Progression Of Glucose Intolerance Research Articles

Role of Atorvastatin in the Development and Progression of Glucose Intolerance in Albino Rabbits: An In-vivo Experimental Study

Introduction: Type 2 diabetes is associated with obesity and dyslipidemia, which are risk factors for cardiovascular disease. The Food and Drug Administration (FDA)-approved indications for statins are being broadened due to their lipid-lowering and pleiotropic effects; statins are currently among the most widely used drugs in patients with and without diabetes. Aim: To evaluate the role of atorvastatin at different doses in the development and progression of glucose intolerance or diabetes in albino rabbits. Materials and Methods: An in-vivo experimental study on rabbits was conducted over a total duration of eight months in the Department of Pharmacology at SCB Medical College, Cuttack, Odisha, India. The animals were divided into five groups of six rabbits each. Atorvastatin at 4 mg/kg and 2 mg/kg was calculated based on human doses corresponding to 80 mg and 40 mg, respectively. Both doses were administered to non diabetic rabbits, and 4 mg/kg atorvastatin was administered to alloxan-induced diabetic rabbits orally for six months daily. Diabetes was induced in two groups of rabbits by administering 100 mg/kg alloxan monohydrate in a 5% (w/v) solution in sterile saline intravenously. Rabbits with stabilised moderate diabetes, characterised by a fasting blood glucose level above 200 mg/ dL (at least one month after alloxan injection), were used for the experiments. The effect of atorvastatin on glucose tolerance was assessed by determining Fasting Blood Sugar (FBS) and Glycated Haemoglobin (HbA1c) levels. The results were compared with those of normal and diabetic control rabbits and statistically analysed using Analysis of Variance (ANOVA) and Repeated Measures ANOVA (RMANOVA), followed by appropriate post-hoc analysis. Results: Atorvastatin at a high dose resulted in a 26.74% increase in FBS and a 20.50% increase in HbA1c; at the standard dose, it produced a 21.3% increase in FBS and a 17.99% increase in HbA1c, respectively. The diabetic group receiving high doses also showed a significant increase in FBS (11.7%) and HbA1c (10.25%). The increase in blood glucose parameters was significant in the high-dose group from the fourth month of statin therapy and in the standard-dose group at six months of therapy. Conclusion: The study revealed that atorvastatin at both doses significantly contributed to the initiation and progression of glucose intolerance in diabetic and non diabetic rabbits.

Artificial Intelligence Uncovered Clinical Factors for Cardiovascular Events in Myocardial Infarction Patients with Glucose Intolerance.

Glucose intolerance (GI), defined as either prediabetes or diabetes, promotes cardiovascular events in patients with myocardial infarction (MI). Using the pooled clinical data from patients with MI and GI in the completed ABC and PPAR trials, we aimed to identify their clinical risk factors for cardiovascular events. Using the limitless-arity multiple testing procedure, an artificial intelligence (AI)-based data mining method, we analyzed 415,328 combinations of < 4 clinical parameters. We identified 242 combinations that predicted the occurrence of hospitalization for (1) percutaneous coronary intervention for stable angina, (2) non-fatal MI, (3) worsening of heart failure (HF), and (4) all causes, and we analyzed combinations in 1476 patients. Among these parameters, the use of proton pump inhibitors (PPIs) or plasma glucose levels > 200 mg/dl after 2 h of a 75 g oral glucose tolerance test were linked to the coronary events of (1, 2). Plasma BNP levels > 200 pg/dl were linked to coronary and cardiac events of (1, 2, 3). Diuretics use, advanced age, and lack of anti-dyslipidemia drugs were linked to cardiovascular events of (1, 3). All of these factors were linked to (4). Importantly, each finding was verified by independently drawn Kaplan-Meier curves, indicating that the determined factors accurately affected cardiovascular events. In most previous MI patients with GI, progression of GI, PPI use, or high plasma BNP levels were linked to the occurrence of coronary stenosis or recurrent MI. We emphasize that use of AI may comprehensively uncover the hidden risk factors for cardiovascular events.

Artificial Intelligence Uncovered Clinical Factors for Cardiovascular Events in Myocardial Infarction Patients with Glucose Intolerance in the Cohort of Two Large-Scale ABC and PPAR Clinical Trials

