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Hyperinsulinemia - Top 30 Publications

Oral Insulin Delivery in a Physiologic Context.

Insulin remains indispensable to the treatment of diabetes, but its availability in injectable form only has hampered its timely and broader use. The development of an oral insulin remains an ultimate goal to both enhance ease of use, and to provide therapeutic advantages rooted in its direct delivery to the portal vein and liver. By mimicking the physiological path taken by pancreatic insulin, oral insulin is expected to have a distinct effect on the hepatic aspect of carbohydrate metabolism, hepatic insulin resistance, and, at the same time, avoid hyperinsulinemia and minimize the risk of hypoglycemia. With oral insulin approaching late stages of development, the goal of this review is to examine oral insulin in a physiological context and report on recent progress in its development.

Sex difference of hyperinsulinemia in the C57BL/6J-Daruma (obese) mouse.

The C57BL/6J-Daruma mouse is an animal model of obesity derived from the original genetically obese ICR-Daruma mouse by transfer of the phenotype into the C57BL/6J background by backcrossing into the C57BL/6J strain. Although, like the original ICR-Daruma mouse model, both male and female C57BL/6J-Daruma mice develop obesity, the latter strain shows sex differences in several phenotypes. A sex difference in plasma insulin levels was especially notable in C57BL/6J-Daruma mice; only males showed hyperinsulinemia. Orchiectomy suppressed this hyperinsulinemia completely, whereas testosterone supplementation restored it. Glucose administration increased the plasma glucose level in both male and female Daruma mice to a greater extent than in wild-type control mice. Orchiectomy, but not ovariectomy, decreased the plasma glucose level to that seen in wild-type controls. On the other hand, this effect of orchiectomy was abrogated by testosterone supplementation. The expression of mRNAs for several genes related to insulin resistance was significantly changed in white adipose tissue and liver of C57BL/6J-Daruma mice, especially males, as early as 4 weeks of age. The present results suggest that testosterone may be involved in the hyperinsulinemia shown by male C57BL/6J-Daruma mice and that this strain may be an appropriate animal model for examining the relationship between obesity and sex hormones.

The CD4+ T cell regulatory network mediates inflammatory responses during acute hyperinsulinemia: a simulation study.

Obesity is frequently linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behaviour of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood.

Does a first-degree family history of diabetes impact placental maternal and fetal vascular circulation and inflammatory response?

Heritability of diabetes is associated with hyperinsulinemia, impaired endothelial function, and inflammatory up-regulation. However, no studies have examined whether a family history of diabetes effects placental vascular circulation.

Modulation of natriuretic peptide receptors in human adipose tissue: molecular mechanisms behind the "natriuretic handicap" in morbidly obese patients.

The B-type natriuretic peptide (BNP) hormone plays a crucial role in the regulation of cardiovascular and energy homeostasis. Obesity is associated with low circulating levels of BNP, a condition known as "natriuretic handicap." Recent evidences suggest an altered expression of BNP receptors-both the signaling natriuretic peptide receptors (NPR)-A and the clearance NPR-C receptor-in adipose tissue (AT) as one of the putative causes of natriuretic handicap. The current study aims at clarifying the molecular mechanisms behind the natriuretic handicap, focusing on NPR modulation in the AT of obese and control subjects. The study enrolled 34 obese and 20 control subjects undergoing bariatric or abdominal surgery, respectively. The main clinical and biochemical parameters, including circulating BNP, were assessed. In visceral (VAT) and subcutaneous AT (SAT) samples, collected during surgery, the adipocytes and stromal vascular fraction (SVF) expression of NPR-A and NPR-C and the SVF secretion of interleukin 6 (IL-6) were determined. Both VAT and SAT from obese patients expressed a lower NPR-A/NPR-C ratio in adipocytes and the SVF secreted a higher level of IL-6, compared with the controls. Moreover, NPR-A/NPR-C ratio expressed by VAT and SAT adipocytes negatively correlated with body mass index, insulin, the Homeostasis Model Assessment of Insulin resistance, and IL-6 secreted by SVF, and the expression of the clearance receptor NPR-C, in both the VAT and SAT adipocytes, showed a negative correlation with circulating BNP. Overall, insulin resistance/hyperinsulinemia and AT inflammation (ie, high level of IL-6) are the major determinants of the lower NPR-A/NPR-C ratio in adipocytes, thus contributing to the natriuretic handicap in obese subjects.

