glucose control. This provided for a further decline in insulin resistance and insulin requirements. We suggest that the best candidate for successful GLP-1 analogs therapy is an obese, overtreated and compliant T2DM person. Changes in Metabolic Index (MI) rather than surrogate glycemic parameters (HbA1C) are better predictors of a successful T2DM therapy. Neither the duration of diabetes nor the length of insulin therapy in the past is likely to have a critical role in predicting success. These findings are proof-of-concept of our Gravicentric theory in T2DM.

Effects of bariatric surgery on kidney diseases, cardiovascular diseases, mortality and severe hypoglycaemia among patients with Type 2 diabetes mellitus.

Bariatric surgery has been widely indicated for the management of obesity and related comorbidities. However, there are uncertainties pertaining to the risks of post-bariatric severe hypoglycaemia (SH), cardiovascular diseases (CVDs), end-stage kidney diseases (ESKDs) and all-cause mortality in obese patients with Type 2 diabetes mellitus (T2DM), especially among Asian populations. A retrospective population-based cohort of 1702 obese T2DM patients who were free of CVD and ESKD were assembled based on the 2006-17 Hospital Authority database. One-to-five propensity-score matching was used to balance baseline covariates between patients in bariatric surgery and control groups. Incidence rates (IRs) of SH, CVD, Stage 4/5 chronic kidney diseases (CKD), ESKD and all-cause mortality events for two groups were calculated. Hazard ratios (HR) for SH, CVD and Stage 4/5 CKD events were assessed using Cox-proportional hazard models. Changes in estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) were measured up to 60 months. Over a mean follow-up period of 32 months with 5725 person-years, cumulative incidences of mortality, CVD, Stage 4/5 CKD, ESKD and SH were 0, 0.036, 0.050, 0.017 and 0.020, respectively. The surgery group had a significant reduction in risk of CVD events (HR = 0.464, P = 0.015) and no occurrence of mortality events. However, there were no significant differences in risks of SH [HR = 0.469, 95% confidence interval (CI): 0.204-1.081], Stage 4/5 CKD (HR =0.896, 95% CI: 0.519-1.545) and ESKD (HR = 0.666, 95% CI: 0.264-1.683) between two groups, although IRs were lower in the surgery group. Surgical patients had significantly higher eGFR within 12 months and had significantly lower UACR until 48 months. Among obese T2DM patients, bariatric surgery lowered the risk of CVD and mortality, and was beneficial towards the kidney outcomes.

Do different bariatric surgical procedures influence plasma levels of matrix metalloproteinase-2, -7, and -9 among patients with type 2 diabetes mellitus?

BACKGROUNDBariatric surgery is an efficient strategy for body weight and type 2 diabetes mellitus (T2DM) management. Abnormal lipid deposition in visceral organs, especially the pancreas and liver, might cause beta-cell dysfunction and insulin resistance. Extracellular matrix (ECM) remodeling allows adipose expansion, and matrix metalloproteinases (MMPs) play essential roles in ECM construction. MMP-2 and MMP-9 are the substrates of MMP-7. Different studies have reported that MMP-2, -7, and -9 increase in patients with obesity and metabolic syndromes or T2DM and are considered biomarkers in obesity and hyperglycemia patients.AIMTo prospectively investigate whether MMP-2, MMP-7, and MMP-9 differ after two bariatric surgeries: Gastric bypass (GB) and sleeve gastrectomy (SG).METHODSWe performed GB in 23 and SG in 19 obese patients with T2DM. We measured body weight, waist circumference, body mass index (BMI), and serum concentrations of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting blood sugar (FBS), hemoglobin A1c (HbA1c), C-peptide, homeostasis model assessments of insulin resistance, and MMP-2, MMP-7, and MMP-9 levels at baseline and at 3, 12, and 24 mo post-operation.RESULTSTwenty-three patients aged 44.7 ± 9.7 years underwent GB, and 19 patients aged 40.1 ± 9.1 years underwent SG. In the GB group, BMI decreased from 30.3 ± 3.4 to 24.4 ± 2.4 kg/m2, HbA1c decreased from 9.2% ± 1.5% to 6.7% ± 1.4%, and FBS decreased from 171.6 ± 65.0 mg/dL to 117.7 ± 37.5 mg/dL 2 years post-operation (P < 0.001). However, the MMP-2, MMP-7, and MMP-9 levels pre- and post-GB were similar even 2 years post-operation (P = 0.107, 0.258, and 0.466, respectively). The SG group revealed similar results: BMI decreased from 36.2 ± 5.1 to 26.9 ± 4.7 kg/m2, HbA1c decreased from 7.9% ± 1.7% to 5.8% ± 0.6%, and FBS decreased from 138.3 ± 55.6 mg/dL to 95.1 ± 3.1 mg/dL (P < 0.001). The serum MMP-2, -7, and -9 levels pre- and post-SG were not different (P = 0.083, 0.869, and 0.1, respectively).CONCLUSIONImprovements in obesity and T2DM induced by bariatric surgery might be the result of MMP-2, -7, or -9 independent pathways.