Background: Glucose intolerance (GI), defined as either prediabetes or diabetes, promotes cardiovascular events in patients with myocardial infarction (MI). Using the pooled clinical data from patients with MI and GI in the completed ABC and PPAR trials, we aimed to identify their clinical risk factors for cardiovascular events. Methods: Using the limitless-arity multiple testing procedure, an artificial intelligence (AI)-based data mining method, we analyzed 415,328 combinations of <4 clinical parameters. Findings: We identified 242 combinations that predicted the occurrence of hospitalization for (1) percutaneous coronary intervention for stable angina, (2) non-fatal MI, (3) worsening of heart failure (HF), and (4) all causes, and we analyzed combinations in 1,476 patients. Among these parameters, plasma glucose levels >200 mg/dl after 2 hours of a 75g oral glucose tolerance test or the use of proton pump inhibitors (PPIs) predicted the coronary events of (1, 2). Plasma BNP levels >200pg/dl predicted coronary and cardiac events of (1, 2, 3). Diuretics use, advanced age, and lack of anti-dyslipidemia drugs were predictors of cardiovascular events of (1, 3). These factors were linked to (4). Importantly, each finding was verified by independently drawn Kaplan–Meier curves, indicating that the determined factors accurately predicted cardiovascular events. Interpretation: In most previous MI patients with GI, progression of GI or PPI use predicted the occurrence of coronary stenosis; recurrent MI and high plasma BNP levels predicted the subsequent worsening of HF. We emphasize that use of AI is effective to comprehensively uncover the clinical risk factors of cardiovascular events. Trial Registration: This study was a sub-analysis of the ABC Study (Alpha-glucosidase-inhibitor Blocks Cardiac Events in Patients with Myocardial Infarction and Impaired Glucose Tolerance; ClinicalTrials.gov identification number: NCT00212017) and the Pioglitazone Protects DM Patients Against Re-Infarction Study (PPAR; Clinicaltrials.gov identification number: NCT00212004 and UMIN: No. 000091). Funding Statement: Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan; Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and Grants-in-Aid from the Japan Agency for Medical Research and Development. Declaration of Interests: No relationship to industry for K.S., H.F, Y.M.,J.K., S.I, and T.W. MK reports grants from Japanese government, grants from Japan Heart Foundation, grants from Japan Agency for Medical Research and Development , personal fees from Daiichi-Sankyo, personal fees from Pfizer, grants and personal fees from Ono, personal fees from Bayer, grants and personal fees from Novartis, grants and personal fees from Bheringer, grants and personal fees from Tanabe-Mitubishi, personal fees from Japan Medical Data Center, grants and personal fees from Takeda, grants and personal fees from Astra Zeneca, outside the submitted work. Ethics Approval Statement: Approval was obtained from the institutional review boards and ethics committees of all involved hospitals and all patients provided written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki and the Japanese Ethical Guidelines for Clinical Research.

Progression of glucose intolerance and cardiometabolic risk factors over a decade in Chinese women with polycystic ovary syndrome: A case-control study.

BackgroundPolycystic ovary syndrome (PCOS) is associated with increased metabolic risk, though data on long-term follow-up of cardiometabolic traits are limited. We postulated that Chinese women with PCOS would have higher risk of incident diabetes and cardiometabolic abnormalities than those without PCOS during long-term follow-up.Methods and findingsOne hundred ninety-nine Chinese women with PCOS diagnosed by the Rotterdam criteria and with a mean age of 41.2 years (SD = 6.4) completed a follow-up evaluation after an average of 10.6 ± 1.3 years. Two hundred twenty-five women without PCOS (mean age: 54.1 ± 6.7 years) who underwent baseline and follow-up evaluation over the same period were used for comparison. Progression of glycaemic status of women both with and without PCOS was assessed by using 75-g oral glucose tolerance test (OGTT) screening with the adoption of 2009 American Diabetes Association diagnostic criteria. The frequency of impaired glucose regulation, hypertension, and hyperlipidaemia of women with PCOS at follow-up has increased from 31.7% (95% CI 25.2%–38.1%) to 47.2% (95% CI 40.3%–54.2%), 16.1% (95% CI 11.0%–21.2%) to 34.7% (95% CI 28.1%–41.3%), and 52.3% (95% CI 45.3%–59.2%) to 64.3% (95% CI 57.7%–71.0%), respectively. The cumulative incidence of diabetes mellitus (DM) in follow-up women with PCOS is 26.1% (95% CI 20.0%–32.2%), almost double that in the cohort of women without PCOS (p < 0.001). Age-standardised incidence of diabetes among women with PCOS was 22.12 per 1,000 person-years (95% CI 10.86–33.37) compared with the local female population incidence rate of 8.76 per 1,000 person-years (95% CI 8.72–8.80) and 10.09 per 1,000 person-years (95% CI 4.92–15.26, p < 0.001) for women without PCOS in our study. Incidence rate for women with PCOS aged 30–39 years was 20.56 per 1,000 person-years (95% CI 12.57–31.87), which is approximately 10-fold higher than that of the age-matched general female population in Hong Kong (1.88 per 1,000 person-years, [95% CI 1.85–1.92]). The incidence rate of type 2 DM (T2DM) of both normal-weight and overweight women with PCOS was around double that of corresponding control groups (normal weight: 8.96 [95% CI 3.92–17.72] versus 4.86 per 1,000 person-years [95% CI 2.13–9.62], p > 0.05; overweight/obese: 28.64 [95% CI 19.55–40.60] versus 14.1 per 1,000 person-years [95% CI 8.20–22.76], p < 0.05). Logistic regression analysis identified that baseline waist-to-hip ratio (odds ratio [OR] = 1.71 [95% CI 1.08–2.69], p < 0.05) and elevated triglyceride (OR = 6.63 [95% CI 1.23–35.69], p < 0.05) are associated with the progression to T2DM in PCOS. Limitations of this study include moderate sample size with limited number of incident diabetes during follow-up period and potential selection bias.ConclusionsHigh risk of diabetes and increased cardiovascular disease risk factors among Chinese women with PCOS are highlighted in this long-term follow-up study. Diabetes onset was, on average, 10 years earlier among women with PCOS than in women without PCOS.

