Disturbed Glucose Research Articles

434-P: Diabetes in Patients with Pancreatic Cancer: Relationship of Tumor Grade with Glycemic Control

Diseases of the exocrine pancreas can result in impaired function of the endocrine pancreas with disturbed glucose homeostasis and ultimately overt diabetes mellitus. In diabetes which develops secondary to pancreatic carcinoma (type 3c diabetes or diabetes of the exocrine pancreas, DEP), the relationship between disturbed glycemic control and carcinoma is not fully understood. We hypothesized that the severity of pancreatic carcinoma positively associates with the degree of impairment of glycemic control. In 92 patients with potentially resectable pancreas neoplasm without diabetes (NOD, n=53, age 67±2 years, BMI 24.8±0.5 kg/m2), DEP (n=20, 71±3 years, 25.3±1.0 kg/m2) or preexisting type 2 diabetes (T2D, n=19, 71±3 years, 27.1±0.8 kg/m2), preoperative fasting glucose, insulin and HbA1c were measured. Pancreatic carcinoma was assessed by TNM classification and tumor grading. Patients with DEP or T2D had higher fasting glycemia (135±9 vs. 142±11 mg/dl), HbA1c (55±3 vs. 58±3 mmol/mol) and insulin resistance, as assessed by homeostatic model assessment for insulin resistance (HOMA-IR) (4.1±1.0 vs. 3.7±0.5), than NOD patients (88±2 mg/dl, 38±1 mmol/mol, 2.0 ± 0.3; all p<0.01). Tumor grading revealed that patients with tumor grade G3 had higher levels of fasting glucose (124±36 mg/dl) and HbA1c (53±2 mmol/mol) compared to patients with non-malignant neoplastic lesions (103±38 mg/dl, 42±2 mmol/mol; all p<0.01). Distribution patterns of tumor grades differed between DEP and T2D (p<0.05) and NOD (p<0.001), respectively. Particularly, the prevalence of G3 tumors was higher in DEP (79%) than in T2D (33%) or NOD patients (16%). Tumor stages did not relate to glycemic control. In conclusion, patients with pancreas carcinoma exhibit a higher diabetes prevalence, which relates to higher tumor grades but not stages. Disclosure J. Boeddeker: None. V. Burkart: None. K. Strassburger: None. P.E. Goretzki: None. W. Knoefel: None. C. Moebius: None. N. Hinsch: None. I. Esposito: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. K. Muessig: None. Funding German Ministry of Culture and Science of the State of North Rhine-Westphalia; German Federal Ministry of Health; German Federal Ministry of Education and Research; German Center for Diabetes Research

Feasibility and Effectiveness of Electrochemical Dermal Conductance Measurement for the Screening of Diabetic Neuropathy in Primary Care. Decoding Study (Dermal Electrochemical Conductance in Diabetic Neuropathy).

Diabetes mellitus (DM) is the leading cause of polyneuropathy in the Western world. Diabetic neuropathy (DNP) is the most common complication of diabetes and is of great clinical significance mainly due to the pain and the possibility of ulceration in the lower limbs. Early detection of neuropathy is essential in the medical management of this complication. Early unmyelinated C-fiber dysfunction is one of the typical findings of diabetic neuropathy and the first clinical manifestation of dysfunction indicating sudomotor eccrine gland impairment. In order to assess newly developed technology for the measurement of dermal electrochemical conductance (DEC), we analyzed the feasibility and effectiveness of DEC (quantitative expression of sudomotor reflex) as a screening test of DNP in primary health care centers. The study included 197 people (with type 2 diabetes, prediabetes and normal tolerance) who underwent all the protocol tests and electromyography (EMG). On comparing DEC with EMG as the gold standard, the area under the receiver operating characteristic (ROC) curve (AUC, area under the curve) was 0.58 in the whole sample, AUC = 0.65 in the diabetes population and AUC = 0.72 in prediabetes, being irrelevant in subjects without glucose disturbances (AUC = 0.47). Conclusions: In usual clinical practice, DEC is feasible, with moderate sensitivity but high specificity. It is also easy to use and interpret and requires little training, thereby making it a good screening test in populations with diabetes and prediabetes. It may also be useful in screening general populations at risk of neuropathy.

