Nesidioblastosis and Subsequent Diabetes Mellitus in a Dog with Hyperinsulinemic Hypoglycemia Treated with Partial Pancreatectomy.

A 6.5 yr old castrated male mixed-breed dog was presented for clinical signs associated with hypoglycemia. Hyperinsulinemic hypoglycemia was diagnosed as the cause of the persistent hypoglycemia. No obvious pancreatic mass was seen on abdominal computed tomography and exploratory laparotomy. A partial pancreatectomy was performed with the suspicion of an insulinoma-causing hyperinsulinemic hypoglycemia. Nesidioblastosis was diagnosed based clinical, biochemical, and histopathologic findings. There was beta cell hyperplasia and no evidence of neoplasia. The dog was euglycemic postoperatively after a partial pancreatectomy. Long-term follow-up after 2 yr revealed that the dog was diagnosed with diabetes mellitus.

Circularity of islets is a distinct marker for the pathological diagnosis of adult non-neoplastic hyperinsulinemic hypoglycemia using surgical specimens.

BACKGROUND: Adult non-neoplastic hyperinsulinemic hypoglycemia (ANHH), also known as adult-onset nesidioblastosis, is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. This disease is characterized by diffuse hyperplasia of pancreatic endocrine cells and is diagnosed by a pathological examination. While diagnostic criteria for this disease have already been proposed, we established more quantitative criteria for evaluating islet morphology. METHODS: We measured the number, maximum diameter, total area, and circularity (representing how closely islets resemble perfect spheres) of islets contained in representative sections of ANHH (n = 4) and control cases (n = 5) using the NIS-Elements software program. We also measured the average cell size, percentage of cells with enlarged nuclei, and percentage of cells with recognizable nucleoli for each of three representative islets. We also assessed the interobserver diagnostic concordance of ANHH between five experienced and seven less-experienced pathologists. RESULTS: There was no significant difference in the number, maximum diameter, or total area of islets between the two groups, even after correcting for these parameters per unit area. However, the number of islets with low circularity (< 0.71) per total area of the pancreatic parenchyma was significantly larger in ANHH specimens than in controls. We also found that the percentage of cells with recognizable nucleoli was significantly higher in the ANHH group than in the controls. There were no significant differences in the average cell size or the number of cells with enlarged nuclei between the groups. The correct diagnosis rate with the blind test was 47.5% ± 6.12% for experienced pathologists and 50.0% ± 8.63% for less-experienced pathologists, with no significant differences noted. CONCLUSIONS: Low circularity, which indicates an irregular islet shape, referred to as "irregular shape and occasional enlargement of islets" and "lobulated islet structure" in a previous report, is a useful marker for diagnosing ANHH. An increased percentage of recognizable nucleoli, corresponding to "macronucleoli in ß-cells," has potential diagnostic value.

Sleeve Gastrectomy-Induced Weight Loss Increases Insulin Clearance in Obese Mice.

Sleeve gastrectomy (SG) successfully recovers metabolic homeostasis in obese humans and rodents while also resulting in the normalization of insulin sensitivity and insulinemia. Reduced insulin levels have been attributed to lower insulin secretion and increased insulin clearance in individuals submitted to SG. Insulin degradation mainly occurs in the liver in a process controlled, at least in part, by the insulin-degrading enzyme (IDE). However, research has yet to explore whether liver IDE expression or activity is altered after SG surgery. In this study, C57BL/6 mice were fed a chow (CTL) or high-fat diet (HFD) for 10 weeks. Afterward, the HFD mice were randomly assigned to two groups: sham-surgical (HFD-SHAM) and SG-surgical (HFD-SG). Here, we confirmed that SG improves glucose-insulin homeostasis in obese mice. Additionally, SG reduced insulinemia by reducing insulin secretion, assessed by the analysis of plasmatic C-peptide content, and increasing insulin clearance, which was evaluated through the calculation of the plasmatic C-peptide:insulin ratio. Although no changes in hepatic IDE activity were observed, IDE expression was higher in the liver of HFD-SG compared with HFD-SHAM mice. These results indicate that SG may be helpful to counteract obesity-induced hyperinsulinemia by increasing insulin clearance, likely through enhanced liver IDE expression.

