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Hyperinsulinemia - Top 30 Publications

Study of insulin vascular sensitivity in aortic rings and endothelial cells from aged rats subjected to caloric restriction: Role of perivascular adipose tissue.

The prevalence of metabolic syndrome is dramatically increasing among elderly population. Metabolic syndrome in aged individuals is associated with hyperinsulinemia and insulin resistance both in metabolic tissues and in the cardiovascular system, with this fact being associated with the cardiometabolic alterations associated to this condition. Caloric restriction (CR) improves insulin sensitivity and is one of the dietetic strategies most commonly used to enlarge life and to prevent aging induced cardiovascular alterations. The aim of this study was to analyze the possible beneficial effects of CR in aging-induced vascular insulin resistance both in aortic rings and in primary culture of endothelial cells. In addition, the inflammatory profile of perivascular adipose tissue (PVAT) and its possible role in the impairment of vascular insulin sensitivity associated with aging was also assessed. Three experimental groups of male Wistar rats were used: 3 (3m), 24 (24m) fed ad libitum and 24months old rats subjected to 20% CR during their three last months of life (24m-CR). Aorta rings surrounded or not by PVAT were mounted in an organ bath and precontracted with phenylephrine (10(-7.5)M). Changes in isometric tension were recorded in response to cumulative insulin concentrations (10(-8)-10(-5.5)M) in the presence or absence of L-NAME (10(-4)M). Aortic rings and primary aortic endothelial cells were incubated in presence/absence of insulin (10(-7)M) and the activation of the PI3K/Akt and MAPK pathways as well as nitrite and nitrates concentrations and the mRNA levels of eNOS, insulin receptor, and GLUT-4 were assessed. CR prevented the aging-induced decrease in the vasodilator response to insulin and the aging-induced increase in the vasoconstrictor response to high insulin concentrations. Changes between 24m and 24m-CR aorta rings were abolished in the presence of L-NAME. CR induced-improvement in insulin vascular sensitivity was related with activation of the PI3K/Akt both in aortic rings and in aortic endothelial cells in response to insulin. CR attenuated the overexpression of iNOS, TNF-α and IL-1β in the PVAT of aged rats although aortic rings surrounded by PVAT from 24m rats showed and increased vasorelaxation in response to insulin compared to aortic rings from 3m and 24m-CR rats. In conclusion, a moderate protocol of CR improves insulin vascular sensitivity and prevents the aging induced overexpression of pro-inflammatory cytokines in PVAT.

Continuous glucose monitoring in neonates: a review.

Continuous glucose monitoring (CGM) is well established in the management of diabetes mellitus, but its role in neonatal glycaemic control is less clear. CGM has provided important insights about neonatal glucose metabolism, and there is increasing interest in its clinical use, particularly in preterm neonates and in those in whom glucose control is difficult. Neonatal glucose instability, including hypoglycaemia and hyperglycaemia, has been associated with poorer neurodevelopment, and CGM offers the possibility of adjusting treatment in real time to account for individual metabolic requirements while reducing the number of blood tests required, potentially improving long-term outcomes. However, current devices are optimised for use at relatively high glucose concentrations, and several technical issues need to be resolved before real-time CGM can be recommended for routine neonatal care. These include: 1) limited point accuracy, especially at low or rapidly changing glucose concentrations; 2) calibration methods that are designed for higher glucose concentrations of children and adults, and not for neonates; 3) sensor drift, which is under-recognised; and 4) the need for dynamic and integrated metrics that can be related to long-term neurodevelopmental outcomes. CGM remains an important tool for retrospective investigation of neonatal glycaemia and the effect of different treatments on glucose metabolism. However, at present CGM should be limited to research studies, and should only be introduced into routine clinical care once benefit is demonstrated in randomised trials.

Feasibility of domestic (18)F-DOPA PET/CT scanning in the differential diagnosis of pancreatic lesions in children with hyperinsulinemic hypoglycemia.