1703-P: Altered UCP1 Expression in ADSC-Derived Beige Adipocytes Determines Mitochondrial ROS Production in T2DM Patients

Background: Under normal physiological conditions, adipose derived stem cells (ADSC) maintain adipose tissue homeostasis by responding to metabolic loading through proliferation and differentiation. Nevertheless, in T2DM their properties might be compromised. ADSC give rise to thermogenic beige adipocytes that make a significant contribution into excess energy utilization in obesity. We compared ADSC response to beiging inductors in obese patients with type 2 diabetes mellitus (T2DM) and with normal glucose tolerance (NGT). Methods: We collected subcutaneous fat biopsies from 5 obese NGT (BMI&amp;gt;35kg/m2) and 5 obese T2DM patients during bariatric surgery. ADSC were enzymatically isolated and underwent white and beige adipogenic differentiation. UCP-1 level was evaluated by RT-PCR and Western blot. Expression of lipid metabolism and electron transport chain (ETC) genes were analyzed by RT-PCR. ROS production was evaluated by fluorescent microscopy. Results: UCP-1 expression was decreased in beige adipocytes from T2DM patients in mRNA and protein levels. Nevertheless, expression and phosphorylation of lipolytic proteins were equal in beige adipocytes of NGT and T2DM groups. Expression analysis of ETC genes also has not shown any statistically significant differences. All the while, we revealed increased mitochondrial ROS production in T2DM beige adipocytes during beige differentiation. Conclusions: These results indicate association of ADSC thermogenic potential and T2DM development. Decreased UCP1 level in complex with normal lipolysis and ETC activity in beige adipocytes from T2DM patients may be liable to elevated ROS level, known to initiate mitochondria damage and insulin resistance. Disclosure S. Michurina: None. I. Stafeev: None. I. Sklyanik: None. E. Shestakova: Employee; Spouse/Partner; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharma K.K., Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. A. Yurasov: None. K. Yahyaev: None. E. Ratner: None. M. Menshikov: None. M.V. Shestakova: None. Y.V. Parfyonova: None. Funding Russian Science Foundation (17-15-01435)

P1039BARIATRIC SURGERY AND RISKS OF RENAL DISEASES, CARDIOVASCULAR DISEASES AND MORTALITY AMONG PATIENTS WITH TYPE 2 DIABETES MELLITUS

Abstract Background and Aims To measure and compare the risks of end-stage renal diseases (ESRD), cardiovascular diseases (CVD), all-cause mortality between obese type 2 diabetes mellitus (T2DM) patients with and without bariatric surgery. Method A retrospective population-based cohort of 1,690 obese T2DM patients who were free of ESRD and CVD were assembled based on 2006-2017 Hospital Authority database. One-to-five propensity-score matching was used to balance baseline covariates between patients in bariatric surgery and control groups. Incidence rates (IR) of stage 4/5 chronic renal diseases, ESRD, CVD and all-cause mortality events for two groups were calculated. Hazard ratios (HR) for stage 4/5 chronic renal diseases, ESRD, CVD events were assessed using Cox proportional hazard models. Changes in estimated glomerular filtration rate (eGFR), and urine albumin-creatinine ratio (UACR) were measured up to 60 months. Results Over a mean follow-up period of 34 months with 863 person-years, cumulative incidences of mortality, stage 4/5 chronic kidney diseases, ESRD and CVD for surgical patients were 0, 0.050, 0.017, and 0.036, respectively. Surgical patients had reduced IR of all-cause mortality, stage 4/5 chronic kidney diseases, ESRD and CVD (IR=0, 1.784, 0.587 and 1.321 per 100 person-years, respectively) than control patients (IR=1.954, 2.028, 0.914 and 2.814 per 100 person-years, respectively). Surgery group had a significant reduction in risk of CVD events (HR=0.464, P=0.015), and no occurrence of mortality events. However, the IR of stage 4/5 chronic kidney diseases and ESRD of the two groups were not significantly different. Surgical patients had significantly higher eGFR within 12 months, and had significantly lower until 48 months. Conclusion Among obese T2DM patients, bariatric surgery lowered the risk of CVD and mortality, and was beneficial towards the kidney outcomes of eGFR up to 36 months.