1505-P: Plasma Glucose Level at 1h Post 75g OGTT Is the Best Predictor of the Development of Glucose Intolerance in Subjects with Normal Glucose Tolerance—The Toon Health Study

Background: Although glucose intolerance (GI) is diagnosed by fasting and 2h plasma glucose (PG) levels during a 75g OGTT, the upper limit of 1h PG level remains to be undefined in subjects with NGT. Previous report focusing on changes from NGT + IGT to diabetes has reported that 1h PG with ≥155 mg/dl is the risk for future diabetes in the world. However, IGT is well known as a risk factor for cardiovascular disease, few studies have focused on changes from NGT to GI. We therefore conducted a 5-year prospective study intended for NGT subjects to clarify the best predictor of the development of GI. Methods: To diagnose GI, we performed a 75gOGTT. We enrolled 1383 NGT subjects from The Toon Health Study. Finally, we analyzed 981 individuals with NGT who had a repeat health checkup. To investigate valuable predictive factors of progression of GI, we performed ROC curve analyses and compared fasting PG, 1h post OGTT, 2h post OGTT, and HbA1c. Results: ROC curve analyses revealed that 1h post OGTT was the best predictor of the development of GI in NGT (sensitivity 66%, specificity 74%, at a cutoff value of 149 mg/dl). In NGT with 1h PG&amp;gt;149mg/dl, odd ratio for the development of GI was 4.7 (95% CI: 3.25-6.80) compared to the reference after adjustment for age, sex, and BMI (p&amp;lt;0.0001). Conclusions: PG level at 1h post 75g OGTT was the best predictor of the development of GI in NGT. Disclosure M. Takakado: None. Y. Takata: None. T. Hadate: None. Y. Matsushita: None. R. Kawamura: None. K. Maruyama: None. I. Saito: None. H. Osawa: None.

The main mechanism associated with progression of glucose intolerance in older patients with cystic fibrosis is insulin resistance and not reduced insulin secretion capacity

BackgroundAging cystic fibrosis (CF) patients are at high risk of developing CF-related diabetes (CFRD). Decrease in insulin secretion over time is the main hypothesis to explain this increasing prevalence but mechanisms are still not well elucidated. The objective is to assess evolution of glucose tolerance and insulin secretion/sensitivity in aging CF patients. MethodsThis is a retro-prospective observational analysis in the older adult CF patients from the Montreal Cystic Fibrosis Cohort (n = 46; at least 35 years old at follow-up) and followed for at least 4 years. Baseline and follow-up (last visit to date) 2-h oral glucose tolerance test (OGTT with glucose and insulin measurements every 30 min) were performed. Pulmonary function test (FEV1) and anthropometric data were measured the same day. Insulin sensitivity was measured by the Stumvoll index. ResultsAfter a mean follow-up of 9.9 ± 2.6 years, mean age at follow-up was 43.5 ± 8.1 years old. An increase of body weight (+2.6 ± 6.5 kg, p = 0.01) and a decrease in pulmonary function (FEV1; 73.4 ± 21.2% to 64.5 ± 22.4%, p ≤ 0.001) were observed. Overall, insulin secretion is maintained at follow-up but all OGTT glucose values increased (for all values, p ≤ 0.028). At follow-up, 28.3% of patients had a normal glucose tolerance while 71.7% had abnormal glucose tolerance (AGT). AGT patients decreased their insulin sensitivity over time (p = 0.029) while it remained the same in NGT patients (p = 0.917). ConclusionIn older CF patients, the progression of impaired glucose tolerance is occurring with stable insulin secretion but reduced insulin sensitivity.

JMJD2B/KDM4B inactivation in adipose tissues accelerates obesity and systemic metabolic abnormalities.