Objective: To study the feasibility of (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography/Computed tomography ((18)F-DOPA PET/CT) scanning in the localization and differential diagnosing of focal versus diffuse form of pancreas lesions in patients with hyperinsulinemic hypoglycemia (HH). Method: Twenty-four patients were diagnosed with HH between January, 2016 and February, 2017 in the Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University using an integrated clinical and biochemical diagnostic protocol, domestic (18)F-DOPA PET/CT imaging technique were applied after MRI and ultrasound failed to detect pancreas lesions. Pancreas (18)F-DOPA standardized uptake values (SUV) were measured, and pancreas' lesions were dually analyzed via visual method and pancreas percentage SUV method. Among these patients, 9 patients received surgical pancreatic lesion resections, the correlations among surgical outcomes, histopathological findings and (18)F-DOPA PET/CT scan results were analyzed. Result: Seven patients were detected with focal form of pancreas lesions, the mean peak of SUV was 4.7±1.7(2.6-7.1), and 17 patients were found to have diffuse form lesions after (18)F-DOPA-PET/CT scanning. Among the 24 cases, 9 patients (7 showed focal and 2 showed diffuse (18)F-DOPA PET/CT pancreatic uptake)were euglycemic without any medical support after surgery; the resected pancreatic tissue histopathological results were consistent with that of PET/CT imaging. Only one patient, who responded to medical treatment before surgery, had temporary hyperglycemia after operation. Conclusion: Domestic (18)F-DOPA PET/CT could successfully locate and differentiate the pancreatic lesions and thus improve the success of surgery.

Long-term feeding of high-fat plus high-fructose diet induces isolated impaired glucose tolerance and skeletal muscle insulin resistance in miniature pigs.

During the prediabetic development, the changes in β-cell function and tissue-specific insulin resistance have been described. However, there are conflicting views in insulin secretory capacity between early clinical observation and recent proposed mathematical model. On the basis of digestive and metabolic similarities with humans, swine have great potential as an animal model to investigate the progressive mechanisms of prediabetes. The aim of this study was to investigate the insulin secretory response and tissue-specific insulin resistance in a dietary-induced prediabetic porcine model.

Dietary Recommendations in Metabolic Vascular Syndrome.

Cardiovascular disease is the number one cause of death globally. Poor diet constitutes a key factor in the initiation and progression of cardiovascular disease and has become the leading risk factor for disability and death worldwide. Therefore, addressing suboptimal nutrition is of key prognostic relevance in primary and secondary prevention of metabolic vascular syndrome.Metabolic vascular syndrome is a multidimensional network of acquired cardiometabolic risk factors closely related to insulin resistance (IR) and concomitant hyperinsulinemia. IR, being the underlying cause of metabolic vascular syndrome and certain types of cancer, should attract the attention of every clinician. As changes in lipoprotein metabolism are one of the earliest indicators of metabolic dysfunction, a relevant biomarker for identifying individuals with IR is the TAG/HDL-C ratio.IR - and concomitant metabolic vascular risk - can be effectively treated by lifestyle intervention. If IR is present, dietary carbohydrate restriction has consistently been shown to be superior to dietary fat restriction in reversing metabolic dysfunction. The beneficial effects of carbohydrate restricted diets on metabolic vascular risk are independent of BMI - diet quality therefore confers patient benefit beyond weight reduction.The effect of single nutrients on isolated lipid surrogate markers such as LDL-C does not capture their global effect on metabolic vascular risk.Targeting IR with a low glycemic load, real food diet will reduce overall energy density and will improve all risk factors of metabolic vascular syndrome. In particular, replacing refined carbohydrates with healthy fats in the context of a Mediterranean style-, low carbohydrate and calorie-unrestricted dietary pattern has been shown to significantly reduce burden of metabolic vascular disease.

Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes.

Pancreatic beta cells sense changes in nutrients during the cycles of fasting and feeding and release insulin accordingly to maintain glucose homeostasis. Abnormal beta cell nutrient sensing resulting from gene mutations leads to hypoglycemia or diabetes. Glucokinase (GCK) plays a key role in beta cell glucose sensing. As one form of congenital hyperinsulinism (CHI), activating mutations of GCK result in a decreased threshold for glucose-stimulated insulin secretion and hypoglycemia. In contrast, inactivating mutations of GCK result in diabetes, including a mild form (MODY2) and a severe form (permanent neonatal diabetes mellitus (PNDM)). Mutations of beta cell ion channels involved in insulin secretion regulation also alter glucose sensing. Activating or inactivating mutations of ATP-dependent potassium (KATP ) channel genes result in severe but completely opposite clinical phenotypes, including PNDM and CHI. Mutations of the other ion channels, including voltage-gated potassium channels (Kv 7.1) and voltage-gated calcium channels, also lead to abnormal glucose sensing and CHI. Furthermore, amino acids can stimulate insulin secretion in a glucose-independent manner in some forms of CHI, including activating mutations of the glutamate dehydrogenase gene, HDAH deficiency, and inactivating mutations of KATP channel genes. These genetic defects have provided insight into a better understanding of the complicated nature of beta cell fuel-sensing mechanisms.

