Development Of Glucose Intolerance Research Articles

SUN-LB121 Nifedipine Worsens Glucose Tolerance in C57BL/6J Mice Exposed to Intermittent Hypoxia

Background: Intermittent hypoxemia (IH), a pathognomonic component of obstructive sleep apnea (OSA), has been independently associated with development of glucose intolerance, insulin resistance, and type 2 diabetes. L-type calcium channel blockers (CCB) influence glucose homeostasis including insulin sensitivity and secretion. To date, the potential impact of the combined effects of L-type CCB and IH on fasting glycemia and glucose tolerance have not been examined. The objective of this study was to determine whether CCB alters glucose metabolism in a murine model of IH. Methods: Adult male C57BL6/J mice (age 19-week-old) were exposed to IH using an automated system with specially-modified cages that oscillated FiO2from 21% to 5.5% at a target rate of 60 events/h during a 12 h (7am – 7pm) light cycle to simulate severe OSA for 5 days. The L-type CCB, nifedipine, or vehicle (polyethleneglycol-400) were administered at a dose of 20mg/kg/day via subcutaneous osmotic pumps (Alzet model 2001). Mice were exposed to IH or intermittent air (IA) with four resulting groups: IA-vehicle (n=12), IH-vehicle (n=16), IA–nifedipine (n=10), and IH–nifedipine (n=13). Fasting glucose, intraperitoneal glucose tolerance test, and insulin levels were obtained after exposures. Results: In the absence of a L-type CCB, IH increased fasting (105.1 vs. 71.2 mg/dL; p<0.001) and 2-hour glucose levels (104.8 vs. 82.0 mg/dL; p=0.003). The area under the glucose tolerance curve (AUC) was also higher with IH than IA in mice treated with vehicle (17896.3 vs.13965.8 mg-min/dL; p<0.001). Although the effects of IH on fasting glucose levels were comparable with and without L-type CCB treatment, the 2-hour glucose levels and the AUCs were substantially different. A statistically significant interaction was noted for the 2-hr glucose levels between IH and treatment with a L-type CCB (IH-CCB: 193.7; IH-V: 122.6; IA-CCB: 103.5; and IA-V: 82.0 mg/dL; p<0.05 for interaction between IH and CCB). Finally, the AUC for IH-CCB treated mice was significantly higher than the AUC for IH-V treated mice (IH-CCB: 30223.1; IH-V: 17896.3. mg-min/dL; p=0.0001) Conclusions: In a murine model of IH, treatment with an L-type CCB exacerbates the deleterious effects of IH on glucose tolerance. Thus, use of CCB in patients with OSA should take into consideration these unfavorable effects particularly in those who are metabolically compromised.

SAT-LB104 Maternal Non-Nutritive Sweeteners Consumption Perturbs Development of Melanocortin Circuits Causing Long-Term Metabolic Alterations in the Offspring

Maternal Non-Nutritive Sweeteners Consumption Perturbs Development of Melanocortin Circuits Causing Long-Term Metabolic Alterations in the Offspring Soyoung Park1, Alice Jang1, Josephine Lowy1, Sebastien G Bouret2 1Developmental Neuroscience & Diabetes and Obesity Programs, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, USA. 2 Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Jean-Pierre Aubert Research Centre, UMR-S 1172, Lille, 59000, France.With the growing prevalence of obesity and diabetes, including among pregnant women, non-nutritive sweeteners (NNS) have been widely used as an alternative to sugar in the attempt to deliver a sweet taste without excessive caloric load. However, there is little evidence regarding their biological effects particularly during critical periods of growth and development. In this study, we aimed to investigate whether maternal NNS consumption causes long-term neurodevelopmental and metabolic perturbations in the offspring. Adult female wild-type mice were exposed to either water (control), aspartame (0.03%), or rebaudioside A (0.02%) throughout pregnancy and lactation. Adult male, but not female, offspring from both aspartame- and rebaudioside A-exposed dams displayed increased adiposity and developed glucose intolerance. Moreover, maternal NNS consumption impaired pro-opiomelanocortin axonal projections to the paraventricular nucleus of the hypothalamus as well as reduced parasympathetic innervation of pancreatic islets. Taken together, our data indicate that maternal NNS consumption causes neurodevelopmental abnormalities in the offspring that may contribute to lifelong metabolic dysregulations.