Obesity is a serious global health issue; however, the roles of genetics and epigenetics in the onset and progression of obesity are still not completely understood. The aim of this study was to determine the role of Kdm4b, which belongs to a subfamily of histone demethylases, in adipogenesis and fat metabolism in vivo. We established conditional Kdm4b knockout mice. Inactivation of Kdm4b in adipocytes (K4bKO) induced profound obesity in mice on a high fat diet (HFD). The HFD-fed K4bKO mice exhibited an increased volume of fat mass and higher expression levels of adipogenesis-related genes. In contrast, the genes involved in energy expenditure and mitochondrial functions were down-regulated. Supporting these findings, the energy expenditure of Kdm4b-deficient cells was markedly decreased. In addition, progression of glucose intolerance and hepatic steatosis with hepatocellular damages was observed. These data indicate that Kdm4b is a critical regulator of systemic metabolism via enhancing energy expenditure in adipocytes.

Heterogeneity of autophagic status in pancreatic β cells under metabolic stress

Autophagy in β cells has been demonstrated to play a pivotal role in cellular homeostasis and the progression of glucose intolerance. Although autophagic activity is affected by metabolic stress both in vivo and in vitro, it remains unclear as to what extent the autophagic status in each β cell is different from its neighboring cells.To address this question, GFP-LC3 reporter mice, which can visualize the autophagic status of each β cell as green-fluorescent puncta, were crossed with obese diabetic db/db mice. Imaging of green-fluorescent puncta in the islets of GFP-LC3 mice revealed that β cells are a heterogeneous population, as the density of GFP-LC3 puncta in each cell was variable. Furthermore, the variability was greater in GFP-LC3; db/db mice than in non-diabetic GFP-LC3; db/+ mice. Furthermore, when GFP-LC3 mice were treated with a low dose of S961, which antagonizes insulin signaling without inducing overt hyperglycemia, the number of β cells with a high density of GFP puncta was increased, suggesting that insulin resistance affects autophagic status independently of glucose profiles. These results suggest that pancreatic β cells under metabolic stress are heterogeneous regarding their autophagic status, which provides insights into the cellular dynamics of each β cell rather than the whole β-cell population.

The relationship between bile acid concentration, glucagon-like-peptide 1, fibroblast growth factor 15 and bile acid receptors in rats during progression of glucose intolerance

BackgroundRecent studies show that bile acids are involved in glucose and energy homeostasis through activation of G protein coupled membrane receptor (TGR5) and farnesoid X receptor (FXR). A few researches have explored changes of TGR5 and FXR in animals with impaired glucose regulation. This study aimed to observe changes of plasma total bile acids (TBA), glucagon-like-peptide 1 (GLP-1), fibroblast growth factor 15 (FGF15), intestinal expressions of TGR5 and FXR, and correlations between them in rats with glucose intolerance.MethodsBesides plasma fasting glucose, lipid, TBAs, alanine transaminase (ALT), active GLP-1(GLP-1A) and FGF15, a postprandial meal test was used to compare responses in glucose, insulin and GLP-1A among groups. The expressions of TGR5 and FXR in distal ileum and ascending colon were quantified by real-time PCR and western blot.ResultsTGR5 expression was significantly decreased in distal ileum in DM group compared to other groups, and TGR5 and FXR expressions in ascending colon were also decreased in DM group compared to other groups. Correlation analysis showed correlations between TBA and GLP-1A or FGF15. GLP-1A was correlated with TGR5 mRNA expression in colon, and FGF15 was correlated with FXR mRNA expression in colon.ConclusionsThese results indicates that bile acid-TGR5/FXR axis contributes to glucose homeostasis.

Cardio-metabolic profile of subjects with early stages of glucose intolerance and cardiovascular autonomic dysfunction.

The present study evaluates the cardio-metabolic profile of subjects with early stages of glucose intolerance and presence of cardiovascular autonomic dysfunction (CAD). 478 subjects, of mean age 49.3±13.7years and mean BMI 31.0±6.2kg/m2, divided according to glucose tolerance: 130 with normal glucose tolerance, 227 with prediabetes, and 121 with newly-diagnosed type 2 diabetes, were enrolled. Glucose tolerance was studied during OGTT applying 2006 WHO criteria. Anthropometric indices, blood pressure, HbA1c, serum lipids, hsCRP, and albumin-to-creatinine ratio (ACR) were measured. Body fat distribution was estimated by a bioimpedance method (InBody720, BioSpace). Tissue AGEs accumulation was assessed by skin autofluorescence (AGE-Reader-DiagnOptics™). CAD was assessed by ANX-3.0 method. CAD was found in 24.1% of subjects with any disorder of glucose tolerance in comparison to 12.3% in NGT, OR 2.0 (95% CI: 1.2-3.2), p=0.005. Sympathetic and parasympathetic tone declined with the progression of glucose intolerance. Age, waist circumference, visceral fat area, fasting and 120-min plasma glucose, HbA1c, AGEs, ACR and QTc interval were higher in subjects with CAD, p<0.05. In a logistic regression analysis the panel of age >53years (76% sensitivity, 61% specificity), HbA1c >6.0% (66% sensitivity, 60% specificity), QTc interval >423ms (65% sensitivity, 61% specificity) and presence of arterial hypertension (83% sensitivity, 55% specificity) was related to the presence of CAD - AUC 0.778 (95% CI: 0.73-0.83), p<0.001. Our results demonstrate a high prevalence of CAD in early stages of glucose dysmetabolism. Age, HbA1c, QTc interval and presence of arterial hypertension are related to the presence of CAD in this population.