CD19(+)CD24(hi)CD38(hi) regulatory B cells are associated with insulin resistance in type I Hashimoto's thyroiditis in Chinese females.

Hashimoto's thyroiditis (HT) is typically associated with insulin resistance. The aim of the present study was to investigate the role of regulatory B cells (Bregs) in insulin resistance in patients with HT. A total of 52 female patients with type I HT and 35 matched healthy volunteers were enrolled. Demographic and laboratorial data were collected. A 75 g oral glucose tolerance test was performed on each subject. Flow cytometry was performed to evaluate the levels of CD19(+)CD24(hi)CD38(hi) Bregs in peripheral blood. Patients with HT exhibited significantly higher postprandial insulin levels (P<0.01), but normal glucose levels. The level of CD19(+)CD24(hi)CD38(hi) Bregs in patients with HT decreased significantly (P=0.0002) compared with the controls. Pearson's linear correlation model revealed a significant, negative association between anti-thyroid peroxidase antibodies (TPOAb) and homeostasis model assessment of β cell (r=-0.313, P=0.014). The same correlation model revealed a significant, negative association between TPOAb and the disposition index (DI; r=-0.305, P=0.017), and between anti-thyroglobulin antibodies and DI (r=-0.321, P=0.013). Patients with a decreased ratio of CD19(+)CD24(hi)CD38(hi) Bregs to CD19(+) lymphocytes exhibited higher levels of total cholesterol and low-density lipoprotein cholesterol. A decrease in the ratio of CD19(+)CD24(hi)CD38(hi) Bregs to lymphocytes was a significant independent risk factor for hyperinsulinemia (odds ratio=1.372, P=0.035). A decrease in peripheral blood CD19(+)CD24(hi)CD38(hi) Bregs is associated with insulin resistance in HT patients, and was an independent risk factor for postprandial hyperinsulinemia. The present study provided a novel insight into the development of effective therapeutic strategies targeting immune mechanisms associated with HT.

Male brown fat-specific double knockout of IGFIR/IR: Atrophy, mitochondrial fission failure, impaired thermogenesis and obesity.

It is unknown how the lack of IR (insulin receptor)/ IGFIR (insulin like growth factor receptor) in a tissue-specific manner does affect brown fat development and mitochondrial integrity and function and its impact on the redistribution of the adipose organ and the metabolic status. To address this important issue, we have developed the IR/IGFIR double knockout in brown adipose tissue-specific manner (DKO). Lack of those receptors caused a severe brown fat atrophy, an enhanced beige cell clusters in inguinal fat, loss of mitochondrial mass, mitochondrial damage related to cristae disruption, and the loss of proteins involved in autophagosome formation, mitophagy, mitochondrial quality control and dynamics and thermogenesis. More importantly, DKO mice showed an impaired thermogenesis upon cold exposure based on a failure in the mitochondrial fission mechanisms and a much lower UCP-1 (uncoupling protein 1) transcription rate and content. As a result, DKO under normal conditions showed an obesity susceptibility revealed by increased body fat mass and insulin resistance. Upon high fat diet, DKO mice displayed frank obesity as shown by increased body weight, increased adiposity, insulin resistance, hyperinsulinemia and hypertriglyceridemia, all consistent with a metabolic syndrome. Collectively, our data suggest a cause and effect relationship between a failure in the brown fat thermogenesis and an increased adiposity and obesity.

Early-onset severe obesity due to complete deletion of the leptin gene in a boy.

Monogenic obesity results from single gene mutations. Extreme obesity starting at an early age, especially in infancy, which is associated with endocrinopathy and metabolic disturbances is key to the diagnosis of monogenic obesity.

Deletion of Protein Kinase D1 in Pancreatic Beta Cells Impairs Insulin Secretion in High-Fat Fed Mice.