A case report of methadone-associated hypoglycemia in an 11-month-old male.

Methadone is a synthetic μ-opioid receptor agonist that is used in the management of pain, neonatal abstinence withdrawal syndrome, and opioid dependence. Overdose can cause miosis, respiratory depression, and central nervous system depression. Rarely, hypoglycemia has been reported. We present the case of an 11-month-old male who developed hypoketotic, hyperinsulinemic, hypoglycemia after an acute, unintentional methadone exposure.

Insulin and the polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy among women during reproductive age. PCOS is characterised by hyperandrogenaemia, hyperinsulinaemia, and deranged adipokines secretion from the adipose tissue. In addition to the reduced insulin sensitivity, PCOS women exhibit β-cell dysfunction as well. Low birth weight and foetal exposure to androgens may contribute to the development of the PCOS phenotype during life. Further metabolic complications lead to dyslipidaemia, worsening obesity and glucose tolerance, high prevalence of metabolic syndrome, and greater susceptibility to diabetes. PCOS women show age-related existence of hypertension, and subtle endothelial and vascular changes. Adverse reproductive outcomes include anovulatory infertility, and unrecognised potentiation of the hormone-dependent endometrial cancer. The main therapeutic approach is lifestyle modification. Metformin is the primary insulin-sensitising drug to be used as an adjuvant therapy to lifestyle modification in patients with insulin resistance and impaired glucose tolerance, as well as in those referred to infertility treatment. Thiazolidinediones should be reserved for women intolerant of or refractory to metformin, while glucagon-like peptide 1 analogues has a potential therapeutic use in obese PCOS women. Randomised clinical trials and repetitive studies on different PCOS phenotypes for the preventive actions and therapeutic options are still lacking, though.

Regulation of testicular steroidogenesis by Foxa3 via transcriptional modulation of ERα signaling in type 2 diabetes mellitus (T2DM).

Although both insulin and estrogen receptor α (ERα) are known to exert inhibitory effects on testicular steroidogenesis, it remains unknown whether these pathways regulate testosterone (T) production under certain pathological conditions [e.g., type 2 diabetes mellitus (T2DM)] in a coordinated manner. Here, we found that the expression of forkhead box protein A3 (Foxa3), an essential transcriptional regulator engaged in adipogenesis and energy metabolism, was significantly down-regulated in the Leydig cells (LCs) from T-deficient T2DM mice. Functionally, upon hCG stimulation, Foxa3 recruits to the Esr1 promoter and suppresses the transactivation of Esr1 gene. Disruption of this recruitment by T2DM-elicited hyperinsulinemia led to abnormal activation of ERα pathway, inhibited steroidogenic enzyme genes expression, and thus caused inadequate T production. Therapeutically, insulin-impaired and Foxa3 ablation-compromised steroidogenesis were effectively rescued by a pharmacological inhibitor of the ERα pathway. These findings reveal an obligatory coregulatory role of Foxa3 in the regulation of ERα expression and of the Foxa3/ERα cascade, at least in part, in the pathogenesis of androgen deficiency caused by T2DM.

Oral application of a periodontal pathogen impacts SerpinE1 expression and pancreatic islet architecture in prediabetes.