Prevalencia de hiperinsulinismo patológico post carga de glucosa y su relación con factores de riesgo cardiovascular, en adultos no diabéticos con insulinemia basal normal / Prevalence of pathologic hyperinsulinism after a glucose load charge: its relation to cardiovascular risk factors

Introducción: 25% de personas con hiperinsulinismo desarrolla diabetes 3-5 años luego del primer diagnóstico y 70% lo hará en el resto de la vida. Intervenir los niveles de glicemia desde que se detecta hiperinsulinemia evita la progresión a diabetes y restaura el metabolismo glicémico. Objetivos: Determinar la prevalencia de hiperinsulinismo patológico post-carga de glucosa (HPPG) y su relación con factores de riesgo cardiovascular en adultos 100 UI/ml a las 2 horas), sexo, hipertensión arterial, dislipidemia, malnutrición por exceso, sedentarismo, tabaquismo, ateromatosis e infarto miocárdico documentado. Con STATA 17 se calculó la prevalencia de variables en población general y según categoría de HPPG y se evaluó la significancia con prueba exacta de Fisher. Se compararon medias con ANOVA y t-test con nivel de significancia <0,05. Se usó regresión binomial para estimar Razón de Prevalencia e intervalos de confianza en variables cuantitativas y cualitativas. Resultados: la prevalencia de HPPG fue 41%. La edad promedio 37,5 años, el sexo masculino 52,9%, la hipertensión-arterial 40,5% y la dislipidemia 74,4%. Al comparar las poblaciones con y sin HPPG existieron diferencia estadísticamente significativa en las variables dislipidemia, hipertensión-arterial, malnutrición por exceso y sexo-masculino. La razón de prevalencia alcanzó a un 62%, 37%, 59% y 20% respectivamente. Conclusión: Se encontró una alta prevalencia de HPPG. Los factores de riesgo asociados a ella fueron dislipidemia, hipertensión arterial, malnutrición por exceso y sexo masculino. Esto sugiere que encontrar HPPG puede ser de utilidad para detectar precozmente a la población con un mayor riesgo de enfermedad cardiovascular.

Introduction: 25% of people with hyperinsulinism develop diabetes 3-5 years after the first diagnosis and 70% will do so in the rest of their lives. To control glycemia levels as soon as hyperinsulinemia is detected, progression to diabetes is prevented and glycemic metabolism is restored. Aim: To determine the prevalence of post-glucose load pathological hyperinsulinism (HPPG) and its relationship with cardiovascular risk factors in adults 100 uIU/ ml at 2 hours), sex, hypertension, dyslipidemia, excess malnutrition due to, sedentary lifestyle, smoking, documented atheromatosis and myocardial infarction. The prevalence of variables in the general population was calculated and, in relation to the HPPG category, significance is evaluated with Fisher's exact test. Finally means are compared with ANOVA and t-test. With significance level <0.05. Binomial regression was used to estimate the prevalence ratio and confidence intervals in quantitative and qualitative variables. Statistical analysis was performed with the STATA 17 software. Results: HPPG prevalence was 41%, mean age 37.5 years, male sex 52.9%, arterial hypertension 40.5% and dyslipidemia 74.4%. Un relation to the presence of HPPG a statistically significant difference in the variables dyslipidemia, arterial hypertension, malnutrition due to excess and male sex was found. The prevalence ratios were 62%, 37%, 59% and 20%, respectively. Conclusion: A high prevalence of HPPG was found. Risk factors associated to HPPG were dyslipidemia, arterial hypertension, malnutrition due to excess and male sex. Thus, HPPG can play a role in the early detection of a higher risk of cardiovascular disease in the general population.

A multi-center study on glucometabolic response to bariatric surgery for different subtypes of obesity.