Patient Education: Preventing Progression of Type 2 Diabetes: The Reflex to Use Pharmacological Therapy

Primary care providers are often neglectful of lifestyle interventions in the management of the progression of glucose intolerance to type 2 diabetes. Several studies have examined the benefits of pharmacologic therapy in conjunction with lifestyle modification to delay or retard this progression. This article focuses on 3 of these studies: the DREAM trial, the ADOPT trial, and the Finnish Diabetes Study. All reinforce the use and effectiveness of thiazolidinediones in the prevention of progression, yet active lifestyle intervention complements and maintains a lower diabetes risk over time.

Impaired glucose tolerance attenuates bone accrual by promoting the maturation of osteoblasts: Role of Beclin1-mediated autophagy

Patients with type 2 diabetes mellitus (T2DM) experience a 1.5–3.5 fold increase in fracture risk, but the mechanisms responsible for these alterations in bone biomechanical properties remain elusive. Macroautophagy, often referred to as autophagy, is regulated by signaling downstream of the insulin receptor. Metabolic changes associated with the progression of glucose intolerance have been shown to alter autophagy in various tissues, but limited information is available in relation to bone cells. The aim of this study was to (a) investigate whether autophagy is altered in bone tissue during impaired glucose tolerance, and (b) determine how autophagy impacts osteoblast differentiation, activity, and maturation. Four-week-old, male C57BL/6 mice were fed a control (Con) or high fat (HF) diet for 2, 8, or 16wks. Mice on the HF diet demonstrated elevated fasting blood glucose and impaired glucose tolerance. Reduced trabecular bone in the femoral neck was evident in the mice on the HF diet by 8wks compared to Con mice. Histological evaluation of the tibia suggested that the high fat diet promoted terminal differentiation of the osteoblast to an osteocyte. This shift of the osteoblasts towards a non-mineralizing, osteocyte phenotype appears to be coordinated by Beclin1-mediated autophagy. Consistent with these changes in the osteoblast in vivo, the induction of autophagy was able to direct MC3T3-E1 cells towards a more mature osteoblast phenotype. Although these data are somewhat observational, further investigation is warranted to determine if Beclin1-mediated autophagy is essential for the terminal differentiation of the osteoblasts and whether autophagy is having a protective or deleterious effect on bone in T2DM.

Microflora Disturbance during Progression of Glucose Intolerance and Effect of Sitagliptin: An Animal Study.

Background. Emerging evidences have shown a close interplay between obesity, diabetes, and intestinal flora disturbance. Dipeptidyl peptidase-4 inhibitor, exemplified by sitagliptin, is highly efficacious in treating type 2 diabetes (T2DM), yet little is known if sitagliptin exerts beneficial effects on microbiota associated with obesity and T2DM. We evaluated changes of gut microbiota following the induction of obesity and T2DM in a streptozotocin treated high fat/high carbohydrate fed (HF/HC-STZ) rat model and explored the effect of sitagliptin on gut microbiota for HF/HC-STZ rats. Methods. Sitagliptin was administered via oral gavage to diabetic rats. Fecal DNA extraction and 454 pyrosequencing based on analysis of 16S rRNA genes was utilized to determine the overall structure of microbiota in fecal DNA samples. Results. Results showed that, at the level of phylum, there was higher abundance of Firmicutes and Tenericutes and less abundance of Bacteroidetes in obese rats compared to their lean counterparts. At the level of genus, short-chain fatty acid- (SCFA-) producing bacteria, Blautia, Roseburia, and Clostridium, and probiotics Lactobacillus, Bifidobacterium, and so forth were identified significantly different from each other among conditions. Conclusion. Marked shifts of the gut microbiota structure were observed in the rats during development of glucose intolerance. Intestinal flora changed in the process of glucose intolerance, and treatment of sitagliptin moderately corrected the dysbiosis of microbiota in T2DM.

Glucose Homeostatic Law: Insulin Clearance Predicts the Progression of Glucose Intolerance in Humans.