Effect of stevia on the gut microbiota and glucose tolerance in a murine model of diet-induced obesity.

Artificial sweeteners have been shown to induce glucose intolerance by altering the gut microbiota; however, little is known about the effect of stevia. Here, we investigate whether stevia supplementation induces glucose intolerance by altering the gut microbiota in mice, hypothesizing that stevia would correct high fat diet-induced glucose intolerance and alter the gut microbiota. Mice were split into four treatment groups: low fat, high fat, high fat + saccharin and high fat + stevia. After 10 weeks of treatment, mice consuming a high fat diet (60%kcal from fat) developed glucose intolerance and gained more weight than mice consuming a low fat diet. Stevia supplementation did not impact body weight or glucose intolerance. Differences in species richness and relative abundances of several phyla were observed in low fat groups compared to high fat, stevia and saccharin. We identified two operational taxonomic groups that contributed to differences in beta-diversity between the stevia and saccharin groups: Lactococcus and Akkermansia in females and Lactococcus in males. Our results demonstrate that stevia does not rescue high fat diet-induced changes in glucose tolerance or the microbiota, and that stevia results in similar alterations to the gut microbiota as saccharin when administered in concordance with a high fat diet.

Altered pancreas remodeling following glucose intolerance in pregnancy in mice.

Gestational diabetes mellitus increases the risk of dysglycemia postpartum, in part, due to pancreatic β-cell dysfunction. However, no histological evidence exists comparing endocrine pancreas after healthy and glucose-intolerant pregnancies. This study sought to address this knowledge gap, in addition to exploring the contribution of an inflammatory environment to changes in endocrine pancreas after parturition. We used a previously established mouse model of gestational glucose intolerance induced by dietary low protein insult from conception until weaning. Pancreas and adipose samples were collected at 7, 30 and 90 days postpartum for histomorphometric and cytokine analyses, respectively. Glucose tolerance tests were performed prior to euthanasia and blood was collected via cardiac puncture. Pregnant female mice born to dams fed a low protein diet previously shown to develop glucose intolerance at late gestation relative to controls continued to be glucose intolerant until 1 month postpartum. However, glucose tolerance normalized by 3 months postpartum. Glucose intolerance at 7 days postpartum was associated with lower beta- and alpha-cell fractional areas and higher adipose levels of pro-inflammatory cytokine, interleukin-6. By 3 months postpartum, a compensatory increase in the number of small islets and a higher insulin to glucagon ratio likely enabled euglycemia to be attained in the previously glucose-intolerant mice. The results show that impairments in endocrine pancreas compensation in hyperglycemic pregnancy persist after parturition and contribute to prolonged glucose intolerance. These impairments may increase the susceptibility to development of future type 2 diabetes.

Dyslipidemia is not associated with the development of glucose intolerance or diabetes in cystic fibrosis

BackgroundA high-fat, high-calorie diet is recommended in patients with cystic fibrosis (CF) as it improves nutritional status, respiratory health and longevity. In the general population, this diet is associated with the risk of diabetes. It is unknown whether dyslipidemic changes might contribute to the development of CF-related diabetes (CFRD). ObjectiveThis study aimed to (i) characterize dyslipidemia and (ii) examine the association between dyslipidemia and development of glucose intolerance. MethodsProspective observational study with serial assessments of pulmonary function, glucose tolerance, and lipid profile. Due to intrinsically low total, HDL and LDL cholesterol in patients with CF, subjects were characterized as having dyslipidemia if they had i) HDL in the lowest quartile and/or ii) hypertriglyceridemia (≥1.7 mmol/L). ResultsA total of 256 patients with CF were included (age: 25.5 ± 7.7 years; BMI: 21.7 ± 3.0 kg/m2; FEV1%: 73.2 ± 22.1%; pancreatic insufficiency: 87%). Amongst these patients, 22.7% had low HDL, 9.0% had hypertriglyceridemia and 3.9% had mixed dyslipidemia. There were no differences in HbA1c (p = 0.583) or estimated insulin resistance [HOMA-IR (p = 0.206) or Stumvoll index (p = 0.397)]. Patients with hypertriglyceridemia had higher fat mass (p = 0.038) and fewer had pancreatic insufficiency. Lipid profiles were similar between subjects with CF and subjects with de novo CFRD. There was no effect of low HDL or hypertriglyceridemia on the development of CFRD over 10 years (p = 0.683). ConclusionIn adult patients with CF, dyslipidemia is not associated with the risk of developing hyperglycemia or CFRD.