Objectives: To assess the benefit of a bariatric surgery in four artificial intelligence-identified metabolic (AIM) subtypes of obesity with respect to the improvement of glucometabolism and the remission of diabetes and hyperinsulinemia. Methods: This multicenter retrospective study prospectively collected data from five hospitals in China from 2010 to 2021. At baseline 1008 patients who underwent a bariatric surgery were enrolled (median age 31 years; median BMI 38.1kg/m2; 57.40% women) and grouped into the four AIM subtypes. Baseline and follow-up data (506 and 359 patients at 3- and 12-month post-surgery) were collected for longitudinal effect analysis. Results: Out of the four AIM subgroups, hypometabolic obesity (LMO) group was characterized by decompensated insulin secretion and high incidence of diabetes (99.2%) pre-surgery. After surgery, 62.1% of LMO patients with diabetes achieved remission, lower than the other three subgroups. Still, the bariatric surgery significantly reduced their blood glucose (median HbA1c decreased by 27.2%). The hypermetabolic obesity-hyperinsulinemia (HMO-I) group was characterized by severe insulin resistance and high incidence of hyperinsulinemia (87.8%) pre-surgery, which had been greatly alleviated post-surgery. For both metabolic healthy obesity (MHO) and hypermetabolic obesity-hyperuricemia (HMO-U) groups who showed a relatively healthy glucometabolism pre-surgery, rate of glucometabolic comorbidities improved moderately post-surgery. Conclusion: In terms of glucometabolism, the four AIM subtypes of patients benefited differently from a bariatric surgery, which significantly relieved hyperglycemia and hyperinsulinemia for the LMO and HMO-I patients, respectively. The AIM-based subtypes may help better inform clinical decisions on bariatric surgery and patient counseling pertaining to post-surgery outcomes.

[Hyperinsulinemia and age-related diseases: interrelations and approaches to treatment].

Hyperinsulinemia is closely related with insulin resistance, that is the key mechanism for the progression of age-related diseases. A lot of aspects of hyperinsulinemia and interrelations between the mentioned conditions are very scarcely covered in Russian publications. The present review is designed to fill the gaps in understanding the causal relationships between hyperinsulinemia, insulin resistance, age-related diseases and lifestyle factors. Material and methods. Based on sources from PubMed and Google Scholar, using the keywords "hyperinsulinemia" + "chronic disease" OR "age-related disease" the authors analyzed the causes of hyperinsulinemia, the mechanisms of its influence on various aspects of insulin resistance, and the role of hyperinsulinemia in pathogenesis of a wide range of clinical syndromes and age-related diseases. Consideration of the effects that lifestyle factors produce on hyperinsulinemia opens up opportunities for its correction. Results. The major causes of hyperinslinemia are improper diet and nutrition regime (frequent meals and excess of highly glycemic food, too short fasting window), along with other factors causing hyperreactivity of pancreatic beta-cells (fructose, systemic inflammation, oxidative stress, low vitamin D level, etc.). Hyperinsulinemia affects cellular energy balance (primarily, in liver, muscle, brain and adipose tissue); a major factor is suppression of 5'AMP-activated protein kinase (AMPK) along with stimulation of mitogen-activated protein kinase. Insulin resistance is a consequence of AMPK inhibition, an adaptive response designed to preserve cellular homeostasis. Conclusion. Obesity, metabolic syndrome, chronic systemic inflammation, age-related syndromes and diseases (including arterial hypertension, atherosclerosis, neurodegenerative diseases, tumors, osteoarthritis, sarcopenia, etc.) can be considered as clinical manifestations of the body's systemic adaptation to hyperinsulinemia in the form of insulin resistance. Available approach to reduce insulin resistance is correction of lifestyle factors to mitigate hyperinsulinemia and restore AMPK activity. The revealed causal relationships can provide background for personalized strategy of prevention and treatment for age-related diseases through reduction of insulin resistance and correction of energy homeostasis.

Prandial hepatic glucose production during hypoglycemia is altered after gastric bypass surgery and sleeve gastrectomy.