Epidemiological studies suggest a close association between periodontitis and prediabetes/insulin resistance (IR) but whether periodontitis causes prediabetes in humans is not known. Using various animal models, we have recently established that periodontitis can be an initiator of prediabetes, which is characterized by glucose intolerance, hyperinsulinemia and IR. In addition, our in vitro studies indicated that Porphyromonas gingivalis (Pg) induced insulin secretion in MIN6 β cells and this induction was in part SerpinE1 (plasminogen activator inhibitor 1, PAI1) dependent. However, the mechanism(s) by which periodontitis induces prediabetes is not known. As α and β cells in pancreatic islets are the major modulators of glucose levels, we investigated whether experimental periodontitis by oral application of a periodontal pathogen caused molecular and/or cellular alterations in pancreatic islets and whether SerpinE1 was involved in this process.

Development of Pulmonary Hypertension During Treatment with Diazoxide: A Case Series and Literature Review.

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy. The mainstay of medical management for CHI is diazoxide. Diazoxide inhibits insulin release from the pancreas, but also causes smooth muscle relaxation and fluid retention so it is typically given with chlorothiazide. In July 2015, the FDA issued a drug safety communication warning that pulmonary hypertension (PH) had been reported in 11 infants being treated with diazoxide and that the PH resolved with withdrawal of diazoxide. All three of the cases in our hospital were admitted to the neonatal intensive care unit (NICU) for hypoglycemia. All patients received thorough radiologic and laboratory evaluations related to their diagnosis of CHI. All initially improved when diazoxide was initiated. Case 1 and case 3 were discharged from the NICU on diazoxide and chlorothiazide. Case 2 developed pulmonary hypertension while still in the NICU days after an increase in diazoxide dosing. Case 1 presented to the emergency room in respiratory distress shortly after discharge from the NICU with evidence of PH and heart failure. Case 3 presented to the emergency room after 2 weeks at home due to a home blood glucose reading that was low and developed PH and heart failure while an inpatient. Discontinuation of diazoxide led to resolution of all three patients' PH within approximately one week. The experience of our hospital indicates that pulmonary hypertension may be more common than previously thought in infants taking diazoxide. It is unclear if these symptoms develop slowly over time or if there is some other, as yet undescribed, trigger for the pulmonary hypertension. Our hospital's experience adds to the body of evidence and suggests these infants may benefit from more surveillance with echocardiography.

Correlation of disease severity with body weight and high fat diet in the FATZO/Pco mouse.

Obesity in many current pre-clinical animal models of obesity and diabetes is mediated by monogenic mutations; these are rarely associated with the development of human obesity. A new mouse model, the FATZO mouse, has been developed to provide polygenic obesity and a metabolic pattern of hyperglycemia and hyperinsulinemia, that support the presence of insulin resistance similar to metabolic disease in patients with insulin resistance/type 2 diabetes. The FATZO mouse resulted from a cross of C57BL/6J and AKR/J mice followed by selective inbreeding for obesity, increased insulin and hyperglycemia. Since many clinical studies have established a close link between higher body weight and the development of type 2 diabetes, we investigated whether time to progression to type 2 diabetes or disease severity in FATZO mice was dependent on weight gain in young animals. Our results indicate that lighter animals developed metabolic disturbances much slower and to a lesser magnitude than their heavier counterparts. Consumption of a diet containing high fat, accelerated weight gain in parallel with disease progression. A naturally occurring and significant variation in the body weight of FATZO offspring enables these mice to be identified as low, mid and high body weight groups at a young age. These weight groups remain into adulthood and correspond to slow, medium and accelerated development of type 2 diabetes. Thus, body weight inclusion criteria can optimize the FATZO model for studies of prevention, stabilization or treatment of type 2 diabetes.

Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse.