Beta-cell adaptation to insulin resistance is necessary to maintain glucose homeostasis in obesity. Failure of this mechanism is a hallmark of type 2 diabetes (T2D). Hence, factors controlling functional beta-cell compensation are potentially important targets for the treatment of T2D. Protein kinase D1 (PKD1) integrates diverse signals in the beta cell and plays a critical role in the control of insulin secretion. However, the role of beta-cell PKD1 in glucose homeostasis in vivo is essentially unknown. Using beta-cell specific, inducible PKD1 knock-out mice (βPKD1KO), we examined the role of beta-cell PKD1 under basal conditions and during high-fat feeding. βPKD1KO mice under chow diet presented no significant difference in glucose tolerance or insulin secretion compared to mice expressing the Cre transgene alone; however, when compared to wild-type mice, both groups developed glucose intolerance. Under high-fat diet, deletion of PKD1 in beta cells worsened hyperglycemia, hyperinsulinemia and glucose intolerance. This was accompanied by impaired glucose-induced insulin secretion both in vivo in hyperglycemic clamps and ex vivo in isolated islets from high-fat fed βPKD1KO mice, without changes in islet mass. This study demonstrates an essential role for PKD1 in the beta-cell adaptive secretory response to high-fat feeding in mice.

Protein kinase C δ-dependent regulation of Ubiquitin-proteasome system function in breast cancer.

Besides the crucial role of hyperinsulinemia in the development of breast cancer with Type 2 diabetes mellitus (T2DM), it has been shown that hyperglycemia could contribute to promote cancer progression. A remarkable association within hyperglycemia, PKCδ and Ubiquitin-proteasome system (UPS) has been reported, suggesting that PKCδ may mediate high glucose-induced UPS activation in breast cancer cells. Although the independent effects of PKCδ or UPS on breast cancer and T2DM are increasingly supported by experimental evidence, the complex interactional link between PKCδ and UPS is still unclear. Hence, we focus on the relationship between PKCδ and UPS in breast cancer with T2DM. We hypothesize that PKCδ may have the function to regulate the activity of UPS. Further, we speculate that PKCδ combine with proteasome α2 promoter, that indicate PKCδ regulate the function of UPS by change the composition of proteasome. Therefore, we surmise that PKCδ mediated high glucose-induced UPS activation in breast cancer cells, and specific PKCδ inhibitor rottlerin significantly suppressed elevated glucose induced the activity of UPS. We hope that our paper will stimulate further studies the relationship between PKCδ and UPS, and a new targeted therapy and early medical intervention for PKCδ could be a useful option for breast cancer cases complicated with T2DM or hyperglycemia.

Vildagliptin increases butyrate-producing bacteria in the gut of diabetic rats.

Emerging evidence supports a key role for the gut microbiota in metabolic diseases, including type 2 diabetes (T2D) and obesity. The dipeptidyl peptidase-4 inhibitor vildagliptin is highly efficacious in treating T2D. However, whether vildagliptin can alter the gut microbiome is still unclear. This study aimed to identify whether vildagliptin modifies the gut microbiota structure during T2D treatment. Diabetic Sprague-Dawley (SD) rats were induced by a high-fat diet and streptozotocin injection (HFD/STZ). Diabetic rats were orally administered a low dose of vildagliptin (LV, 0.01 g/kg/d vildagliptin), high dose of vildagliptin (HV, 0.02 g/kg/d vildagliptin), or normal saline for 12 weeks. Fasting blood glucose, blood glucose after glucose loading, and serum insulin levels were significantly reduced in the LV and HV groups compared with those in the T2D group. The serum GLP-1 level increased more in the vildagliptin-treated group than in the T2D group. Pyrosequencing of the V3-V4 regions of 16S rRNA genes revealed that vildagliptin significantly altered the gut microbiota. The operational taxonomic units (OTUs) and community richness (Chao1) index were significantly reduced in the vildagliptin and diabetic groups compared with those in the control group. At the phylum level, a higher relative abundance of Bacteroidetes, lower abundance of Firmicutes, and reduced ratio of Fimicutes/Bacteroidetes were observed in the vildagliptin-treated group. Moreover, vildagliptin treatment increased butyrate-producing bacteria, including Baceroides and Erysipelotrichaeae, in the diabetic rats. Moreover, Lachnospira abundance was significantly negatively correlated with fasting blood glucose levels. In conclusion, vildagliptin treatment could benefit the communities of the gut microbiota.

Generation of a KCNJ11 homozygous knockout human embryonic stem cell line WAe001-A-12 using CRISPR/Cas9.

The ATP-sensitive potassium channel is an octameric complex, and one of its subunits, namely Kir6.2, is encoded by the KCNJ11 gene. Mutations in KCNJ11 result in hyperinsulinism or diabetes mellitus, associated with abnormal insulin secretion. Here, using CRISPR/Cas9 editing, we established a homozygous mutant KCNJ11 cell line, WAe001-A-12, which was generated by a 62-bp deletion in the coding sequence of the human embryonic stem cell line H1. It was confirmed that this deletion in the KCNJ11 gene did not affect the protein expression levels of key pluripotent factors. Additionally, normal karyotype and differentiation potency were observed for the cell line.