The Association of Dietary Intakes and Gut Microbiota in Korean Lean and Obese Patients with Type 2 Diabetes

Abstract Objectives Several studies have reported that dysbiosis of the gut microbiota as a key role in rapid progression of insulin resistance and type 2 diabetes mellitus (T2DM). The diet can affect the composition and proper function of the gut microbiota. However, the association of diets, blood parameters, and gut microbiota studies have not been fully investigated in Korean subjects. Thus, the aim of this study was to characterize and compare the dietary intake, blood parameters, and gut microbiota in Korean lean and obese T2DM patients. Methods T2DM patients were recruited. We are classified as obese group (ODM; body mass index (BMI) ≥ 25 kg/m2) and lean group (LDM; BMI &amp;lt; 25 kg/m2). The anthropometric data, body composition, and blood parameters were measured. 3-day food record evaluation was used to analyze dietary intake using computer aided nutritional program (version. 5.0). The gut microbiota was investigated by quantitative real-time PCR. The collected data were analyzed statistically using SPSS statistics (version 25.0). Results Body weight, body fat mass, and % body fat of the ODM group were significantly higher than the LDM group. Compared with the ODM group, serum adropin and adiponectin of the LDM group were significant higher, whereas serum leptin of the LDM group was significant lower. The intakes of energy, fat, cholesterol, and protein in the ODM group tended to be higher in comparison the LDM group, although the difference was not significant. The difference of gut microbiota between the LDM and ODM groups was not found. However, the Firmicutes/Bacteroidetes ratio was significantly increased in accordance with BMI, the Prevotella was also positive correlated with PUFA intake. In ODM group, the consumption of vegetables was positively correlated with the Lactobacillus. Conclusions We found that the diet can affect the composition of gut microbiota and the effects of diet were different depending of the body weight in Korean T2DM patients. Funding Sources This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP).

Effect of liraglutide on epicardial adipose tissue thickness with echocardiography in patients with obese type 2 diabetes mellitus

Liraglutide, an analogue of glucagon-like peptide 1 (GLP-1), indicated for the treatment of type 2 diabetes mellitus (T2DM), has shown the effect on loss of weight and adipose deposits. The study was to evaluate the effect of liraglutide on epicardial adipose tissue (EAT) with echocardiography in patients with obese T2DM controlled on liraglutide monotherapy. A single-arm follow-up research was performed in our study. Thirty-six subjects with obese T2DM were enrolled in the study, who were administered with liraglutide monotheraphy daily. The study period was 3 months. EAT thickness was measured with echocardiography both before and after treatment in each subject; meanwhile, anthropometrics and biochemicals (fasting blood glucose and hemoglobinA1c) were also conducted. EAT thickness decreased significantly after three-month treatment, from 9.14 ± 2.39 to 6.42 ± 1.48 mm (p < 0.05). Anthropometrics including body weight, body mass index (BMI), waist circumference (WC), hip circumference (HC), and some biochemicals including fasting blood glucose (FBG), hemoglobinA1c (HbA1c), C-peptide, insulin, HOMA-IR, AST, ALT, and urinary albumin significantly improved (totally p< 0.05). Interestingly, the variation of EAT thickness had positive correlation with the variations of WC, HC, and BMI. Liraglutide is beneficial to the decrease of EAT. EAT thickness can be measured with echocardiography to evaluate the effect of liraglutide in obese T2DM patients.

Serum leptin, resistin, and adiponectin levels in obese and non-obese patients with newly diagnosed type 2 diabetes mellitus: A population-based study.

Disturbances in adipocytokine profiles can contribute to peripheral insulin resistance and impairment of insulin production, which are 2 primary pathophysiological mechanisms involved in type 2 diabetes mellitus (T2DM). Previous studies of disturbed adipocytokine profiles have resulted in ambiguous findings; therefore, we conducted the current study comparing leptin, resistin, and adiponectin concentrations in patients with newly diagnosed T2DM who had normal body mass index (BMI) and those who were obese.We studied a population-based cohort of healthy participants and those with newly diagnosed T2DM. A normal BMI group was randomly selected; age- and sex-matched obese participants were recruited. Circulating leptin, resistin, and adiponectin concentrations were measured and compared between groups using analysis of variance; binary logistic regression analysis was then performed to compare the normal BMI and obese groups.In total, 85 healthy participants and 38 patients with diabetes (19 with normal BMI and 17 who were obese) were enrolled. After adjustment for BMI and waist circumference, the median leptin concentration was higher in the obese group (6.77 (3.89–10.73) ng/mL) than in the normal BMI group (1.69 (0.80–3.89) ng/mL) (P = .007), whereas the median adiponectin concentration was lower in the obese group (1.03 (0.75–2.36) μg/mL vs 3.36 (0.59–7.63) μg/mL, P = .03). In addition, the adiponectin/leptin ratio was higher in the normal BMI group (145.6 (41.3–495.9) ng/mL) than in the obese group (20.55 (8.74–36.94) ng/mL, P = .002).Compared with the normal BMI T2DM group, the obese T2DM group exhibited a disturbed adipocytokine profile in the form of a significantly increased leptin concentration and reduced adiponectin level. Further studies are needed to determine the causal relationship for this difference and evaluate its importance for personalized diabetic treatment.

Distinct cardiac energy metabolism and oxidative stress adaptations between obese and non-obese type 2 diabetes mellitus.