AIMS/HYPOTHESIS: Roux-en Y gastric bypass surgery (GB) and sleeve gastrectomy (SG) alter prandial glucose metabolism, producing lower nadir glucose values and predisposing susceptible individuals to prandial hypoglycemia. The glycemic phenotype of GB or SG is associated with prandial hyperinsulinemia and hyperglucagonemia along with an increased influx of ingested glucose. Following insulin-induced hypoglycemia, glucagon is the most important stimulus for hepatic glucose production (HGP). It is unclear whether prandial hyperglucagonemia after GB or SG changes HGP under hyperinsulinemic hypoglycemia conditions. This study examined the hypothesis that prandial glucose production is reduced after GB and SG during hypoglycemia. METHODS: Glucose kinetics and islet-cell and gut hormone secretion during hyperinsulinemic (120 mU.m-2.min-1) hypoglycemic clamp (~3.2 mM) were measured before and after mixed meal ingestion in 9 non-diabetic subjects with GB, 7 with SG, and 5 matched non-operated controls (CN). RESULTS: Systemic appearance of ingested glucose was faster in GB compared to SG, and in SG compared to CN (p < 0.05). Subjects with GB and SG had greater plasma glucagon levels after eating (AUCGlucagon) compared to CN (p < 0.05). But prandial HGP response during insulin-induced hypoglycemia (AUCHGP) was smaller and shorter in duration in surgical groups (p < 0.05). In the absence of meal stimuli, however, glucose counterregulatory response to hypoglycemia was comparable among the 3 groups during hyperinsulinemic clamp. CONCLUSION: After bariatric surgery, prandial glucose counterregulatory response to hypoglycemia is impaired. Considering post-meal hyperglucagonemia after GB or SG the blunted HGP response suggests a lower sensitivity of liver to glucagon that can predispose to hypoglycemia in this population.

A low n-6 to n-3 polyunsaturated fatty acid ratio diet improves hyperinsulinaemia by restoring insulin clearance in obese youth.

AIM: To examine the determinants and metabolic impact of the reduction in fasting and postload insulin levels after a low n-6 to n-3 polyunsaturated fatty acid (PUFA) ratio diet in obese youth. MATERIALS AND METHODS: Insulin secretion and clearance were assessed by measuring and modelling plasma insulin and C-peptide in 17 obese youth who underwent a nine-point, 180-minute oral glucose tolerance test (OGTT) before and after a 12-week, eucaloric low n-6:n-3 polyunsaturated fatty acid (PUFA) ratio diet. Hepatic fat content was assessed by repeated abdominal magnetic resonance imaging. RESULTS: Insulin clearance at fasting and during the OGTT was significantly increased after the diet, while body weight, glucose levels, absolute and glucose-dependent insulin secretion, and model-derived variables of ß-cell function were not affected. Dietary-induced changes in insulin clearance positively correlated with changes in whole-body insulin sensitivity and ß-cell glucose sensitivity, but not with changes in hepatic fat. Subjects with greater increases in insulin clearance showed a worse metabolic profile at enrolment, characterized by impaired insulin clearance, ß-cell glucose sensitivity, and glucose tolerance, and benefitted the most from the diet, achieving greater improvements in glucose-stimulated hyperinsulinaemia, insulin resistance, and ß-cell function. CONCLUSIONS: We showed that a 12-week low n-6:n-3 PUFA ratio diet improves hyperinsulinaemia by increasing fasting and postload insulin clearance in obese youth, independently of weight loss, glucose concentrations, and insulin secretion.

Effects of hypercaloric diet-induced hyperinsulinemia and hyperlipidemia on the ovarian follicular development in mice.