Hyperuricemia Predisposes to the Onset of Diabetes via Promoting Pancreatic β-Cell Death in Uricase-Deficient Male Mice.

Clinical studies have shown a link between hyperuricemia (HU) and diabetes, while the exact effect of soluble serum urate on glucose metabolism remains elusive. This study aims to characterize the glucose metabolic phenotypes and investigate the underlying molecular mechanisms using a novel spontaneous HU mouse model in which the uricase (Uox) gene is absent. In an attempt to study the role of HU in glycometabolism, we implemented external stimulation on Uox knockout (KO) and wild-type (WT) males with a high-fat diet (HFD) and/or injections of multiple low-dose streptozotocin (MLD-STZ) to provoke the potential role of urate. Notably, while Uox-KO mice developed glucose intolerance in the basal condition, no mice spontaneously developed diabetes, even with aging. HFD-fed Uox-KO mice manifested similar insulin sensitivity compared with WT controls. HU augmented the existing glycometabolism abnormality induced by MLD-STZ and eventually led to diabetes, as evidenced by the increased random glucose. Reduced β-cell masses and increased terminal deoxynucleotidyl TUNEL-positive β-cells suggested that HU-mediated diabetes was cell death dependent. However, urate-lowering therapy (ULT) cannot ameliorate the diabetes incidence or reverse β-cell apoptosis with significance. ULT displayed a significant therapeutic effect of HU-crystal–associated kidney injury and tubulointerstitial damage in diabetes. Moreover, we present transcriptomic analysis of isolated islets, using Uox-KO versus WT mice and streptozotocin-induced diabetic WT (STZ-WT) versus diabetic Uox-KO (STZ-KO) mice. Shared differentially expressed genes of HU primacy revealed Stk17β is a possible target gene in HU-related β-cell death. Together, this study suggests that HU accelerates but does not cause diabetes by inhibiting islet β-cell survival.

Hepatocyte-specific deletion of Ppar\u03b1 promotes NAFLD in the context of obesity

Peroxisome proliferator activated receptor α (PPARα) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Pparα in hepatocytes spontaneously develop steatosis without obesity in aging. Steatosis can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. In the current study, we investigated the role of hepatocyte PPARα in a preclinical model of steatosis. For this, we used High Fat Diet (HFD) feeding as a model of obesity in C57BL/6 J male Wild-Type mice (WT), in whole-body Pparα- deficient mice (Pparα−/−) and in mice lacking Pparα only in hepatocytes (Pparαhep−/−). We provide evidence that Pparα deletion in hepatocytes promotes NAFLD and liver inflammation in mice fed a HFD. This enhanced NAFLD susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPARα activity predominantly contributes to the metabolic response to HFD. Taken together, our data support hepatocyte PPARα as being essential to the prevention of NAFLD and that extra-hepatocyte PPARα activity contributes to whole-body lipid homeostasis.

Targeting Metabolic Consequences of Insulin Resistance in Polycystic Ovary Syndrome by D-chiro-inositol and Emerging Nutraceuticals: A Focused Review.

Polycystic ovary syndrome (PCOS) is a complex disorder associated with ovarian dysfunction, infertility, menstrual irregularity, and hormonal impairments. Over the last decade, several studies have shown that some PCOS women have insulin resistance (InsR) and hyperinsulinemia, apart from being overweight or obese. Therefore, a crucial clinical aspect is that PCOS patients might develop glucose intolerance and type 2 diabetes. Insulin-sensitizing drugs have been used as first-line treatment to improve hyperinsulinemia in women with PCOS. Although reducing PCOS symptoms and signs, several used insulin-sensitizer drugs may induce side effects, which reduces compliance. D-chiro-inositol (DCI), which is a naturally occurring stereoisomer of inositol, has been classified as an insulin-sensitizer and seems to mitigate multiple InsR-related metabolic alterations in PCOS with a safe profile. However, according to a multi-targeted design, the supplementation with DCI can be synergistically integrated by combining other potential insulin-sensitizing drugs and/or nutraceuticals. The literature provides the initial support for using several unexplored nutraceutical interventions that may target relevant metabolic abnormalities associated with InsR in PCOS. With a need to promote interest in clinical research, this review aims to discuss the efficacy of DCI and the role of emerging nutraceuticals for managing InsR in PCOS.