Glucomannans Alleviated the Progression of Diabetic Kidney Disease by Improving Kidney Metabolic Disturbance.

This study is aimed to investigate the kidney protective effects of glucomannans from Dendrobium officinale stem, konjac, and Aloe vera leaves on type 2 diabetic rats and explore its potential mechanisms. Pathological and metabolomics analysis methods are adopted in this study. Compared with the model group, lower levels of fasting blood glucose, serum insulin, and glycated serum protein are observed in glucomannan-treated groups. Concentrations of serum low-density lipoprotein cholesterol, total cholesterol, triacylglycerols, and nonesterified fatty acid are significantly decreased by glucomannan treatment. Furthermore, glucomannan treatment significantly decreased the levels of uric acid, creatinine, urea in serum, and glycosuria, ketone body, and protein in the urine. Histopathological analysis showed that glucomannan treatment normalized the architecture of glomerulus. Metabolomic analysis indicated glucomannan treatment could improve urea cycle, metabolism of lipid, glucose, and amino acids on diabetes. In particular, the konjac glucomannan treatment is more effective in lipid and glucose regulation. Glucomannan from D. officinale is more effective in balancing the urea cycle and amino acid metabolism. The disturbance of lipid, glucose, and amino acid metabolism is closely associated with the advancement of diabetic kidney disease, and glucomannan treatment could be efficient in the management of diabetic kidney disease.

Exercise ameliorates the FGF21-adiponectin axis impairment in diet-induced obese mice.

ObjectiveThe protective effects of exercise against glucose dysmetabolism have been generally reported. However, the mechanism by which exercise improves glucose homeostasis remains poorly understood. The FGF21–adiponectin axis participates in the regulation of glucose metabolism. Elevated levels of FGF21 and decreased levels of adiponectin in obesity indicate FGF21–adiponectin axis dysfunction. Hence, we investigated whether exercise could improve the FGF21–adiponectin axis impairment and ameliorate disturbed glucose metabolism in diet-induced obese mice.MethodsEight-week-old C57BL/6J mice were randomly assigned to three groups: low-fat diet control group, high-fat diet group and high-fat diet plus exercise group. Glucose metabolic parameters, the ability of FGF21 to induce adiponectin, FGF21 receptors and co-receptor levels and adipose tissue inflammation were evaluated after 12 weeks of intervention.ResultsExercise training led to reduced levels of fasting blood glucose and insulin, improved glucose tolerance and better insulin sensitivity in high-fat diet-induced obese mice. Although serum FGF21 levels were not significantly changed, both total and high-molecular-weight adiponectin concentrations were markedly enhanced by exercise. Importantly, exercise protected against high-fat diet-induced impaired ability of FGF21 to stimulate adiponectin secretion. FGF21 co-receptor, β-klotho, as well as receptors, FGFR1 and FGFR2, were upregulated by exercise. We also found that exercise inhibited adipose tissue inflammation, which may contribute to the improvement in the FGF21–adiponectin axis impairment.ConclusionsOur data indicate exercise protects against high-fat diet-induced FGF21–adiponectin axis impairment, and may thereby exert beneficial effects on glucose metabolism.

Metabolomic analysis reveals metabolic characteristics of children with short stature caused by growth hormone deficiency.

The diagnosis of short stature (SS) is of widespread importance for later treatment. In the present paper, a metabolomic method was used to analyze the metabolic characteristics of SS children caused by endocrine metabolic diseases in order to understand the underlying biochemical mechanism and provide a potential intervention strategy for SS. According to the clinical diagnosis and family investigation, all patients with SS were confirmed to be due to the endocrine disorders, especially GH deficiency (GHD). A nuclear magnetic resonance (NMR)-based metabolomic analysis of serum was used to identify the metabolic changes in 45 SS children from the 35 healthy controls (HCs). The disturbed metabolic network related to SS was correspondingly derived from the differential metabolites. The SS children demonstrated higher serum levels of citrate, phenylalanine, creatinine, and tyrosine and lower serum levels of glucose, serine, betaine, inositol, lysine, glycerol, and glutamine compared with the HCs. The results demonstrated that the disturbed glucose metabolism and metabolism and biosynthesis of amino acids are typical metabolic features of SS, and the lower levels of lysine and glutamine are the metabolic characterization of the affected growth axes and stress state of SS, respectively. The significant changes of those serum metabolites are able to be regarded as potential biomarkers for the diagnosis of SS. Accordingly, supplemental betaine in dietary pattern, the improvement of glycometabolism, and endogenous replenishment of lysine and glutamine allow the possible treatment strategy for SS.