The FATZO/Pco mouse is the result of a cross of the C57BL/6J and AKR/J strains. The crossing of these two strains and the selective inbreeding for obesity, insulin resistance and hyperglycemia has resulted in an inbred strain exhibiting obesity in the presumed presence of an intact leptin pathway. Routinely used rodent models for obesity and diabetes research have a monogenic defect in leptin signaling that initiates obesity. Given that obesity and its sequelae in humans are polygenic in nature and not associated with leptin signaling defects, the FATZO mouse may represent a more translatable rodent model for study of obesity and its associated metabolic disturbances. The FATZO mouse develops obesity spontaneously when fed a normal chow diet. Glucose intolerance with increased insulin levels are apparent in FATZO mice as young as 6 weeks of age. These progress to hyperglycemia/pre-diabetes and frank diabetes with decreasing insulin levels as they age. The disease in these mice is multi-faceted, similar to the metabolic syndrome apparent in obese individuals, and thus provides a long pre-diabetic state for determining the preventive value of new interventions. We have assessed the utility of this new model for the pre-clinical screening of agents to stop or slow progression of the metabolic syndrome to severe diabetes. Our assessment included: 1) characterization of the spontaneous development of disease, 2) comparison of metabolic disturbances of FATZO mice to control mice and 3) validation of the model with regard to the effectiveness of current and emerging anti-diabetic agents; rosiglitazone, metformin and semaglutide.

Glucose and Lipid Dysmetabolism in a Rat Model of Prediabetes Induced by a High-Sucrose Diet.

Glucotoxicity and lipotoxicity are key features of type 2 diabetes mellitus, but their molecular nature during the early stages of the disease remains to be elucidated. We aimed to characterize glucose and lipid metabolism in insulin-target organs (liver, skeletal muscle, and white adipose tissue) in a rat model treated with a high-sucrose (HSu) diet. Two groups of 16-week-old male Wistar rats underwent a 9-week protocol: HSu diet (n = 10)-received 35% of sucrose in drinking water; Control (n = 12)-received vehicle (water). Body weight, food, and beverage consumption were monitored and glucose, insulin, and lipid profiles were measured. Serum and liver triglyceride concentrations, as well as the expression of genes and proteins involved in lipid biosynthesis were assessed. The insulin-stimulated glucose uptake and isoproterenol-stimulated lipolysis were also measured in freshly isolated adipocytes. Even in the absence of obesity, this rat model already presented the main features of prediabetes, with fasting normoglycemia but reduced glucose tolerance, postprandial hyperglycemia, compensatory hyperinsulinemia, as well as decreased insulin sensitivity (resistance) and hypertriglyceridemia. In addition, impaired hepatic function, including altered gluconeogenic and lipogenic pathways, as well as increased expression of acetyl-coenzyme A carboxylase 1 and fatty acid synthase in the liver, were observed, suggesting that liver glucose and lipid dysmetabolism may play a major role at this stage of the disease.

Exercise training modulates the hepatic renin-angiotensin system in fructose-fed rats.

The renin-angiotensin system (RAS) has been implicated in the development of metabolic syndrome. We investigated whether the hepatic RAS is modulated by exercise training and if this modulation improves the deleterious effects of fructose overload in rats. Male Wistar rats were divided into (n = 8 each) control (CT), exercise control (CT-Ex), high fructose (HFr) and exercise high fructose (HFr-Ex) groups. Fructose-drinking rats received D-fructose (100 g L(-1) ). After two weeks, CT-Ex and HFr-Ex rats were assigned to a treadmill training protocol at moderate-intensity for eight weeks (60 min day(-1) , four days/week). We assessed body mass, glucose and lipid metabolism, hepatic histopathology, ACE and ACE2 activity, angiotensin concentration, the expression profile of proteins affecting hepatic RAS, gluconeogenesis and inflammation. Neither fructose overload nor exercise training influenced body mass gain and serum ACE and ACE2 activity. The HFr group showed hyperinsulinemia, but exercise training normalized this parameter. Exercise training was effective in preventing hepatic steatosis as well as triacylglycerol and glycogen accumulation. Furthermore, exercise improved the response to the deleterious effects of HFr overload by normalizing the gluconeogenesis pathway as well as the protein levels of IL-6 and TNF-alpha. The HFr rats displayed increased hepatic ACE activity and protein expression and Ang II concentration which were attenuated by exercise training. Exercise training restored the ACE2/Ang (1-7)/Mas receptor axis. Exercise training may favor the counter-regulatory ACE2/Ang (1-7)/Mas receptor axis over the classical RAS (ACE/Ang II/AT1R axis), which could be responsible for the decrease of metabolic dysfunction and the prevention of non-alcoholic fatty liver disease (NAFLD). This article is protected by copyright. All rights reserved.