Background: Little is known about the pathophysiological diversity of myocardial injury in type 2 diabetes mellitus (T2DM), but analyzing these differences is important for the accurate diagnosis and precise treatment of diabetic cardiomyopathy. This study aimed to elucidate the key cardiac pathophysiological differences in myocardial injury between obese and non-obese T2DM from mice to humans.Methods: Obese and non-obese T2DM mouse models were successfully constructed and observed until systolic dysfunction occurred. Changes in cardiac structure, function, energy metabolism and oxidative stress were assessed by biochemical and pathological tests, echocardiography, free fatty acids (FFAs) uptake fluorescence imaging, transmission electron microscopy, etc. Key molecule changes were screened and verified by RNA sequencing, quantitative real-time polymerase chain reaction and western blotting. Further, 28 human heart samples of healthy population and T2DM patients were collected to observe the cardiac remodeling, energy metabolism and oxidative stress adaptations as measured by pathological and immunohistochemistry tests.Results: Obese T2DM mice exhibited more severe cardiac structure remodeling and earlier systolic dysfunction than non-obese mice. Moreover, obese T2DM mice exhibited severe and persistent myocardial lipotoxicity, mainly manifested by increased FFAs uptake, accumulation of lipid droplets and glycogen, accompanied by continuous activation of the peroxisome proliferator activated receptor alpha (PPARα) pathway and phosphorylated glycogen synthase kinase 3 beta (p-GSK-3β), and sustained inhibition of glucose transport protein 4 (GLUT4) and adipose triglyceride lipase (ATGL), whereas non-obese mice showed no myocardial lipotoxicity characteristics at systolic dysfunction stage, accompanied by the restored PPARα pathway and GLUT4, sustained inhibition of p-GSK-3β and activation of ATGL. Additionally, both obese and non-obese T2DM mice showed significant accumulation of reactive oxygen species (ROS) when systolic dysfunction occurred, but the NF-E2-related factor 2 (Nrf2) pathway was significantly activated in obese mice, while was significantly inhibited in non-obese mice. Furthermore, the key differences found in animals were reliably verified in human samples.Conclusion: Myocardial injury in obese and non-obese T2DM may represent two different types of complications. Obese T2DM individuals, compared to non-obese individuals, are more prone to develop cardiac systolic dysfunction due to severe and persistent myocardial lipotoxicity. Additionally, anti-oxidative dysfunction may be a key factor leading to myocardial injury in non-obese T2DM.

ADROPIN - POTENTIAL LINK IN CARDIOVASCULAR PROTECTION FOR OBESE MALE TYPE 2 DIABETES MELLITUS PATIENTS TREATED WITH LIRAGLUTIDE.

SUMMARYThe aim of this study was to determine plasma adropin concentration and parameters of insulin resistance in obese male type 2 diabetes mellitus (T2DM) patients before and after 3-month liraglutide treatment. In this interventional study, we enrolled 15 obese male T2DM patients with body mass index (BMI) >35 kg/m2, uncontrolled disease and HbA1c >7.5%, having previously taken taking two oral antidiabetic drugs. We modified their therapy to metformin and liraglutide for the next three months. After three months of liraglutide treatment, we observed significant decrease in body weight (from 111.5±18.7 kg to 109.2±17.5 kg, p=0.016) and BMI (from 40.9±7.3 to 40.1±7.0 kg/m2, p=0.021). Plasma adropin concentration increased significantly (p=0.003) compared with baseline. Fasting plasma insulin level decreased from 17.79±6.53 to 13.38±3.51 mU/L (p=0.002), fasting plasma glucose level decreased from 8.66±3.07 to 7.41±2.21 mmol/L (p=0.004) and HbA1c decreased from 7.98±0.70% to 7.26±0.36% (p=0.003). Insulin resistance presented as HOMA-IR decreased significantly from 7.30±5.19 to 4.52±2.61 (p=0.002). Systolic blood pressure, lipid status, liver and kidney function improved, but not reaching statistical significance. Treating obese male T2DM patients with liraglutide resulted in a significantly higher plasma adropin concentration, significant weight loss and improved parameters of insulin resistance, i.e. decreased fasting plasma insulin, plasma glucose levels and HOMA-IR.