Atypical PKC, PKCλ/ι, activates β-secretase and increases Aβ1-40/42 and phospho-tau in mouse brain and isolated neuronal cells, and may link hyperinsulinemia and other aPKC activators to development of pathological and memory abnormalities in Alzheimer's disease.

Hyperinsulinemia activates brain Akt and PKC-λ/ι and increases Aβ1-40/42 and phospho-tau in insulin-resistant animals. Here, we examined underlying mechanisms in mice, neuronal cells, and mouse hippocampal slices. Like Aβ1-40/42, β-secretase activity was increased in insulin-resistant mice and monkeys. In insulin-resistant mice, inhibition of hepatic PKC-λ/ι sufficient to correct hepatic abnormalities and hyperinsulinemia simultaneously reversed increases in Akt, atypical protein kinase C (aPKC), β-secretase, and Aβ1-40/42, and restored acute Akt activation. However, 2 aPKC inhibitors additionally blocked insulin's ability to activate brain PKC-λ/ι and thereby increase β-secretase and Aβ1-40/42. Furthermore, direct blockade of brain aPKC simultaneously corrected an impairment in novel object recognition in high-fat-fed insulin-resistant mice. In neuronal cells and/or mouse hippocampal slices, PKC-ι/λ activation by insulin, metformin, or expression of constitutive PKC-ι provoked increases in β-secretase, Aβ1-40/42, and phospho-thr-231-tau that were blocked by various PKC-λ/ι inhibitors, but not by an Akt inhibitor. PKC-λ/ι provokes increases in brain β-secretase, Aβ1-40/42, and phospho-thr-231-tau. Excessive signaling via PKC-λ/ι may link hyperinsulinemia and other PKC-λ/ι activators to pathological and functional abnormalities in Alzheimer's disease.

Decreased homocysteine trans-sulfuration in hypertension with hyperhomocysteinemia: relationship with insulin resistance.

Homocysteine is an independent cardiovascular risk factor and is increased in essential hypertension. Insulin stimulates homocysteine catabolism in healthy individuals. However, the mechanisms of hyperhomocysteinemia and its relationship with insulin resistance in essential hypertension are unknown.

Artesunate prevents rats from the clozapine-induced hepatic steatosis and elevation in plasma triglycerides.

Clozapine is an atypical antipsychotic with therapeutic efficacy in treatment-resistant schizophrenia patients and low incidence of extrapyramidal side effects. However, the use of clozapine has been limited by its adverse effects on metabolism. Artesunate is a semisynthetic derivative of artemisinin and was shown to decrease the plasma cholesterol and triglyceride in rabbits and rats in recent studies. The aim of this study was to examine possible effects of artesunate on the clozapine-induced metabolic alterations in rats given saline, clozapine, artesunate, or clozapine plus artesunate for 6 weeks. The clozapine group showed significantly high plasma levels of triglyceride, hepatic steatosis, and fibrosis along with high levels of C-reactive protein, alanine aminotransferase, and aspartate aminotransferase compared to the saline group. But the treatment had no effect on weight gain and caused no hyperglycemia, hyperinsulinemia, and behavioral changes in the rats. More significantly, these clozapine-induced changes were not seen in rats coadministered with clozapine plus artesunate. These results added evidence supporting psychiatrists to try add-on treatment of artesunate in schizophrenia patients to ameliorate clozapine-induced adverse metabolic effects.

The diagnosis and management of congenital and adult-onset hyperinsulinism (nesidioblastosis) - literature review.

Congenital and adult-onset hyperinsulinism (CHI) must be taken under consideration in the differential diagnosis of hypoglycaemia symptoms with endogenous hyperinsulinism, especially in cases in which there was failure to find an insulinoma. Histological examination is necessary for a definitive diagnosis. CHI is a disorder with three histopathological variants: focal CHI, diffuse CHI, and atypical CHI. These variants are clinically indistinguishable. According to published statistics, 0.5 to 5% of nesidioblastosis cases occur in adults. Clinical manifestation ranges from mildly symptomatic up to life-threatening hypoglycaemia. Early diagnosis and treatment are important in young and very young patients because early treatment accounts for favourable mental outcomes.

Dietary Anthocyanins and Insulin Resistance: When Food Becomes a Medicine.