Homeostatic control of blood glucose is regulated by a complex feedback loop between glucose and insulin, of which failure leads to diabetes mellitus. However, physiological and pathological nature of the feedback loop is not fully understood. We made a mathematical model of the feedback loop between glucose and insulin using time course of blood glucose and insulin during consecutive hyperglycemic and hyperinsulinemic-euglycemic clamps in 113 subjects with variety of glucose tolerance including normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). We analyzed the correlation of the parameters in the model with the progression of glucose intolerance and the conserved relationship between parameters. The model parameters of insulin sensitivity and insulin secretion significantly declined from NGT to IGT, and from IGT to T2DM, respectively, consistent with previous clinical observations. Importantly, insulin clearance, an insulin degradation rate, significantly declined from NGT, IGT to T2DM along the progression of glucose intolerance in the mathematical model. Insulin clearance was positively correlated with a product of insulin sensitivity and secretion assessed by the clamp analysis or determined with the mathematical model. Insulin clearance was correlated negatively with postprandial glucose at 2h after oral glucose tolerance test. We also inferred a square-law between the rate constant of insulin clearance and a product of rate constants of insulin sensitivity and secretion in the model, which is also conserved among NGT, IGT and T2DM subjects. Insulin clearance shows a conserved relationship with the capacity of glucose disposal among the NGT, IGT and T2DM subjects. The decrease of insulin clearance predicts the progression of glucose intolerance.

Irisin levels in the progression of diabetes in sedentary women

ContextThe recently discovered peptide irisin has been hypothesized to be a regulator of body metabolism. However, studies ended up with controversial results. In the present study, we aimed to investigate irisin levels in sedentary women at different stages of prediabetes. Design, setting, and subjectsWe performed a cross-sectional analysis of circulating levels of irisin in 263 females similar for age and body mass index (BMI) and the groups included 52 normal glucose tolerance (NGT), 60 isolated impaired fasting glucose (IFG), 36 isolated impaired glucose tolerance (IGT), 65 both IFG and IGT and 50 type 2 diabetic patients. All patients were exercising less than 150min/week. ResultsPlasma irisin levels were significantly lower in IFG+IGT (2.86±0.6μg/mL, p: 0.019) and T2DM (2.83±0,5μg/mL, p: 0.005) patients compared to NGT (3.16±0.3μg/mL) patients. After age adjustment there was a negative correlation between irisin and BMI (r: −0.141; p: 0.031), postprandial glucose (PPG) (r: −0.142; p: 0.030), low density lipoprotein-cholesterol (LDL-C) (r: −0.138; p: 0.035) and triglyceride (TG) (r: −0.214; p: 0.001) and a positive correlation between irisin and high density lipoprotein-cholesterol (HDL-C) (r:.142; p: 0.030). After adjustment for age and BMI; PPG (r: −0. 137; p: 0.037), LDL-C (r: −0. 143; p: 0.029) and TG (r: −0.203; p: 0.002) were considered to correlate with irisin levels. Subgroup analysis revealed that TG levels were correlated with irisin levels in IFG (r: −0.347; p: 0.014) and IGT (r: −0.397; p: 0.030) patients. ConclusionIn our cohort of sedentary women, irisin levels were lower in patients with IFG+IGT and with diabetes than in patients with NGT. There is no correlation between irisin levels and BMI. Irisin is a myokine decreasing gradually with the progression of glucose intolerance and T2DM and is not correlated with BMI in sedentary women.

Postprandial glucagon-like peptide-1 secretion is increased during the progression of glucose intolerance and obesity in high-fat/high-sucrose diet-fed rats.

Glucagon-like peptide-1 (GLP-1) is secreted by distal enteroendocrine cells in response to luminal nutrients, and exerts insulinotropic and anorexigenic effects. Although GLP-1 secretory responses under established obese or diabetic conditions have been studied, it has not been investigated whether or how postprandial GLP-1 responses were affected during the progression of diet-induced obesity. In the present study, a meal tolerance test was performed every week in rats fed a high-fat and high-sucrose (HF/HS) diet to evaluate postprandial glycaemic, insulin and GLP-1 responses. In addition, gastric emptying was assessed by the acetaminophen method. After 8 weeks of HF/HS treatment, portal vein and intestinal mucosa were collected to examine GLP-1 production. Postprandial glucose in response to normal meal ingestion was increased in the HF/HS group within 2 weeks, and its elevation gradually returned close to that of the control group until day 50. Slower postprandial gastric emptying was observed in the HF/HS group on days 6, 13 and 34. Postprandial GLP-1 and insulin responses were increased in the HF/HS group at 7 weeks. Higher portal GLP-1 and insulin levels were observed in the HF/HS group, but mucosal gut hormone mRNA levels were unchanged. These results revealed that the postprandial GLP-1 response to meal ingestion is enhanced during the progression of diet-induced glucose intolerance and obesity in rats. The boosted postprandial GLP-1 secretion by chronic HF/HS diet treatment suggests increased sensitivity to luminal nutrients in the gut, and this may slow the establishment of glucose intolerance and obesity.