Prenatal caffeine exposure induced high susceptibility to metabolic syndrome in adult female offspring rats and its underlying mechanisms.

Our previous studies have demonstrated that prenatal caffeine exposure (PCE) induced an intrauterine programming of hypothalamic-pituitary-adrenal axis (HPAA)-associated neuroendocrine metabolism in 3-month-old offspring rats. In this study, we aimed to confirm this programming disorder and high susceptibility to metabolic syndrome (MS) in 10-month-old female PCE offspring with postnatal catch-up growth. We found that PCE female offspring rats showed decreased bodyweight but a higher rate of weight gain after birth. Moreover, in the offspring, basal hyperinsulinemia and insulin resistance were observed before unpredictable chronic stress (UCS), but serum total cholesterol (TCH) levels and triglyceride/high-density lipoprotein-cholesterol (TG/HDL-C), TCH/HDL-C and low-density lipoprotein-cholesterol/HDL-C (LDL-C/HDL-C) ratio changes were increased after UCS, accompanied by morphological damage of the related tissues. These results suggested that PCE adult female offspring rats were highly susceptible to MS, which is related to HPAA-associated neuroendocrine-metabolic programming disorder.

Insulin signaling: An opportunistic target to minify risk of Alzheimer's disease.

Alzheimer's disease (AD) is progressive neurodegenerative disorder characterized by accumulation of senile plaques, neurofibrillary tangles (NFT) and neurodegeneration. The diabetes mellitus (DM) is one of the risk factors for AD pathogenesis by impairment in insulin signaling and glucose metabolism in central as well as peripheral system. Insulin resistance, impaired glucose and lipid metabolism lead to the Aβ (Aβ) aggregation, Tau phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, memory impairment and also mark over Aβ transport through central to peripheral and vice versa. Several pathways, like enzymatic degradation of Aβ, forkhead box protein O1 (FOXO) signaling, insulin signaling shared common pathological mechanism for both AD and DM. Recent evidence showed that hyperinsulinemia and hyperglycemia affect the onset and progression of AD differently. Some researchers have suggested that hyperglycemia influences vascular tone, while hyperinsulinemia may underlie mitochondrial deficit. The objective of this review is to determine whether existing evidence support the concept that impairment in insulin signaling and glucose metabolism play an important role in pathogenesis of AD. In the first part of this review, we tried to explain the interconnecting link between AD and DM, whereas the second part includes more information on insulin resistance and its involvement in AD pathogenesis. In this review, we have focused more toward the AD treatment by targeting insulin signaling like anti-diabetic, antioxidant, nutraceuticals and dietary supplements. To date, more researches should be done in this field in order to explore the pathways in insulin signaling, which might ameliorate the treatment options and reduce the risk of AD due to DM.

A High-Fructose-High-Coconut Oil Diet Induces Dysregulating Expressions of Hippocampal Leptin and Stearoyl-CoA Desaturase, and Spatial Memory Deficits in Rats.