Insulin resistance is an abnormal physiological state that occurs when insulin from pancreatic β-cells is unable to trigger a signal transduction pathway in target organs such as the liver, muscles and adipose tissues. The loss of insulin sensitivity is generally associated with persistent hyperglycemia (diabetes), hyperinsulinemia, fatty acids and/or lipid dysregulation which are often prevalent under obesity conditions. Hence, insulin sensitizers are one class of drugs currently employed to treat diabetes and associated metabolic disorders. A number of natural products that act through multiple mechanisms have also been identified to enhance insulin sensitivity in target organs. One group of such compounds that gained interest in recent years are the dietary anthocyanins. Data from their in vitro, in vivo and clinical studies are scrutinized in this communication to show their potential health benefit through ameliorating insulin resistance. Specific mechanism of action ranging from targeting specific signal transduction receptors/enzymes to the general antioxidant and anti-inflammatory mechanisms of insulin resistance are presented.

Leptin-adiponectin imbalance as a marker of metabolic syndrome among Chinese children and adolescents: The BCAMS study.

Leptin and adiponectin have opposite effects on subclinical inflammation and insulin resistance, both involved in the development of metabolic syndrome (MS). We aimed to investigate whether leptin/adiponectin ratio (L/A), as a marker of these two adipokines imbalance, may improve diagnosis of MS in children and adolescents, and determined its cut-off value in the diagnosis of MS.

Mycoprotein represents a bioavailable and insulinotropic non-animal-derived dietary protein source: a dose-response study.

The anabolic potential of a dietary protein is determined by its ability to elicit postprandial rises in circulating essential amino acids and insulin. Minimal data exist regarding the bioavailability and insulinotropic effects of non-animal-derived protein sources. Mycoprotein is a sustainable and rich source of non-animal-derived dietary protein. We investigated the impact of mycoprotein ingestion, in a dose-response manner, on acute postprandial hyperaminoacidaemia and hyperinsulinaemia. In all, twelve healthy young men completed five experimental trials in a randomised, single-blind, cross-over design. During each trial, volunteers consumed a test drink containing either 20 g milk protein (MLK20) or a mass matched (not protein matched due to the fibre content) bolus of mycoprotein (20 g; MYC20), a protein matched bolus of mycoprotein (40 g; MYC40), 60 g (MYC60) or 80 g (MYC80) mycoprotein. Circulating amino acid, insulin and uric acid concentrations, and clinical chemistry profiles, were assessed in arterialised venous blood samples during a 4-h postprandial period. Mycoprotein ingestion resulted in slower but more sustained hyperinsulinaemia and hyperaminoacidaemia compared with milk when protein matched, with overall bioavailability equivalent between conditions (P>0·05). Increasing the dose of mycoprotein amplified these effects, with some evidence of a plateau at 60-80 g. Peak postprandial leucine concentrations were 201 (sem 24) (30 min), 118 (sem 10) (90 min), 150 (sem 14) (90 min), 173 (sem 23) (45 min) and 201 (sem 21 (90 min) µmol/l for MLK20, MYC20, MYC40, MYC60 and MYC80, respectively. Mycoprotein represents a bioavailable and insulinotropic dietary protein source. Consequently, mycoprotein may be a useful source of dietary protein to stimulate muscle protein synthesis rates.

A Missense Variant rs4645843 in TNF-α Gene Is a Risk Factor of Polycystic Ovary Syndrome in the Uygur Population.

Polycystic ovary syndrome (PCOS) is a complex endocrine syndrome, resulting from the interaction of gene variants and environmental factors. PCOS is viewed as a proinflammatory state and is characterized by hyperandrogenism, hyperinsulinemia, and over-weight. In China, the incidence of PCOS is higher in the Uygur population than that in the Chinese Han population. The association of the tumor necrosis factor α (TNF-α) gene with PCOS remains to be clarified. Here, we investigated the association of TNF-α polymorphisms with PCOS in the Uygur population (393 patients with PCOS and 381 healthy subjects). Two single-nucleotide polymorphisms in TNF-α were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method: rs1800629 (-308G/A polymorphism), a commonly tested variant and rs4645843 (6213C/T polymorphism) that causes a Pro-to-Leu substitution at position 84, the most damaging variant of TNF-α based on in silico analysis. We thus found that both the genotypic and allelic distributions of rs4645843 were significantly different between PCOS and control groups (p = 0.03 and 0.024, respectively), whereas those of rs1800629 were similar between the groups. Furthermore, rs4645843 was significantly associated with serum testosterone levels and the score of Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), but no such association was found with rs1800629. Importantly, both rs4645843 and rs1800629 were significantly associated with higher body mass index (p < 0.05). This is the first study that shows the association of TNF-α gene with PCOS in the Uygur population. The TNF-α gene may influence the pathogenesis of PCOS through regulating testosterone level, obesity and HOMA-IR.