Long-term hypercaloric diets may adversely affect the development of ovarian follicles. We investigated the effects of high sugar (HS), high fat low sugar (HFLS), and high fat normal sugar (HFNS) diets on the ovarian follicle development in mice fed with these diets as compared to those fed with normal diet (control) for 180 days. Body weight, gonadal fat, glucose, lipid, insulin, estrous cycle, sex hormones and ovarian tissues were examined, and metabolism-related protein expression in the ovaries was evaluated by immunoblotting. The mice fed with hypercaloric diets showed hyperinsulinemia and hyperlipidemia, and exhibited heavier body and gonadal fat weights, longer estrous cycles, and fewer preantral and antral follicles than mice fed with normal diet. The sex hormone levels in the blood were similar to those in controls, except for significantly elevated estradiol levels in the HS diet group. The AMPKα phosphorylation was reduced, while AKT phosphorylation and caspase-3 levels were increased in the ovarian tissues of mice in all three hypercaloric diet groups than those in control. Taken together, the results suggest hyperinsulinemia and hyperlipidemia as possible mechanisms that impair the development of ovarian follicles in response to long-term exposure to unhealthy hypercaloric diets.

The role of maternal diet on offspring hyperinsulinaemia and adiposity after birth: a systematic review of randomised controlled trials.

In utero diet may be directly related to the risk of fetal hyperinsulinaemia and offspring metabolic health. This review examines the relationship between maternal dietary exposures and sub-clinical fetal hyperinsulinaemia and neonatal adiposity. Articles were identified in MEDLINE, Web of Science, Cochrane Controlled Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, SCOPUS, and SPORTDiscus (September 2019-March 2021) using the preferred reporting items for systematic reviews and meta-analyses guidelines. PROSPERO registration ID CRD42020146453. Studies were selected by two independent reviewers. Randomised controlled trials (RCT) involving a dietary intervention with pregnant women (healthy pregnancy, gestational diabetes mellitus and obesity) and reporting fetal cord-blood insulin, c-peptide, glucose or adiposity estimates were included. One author extracted all information on main study characteristics and outcomes. Risk of bias was assessed using the Cochrane Collaboration's bias risk assessment tool. A total of 733 articles were identified. Fourteen articles from 11 RCTs (3614 participants) were included. Studies reviewed showed no specific effect of maternal diet on neonatal cord blood insulin, c-peptide or glucose levels. Infants born to mothers who followed a low glycaemic load (GL) had lower skin fold thickness compared to controls. Interventions that provided individualised nutrition counselling to women with obesity or previous infant born > 4 kg were also associated with lower adiposity. The studies reviewed suggest that lifestyle-based dietary interventions to improve glycaemia (low GL) have a protective effect against excess adiposity. Future studies should incorporate multi-modal interventions with dietary counselling to support lifestyle changes throughout gestation and include assessments of maternal insulin resistance at recruitment.

Chronic cerebral hypoperfusion in male rats results in sustained HPA activation and hyperinsulinemia.

Vascular contributions to cognitive impairment and dementia (VCID) is a spectrum of cognitive deficits caused by cerebrovascular disease, for which insulin resistance is a major risk factor. A major cause of VCID is chronic cerebral hypoperfusion (CCH). Under stress, sustained hypothalamic-pituitary-adrenal axis (HPA) activation can result in insulin resistance. Little is known about the effects of CCH on the HPA axis. We hypothesized that CCH causes sustained HPA activation and insulin resistance. Male rats were subjected to bilateral carotid artery stenosis (BCAS) for 12 wk to induce CCH and VCID. BCAS reduced cerebral blood flow and caused memory impairment. Plasma adrenocorticotropic hormone was increased in the BCAS rats (117.2 ± 9.6 vs. 88.29 ± 9.1 pg/mL, BCAS vs. sham, P = 0.0236), as was corticosterone (220 ± 21 vs. 146 ± 18 ng/g feces, BCAS vs. sham, P = 0.0083). BCAS rats were hypoglycemic (68.1 ± 6.1 vs. 76.5 ± 5.9 mg/dL, BCAS vs. sham, P = 0.0072), with increased fasting insulin (481.6 ± 242.6 vs. 97.94 ± 40.02 pmol/L, BCAS vs. sham, P = 0.0003) indicating that BCAS rats were insulin resistant [homeostasis model assessment of ß-cell function-insulin resistance (HOMA-IR): 11.71 ± 6.47 vs. 2.62 ± 0.93; BCAS vs. control, P = 0.0008]. Glucose tolerance tests revealed that BCAS rats had lower blood glucose areas under the curve (AUCs) than controls (250 ± 12 vs. 326 ± 20 mg/dL/h, BCAS vs. sham, P = 0.0075). These studies indicate that CCH causes sustained activation of the HPA and results in insulin resistance, a condition that is expected to worsen VCID.NEW & NOTEWORTHY Cerebrovascular disease and insulin resistance are two major risk factors for the development of dementia. Here, we demonstrate that chronic cerebral hypoperfusion results in glucocorticoid excess and hyperinsulinemia. This study indicates that chronic cerebral hypoperfusion, glucocorticoid excess, and insulin resistance participate in a detrimental cycle that could exacerbate cerebral vascular disease and dementia.