Metabolic syndrome in a sample of Egyptian adolescent girls and its association with apolipoprotein E.

Obesity and its metabolic complications are increasing in childhood and extend to adulthood. The aims of this study were to assess the prevalence of metabolic syndrome (MS) in a sample of Egyptian adolescent girls and investigate its association with apolipoprotein E. A cross-sectional study design was used, including 200 Egyptian adolescent girls aged between 12 and 18 years. They were subjected to blood pressure (BP) measurement, anthropometric measurements (weight, height and waist circumference (WC)), laboratory investigations (fasting glucose and lipid profile) and molecular analysis (Apo E). Overweight/obese girls were suffering significantly, more than normal-weight girls, from hypertension (66.7 vs. 40.8%), diabetes diagnosed by elevated fasting blood glucose (46.7 vs. 31.2%) and low high-density lipoprotein (HDL) (64 vs. 59.2%). Girls with MS had significantly higher values of body mass index Z-score, WC, BP, cholesterol and triglycerides and significantly lower HDL. Allele E3 (59.1 vs. 55.1%) was more frequent among girls with MS, while allele E4 (41 vs. 36.4) was more frequent among girls without MS. MS was the most prominent among girls with the E3/E4 genotype (35.7%), who had the highest frequency of elevated cholesterol, triglycerides, low-density lipoprotein and blood glucose, while girls with the E2/E4 genotype, which was rare among both groups, had the highest frequency of elevated BP (68.8%) and low HDL (71.4%). MS was significantly more prominent among overweight/obese adolescent girls with the E3/E4 genotype, who had the highest frequency of disturbed lipid profile and blood glucose.

Hepatic stress associated with pathologies characterized by disturbed glucose production

The liver is an organ with many facets, including a role in energy production and metabolic balance, detoxification and extraordinary capacity of regeneration. Hepatic glucose production plays a crucial role in the maintenance of normal glucose levels in the organism i.e. between 0.7 to 1.1 g/l. The loss of this function leads to a rare genetic metabolic disease named glycogen storage disease type I (GSDI), characterized by severe hypoglycemia during short fasts. On the contrary, type 2 diabetes is characterized by chronic hyperglycemia, partly due to an overproduction of glucose by the liver. Indeed, diabetes is characterized by increased uptake/production of glucose by hepatocytes, leading to the activation of de novo lipogenesis and the development of a non-alcoholic fatty liver disease. In GSDI, the accumulation of glucose-6 phosphate, which cannot be hydrolyzed into glucose, leads to an increase of glycogen stores and the development of hepatic steatosis. Thus, in these pathologies, hepatocytes are subjected to cellular stress mainly induced by glucotoxicity and lipotoxicity. In this review, we have compared hepatic cellular stress induced in type 2 diabetes and GSDI, especially oxidative stress, autophagy deregulation, and ER-stress. In addition, both GSDI and diabetic patients are prone to the development of hepatocellular adenomas (HCA) that occur on a fatty liver in the absence of cirrhosis. These HCA can further acquire malignant traits and transform into hepatocellular carcinoma. This process of tumorigenesis highlights the importance of an optimal metabolic control in both GSDI and diabetic patients in order to prevent, or at least to restrain, tumorigenic activity during disturbed glucose metabolism pathologies.