We investigated the effects of high-fructose-high-fat diets with different fat compositions on metabolic parameters, hippocampal-dependent cognitive function, and brain leptin (as well as stearoyl-CoA desaturase (SCD1) mRNA expressions). Thirty-two male Wistar rats were divided into 3 groups, a control group (n = 8), a high-fructose soybean oil group (37.5% of fat calories, n = 12), and a high-fructose coconut oil group (37.5% of fat calories, n = 12) for 20 weeks. By the end of the study, the coconut oil group exhibited significantly higher serum fasting glucose, fructosamine, insulin, leptin, and triglyceride levels compared to those of the control and soybean oil groups. However, hippocampal leptin expression and leptin receptor mRNA levels were significantly lower, while SCD1 mRNA was significantly higher in rats fed the high-fructose-high-coconut oil diet than in rats fed the other experimental diets. In addition, the coconut oil group spent significantly less time in the target quadrant on the probe test in the Morris water maze (MWM) task. Rats fed the high-fructose-high-coconut oil diet for 20 weeks were prone to develop hyperglycemia, hyperinsulinemia, hyperleptinemia, and hypertriglyceridemia. These metabolic consequences may contribute to hippocampal-dependent memory impairment, accompanied by a lower central leptin level, and a higher SCD1 gene expression in the brain.

Familial partial lipodystrophy and proteinuric renal disease due to a missense c.1045C > T LMNA mutation.

Proteinuric renal disease is prevalent in congenital or acquired forms of generalized lipodystrophy. In contrast, an association between familial partial lipodystrophy (FPLD) and renal disease has been documented in very few cases. A 22-year-old female patient presented with impaired glucose tolerance, hyperinsulinemia, hirsutism and oligomenorrhea. On examination, there was partial loss of subcutaneous adipose tissue in the face, upper and lower limbs, bird-like facies with micrognathia and low set ears and mild acanthosis nigricans. Laboratory investigations revealed hyperandrogenism, hyperlipidemia, elevated serum creatine kinase and mild proteinuria. A clinical diagnosis of FPLD of the non-Dunnigan variety was made; genetic testing revealed a heterozygous c.1045C > T mutation in exon 6 of the LMNA gene, predicted to result in an abnormal LMNA protein (p.R349W). Electromyography and muscle biopsy were suggestive of non-specific myopathy. Treatment with metformin and later with pioglitazone was initiated. Due to worsening proteinuria, a renal biopsy was performed; histological findings were consistent with mild focal glomerular mesangioproliferative changes, and the patient was started on angiotensin-converting enzyme inhibitor therapy. This is the fourth report of FPLD associated with the c.1045C > T missense LMNA mutation and the second with co-existent proteinuric renal disease. Patients carrying this specific mutation may exhibit a phenotype that includes partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy.

Pilot randomized controlled trial of a mindfulness-based group intervention in adolescent girls at risk for type 2 diabetes with depressive symptoms.

(1) Evaluate feasibility and acceptability of a mindfulness-based group in adolescent girls at-risk for type 2 diabetes (T2D) with depressive symptoms, and (2) compare efficacy of a mindfulness-based versus cognitive-behavioral group for decreasing depressive symptoms and improving insulin resistance.

Yogurt Is a Low-Glycemic Index Food.

High yogurt intake is associated with a reduced risk of type 2 diabetes (T2DM). Although several mechanisms could explain this association, this paper addresses the glycemic and insulinemic impact of yogurt. There is evidence that low-glycemic index (GI) and low-glycemic load (GL) diets are associated with a reduced risk of T2DM. The 93 GI values for yogurt in the University of Sydney's GI database have a mean ± SD of 34 ± 13, and 92% of the yogurts are low-GI (≤55). The 43 plain yogurts in the database have a lower GI than the 50 sweetened yogurts, 27 ± 11 compared with 41 ± 11 (P < 0.0001). This difference is not explained by sugar, per se, but rather by the higher protein-to-carbohydrate ratio in plain yogurt. Although yogurt has a low GI, its insulinemic index (II) is higher than its GI. High insulin responses may be deleterious because hyperinsulinemia is associated with an increased risk of T2DM. Nevertheless, this may not be a concern for yogurt because, although its II is higher than its GI, the II of yogurt is within the range of II values for nondairy low-GI foods. In addition, mixed meals containing dairy protein elicit insulin responses similar to those elicited by mixed meals of similar composition containing nondairy protein. Because the GI of yogurt is lower than that of most other carbohydrate foods, exchanging yogurt for other protein and carbohydrate sources can reduce the GI and GL of the diet, and is in line with recommended dietary patterns, which include whole grains, fruits, vegetables, nuts, legumes, fish, vegetable oils, and yogurt.