Comparison of Insulin Resistance in Lean and Obese Adults with Type 2 Diabetes Mellitus- A Cross-sectional Study

Introduction: Insulin Resistance (IR) can develop into type 2 diabetes mellitus and is closely associated with obesity. However, the non-obese population has also shown a predisposition to the risk of IR due to genetics. Aim: To assess the relationship between IR and obesity in Type 2 Diabetes Mellitus (T2DM) by comparing the proportion of subjects with IR in lean and obese T2DM and to identify the factors predicting IR in T2DM. Materials and Methods: A cross-sectional, hospital-based study was done at Department of Medicine of RL Jalappa hospital, Kolar, Karnataka on 106 T2DM patients aged &gt;18 years. The study population was grouped into lean (BMI &lt;19 kg/m2) and obese adults (BMI &gt;30 kg/m2). IR was calculated using Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) and was considered as primary outcome variable. Obesity was considered as primary explanatory variable. Age, Gender, fasting insulin, C-peptide, Fasting Blood Sugar, Glycated haemoglobin (GHB or HbA1c) were the other explanatory variables. Descriptive analysis was carried out using mean and standard deviation for quantitative variables, frequency and proportion for categorical variables. Chi-square test was used to test statistical significance between the groups. Univariate logistic regression analysis was done to identify the predictors of IR. IBM Statistical Package for Social Sciences (SPSS) version 22 was used for statistical analysis. The p-value &lt;0.05 was considered to be statistically significant. Results: The 106 subjects involved in the study had a mean age of 53.88±9.21 years. 44 subjects (41.5%) had IR. Obese to lean diabetic patients were in the ratio of 1:4. The proportion of obese diabetic subjects was (n=84, 79.2%) whereas lean diabetics were (n=22, 20.8%). The proportion of obese diabetic subjects with IR was 38.1% while the proportion of lean diabetic subjects with IR was 54.55%, but this difference was statistically not significant (p=0.163). On univariate logistic regression analysis, fasting insulin (odds ratio of 2.442 with 95% CI of 1.665 to 3.851, p&lt;0.001**) and C-peptide (odds ratio of 1.446 with 95% CI of 1.123, p=0.004) were statistically significant factors attributing to IR. Conclusion: There was no significant relationship between IR and obesity. IR was independently associated with Fasting insulin levels and C-peptide levels.

Studies on Status of Oxidative Stress related Molecules and Enzymes in Obese with and without Diabetes in the Northern region of India

This study was done to assess the interrelationship of “oxidative stress-related molecules & enzymes” with obesity and diabetes. Xanthine oxidase (XO), malondialdehyde (MDA) representing lipid peroxidation and protein oxidative stress parameters such as advanced oxidation of protein products (AOPP), protein carbonyls (PC) and antioxidant enzyme activities in obese with or without type 2 diabetes mellitus (T2DM) were studied. This study enrolled 41 healthy controls, 41 obese non-diabetics, and 41obese T2DM patients. Biochemical parameters related to diabetes, oxidative stress and antioxidant enzymes were measured in all groups. The levels of XO, MDA, AOPP, and PC were significantly increased in obese with and without T2DM as compared to healthy controls (P < 0.001). However levels of antioxidants such as reduced glutathione (GSH) and activity of superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), glutathione peroxidase (GPx) were significantly decreased in obese with and without T2DM as compared to healthy control (P < 0.001 or P < 0.05). Positive correlations were found among XO with MDA (P = 0.006), PC (P = 0.012) in obese non-diabetic subjects and with MDA (P < 0.001), AOPP (P = 0.026), and PC (P = 0.003) in obese T2DM patients. Positive correlation were seen in MDA with AOPP (P = 0.017), PC (P = 0.046) in obese non-diabetic subjects and MDA with AOPP (P < 0.001), PC (P < 0.001) in obese T2DM patients. Also observed a significant correlation between AOPP and PC (P < 0.001) in both groups of obese. The present study results suggest that increased activity of xanthine oxidase, higher lipid peroxide generation, and higher levels of protein oxidative stress parameters (AOPP and PC) may be a most considerable mechanism in reducing the activity of antioxidant enzymes in obese with and without diabetic groups as compared to control group. However, extent of derangements is lower in obese subjects as compared to diabetic patients, thereby suggesting that obese subjects have a higher risk of diabetes as well as early onset of diabetes.

Differential Expression of Human N-Alpha-Acetyltransferase 40 (hNAA40), Nicotinamide Phosphoribosyltransferase (NAMPT) and Sirtuin-1 (SIRT-1) Pathway in Obesity and T2DM: Modulation by Metformin and Macronutrient Intake.

BackgroundInteractions between environmental factors, such as diet and lifestyle, and metabolic pathways are pivotal in understanding aging mechanisms. hNAA40, Nicotinamide phosphoribosyltransferase (NAMPT), and NAD-dependent protein deacetylase sirtuin-1 (SIRT-1) have been shown to exert important biological processes, including stress response and aging.MethodshNAA40, NAMPT, and SIRT-1 mRNA expression in peripheral blood mononuclear cells (PBMC) were quantitated in 30 lean adult volunteers of normal weight, 30 obese, 20 drug-naïve obese Type 2 diabetes mellitus (T2DM), and 30 obese T2DM on Metformin. Similarly, hNAA40, NAMPT, and SIRT-1 expression in PBMC were quantitated in 36 normal healthy adults randomly assigned to three different groups (Glucose or Whey proteins or lipids; 300 kcal). Blood samples were obtained at 1, 2, and 3 hrs after the macronutrient intake.ResultsThere was an increase in hNAA40 and a decrease in NAMPT and SIRT-1 expression in PBMC from T2DM. Metformin treatment reverted hNAA40, NAMPT, and SIRT-1 expression levels to normal levels. Glucose intake resulted in a significant increase in expression of hNAA40 at 1 hr and decreased significantly at 3 hrs post intake. Lipid intake resulted in an increase in expression of hNAA40 at 2 hr post intake and returned to normal levels at 3 hrs. Neither glucose nor lipid intake resulted in a significant change in NAMPT or SIRT-1 expression. Whey proteins resulted in significantly lower expression of NAMPT at 3 hrs and did not alter the expression levels of SIRT-1 significantly.ConclusionhNAA40, NAMPT, and SIRT-1 pathway could play a role in the determination of the healthy life-span. Metformin modulates this pathway.