A new animal model of insulin-glucose dynamics in the intraperitoneal space enhances closed-loop control performance

Current artificial pancreas systems (AP) operate via subcutaneous (SC) glucose sensing and SC insulin delivery. Due to slow diffusion and transport dynamics across the interstitial space, even the most sophisticated control algorithms in on-body AP systems cannot react fast enough to maintain tight glycemic control under the effect of exogenous glucose disturbances caused by ingesting meals or performing physical activity. Recent efforts made towards the development of an implantable AP have explored the utility of insulin infusion in the intraperitoneal (IP) space: a region within the abdominal cavity where the insulin-glucose kinetics are observed to be much more rapid than the SC space. In this paper, a series of canine experiments are used to determine the dynamic association between IP insulin boluses and plasma glucose levels. Data from these experiments are employed to construct a new mathematical model and to formulate a closed-loop control strategy to be deployed on an implantable AP. The potential of the proposed controller is demonstrated via in-silico experiments on an FDA-accepted benchmark cohort: the proposed design significantly outperforms a previous controller designed using artificial data (time in clinically acceptable glucose range: 97.3 ± 1.5% vs. 90.1 ± 5.6%). Furthermore, the robustness of the proposed closed-loop system to delays and noise in the measurement signal (for example, when glucose is sensed subcutaneously) and deleterious glycemic changes (such as sudden glucose decline due to physical activity) is investigated. The proposed model based on experimental canine data leads to the generation of more effective control algorithms and is a promising step towards fully automated and implantable artificial pancreas systems.

Endoplasmic reticulum proteostasis control and gastric cancer

The endoplasmic reticulum (ER) is the primary organelle responsible for the synthesis, modification, folding and secretion of proteins, especially in specialized secretory cells. It also contributes to the maintenance of cellular functions, such as Ca2+ storage, lipogenesis, gluconeogenesis, and organelle biogenesis. Cellular stress conditions, such as glucose deprivation, hypoxia and disturbance of Ca2+ homeostasis, may increase the risk of protein misfolding and perturb proteostasis. This activates ER stress and triggers the unfolded protein response (UPR), leading to either the restoration of homeostasis or cell death. ER stress and UPR have been shown to play crucial roles in the pathogenesis, progression and treatment response of various cancers. In gastric cancer (GC), one of the most aggressive cancer types, critical functions of ER stress signaling have also started to emerge. Herein, we summarize the current knowledge linking ER stress and UPR to GC; we also discuss the possible nodes of therapeutic intervention and propose directions of future research.

Impact of apolipoprotein A1- or lecithin:cholesterol acyltransferase-deficiency on white adipose tissue metabolic activity and glucose homeostasis in mice

High density lipoprotein (HDL) has attracted the attention of biomedical community due to its well-documented role in atheroprotection. HDL has also been recently implicated in the regulation of islets of Langerhans secretory function and in the etiology of peripheral insulin sensitivity. Indeed, data from numerous studies strongly indicate that the functions of pancreatic β-cells, skeletal muscles and adipose tissue could benefit from improved HDL functionality. To better understand how changes in HDL structure may affect diet-induced obesity and type 2 diabetes we aimed at investigating the impact of Apoa1 or Lcat deficiency, two key proteins of peripheral HDL metabolic pathway, on these pathological conditions in mouse models. We report that universal deletion of apoa1 or lcat expression in mice fed western-type diet results in increased sensitivity to body-weight gain compared to control C57BL/6 group. These changes in mouse genome correlate with discrete effects on white adipose tissue (WAT) metabolic activation and plasma glucose homeostasis. Apoa1-deficiency results in reduced WAT mitochondrial non-shivering thermogenesis. Lcat-deficiency causes a concerted reduction in both WAT oxidative phosphorylation and non-shivering thermogenesis, rendering lcat−/− mice the most sensitive to weight gain out of the three strains tested, followed by apoa1−/− mice. Nevertheless, only apoa1−/− mice show disturbed plasma glucose homeostasis due to dysfunctional glucose-stimulated insulin secretion in pancreatic β-islets and insulin resistant skeletal muscles. Our analyses show that both apoa1−/− and lcat−/− mice fed high-fat diet have no measurable Apoa1 levels in their plasma, suggesting no direct involvement of Apoa1 in the observed phenotypic differences among groups.