Genetic Predisposition to Abdominal Obesity and Cardiometabolic Risk-Reply.

Genetic Predisposition to Abdominal Adiposity and Cardiometabolic Risk.

Pregnancy in CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease caused by NOTCH3 gene mutations. CADASIL women are frequently considered at high risk of systemic vascular events during pregnancy and often prescribed with antithrombotic drugs. This decision is not evidence-based considering the lack of data about pregnancy outcome in CADASIL. We describe our experience on pregnancy in CADASIL patients.

Which origin for polycystic ovaries syndrome: Genetic, environmental or both?

Polycystic ovaries syndrome (PCOS), the most common female endocrine disorder, affects 7-10% of women of childbearing age. It includes ovarian hyperandrogenism, impaired follicular maturation, anovulation and subfertility. Insulin resistance, although present in most cases, is not necessary for diagnosis. It increases hyperandrogenism and long-term metabolic, cardiovascular and oncological risks. The origin of hyperandrogenism and hyperinsulinemia has a genetic component, as demonstrated by familial aggregation studies and recent identification of associated genomic variants, conferring a particular susceptibility to the syndrome. However, experimental and epidemiological evidences also support a developmental origin via a deleterious foetal environment, concerning the endocrine status (foetal hyperandrogenism), the nutritional level (intrauterine growth retardation), or the toxicological exposure (endocrine disruptors). Epigenetic changes recently reported in the literature as associated with PCOS, enhance this hypothesis of foetal reprogramming of the future adult ovarian function by environmental factors. Better characterisation of these genetic, epigenetic, or environmental factors, could lead to earlier prevention and more efficient treatments.

Atypical Forms of Congenital Hyperinsulinism In Infancy are Associated with Mosaic Patterns of Immature Islet Cells.

We aimed to characterise mosaic populations of pancreatic islet cells from patients with atypical CHI (CHI-A) and the expression profile of NKX2.2, a key transcription factor expressed in β-cells but suppressed in δ-cells in the mature pancreas.

Severe hyperandrogenemia in postmenopausal woman as a presentation of ovarian hyperthecosis. Case report and mini review of the literature.

Ovarian hyperthecosis (OH) is characterized by the presence of abundant luteinized theca cells in ovaries that secret androgen. It typically presents as severe hyperandrogenism and/or virilization in postmenopausal woman. Here we describe a 66-year old woman with presentation of severe hirsutism, alopecia, clitoromegaly and laboratory finding of significantly elevated serum total testosterone concentration and hyperinsulinemia. Performed imaging studies revealed normal sized, homogeneous ovaries, signs of endometrial hypertrophy and normal adrenal glands. Due to severe hyperandrogenemia and signs of endometrial hypertrophy, the total abdominal hysterectomy with bilateral salpingo-oophorectomy has been performed. Pathological examination revealed OH and endometrial hyperplasia. Androgenic activity of ovarian stromal cells has been confirmed using alpha-inhibin histochemical staining. Postmenopausal hyperandrogenemia is a diagnostic and therapeutic challenge and the imaging studies often may be misleading and require careful and critical consideration.

Nox2 contributes to hyperinsulinemia-induced redox imbalance and impaired vascular function.