Hepatocyte HIF‐1alpha mediates obesity‐induced decreased incretin effects

The decrease in incretin effects is an important etiologic component of type 2 diabetes with unknown mechanisms. In an attempt to understand obesity‐induced changes in liver oxygen homeostasis and its metabolic consequence, we came across a novel finding that liver HIF‐1α expression was increased mainly by soluble factors released from obese adipocytes, leading to decreased incretin effects. In‐depth mouse metabolic phenotyping revealed that obesity increased first‐pass degradation of an incretin hormone GLP‐1 with increased liver DPP4 expression and decreased sinusoidal blood flow rate, reducing active GLP‐1 levels in peripheral circulation. Deletion of hepatocyte HIF‐1α KO blocked these changes induced by obesity: hepatocyte HIF‐1α KO mice were protected from obesity‐induced glucose intolerance without changes in body weight, liver steatosis, or insulin resistance. Deletion of hepatocyte HIF‐2α did not change liver DPP4 expression but improved hepatic steatosis. Our results identify a previously unknown pathway for obesity‐induced impaired beta cell glucose response (incretin effects) and the development of glucose intolerance through inter‐organ communications.

Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma

Thymine DNA glycosylase (TDG) is a nuclear receptor coactivator that plays an essential role in the maintenance of epigenetic stability in cells. Here, we demonstrate that the conditional deletion of TDG in adult mice results in a male-predominant onset of hepatocellular carcinoma (HCC). TDG loss leads to a prediabetic state, as well as bile acid (BA) accumulation in the liver and serum of male mice. Consistent with these data, TDG deletion led to dysregulation of the farnesoid X receptor (FXR) and small heterodimer partner (SHP) regulatory cascade in the liver. FXR and SHP are tumor suppressors of HCC and play an essential role in BA and glucose homeostasis. These results indicate that TDG functions as a tumor suppressor of HCC by regulating a transcriptional program that protects against the development of glucose intolerance and BA accumulation in the liver.

Iron, Insulin and Coronary Heart Disease Emphasis on the Generation of Sudden Death and Occult Diabetes (And Why Donating Blood Can Reduce Cardiovascular Death)