Effects of aerobic exercise and glutamine on oxidative stress and expression of related factors in type 2 diabetic rats

To investigate the effects of aerobic exercise and glutamine (Gln) on anti-oxidative stress and inflammatory factors in type 2 diabetes mellitus (T2MD) rats. Diabetic rat model was induced by streptozotocin (STZ). Fifty 6-week old male SD rats were randomly divided into 5 groups (n=10), including quiet control group (N), diabetes control group (D), diabetic aerobic exercise group (DE), diabetic glutamine group (DG) and diabetic aerobic exercise glutamine group (DEG). After 6 weeks, the related indicators of glucose and lipid metabolism, anti-oxidative stress and inflammatory factors in diabetic rats were detected, and the possible mechanism affecting inflammatory response were explored. Compared with group N, the levels of serum malondialdehyde(MDA), blood glucose, total cholesterol(TC), triglyceride(TG), insulin, leptin and tumor necrosis factor-α(TNF-α) in group D were increased significantly (P＜0.01). Compared with group D, serum levels of MDA, blood glucose, TC, TG, insulin, leptin and TNF-α in three intervention groups were decreased significantly, while the levels of SOD, GSH-Px and adiponectin were increased, and the combined effect was more obvious (P＜0.01). Both aerobic exercise and Gln can relieve the glucose and lipid metabolism and disturbance, oxidative stress injury and inflammation in diabetic rats.

Evaluation of Changes in Insulin Sensitivity in Prepubertal Small for Gestational Age Children Treated with Growth Hormone.

Background:Although growth hormone (GH) therapy for children born small for gestational age (SGA) has been approved for many years, there are still concerns about increasing their risk for insulin resistance and diabetes mellitus type 2. Monitoring of glucose homeostasis is therefore generally recommended, but there is no consensus on either the methods or consequences.Methods and Aims:The aim of our study was to analyze the oral Glucose Tolerance Tests (oGTTs) which were performed yearly from baseline to 4 years of GH therapy in a collective of 93 SGA children, who were prepubertal during the whole follow-up. We looked for correlations with auxological and laboratory data as well as predictive baseline results for glucose homeostasis during further treatment.Results:While glucose levels remained constant, insulin secretion increased from baseline to the first year of GH therapy. Insulin sensitivity index (ISI) showed no significant change afterwards; HOMA1, HOMA2, and QUICKI stabilized after the second year. For all indices mean values never reached pathological levels and no cases of diabetes mellitus were induced. Higher gestational age, lower birth length, and older age at start of GH therapy were associated with lower insulin sensitivity. No predictive factors for later insulin resistance could be found.Conclusion:As expected, in GH-treated prepubertal SGA children insulin resistance was induced, but not to pathological levels. No special risk factors for disturbed glucose homeostasis could be identified. Based on our opinion, performing oGTTs in GH-treated SGA children at baseline and in puberty should remain mandatory, but the current study recommendations regarding further surveillance of glucose homeostasis are questionable.

The synergistic action of antioxidative enzymes - correlations of catalase and superoxide dismutase in the development and during the treatment of type 2 diabetes

Introduction/Objective. The wider literature review of analysis in levels of catalase (CAT) or superoxide dismutase (SOD) enzymes in type 2 diabetes mellitus (T2DM) patients shows no pronounced consistency. We have assumed that the onset of diabetes does not significantly change individual quantities of these enzymes, but instead it changes the relationship of these enzymes. Methods. The study consisted of four groups (n = 30 for each group): obese individuals with disturbed glucose metabolism (subjects with newly diagnosed T2DM) before and after metformin treatment initiation, obese subjects with normal glucose tolerance (NGT) and a control group of healthy normal weight subjects. Appropriate anthropometric measurements and laboratory tests of biochemical parameters and antioxidative enzymes were carried out in all participants. Results. Our study has confirmed that correlation of enzymes CAT and SOD is significantly changed in patients with newly diagnosed T2DM, and that it can be restored by reestablishment of glucose homeostasis with adequate antidiabetic treatment. Conclusion. The applied therapy restores the dynamic balance of CAT and SOD, mainly through the reintegration of the new equilibrium in the enzyme system after achieving better glycemic control. These conclusions are only valid in the initial stages of T2DM treatment.