Insulin resistance promotes vascular endothelial dysfunction and subsequent development of cardiovascular disease. Previously we found that skeletal muscle arteriolar flow-induced dilation (FID) was reduced following a hyperinsulinemic clamp in healthy adults. Therefore, we hypothesized that hyperinsulinemia, a hallmark of insulin resistance, contributes to microvascular endothelial cell dysfunction via inducing oxidative stress that is mediated by NADPH oxidase (Nox) system. We examined the effect of insulin, at levels that are comparable with human hyperinsulinemia on 1) FID of isolated arterioles from human skeletal muscle tissue in the presence and absence of Nox inhibitors and 2) human adipose microvascular endothelial cell (HAMECs) expression of nitric oxide (NO), endothelial NO synthase (eNOS), and Nox-mediated oxidative stress. In six lean healthy participants (mean age 25.5±1.6 y, BMI 21.8±0.9), reactive oxygen species (ROS) were increased while NO and arteriolar FID were reduced following 60min of ex vivo insulin incubation. These changes were reversed after co-incubation with the Nox isoform 2 (Nox2) inhibitor, VAS2870. In HAMECs, insulin-induced time-dependent increases in Nox2 expression and P47(phox) phosphorylation were echoed by elevations of superoxide production. In contrast, phosphorylation of eNOS and expression of superoxide dismutase (SOD2 and SOD3) isoforms showed a biphasic response with an increased expression at earlier time points followed by a steep reduction phase. Insulin induced eNOS uncoupling that was synchronized with a drop of NO and a surge of ROS production. These effects were reversed by Tempol (SOD mimetic), Tetrahydrobiopterin (BH4; eNOS cofactor), and VAS2870. Finally, insulin induced nitrotyrosine formation which was reversed by inhibiting NO or superoxide generation. In conclusions, hyperinsulinemia may reduce FID via inducing Nox2-mediated superoxide production in microvascular endothelial cells which reduce the availability of NO and enhances peroxynitrite formation. Therefore, the Nox2 pathway should be considered as a target for the prevention of oxidative stress-associated endothelial dysfunction during hyperinsulinemia.

Modeling Congenital Hyperinsulinism with ABCC8-Deficient Human Embryonic Stem Cells Generated by CRISPR/Cas9.

Congenital hyperinsulinism (CHI) is a rare genetic disorder characterized by excess insulin secretion, which results in hypoglycemia. Mutation of sulfonylurea receptor 1 (SUR1), encoded by the ABCC8 gene, is the main cause of CHI. Here, we captured the phenotype of excess insulin secretion through pancreatic differentiation of ABCC8-deficient stem cells generated by the CRISPR/Cas9 system. ABCC8-deficient insulin-producing cells secreted higher insulin than their wild-type counterparts, and the excess insulin secretion was rescued by nifedipine, octreotide and nicorandil. Further, we tested the role of SUR1 in response to different potassium levels and found that dysfunction of SUR1 decreased the insulin secretion rate in low and high potassium environments. Hence, pancreatic differentiation of ABCC8-deficient cells recapitulated the CHI disease phenotype in vitro, which represents an attractive model to further elucidate the function of SUR1 and to develop and screen for novel therapeutic drugs.

Diagnosis of congenital hyperinsulinism: Biochemical profiles during hypoglycemia.

To define the ranges of biochemical markers during hypoglycemia for the diagnosis of congenital hyperinsulinism (CHI), using high sensitivity insulin assays.

Testosterone improves the differentiation efficiency of insulin-producing cells from human induced pluripotent stem cells.

Human induced pluripotent stem cells (hiPSCs) may provide potential resource for regenerative medicine research, including generation of insulin-producing cells for diabetes research and insulin production. Testosterone (T) is an androgen hormone which promotes protein synthesis and improves the management of type 2 diabetes in clinical studies. Concurrently, co-existed hyperandrogenism and hyperinsulinism is frequently observed in polycystic ovary syndrome, congenital adrenal hyperplasia and some of Wermer's syndrome. However, the relationship among androgens, insulin and the differentiation of pancreatic β cells is still not fully clear. Here we find that T improves the differentiation efficiency of insulin-producing cells from hiPSCs. The addition of T into routine differentiation formula for pancreatic β cells increases the differentiation efficiency from 12% to 35%. The administration of T promotes the expression of key genes associated with β cells differentiation including NGN3, NEUROD1 and INS. This finding benefits the ongoing process to optimize the differentiation protocol of pancreatic β cells from hiPSCs, and provides some degree of understanding the clinical management of T for type 2 diabetes.