Plasma mitochondrial DNA is elevated in obese type 2 diabetes mellitus patients and correlates positively with insulin resistance.

Cells damaged by mechanical or infectious injury release proinflammatory mitochondrial DNA (mtDNA) fragments into the circulation. We evaluated the relation between plasma levels of mtDNA fragments in obese type 2 diabetes mellitus (T2DM) patients and measures of chronic inflammation and insulin resistance. In 10 obese T2DM patients and 12 healthy control (HC) subjects, we measured levels of plasma cell-free mtDNA with quantitative real-time polymerase chain reaction, and mtDNA damage in skeletal muscle with quantitative alkaline Southern blot. Also, markers of systemic inflammation and oxidative stress in skeletal muscle were measured. Plasma levels of mtDNA fragments, mtDNA damage in skeletal muscle and plasma tumor necrosis factor α levels were greater in obese T2DM patients than HC subjects. Also, the abundance of plasma mtDNA fragments in obese T2DM patients levels positively correlated with insulin resistance. To the best of our knowledge, this is the first published evidence that elevated level of plasma mtDNA fragments is associated with mtDNA damage and oxidative stress in skeletal muscle and correlates with insulin resistance in obese T2DM patients. Plasma mtDNA may be a useful biomarker for predicting and monitoring insulin resistance in obese patients.

Anti-hyperglycemic and anti-hyperlipidemic effects of a special fraction of Luohanguo extract on obese T2DM rats.

Luohanguo (LHG), a traditional Chinese medicine, could clear heat, moisten the lung, soothe the throat, restore the voice, and lubricate intestine and open the bowels. LHG has been utilized for the treatment of sore throats and hyperglycemia in folk medicine as a homology of medicine and food. The hypoglycemic pharmacology of LHG has attracted considerable attention, and mogrosides have been considered to be active ingredients against diabetes mellitus. We have found that these mogrosides could be metabolized into their secondary glycosides containing 1-3 glucose residues in type 2 diabetes mellitus (T2DM) rats in previous studies. These metabolites may be the antidiabetic components of LHG in vivo. Thus far, no reports have been found on reducing blood glucose of mogrosides containing 1-3 glucose residues. The aim of this study was to confirm that mogrosides containing 1-3 glucose residues were the active components of LHG for antidiabetic effects and to understand their potential mechanisms of action. First, the special fraction of mogrosides containing 1-3 glucose residues was separated from a 50% ethanol extract of LHG, and the chemical components were identified by ultra-performance liquid chromatography (UPLC) and named low-polar Siraitia grosvenorii glycosides (L-SGgly). Second, the antidiabetic effects of L-SGgly were evaluated by HFD/STZ-induced (high-fat diet and streptozocin) obese T2DM rats by indexing fasting blood glucose (FBG), fasting insulin (FINS), and insulin resistance, and then compared with other fractions in the separation process. The changes in serum lipid levels were also detected. Finally, possible mechanisms of antidiabetic activity of L-SGgly were identified as increasing GLP-1 levels and activating liver AMPK in T2DM rats. The chemical analysis of L-SGgly showed that they contain 11-oxomogroside V, mogroside V, mogroside III, mogroside IIE, mogroside IIIA1, mogroside IIA1, and mogroside IA1, respectively. The total content of the mogrosides in L-SGgly was 54.4%, including 15.7% mogroside IIA1 and 12.6% mogroside IA1. L-SGgly showed excellent effects on obese T2DM rats compared with the other fractions of LHG extract, including significantly reducing the levels of FBG (p < 0.001) and modifying insulin resistance (p < 0.05). Meanwhile, they could significantly decrease the content of triglyceride (p < 0.01), total cholesterol (p < 0.01), low-density lipoprotein cholesterol (p < 0.01) and free fatty acid (p < 0.001) and increase the content of high-density lipoprotein cholesterol (p < 0.001) in serum of T2DM rats. Moreover, L-SGgly can significantly increase (p < 0.01) GLP-1 levels and decrease (p < 0.01) IL-6 levels in T2DM rat serum. AMPK-activating activity in T2DM rats was also upregulated by L-SGgly, but no statistical significance was shown. L-SGgly, fractions separated from LHG extract, were verified to have obvious anti-hyperglycemic and anti-hyperlipidemic effects on T2DM rats. Furthermore, L-SGgly regulated insulin secretion in T2DM rats by increasing GLP-1 levels. These findings provide an explanation for the antidiabetic role of LHG.