Mechanism(s) of Pancreatic Cancer-induced Diabetes

While long-standing diabetes (DM) modestly increases the risk of pancreatic ductal adenocarcinoma (PC), there is growing evidence that PC frequently causes DM. Up to 85% of PC patients have DM or hyperglycemia, which frequently manifests in the 2 to 3 years preceding the diagnosis of cancer. Conversely, subjects with new-onset DM have a high probability (5-8 folds higher than the population) of being diagnosed with PC within 1-3 years of DM onset. Resection of the PC leads to amelioration of DM. Type 2 DM occurs due to beta cell failure following decades of obesity-associated insulin resistance. As in type 2 DM, beta cell dysfunction and peripheral insulin resistance are seen in PC-induced DM (PC-DM). However, in contrast to type 2 DM, onset and progression of glucose intolerance in PC-DM occur in the face of ongoing, often profound, weight loss. The weight loss precedes the development of DM in PC and occurs months before the onset of cancer cachexia. Studies show that PC is associated with profound insulin resistance that resolves following PC resection. However, the very high frequency of DM suggests that there is associated beta cell dysfunction. There are many hypotheses for how PC might cause DM: a) Is PC-DM simply type 2 DM? Canonical risk factors for DM (age, BMI and family history of DM) are also risk factors for PCDM. However, the fact that new-onset DM and hyperglycemia occur in 85% of PC suggest a PC-specific stressor that profoundly and consistently decompensates glucose homeostasis. b) Could PCDM be a consequence of profound cachexia seen in PC? Cachexia is associated with insulin resistance which could potentially decompensate glues homeostasis, especially in the elderly. This is unlikely to explain PCDM as. c) Could obstruction of the pancreatic duct and consequent pancreatic atrophy cause PCDM? PC is frequently associated with obstructive pancreatitis and distal atrophy. However, onset of DM occurs at a time when CT does not even show a mass. Additionally, insulin levels would be expected to be low in patients with DM due to destruction of islet mass. Insulin levels are relatively high in PCDM, reflecting insulin resistance. d) The most likely explanation for the frequent occurrence of DM in PC is that it is a paraneoplastic phenomenon caused by tumor secreted products. Apart from the clinical and epidemiological evidence noted above, this notion is supported by laboratory data that supernatant from PC cell lines inhibit insulin secretion. Although much remains to be learned, new insights on the pathogenesis of these metabolic alterations in PC have recently emerged. Adrenomedullin, which is over-expressed in PC, was identified as a potential mediator of beta-cell dysfunction in PCDM. Adrenomedullin is a pluripotent hormone with homology semblance to amylin. In the pancreas, its receptors are found on beta cells and its expression is seen specifically in the F cells of the islets. Inhibition of insulin secretion in beta cells induced by supernatant from PC cell lines was replicated by external addition of adrenomedullin and abrogated by its genetic knockdown. Similar effects were seen in orthotopic and subcutaneous in vivo tumor models using adrenomedullin expressing PC cell lines. Further, plasma adrenomedullin levels were higher in PC compared to controls and even higher levels were seen in PCDM. Overexpression of adrenomedullin was seen in surgically resected specimens of PC. These data strongly support the notion that adrenomedullin mediates beta cell dysfunction. The cause of insulin resistance and PCDM-associated weight loss remains unclear, though these appear to be paraneoplastic phenomena as well. PC is associated with a unique mechanism of DM. The onset of DM occurs between 6 months and 365 months before PC diagnosis in 20-25% of patients. At this time patients are otherwise asymptomatic. This suggests that new-onset DM could be biomarker of asymptomatic PC. However, the strategy to use new-onset DM as a marker of asymptomatic PC will succeed only if PC-DM can be distinguished from the more common type2 DM. Identifying the mediators of PC-DM could lead to discovery of novel biomarkers of PC.

Peripheral Neuropathy and Nerve Dysfunction in Individuals at High Risk for Type 2 Diabetes: The PROMISE Cohort.