Chronic inflammation and lipid profile parameters in obese subjects with normal and disturbed glucose metabolism

Introduction/Objective. In different states of increased chronic inflammation, like obesity and diabetes, early changes in lipid metabolism could represent an adaptive response aimed at diminishing the elevated inflammatory reaction. The aim of study was to investigate the impact of glucose tolerance status on relationship between chronic inflammation and lipid metabolism parameters. Methods. The study consisted of four groups (n = 30 for each group): obese individuals with disturbed glucose metabolism (subjects with newly diagnosed type 2 diabetes (T2DM)) before and after metformin treatment initiation, obese subjects with normal glucose tolerance (NGT) and a control group of healthy normal weight subjects. Appropriate anthropometric measurements and laboratory tests were carried out in all participants. Results. Among the sub-group of obese subjects, the association of highly sensitive C reactive protein (hsCRP) with triglycerides and lipoprotein (a) (Lp(a)) was especially pronounced in the group of T2DM subjects before treatment initiation. In this group, the level of inflammation was the highest and correlation coefficients of triglycerides and Lp(a) with hsCRP were significantly different compared with the group of obese without diabetes (r = 0.21 vs. r = -0.36; p = 0.0172) for triglycerides and (r = -0.17 vs. r = 0.36, p = 0.0324) for Lp(a). Correlations of hsCRP with triglycerides and Lp(a) in groups of NGT obese subjects and T2DM subjects after treatment initiation did not differ significantly. Treatment with metformin changed the relationship of hsCRP with triglycerides and Lp(a) to the one which is similar to the relationship observed in obese NGT subjects (r = 0.21 vs. r = 0.38; p = 0.2449) for triglycerides and (r = -0.17 vs. r = -0.27, p = 0.3562) for Lp(a). Conclusion. In subjects with newly diagnosed T2DM, who have the highest level of inflammation, it is probable that the increase in triglycerides is a part of the anti-inflammatory response, whereas Lp(a) is probably produced and used in the reduction of elevated inflammation.

Prediabetes is Characterized by Higher FGF23 Levels and Higher Prevalence of Vitamin D Deficiency Compared to Normal Glucose Tolerance Subjects.

In the last years there is an increasing interest towards the bone as an endocrine organ and the role of bone and calcium-phosphate metabolism markers in a range of metabolic disturbances. The aim of the present study is to assess the changes of calcium phosphate metabolism markers in patients with prediabetes compared to normogycemic controls and their link to glucose disturbances and cardiovascular risk factors. In this study, 80 patients with mean age 50.4±10.6 years were included, divided into 2 age- and BMI-matched groups - group 1 with obesity without glycemic disturbances (n=41) and group 2 with obesity and prediabetes (n=39). Oral glucose tolerance test (OGTT) with measurement of immunoreactive insulin was performed in all participants and levels of PTH, 25(OH)D, FGF23, and Klotho were measured. We found significantly higher levels of FGF23 in patients with prediabetes compared to normal glucose tolerance subjects (10.4±10.7 vs. 5.8±7.3 pg/ml; p=0.03). FGF23 showed a weak positive correlation to fasting blood glucose (r=0.224; p=0.048) but not to blood glucose on the first and second hour of oral glucose tolerance test or insulin levels. There was extremely high prevalence of vitamin D deficiency in both groups. Lower levels of 25(OH)D were observed in prediabetes group, although without statistical significance (p=0.57). Patients with prediabetes have higher FGF23 levels and higher prevalence of vitamin D deficiency compared to normal glucose tolerance subjects. Elevated FGF23 levels seem to be correlated more to elevated fasting blood glucose levels than to insulin resistance state of the patients.

Injury factors alter miRNAs profiles of exosomes derived from islets and circulation.