Dysregulated glucose metabolism promote inflammation in monocytes and macrophages from patients with atherosclerotic coronary artery disease. Men with metabolic syndrome are at increased risk for sudden cardiac death, and the incident sudden death is not explained by obesity or traditional cardiovascular risk factors (Kurl, 2016), but the ingested nutritional iron. Individuals with increased abdominal adiposity exhibit an increased risk of heart failure, in spite of there are oweweigtht or not (Cavalera, 2014), because the insulin resistance contribute to increased myocardial fibrosis in the absence of hypertension (Quilliot, 2005). Iron overload, and plasma viscosity contributes to cardiovascular risk in the general population, particularly in men (Van der A, 2005; Junker, 1998). Iron influences glucose metabolism, even in the absence of significant iron overload, and its reduction may alleviate coronary heart disease and reduced or prevent their complications: High stored or free iron levels (measured by serum ferritin or catalytic iron concentrations) elevate risk for development of coronary atherosclerosis, because labile iron accelerates endothelial dysfunction and originates oxidative injury that promotes systemic and vascular inflammation, phrothrombotic conditions and insulin resistance (Williams, 2002). High serum ferritin is strongly and independently associated with acute myocardial infarction and constitutes a novel risk factor in acute sudden event (Holay, 2012). Iron plays a direct and causal role in diabetes pathogenesis mediated both by β-cell failure and insulin resistance (Simcox, 2013). In the general population, body iron stores are positively associated with the development of glucose intolerance, type 2 diabetes and gestational diabetes. In this way, blood donation significant drops in the incidence of cardiovascular events, as well as in procedures such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting (Holsworth, 2013): frequent blood donations decreased iron stores in healthy volunteers, improving insulin sensitivity and hemodynamic parameters. Iron and oxygen-derived free radicals are important in the pathogenesis of postischemic reperfusion injury and contributes substantially to endothelial dysfunction in acute coronary syndromes (Chekanov, 2002; Duffy, 2001) , and a high iron diet potentially increase ischemic damage induced by transient ischemia and early reperfusion (García-Yébenes, 2012) in animals and humans. Iron, hyperinsulinemia, and hyperglycemia act in concert to up regulate free-radical reactions (Facchini, 2000) and this metal excess accelerated the development of atherosclerosis and its accumulation may promotes illness, particularly, ischemic cardiovascular diseases. Insulin resistance in macrophages promotes formation of a necrotic core in atherosclerotic plaques by enhancing macrophage apoptosis, and exposure it to circulating blood in the event of plaque rupture can precipitate thrombosis, leading to unstable angina pectoris, myocardial infarction and sudden death (Rask.Madsen, 2012, rev). In humans phlebotomy slows progression of peripheral vascular disease and blood donation lowers significantly the risk of myocardial infarction (Salonen, 1998), particularly in insulin-resistant subjects. On the contrary, exogenous iron into healthy individuals provoked endothelial dysfunction accompanied by increased generation of superoxide radical in whole blood (Vinchi, 2014, rev). A causal relationship between pre-diabetes and cardiovascular disease exist (Ford, 2010, rev). Humans lack effective mechanisms to excrete excess iron, and excessive dietary iron uptake cause iron deposition in heart, and pancreas (Kulaksis, 2008) leading to sudden death and occult diabetes mellitus. Iron play an underappreciated role in the development of insulin resistance and insulin resistance-induced heart failure. In a chronic and acute way, Insulin resistance is an early and major factor in the development of heart failure and acute iron induced insulin resistance in cardiomyocytes (Sung, 2019). 1- Introduction 2- Catalytic Iron; Irreversible Oxidizer 3- Excess Hemoglobin and Cardiocerebrovascular Pathology 4- Free Iron as a promoter of Ischemic Heart Disease 5- Excess Ferritin and pathogenesis of Endothelial Dysfunction 6- Hyperinsulinemia as a Sudden Death Promoter. The determining role of Iron 7- Iron accumulated in excess and pathogenesis of Diabetes: High hemoglobin versus High Ferritin 8- Iron and atherosclerosis. The evidence 9- Blood Donation. Cardiovascular Pathology Protector

Maternal N-Acetyl Cysteine Intake Improved Glucose Tolerance in Obese Mice Offspring.

Exposure to certain environmental factors during the early stages of development was found to affect health in adulthood. Among other environmental factors, oxidative stress has been suggested to be involved in fetal programming, leading to elevated risk for metabolic disorders, including type 2 diabetes; however, the possibility that antioxidant consumption during early life may affect the development of diabetes has scarcely been studied. The aim of this study was to investigate the effects of N-acetyl-l-cysteine (NAC) given during pregnancy and lactation on the susceptibility of offspring to develop glucose intolerance at adulthood. C57bl6/J mice were given NAC during pregnancy and lactation. High fat diet (HFD) was given to offspring at an age of 6 weeks for an additional 9 weeks, till the end of the study. Isolated islets of NAC-treated offspring (6 weeks old, before HFD feeding) had an increased efficacy of glucose-stimulated insulin secretion and a higher resistance to oxidative damage. Following HFD feeding, glucose tolerance and insulin sensitivity of NAC-treated offspring were improved. In addition, islet diameter was lower in male offspring of NAC-treated mice compared to their HFD-fed littermates. NAC consumption during early life improves glucose tolerance in adulthood in mice.

Maternal obesity-induced endoplasmic reticulum stress causes metabolic alterations and abnormal hypothalamic development in the offspring.

The steady increase in the prevalence of obesity and associated type II diabetes mellitus is a major health concern, particularly among children. Maternal obesity represents a risk factor that contributes to metabolic perturbations in the offspring. Endoplasmic reticulum (ER) stress has emerged as a critical mechanism involved in leptin resistance and type 2 diabetes in adult individuals. Here, we used a mouse model of maternal obesity to investigate the importance of early life ER stress in the nutritional programming of this metabolic disease. Offspring of obese dams developed glucose intolerance and displayed increased body weight, adiposity, and food intake. Moreover, maternal obesity disrupted the development of melanocortin circuits associated with neonatal hyperleptinemia and leptin resistance. ER stress-related genes were up-regulated in the hypothalamus of neonates born to obese mothers. Neonatal treatment with the ER stress-relieving drug tauroursodeoxycholic acid improved metabolic and neurodevelopmental deficits and reversed leptin resistance in the offspring of obese dams.