Dietary Exposure to Transgenic Rice Expressing the Spider Silk Protein Fibroin Reduces Blood Glucose Levels in Diabetic Mice: The Potential Role of Insulin Receptor Substrate-1 Phosphorylation in Adipocytes.

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR). T2DM is correlated with obesity and most T2DM medications have been developed for enhancing insulin sensitivity. Silk protein fibroin (SPF) from spiders has been suggested as an attractive biomaterial for medical purposes. We generated transgenic rice (TR) expressing SPF and fed it to diabetic BKS.Cg-m+/+Leprdb mice to monitor the changes in blood glucose levels and adipose tissue proteins associated with energy metabolism and insulin signaling. In the present study, the adipocyte size in abdominal fat in TR-SPF-fed mice was remarkably smaller than that of the control. Whereas the adenosine monophosphate-activated protein kinase (AMPK)-activated protein kinase and insulin receptor substrate 1 (IRS1) protein levels were increased in abdominal adipose tissues after TR-SPF feeding, levels of six-transmembrane protein of prostate 2 (STAMP2) proteins decreased. Phosphorylation of AMPK at threonine 172 and IRS1 at serine 307 and tyrosine 632 were both increased in adipose tissues from TR-SPF-fed mice. Increased expression and phosphorylation of IRS1 at both serine 307 and tyrosine 632 in adipose tissues indicated that adipocytes obtained from abdominal fat in TR-SPF-fed mice were more susceptible to insulin signaling than that of the control. STAMP2 protein levels decreased in adipose tissues from TR-SPF-fed mice, indicating that STAMP2 proteins were reducing adipocytes that were undergoing lipolysis. Taken together, this study showed that TR-SPF was effective in reducing blood glucose levels in diabetic mice and that concurrent lipolysis in abdominal adipocytes was associated with alterations of AMPK, IRS1, and STAMP2. Increased IRS1 expression and its phosphorylation by TR-SFP were considered to be particularly important in the induction of lipolysis in adipocytes, as well as in reducing blood glucose levels in this animal model.

Dapagliflozin Add-On Therapy Improves Body Composition and Metabolic Parameters in Overweight Type 2 Diabetic Patients: A Pilot Study

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) inhibit renal glucose reabsorption in the proximal tubules, and reduce plasma glucose, body weight and cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). The data on the effect of SGLT-2i on body composition are conflicting: in some reports, they reduce fat mass, while in other reports, they determine reduction of extra- and intra-cellular fluids. The aim of our pilot study was to investigate the body compartments changes and the effects on glycemia and plasma lipids of add-on SGLT2-i dapagliflozin therapy in poorly controlled overweight/obese T2DM patients. Methods: Fifty-six overweight (body mass index (BMI) > 25) uncontrolled (HbA1c > 53 mmol/mol; 7%) T2DM outpatients were recruited. They were treated with metformin and basal insulin (group A) or metformin (group B). Weight, BMI, waist circumference (WC), fasting blood glucose (FPG), HbA1c, plasma lipids, bioelectric parameters and derived body compartments (phase angle (pA), total body water (TBW), fat free mass (FFM) and fat mass (FM)) were assessed at baseline (T0) and after 16 weeks (T1) of dapagliflozin 10 mg add-on treatment. Student’s t -test and one-way analysis of variance (ANOVA) were used to compare the T0 and T1 data. Results: After 16 weeks, all the patients had weight loss (-3.0 ± 0.6 kg, P < 0.0001) and reduced WC (-2.5 ± 0.6 cm, P < 0.0001). Weight reduction was significant in both groups separately (group A: -2.5 ± 0.3 kg, P <= 0.001; group B: -3.4 ± 0.4 kg, P <= 0.001) and was higher in group B. FFM was not impaired in group A (from 60.2 ± 5.2 to 59.5 ± 8.1 kg; ns) and in group B (from 60.4 ± 6.2 to 59.3 ± 6.6 kg; ns). FM decreased in all the patients (29.9 ± 6.84 kg vs. 26.30 ± 7.4 kg, P < 0.000); a higher reduction was found in group B (-3.6 ± 1.2 kg, P < 0.001) vs. group A (-2.3 ± 1.3 kg, P < 0.001). Metabolic control improved in all the patients: FPG 172 ± 49.4 mg/dL vs. 137 ± 36.8 mg/dL at T1, P < 0.0001; HbA1c 69 ± 9.3 mmol/mol (8.5±1.5%) vs. 60 ± 8.7 mmol/mol (7.6±1.4%), P = 0.000. In group A, insulin dose was reduced by 9.3%. Cholesterol and triglycerides (TG) levels decreased in overall population (181.8 ± 48.8 mg/dL vs. 170.7 ± 40.7, P = 0.003; 172 ± 93 mg/dL vs. 143.2 ± 87.8, P = 0.000). Conclusions: Dapagliflozin add-on therapy induced weight loss and metabolic improvement in overweight and obese T2DM patients. Also insulin-treated patients had weight loss (2.5 kg). Bioelectric impedance analysis (BIA) demonstrated FM loss without FFM impairment and was confirmed to be a simple and effective method to assess body composition in clinical practice. J Endocrinol Metab. 2019;9(4):90-94 doi: https://doi.org/10.14740/jem564