Association Among Obesity, Metabolic Health, and the Risk for Colorectal Cancer in the General Population in Korea Using the National Health Insurance Service-National Sample Cohort.

In Korea, the incidence of colorectal cancer has increased and obesity is on a rising trend because of a Westernized lifestyle in men.

Activation of IGF-1 receptors and Akt signaling by systemic hyperinsulinemia contributes to cardiac hypertrophy but does not regulate cardiac autophagy in obese diabetic mice.

Autophagy plays an important role in the maintenance of normal heart function. However, the role of autophagy in the inulin resistant and diabetic heart is not well understood. Furthermore, the upstream signaling and the downstream targets involved in cardiac autophagy regulation during obesity and type 2 diabetes mellitus (T2DM) are not fully elucidated. The aim of this study was to measure autophagic flux and to dissect the upstream and downstream signaling involved in cardiac autophagy regulation in the hearts of obese T2DM mice. Our study demonstrated that cardiac autophagic flux is suppressed in the heart of obese diabetic (ob/ob) mice due to impaired autophagosome formation. We showed that suppression of autophagy was due to sustained activation of mTOR as we could restore cardiac autophagy by inhibiting mTOR. Moreover, the novel finding of this study is that while IGF-1 receptor-mediated Akt activation contributes to cardiac hypertrophy, it is not involved in mTOR activation and autophagy suppression in obesity and T2DM. In contrast, inhibition of ERK signaling abolished mTOR activation and restored autophagy in the heart of obese diabetic (ob/ob) mice. The study identifies mechanisms regulating cardiac autophagy in obesity and T2DM that are mediated by ERK/mTOR but are distinct from Akt. The findings are of significant importance as they demonstrate for the first time the contribution of IGF-1 receptors (IGF-1R) and Akt signaling in cardiac hypertrophy but not in cardiac autophagy regulation in obesity and T2DM.

Sirolimus precipitating diabetes mellitus in a patient with congenital hyperinsulinaemic hypoglycaemia due to autosomal dominant ABCC8 mutation.

Sirolimus (mTOR inhibitor) is proven to be effective in children with congenital hyperinsulinism (CHI). Studies in animals suggest that sirolimus may have diabetogenic actions. However, its role in precipitating diabetes mellitus (DM) in children with CHI has not been reported.

Serum levels of uncoupling proteins in patients with differential insulin resistance: A community-based cohort study.

The uncoupling protein (UCP) belongs to a family of energy-dissipating proteins in mitochondria. Increasing evidences have indicated that UCPs have immense impact on glucose homeostasis and are key proteins in metabolic syndrome. For applying the findings to clinical practice, we designed a study to explore the association between serum UCPs 1-3 and insulin resistance. This investigation prospectively recorded demographical parameter and collected blood samples of 1071 participants from 4 districts in Northeastern Taiwan during the period from August 2013 to July 2014. Propensity score matching by age and sex in patients with top and bottom third homeostasis model assessment of insulin resistance (HOMA-IR) levels was performed, and 326 subjects were enrolled for further studies. The mean age of the patients was 59.4 years and the majority of them (65.5%) were females. The prevalence of metabolic syndrome was 35.5%. Our results demonstrated that serum UCPs 1-3 were significantly associated with differences in HOMA-IR levels. Multiple logistic regression analysis indicated that low UCP 1 and features of metabolic syndrome, namely hypertension, diabetes, body mass index, and high-density lipoprotein, were independent determinants for high HOMA-IR levels. We thus determined that low serum UCP 1 is a predictor for high resistance to insulin.

Late presentation of necrotizing enterocolitis associated with rotavirus infection in a term infant with hyperinsulinism on octreotide therapy: A case report.

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy that can cause permanent brain damage. Consequently, optimal management is extremely important. Current pharmacologic and surgical treatment were available that included diazoxide and octreotides.

Pathogenesis, Clinical Features and Treatment of Diabetic Cardiomyopathy.