Association of glucose tolerance status with pancreatic β- and α-cell mass in community-based autopsy samples of Japanese individuals: The Hisayama Study.

Aims/IntroductionChanges in histologically quantified β‐ and α‐cell mass during the development of glucose intolerance have not been fully elucidated. The aim of the present study was to explore differences in β‐ and α‐cell mass according to the glucose tolerance status.Materials and MethodsAutopsy samples from a total of 103 individuals (40 with normal glucose tolerance, 31 with prediabetes and 32 with type 2 diabetes mellitus) who underwent a 75‐g oral glucose tolerance test within 5 years before death were selected from 643 community‐based autopsy samples collected from 2002 to 2016. Fractional β‐cell area (BCA) and α‐cell area were quantified with Image Pro Plus software. Associations of BCA and α‐cell area with glucose tolerance status were assessed using a linear regression analysis, and Spearman’s correlation coefficients between glycemic markers and β‐cell function were estimated.ResultsThe mean values of BCA decreased significantly with worsening glucose tolerance status (mean ± standard error 1.85 ± 0.10% in normal glucose tolerance, 1.59 ± 0.11% in prediabetes and 1.17 ± 0.11% in type 2 diabetes mellitus, P for trend < 0.001), whereas there was no significant association between α‐cell area and glucose tolerance status. BCA was inversely correlated with fasting and 2‐h plasma glucose levels during oral glucose tolerance test and glycated hemoglobin measurement, and positively correlated with disposition index (all P < 0.01).Conclusionsβ‐Cell mass decreased significantly with worsening glucose tolerance, from the stage of prediabetes, in the Japanese population. Prevention of declining β‐cell mass before the onset of glucose intolerance is important to reduce the burden of type 2 diabetes mellitus.

Regulation of glucose homeostasis by small extracellular vesicles in normal pregnancy and in gestational diabetes

The mechanisms underpinning maternal metabolic adaptations to a healthy pregnancy and in gestational diabetes mellitus (GDM) remain poorly understood. We hypothesized that small extracellular vesicles (sEVs) isolated from healthy pregnant women promote islet glucose-stimulated insulin secretion (GSIS) and peripheral insulin resistance in nonpregnant mice and that sEVs from GDM women fail to stimulate insulin secretion and cause exacerbated insulin resistance. Small EVs were isolated from plasma of nonpregnant, healthy pregnant, and GDM women at 24-28weeks of gestation. We developed a novel approach in nonpregnant mice involving a mini-osmotic pump for continuous 4-day jugular venous infusion of sEVs and determined their effects on glucose tolerance in vivo and islets and skeletal muscle in vitro. Fasting insulin was elevated in mice infused with pregnant sEVs as compared to sEVs from nonpregnant and GDM women. Mice infused with sEVs from GDM women developed glucose intolerance. GSIS was increased in mice infused with healthy pregnancy sEVs compared to mice receiving nonpregnant sEVs. GSIS and muscle basal insulin signaling, and insulin responsiveness were attenuated in mice infused with GDM sEVs. sEVs represent a novel mechanism regulating maternal glucose homeostasis in pregnancy and we speculate that altered sEV content contributes to the development of GDM.

Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping

Non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D) and obesity are epidemiologically correlated with each other but the causal inter-relationships between them remain incompletely understood. We aimed to explore the causal relationships between the 3 diseases. Using both UK Biobank and publicly available genome-wide association study data, we performed a 2-sample bidirectional Mendelian randomization analysis to test the causal inter-relationships between NAFLD, T2D, and obesity. Transgenic mice expressing the human PNPLA3-I148M isoforms (TghPNPLA3-I148M) were used as an example to validate causal effects and explore underlying mechanisms. Genetically driven NAFLD significantly increased the risk of T2D and central obesity but not insulin resistance or generalized obesity, while genetically driven T2D, body mass index and WHRadjBMI causally increased NAFLD risk. The animal study focusing on PNPLA3 corroborated these causal effects: compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed glucose intolerance and increased visceral fat, but maintained normal insulin sensitivity, reduced body weight, and decreased circulating total cholesterol. Mechanistically, the TghPNPLA3-I148M mice demonstrated decreased pancreatic insulin but increased glucagon secretion, which was associated with increased pancreatic inflammation. In addition, transcription of hepatic cholesterol biosynthesis pathway genes was significantly suppressed, while transcription of thermogenic pathway genes was activated in subcutaneous and brown adipose tissues but not in visceral fat in TghPNPLA3-I148M mice. Our study suggests that lifelong, genetically driven NAFLD causally promotes T2D with a late-onset type 1-like diabetic subphenotype and central obesity; while genetically driven T2D, obesity, and central obesity all causally increase the risk of NAFLD. This causal relationship revealed new insights into how nature and nurture drive these diseases, providing novel hypotheses for disease subphenotyping. Non-alcoholic fatty liver disease, type 2 diabetes and obesity are epidemiologically correlated with each other, but their causal relationships were incompletely understood. Herein, we identified causal relationships between these conditions, which suggest that each of these closely related diseases should be further stratified into subtypes. This is important for accurate diagnosis, prevention and treatment of these diseases.

Serum Ferritin Status of Patients with Type 2 DM Attending OPD of BIRDEM General Hospital

Background: In recent times much is talked about of serum ferritin, an acute phase reactant a marker of iron stores in the body and its association with diabetes mellitus. Studies implicate that increased body iron stores and subclinical hemochromatosis has been associated with the development of glucose intolerance, type 2 diabetes and its micro as well as macrovascular complications.&#x0D; Material &amp; Methods: This study was carried out to examine and to observe for any relationship between serum ferritin with Type 2 diabetes mellitus. Our study populations were included 163. Among them 81 type 2 diabetes patients as a case (M=49,F=32, mean 44.68 age in years)and 82 normal healthy individual as a control ( M=35, F=47 , mean 34.71 in years).&#x0D; Results: Majority were healthy outpatients who had come for regular checkup and were matched with controls. Serum ferritin and FBS were estimated and other investigations. Results showed that although Serum ferritin was in the normal range value it was increased in type 2 diabetes patients than in controls and was statistically significant, we did get a positive correlation with duration of diabetes. It can be concluded that there were positive associations between serum ferritin and FBG, age, sex among study groups.&#x0D; Conclusion: In conclusion our study shows that there is significant correlation between increased serum ferritin in diabetes compared to individuals with normal blood sugars in this part and hyper ferritinemia may be one of the causes for development of insulin resistance before overt diabetes.&#x0D; Anwer Khan Modern Medical College Journal Vol. 11, No. 1: Jan 2020, P 7-10

Investigation of the antioxidant and hypoglycemiant properties of Alibertia edulis (L.C. Rich.) A.C. Rich. leaves