Islets damage is a major abnormality underling diabetes. Recent studies suggested the value of exosomes in diagnosis. This study aimed to investigate the impact of injury factors on the miRNA profiles of islet exosomes and determine whether circulating exosomal miRNAs is suitable as biomarkers of islets damage. Islets were isolated from ICR mice and induced injury in vitro by mixed cytokines (Tumor Necrosis Factor-α, Interleukin -1β and Interferon-γ) or streptozotocin (STZ), and exosomes were derived from the cultural supernatant. Using miRNA microarray analysis, we found 22 and 11 differentially expressed miRNAs in islet exosomes of STZ and cytokines treatment, respectively, including 6 miRNAs as the intersection of two injured conditions. Thereinto, mmu-miR-375-3p and mmu-miR-129-5p could be validated by qRT-PCR. Then, Serum exosomes were isolated from STZ injected mice and subjects with various glucose metabolism states and diabetic duration. qRT-PCR demonstrated exosomal mmu-miR-375-3p dramatically increased in serum of STZ treated mouse prior to the disturbance of blood glucose and insulin. In human serum exosomes, hsa-miR-375-3p was elevated in new-onset diabetes patients. Overall, our results suggest that injury factors changed miRNA profiles of exosomes derived from islets and exosomal miR-375-3p showed promising potential as a biomarker of islets damage.

Insulin function in obese children within the low and high ranges of impaired fasting glycemia.

Impaired fasting glycemia (IFG) reflects an intermediate hyperglycemia in the fasting state. Which fasting glucose level that actually is associated with impaired insulin-glucose homeostasis in children and adolescents with obesity is unknown. The aim of this study was to investigate how insulin and glucose homeostasis in children and adolescents with obesity in Sweden varies within different fasting glucose levels in the non-diabetic range. The subjects, n = 333, were divided into three groups based on their fasting glucose level. Normoglycemic range: up to 5.5 mmol/L (n = 268); the exclusive range the American Diabetes Association (ADA) has for IFG diagnosis: 5.6-6.0 mmol/L (n = 44); and IFG according to World Health Organization: 6.1-6.9 mmol/L (n = 21). The three groups were of similar age, degree of obesity, fasting insulin levels, sex, and migrant background distribution. We used an insulin-modified frequent sample intravenous glucose tolerance test to study acute insulin response (AIR), insulin sensitivity (SI), and disposition index (DI) in children and adolescents with obesity. The main outcome measures were AIR, SI, and DI in three groups based on fasting glucose level. Fasting glucose levels ranging from 5.6 to 6.0 mmol/L were not associated with a lower AIR, SI, or DI compared with the normoglycemic range. However, glucose levels ranging from 6.1 to 6.9 mmol/L were associated with lower AIR and lower DI, but no statistical differences in SI were present. IFG in the exclusive ADA range was not associated with disturbed glucose metabolism. This suggests that IFG contributes to adverse metabolic profile in children differently to what has been described previously in adult obese populations.

Raspberry ketone and Garcinia Cambogia rebalanced disrupted insulin resistance and leptin signaling in rats fed high fat fructose diet

AimObesity is a continually growing pandemic leading to many diseases that affect the overall quality of life. The widely marketed Garcinia cambogia (GC) and Raspberry ketone (RK) were used in this study. Despite their known dietetic effect, however, the metabolomic/signaling pathways involved in this effect are not fully elucidated. Hence, our study comprehends the possible trajectories of their combination against obesity and insulin resistance in addition to exploring their combination merit. Materials and methodsAdult male Wistar rats were divided into 5 groups; viz., normal diet (ND), high fat fructose diet (HFFD), HFFD+GC (600mg/kg), HFFD+RK (55mg/kg) and HFFD+GC+RK. To assess our aim, we determined their effect on body weight, IPGTT, glucose homeostasis (glucose, insulin, HOMA IR), lipid profile parameters and SREBP-1c, oxidative stress markers, insulin and leptin signaling pathways (p-IRS-1/p-AKT/GLUT-4, and leptin/STAT-3), as well as liver and adipose tissue histopathology. ResultsGC/RK combinationcaused weight loss, corrected the disturbed glucose and insulin homeostasis, raised serum levels of HDL anddecreased all other lipid profile parameters. They also increased Nrf-2 expression, ad GSH, as well as p-IRS-1/p-Akt/GLUT-4 cue, while they decreased MDA, leptin/STAT-3 and SREBP-1c content compared to the HFFD group. Furthermore, the GC/RK combination abolished apoptosis, fatty changes and inflammation in hepatocytes and decreased sclerotic blood vessels and congestion in adipose tissue. ConclusionOur study highlights the involvement ofp-IRS-1/p-Akt/GLUT-4, leptin/STAT-3 and SREBP-1c signaling trajectories in the beneficial combination of GC and RK, besides, the efficient rebalance of the redox status, insulin resistance and tissue fat deposition confirmed histopathologically.