Emerging evidence suggests that peripheral neuropathy begins in the early stages of diabetes pathogenesis. Our objective was to describe the prevalence of peripheral neuropathy and nerve dysfunction according to glucose tolerance and metabolic syndrome status and examine how these conditions are associated with neurological changes in individuals at risk for type 2 diabetes. We studied 467 individuals in the longitudinal PROMISE (Prospective Metabolism and Islet Cell Evaluation) cohort. Peripheral neuropathy was defined by Michigan Neuropathy Screening Instrument (MNSI) scores (>2), and the severity of nerve dysfunction was measured objectively by vibration perception thresholds (VPTs) using a neurothesiometer. Metabolic syndrome was defined using the International Diabetes Federation/American Heart Association harmonized criteria. The prevalence of peripheral neuropathy was 29%, 49%, and 50% for normal glycemia, prediabetes, and new-onset diabetes, respectively (P < 0.001 for trend). The mean VPT was 6.5 V for normal glycemia, 7.9 V for prediabetes, and 7.6 V for new-onset diabetes (P = 0.024 for trend). Prediabetes was associated with higher MNSI scores (P = 0.01) and VPTs (P = 0.004) versus normal glycemia, independent of known risk factors. Additionally, progression of glucose intolerance over 3 years predicted a higher risk of peripheral neuropathy (P = 0.007) and nerve dysfunction (P = 0.002). Metabolic syndrome was not independently associated with MNSI scores or VPTs. In individuals with multiple risk factors for diabetes, prediabetes was associated with similar risks of peripheral neuropathy and severity of nerve dysfunction as new-onset diabetes. Prediabetes, but not metabolic syndrome, was independently associated with both the presence of peripheral neuropathy and the severity of nerve dysfunction.

The American Pancreatic Association/Hirshberg Foundation Symposium Celebrating the 10th Anniversary of the Seed Grant Program

The Hirshberg Foundation for Pancreatic Cancer Research was founded by Agi Hirshberg in 1997, following her husband Ronald Hirshberg’s 8-month, 7-day battle with the disease. (http://www.pancreatic.org/). At the time, the Hirshberg family viewed pancreatic cancer as the ‘‘unknown enemy’’ (http:// www.pancreatic.org/site/c.htJYJ8MPIwE/b.8276835/k.66CB/ Agi_Hirshbergs_Story.htm). In the years since Ronald Hirshberg’s death, Agi Hirshberg has made it her mission to unmask the unknown for others facing the same enemy. When patients present with a new diagnosis of pancreatic cancer, most are already in an advanced stage of the disease. Pancreatic cancer is resistant to most chemotherapeutic agents and radiotherapy. These factors combine to make pancreatic cancer a highly lethal disease, and according to the National Cancer Institute (NCI) 2013 estimates, pancreatic cancer was diagnosed in approximately 45,220 US citizens, and some 38,460 died of the disease. 1 The Annual Report to the Nation on the Status of Cancer, 1975Y2009, shows that overall cancer death rates continued to decline in the United States among both men and women, among all major racial and ethnic groups, and for all of the many common cancer sites, including lung, colon and rectum, female breast, and prostate. However, this trend does not hold true for pancreatic cancer. The report demonstrates that death rates continued to increase during the latest time period (2000 through 2009) for pancreatic cancer. 2 Only about 23% of patients with cancer of the pancreas will still be living 1 year after diagnosis, and only about 4% will survive 5 years. Even for those diagnosed with pancreatic cancer that has not spread to other organs or systems, the overall 5-year survival rate approaches only 15%. The Hirshberg Foundation’s vision is to advance pancreatic cancer research and provide information, resources, and support to pancreatic cancer patients and their families. The mission of the Foundation is as follows: & To find a cure for pancreatic cancer in honor of Ron Hirshberg and the thousands of people who are diagnosed with this disease each year. & To create a premier Pancreatic Cancer Center where all needs of pancreatic cancer patients can be met in one location with the most advanced treatment options. & To be recognized as a patient support reference source for

Sex differences in lipid profiles in relation to the progression of glucose abnormalities

In the present study, we investigated the role of changes in blood lipids in the abolition of the lower cardiovascular risk associated with the female gender in individuals with type 2 diabetes mellitus (T2DM). An oral glucose tolerance test (OGTT) was performed in 1091 consecutive patients (478 men and 613 women) and patients were divided into groups as follows: (i) those with normal glucose tolerance (NGT; n = 589); (ii) those with pre-diabetes (pre-T2DM), who were further divided into those with impaired fasting glucose (IFG; n = 212), impaired glucose tolerance (IGT; n = 84), and both IFG and IGT (IFG/IGT; n = 102); and (iii) those with T2DM (n = 104). Total cholesterol, triglycerides, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein (apo) A-I, apoB, and the apoB:apoA-I ratio were determined in each patient. Differences in lipids between the different groups were assessed using Student's t-test. Significantly higher triglyceride levels and an apoB:apoA-I ratio were found in NGT men (P < 0.0001), along with lower HDL-C and apoA-I (P < 0.0001). Men in the pre-T2DM group maintained a higher apoB:apoA-I ratio (P < 0.05) and lower HDL-C (P < 0.0001) compared with women. In the T2DM group, only HDL-C was lower in men compared with women (P < 0.05). The progression of glucose intolerance from NGT to pre-T2DM and T2DM exhibits striking sex differences regarding the lipid profile. The data demonstrate a worsening of plasma lipid composition in women who become diabetic. This could explain, at least in part, the loss of the more favorable cardiovascular risk normally associated with NGT women.