Ethnopharmacological relevanceAlibertia edulis (L.C. Rich.) A.C. Rich is a vegetable species used in Brazilian folk medicine due to it is putative hypoglycemiant effect but has never been pharmacologically investigated. It is popularly used for the control of diabetes, especially in the state of Mato Grosso, Brazil. Following confirmation of the antioxidant activity of A. edulis by Aquino et al. (2017), the aim of this study was to evaluate the effects of leaves of A. edulis aqueous extract (AEAE) on some biochemical parameters in mice fed a high-fat fed. Material and methodsLeaves of A. edulis were air-dried in an oven at 40 °C for 10 days and ground into a fine powder by mechanical milling. The AEAE was prepared by decoction (1:10 w/v) at 97 °C for 15 min, and later filtered and lyophilized. Preliminary phytochemical analysis of the AEAE has been already indetified the presence of caffeic acid, quercetin 3-rhamnosyl-(1 → 6)-galactoside and iridois ioxide, ferulic acid and rutin in decocted leaves (Aquino et al., 2017). In one experiment, the acute oral toxicity AEAE was evaluated at 2,000 mg/kg of body weight. The animals were observed periodically for 14 days. In second experiment, the animals were divided into four groups (n = 5): Control, AEAE 200, AEAE 400 mg/kg and positive control (Metformin 100 mg/kg). In a third experiment, animals were divided into: Control RC (standard diet) (n = 24) and Control HFF (high-fat fed) (n = 24) groups for induction of glucose intolerance. After eight weeks, they were further subdivided into six groups (n = 8 each) RC or HFF with or without AEAE at doses of 200 and 400 mg/kg (2-wk) treatments to assess glucose tolerance. Plasma indicators of glucose tolerance and liver damage, skeletal muscle expression of antioxidant enzymes, and expression of the antioxidant proteins of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and phosphorylated IKK were determined. ResultsThe HF-fed animals developed glucose intolerance which the AEAE failed to revert. Meanwhile, the AEAE treatment did lower the glucose levels in the normolipidic cohorts by virtue of its antioxidant property. It was also observed that the treatment with the AEAE reduced food intake negatively interfering weight accretion. Beyond that, the treatment with AEAE interfered in the SOD and catalase expression and inhibited phosphorylation of IKK thus suggesting that the observed hypoglycemiant power may be related to its known antioxidant potential. No sings of toxicity or hemolysis were detectaed at indicating that, at the concentrations evaluated, the extract was not toxic to normal cells. ConclusionThe AEAE showed a hypoglycemiant effect in the normolipidic mice that received the control diet, but not in those that were made glucose-intolerant by consuming a high-fat fed. The extract also exhibited substantial protection against hemolysis and oxidative stress. Moreover, no signs of toxicity were evident at 2000 mg/kg of body weight.

Adaptation of striated muscles to Wolframin deficiency in mice: Alterations in cellular bioenergetics

BackgroundWolfram syndrome (WS), caused by mutations in WFS1 gene, is a multi-targeting disease affecting multiple organ systems. Wolframin is localized in the membrane of the endoplasmic reticulum (ER), influencing Ca2+ metabolism and ER interaction with mitochondria, but the exact role of the protein remains unclear. In this study we aimed to characterize alterations in energy metabolism in the cardiac and in the oxidative and glycolytic skeletal muscles in Wfs1-deficiency. MethodsAlterations in the bioenergetic profiles in the cardiac and skeletal muscles of Wfs1-knock-out (KO) male mice and their wild type male littermates were determined using high resolution respirometry, quantitative RT-PCR, NMR spectroscopy, and immunofluorescence confocal microscopy. ResultsOxygen consumption without ATP synthase activation (leak) was significantly higher in the glycolytic muscles of Wfs1 KO mice compared to wild types. ADP-stimulated respiration with glutamate and malate was reduced in the Wfs1-deficient cardiac as well as oxidative and glycolytic skeletal muscles. ConclusionsWfs1-deficiency in both cardiac and skeletal muscles results in functional alterations of energy transport from mitochondria to ATP-ases. There was a substrate-dependent decrease in the maximal Complex I –linked respiratory capacity of the electron transport system in muscles of Wfs1 KO mice. Moreover, in cardiac and gastrocnemius white muscles a decrease in the function of one pathway were balanced by the increase in the activity of the parallel pathway. General significanceThis work provides new insights to the muscle involvement at early stages of metabolic syndrome like WS as well as developing glucose intolerance.

GRK2 levels in myeloid cells modulate adipose-liver crosstalk in high fat diet-induced obesity.

Macrophages are key effector cells in obesity-associated inflammation. G protein-coupled receptor kinase 2 (GRK2) is highly expressed in different immune cell types. Using LysM-GRK2+/- mice, we uncover that a reduction of GRK2 levels in myeloid cells prevents the development of glucose intolerance and hyperglycemia after a high fat diet (HFD) through modulation of the macrophage pro-inflammatory profile. Low levels of myeloid GRK2 confer protection against hepatic insulin resistance, steatosis and inflammation. In adipose tissue, pro-inflammatory cytokines are reduced and insulin signaling is preserved. Macrophages from LysM-GRK2+/- mice secrete less pro-inflammatory cytokines when stimulated with lipopolysaccharide (LPS) and their conditioned media has a reduced pathological influence in cultured adipocytes or naïve bone marrow-derived macrophages. Our data indicate that reducing GRK2 levels in myeloid cells, by attenuating pro-inflammatory features of macrophages, has a relevant impact in adipose-liver crosstalk, thus preventing high fat diet-induced metabolic alterations.