Depressive Symptoms and All-Cause Mortality in Older American Indians with Type 2 Diabetes Mellitus.

American Indians experience disproportionately high rates of poor mental health and type 2 diabetes mellitus (T2DM). We examined the association between depressive symptoms and all-cause mortality in older American Indians with T2DM. We used the Native Elder Care Study survey data from community-dwelling American Indians aged 55 years or older, linked to data extracted from participants' electronic health records. We focused on those who had an International Classification of Diseases-Ninth Revision diagnosis of T2DM in their electronic health records. The study was conducted with a federally-recognized tribe with approximately 16,000 enrolled members, most of whom reside on or near tribally-owned lands that span several rural counties. Participants were among the Native Elder Care Study participants with a final analytic sample of 222. We measured depressive symptoms with the Centers for Epidemiologic Studies-Depression (CES-D) scale. We used Cox proportional hazard models to examine the association between depressive symptoms and all-cause mortality in the final analytic sample of 222 subjects. Survival curves revealed that individuals in the third and fourth CES-D scale categories had higher mortality than those in the first and second categories. Mortality risk was significantly higher for participants with CES-D scale scores in the third highest compared with the lowest category (hazard ratio = 2.07; 95% confidence interval = 1.07-4.04), after adjustment for demographic characteristics, health behaviors, obesity, and prevalent T2DM complications. Analyses with the CES-D scale as a continuous variable also showed a positive association with mortality. The impact of mental health on older American Indians with T2DM is often overlooked, yet it is vital to clinical and public health practice. Our findings underscore the importance of addressing the mental health needs of this population, particularly because depression in older patients is often undetected or inadequately treated. J Am Geriatr Soc 67:1940-1945, 2019.

OXIDATIVE STRESS LEVELS ARE INCREASED IN TYPE 2 DIABETES MELLITUS AND OBESITY

Objective: The relationship between obesity, type 2 diabetes mellitus (T2DM) and oxidative stress (OS) is complex and insufficiently studied. Chronic hyperglycemia causes endothelial damage by increasing reactive oxygen species (ROS) production and decreasing the activity of antioxidant enzymes, explaining why OS is a main contributor in T2DM pathogenesis. The adipose tissue is also a source of ROS via low-grade chronic inflammation and deregulation of adipokine secretion. Thus, we aimed to evaluate OS levels in obese T2DM subjects and obese non-T2DM subjects vs. controls. Design and method: OS was measured in 20 T2DM obese patients (mean age 64.85 ± 7.74 years), 20 obese non-T2DM patients (mean age 61.30 ± 10.59 years) and 20 non-obese non-T2DM controls (mean age 64.10 ± 2.26 years). ROS were evaluated via the Free Oxygen Radical Testing (FORT; normal range: < = 2.3 mmol/L H2O2) assay. The total antioxidant capacity was measured by the Free Oxygen Radical Defense (FORD; normal range: 1.07 – 1.53 mmol/L Trolox) test. Results: T2DM obese subjects registered higher FORT (3.33 ± 0.30 vs. 3.10 ± 0.34; p = 0.017) and lower FORD (0.60 ± 0.10 vs. 0.71 ± 0.15; p = 0.008) values compared to their obese non-T2DM counterparts. Both obese T2DM subjects and obese non-T2DM subjects depicted higher FORT and lower FORD values vs. controls (p < 0.001) (Table 1). In obese T2DM subjects, FORT values correlated positively with BMI, LDL-cholesterol, total cholesterol, triglycerides, uric acid and HDL/cholesterol value and negatively with age. FORD values evolved oppositely (Table 2).Conclusions: Obese T2DM subjects recorded higher FORT and lower FORD values vs. obese non-T2DM. In both obese T2DM and obese non-T2DM subjects, OS levels were higher vs. controls. In obese T2DM subjects, ROS levels correlated positively with lipid values, BMI, uric acid and, surprisingly, negatively with age. The total antioxidant capacity evolved oppositely. The negative correlation between age and ROS levels and the positive correlation between FORD and age are paradoxical since the ageing process is associated with higher ROS and lower antioxidant values.