Patients with type 1 and type 2 diabetes mellitus (T1D and T2D) show an increased incidence of heart failure (HF) even after adjustment for well established risk factors for HF such as hypertension and ischaemic heart disease. The resulting specific form of cardiomyopathy is known as diabetic cardiomyopathy" (DCM). Pathogenetic mechanisms underlying DCM are likely to be multifactorial, from altered myocardial metabolism (hyperglycaemia, hyperinsulinaemia, increased circulating fatty acids and trglycerides) to microvascular disease, autonomic neuropathy, and altered myocardial structure with fibrosis. Current medical treatment recommendations from scientific societies on HF in patients with diabetes mellitus (DM) do not differ from those for patients without DM. Regarding the effect of different hypoglycaemic drugs on HF in patients with DM, and considering the best available current evidence, the sodium-glucose-co-transporter 2 inhibitors and metformin seem to be especially advantageous regarding the effects in patients with T2D and HF.

Hexarelin, a Growth Hormone Secretagogue, Improves Lipid Metabolic Aberrations in Nonobese Insulin-Resistant Male MKR Mice.

Despite the occurrence of dyslipidemia and its contribution to the development of insulin resistance in obese subjects, a growing number of studies have described abnormal lipid profiles among leaner persons. For example, individuals with an abnormal paucity or distribution of fat (lipodystrophy) develop severe insulin resistance, dyslipidemia, and hepatic steatosis. Deranged adipocyte metabolism and differentiation contribute to ectopic fat deposition and consequent development of insulin resistance. Growth hormone (GH) therapy has been shown to correct body composition abnormalities in some lipodystrophy patients. However, little is known about the effects of GH-releasing peptides in this regard. Hexarelin, a GH secretagogue, has recently been shown to have beneficial effects on fat metabolism via the CD36 receptor. In this study, the effects of twice daily intraperitoneal injections of hexarelin (200 μg/kg body weight) were examined in nonobese insulin-resistant MKR mice and corresponding wild-type FVB mice for 12 days. Hexarelin treatment significantly improved glucose and insulin intolerance and decreased plasma and liver triglycerides in MKR mice. These beneficial metabolic effects could be due to the improved lipid metabolism and enhanced adipocyte differentiation of white adipose tissue with hexarelin treatment. Interestingly, although food intake of hexarelin-treated MKR mice was significantly increased, this did not change total body weight. Moreover, hexarelin treatment corrected the abnormal body composition of MKR mice, as demonstrated by a decrease in fat mass and an increase in lean mass. Our results suggest a possible application of hexarelin in treatment of lipid disorders associated with the metabolic syndrome.

The role of moderate-to-vigorous physical activity in mediating the relationship between central adiposity and immunometabolic profile in postmenopausal women.

To analyze the role of moderate-to-vigorous physical activity (MVPA) in mediating the relationship between central adiposity and immune and metabolic profile in postmenopausal women.

Nigella sativa Oil and Chromium Picolinate Ameliorate Fructose-Induced Hyperinsulinemia by Enhancing Insulin Signaling and Suppressing Insulin-Degrading Enzyme in Male Rats.

In vivo and in vitro studies suggested that chromium enhances insulin sensitivity by promoting insulin receptor signaling. However, its effect on insulin clearance has not been yet identified. Nigella sativa, a widely used spice, possesses an antidiabetic activity. We, therefore, hypothesized that chromium picolinate may alter insulin clearance by modulating insulin-degrading enzyme (IDE) in insulin-resistant rats. We evaluated also the effect of Nigella sativa oil on insulin signaling and degradation with respect to chromium picolinate. To assess these hypotheses, insulin resistance was induced in 30 male Wistar albino rats through daily oral administration of high-fructose water (HFW, 20% w/v) for 45 days. These rats were then divided into three groups (n = 10/group). They were given either no treatment (control group) or Nigella sativa oil (500 mg/kg bw/day) or chromium picoloinate (200 μg/kg bw/day) orally along with HFW (20% w/v) for 45 days. Nigella sativa oil or chromium picolinate concurrent administration with HFW significantly decreased body weight, serum lipids, glucagon, insulin resistance, and hepatic IDE level but increased its mRNA expression and insulin receptor phosphorlyation as well as high-density lipoprotein cholesterol (HDL-C) level as compared to control group values, suggesting their potential as modulators for insulin signaling and clearance. However, Nigella sativa oil exerted better improvement in feeding efficacy ratio as well as the levels of glucagon, insulin, insulin resistance, hepatic IDE level and insulin receptor phosphorylation than chromium picolinate, suggesting its greater insulin sensitizing capacity. Our data, for the first time, prove that Nigella sativa oil and chromium picolinate monotherapy can reduce fructose-induced insulin resistance by reduction of hepatic IDE protein and activation of insulin receptor signaling.