Cystathionine-\u03b3-lyase expression is associated with mitochondrial respiration during sepsis-induced acute kidney injury in swine with atherosclerosis

BackgroundSepsis is associated with disturbed glucose metabolism and reduced mitochondrial activity and biogenesis, ultimately leading to multiple organ dysfunction, e.g., acute kidney injury (AKI). Cystathionine-γ-lyase (CSE), the major cardiovascular source of endogenous H2S release, is implicated in the regulation of glucose metabolism and mitochondrial activity through a PGC1α-dependent mechanism, and critical for kidney function. Atherosclerosis is associated with mitochondrial dysfunction and reduced CSE expression. Thus, the aim of this post hoc study was to test the hypothesis whether there is an interplay between CSE expression and kidney dysfunction, mitochondrial activity, and oxidative/nitrosative stress in porcine septic AKI with underlying coronary artery disease.MethodsThis study is a post hoc analysis of material from anesthetized and instrumented swine with a high fat diet-induced hypercholesterolemia and atherosclerosis undergoing faecal peritonitis-induced septic shock or sham procedure and intensive care (comprising fluid resuscitation and continuous i.v. noradrenaline (NoA) infusion) for 24 h. Glucose metabolism was quantified from blood 13C6-glucose and expiratory 13CO2/12CO2 isotope enrichment during 13C6-glucose infusion. Mitochondrial activity was determined by high-resolution respirometry. CSE and PGC1α expression, as well as nitrotyrosine formation and albumin extravasation, were quantified by immunohistochemistry of formalin-fixed kidney paraffin sections.ResultsSepsis was associated with lactic acidosis (p = 0.004) and AKI (50% fall of creatinine clearance (CrCl), p = 0.019). While both whole-body glucose production (p = 0.004) and oxidation (p = 0.006) were increased, kidney tissue mitochondrial respiration was reduced (p = 0.028), coinciding with decreased CSE (p = 0.003) and PGC1α (p = 0.003) expression. Albumin extravasation (p = 0.011) and nitrotyrosine formation (p = 0.008) were increased in septic kidneys.ConclusionsSepsis-induced AKI is associated with disturbed mitochondrial respiration and biogenesis, which may be aggravated by oxidative and nitrosative stress. Our results confirm previous data in murine septic shock and porcine hemorrhage and resuscitation on the crucial role of CSE for barrier integrity and kidney function.

Chronic social stress-induced hyperglycemia in mice couples individual stress susceptibility to impaired spatial memory

Stringent glucose demands render the brain susceptible to disturbances in the supply of this main source of energy, and chronic stress may constitute such a disruption. However, whether stress-associated cognitive impairments may arise from disturbed glucose regulation remains unclear. Here we show that chronic social defeat (CSD) stress in adult male mice induces hyperglycemia and directly affects spatial memory performance. Stressed mice developed hyperglycemia and impaired glucose metabolism peripherally as well as in the brain (demonstrated by PET and induced metabolic bioluminescence imaging), which was accompanied by hippocampus-related spatial memory impairments. Importantly, the cognitive and metabolic phenotype pertained to a subset of stressed mice and could be linked to early hyperglycemia 2 days post-CSD. Based on this criterion, ∼40% of the stressed mice had a high-glucose (glucose >150 mg/dL), stress-susceptible phenotype. The relevance of this biomarker emerges from the effects of the glucose-lowering sodium glucose cotransporter 2 inhibitor empagliflozin, because upon dietary treatment, mice identified as having high glucose demonstrated restored spatial memory and normalized glucose metabolism. Conversely, reducing glucose levels by empagliflozin in mice that did not display stress-induced hyperglycemia (resilient mice) impaired their default-intact spatial memory performance. We conclude that hyperglycemia developing early after chronic stress threatens long-term glucose homeostasis and causes spatial memory dysfunction. Our findings may explain the comorbidity between stress-related and metabolic disorders, such as depression and diabetes, and suggest that cognitive impairments in both types of disorders could originate from excessive cerebral glucose accumulation.