Visceral adiposity, inflammation, and hippocampal function in obesity.

The 'apple-shaped' anatomical pattern that accompanies visceral adiposity increases risk for multiple chronic diseases, including conditions that impact the brain, such as diabetes and hypertension. However, distinguishing between the consequences of visceral obesity, as opposed to visceral adiposity-associated metabolic and cardiovascular pathologies, presents certain challenges. This review summarizes current literature on relationships between adipose tissue distribution and cognition in preclinical models and highlights unanswered questions surrounding the potential role of tissue- and cell type-specific insulin resistance in these effects. While gaps in knowledge persist related to insulin insensitivity and cognitive impairment in obesity, several recent studies suggest that cells of the neurovascular unit contribute to hippocampal synaptic dysfunction, and this review interprets those findings in the context of progressive metabolic dysfunction in the CNS. Signalling between cerebrovascular endothelial cells, astrocytes, microglia, and neurons has been linked with memory deficits in visceral obesity, and this article describes the cellular changes in each of these populations with respect to their role in amplification or diminution of peripheral signals. The picture emerging from these studies, while incomplete, implicates pro-inflammatory cytokines, insulin resistance, and hyperglycemia in various stages of obesity-induced hippocampal dysfunction. As in the parable of the five blind wanderers holding different parts of an elephant, considerable work remains in order to assemble a model for the underlying mechanisms linking visceral adiposity with age-related cognitive decline.

Case Report: A Difficult-to-Diagnose Case of Hyperinsulinemic Hypoglycemia Surgically Treated After Developing Acute Pancreatitis.

The patient is a 28-year-old Japanese man diagnosed with severe congenital hyperinsulinemic-hypoglycemia six months after birth. Clinical records revealed no imaging evidence of pancreatic tumor at the time of diagnosis. Subsequently, he had developmental disorders and epilepsy caused by recurrent hypoglycemic attacks. The patient's hypoglycemia improved with oral diazoxide. However, he developed necrotizing acute pancreatitis at 28 years of age, thought to be due to diazoxide. Discontinuation of diazoxide caused persistent hypoglycemia, requiring continuous glucose supplementation by tube feeding and total parenteral nutrition. A selective arterial secretagogue injection test revealed diffuse pancreatic hypersecretion of insulin. He underwent subtotal distal (72%) pancreatectomy and splenectomy. There was no intraoperative visible pancreatic tumor. His hypoglycemia improved after the surgical procedure. The histopathological study revealed a high density of islets of Langerhans in the pancreatic body and tail. There were large islets of Langerhans and multiple neuroendocrine cell nests in the whole pancreas. Nests of neuroendocrine cells were also detected in lymph nodes. The pathological diagnosis was grade 1 neuroendocrine tumor (microinsulinomas) with lymph node metastases. This patient is a difficult-to-diagnose case of hyperinsulinemic hypoglycemia surgically treated after developing acute pancreatitis. We believe this is a unique case of microinsulinomas with lymph metastases diagnosed and treated as congenital hyperinsulinemic hypoglycemia for almost 28 years.

Hyperinsulinemic hypoglycemia in adults. Nesidioblastosis case report and review of the literature.

Hypoglycemia due to endogenous hyperinsulinism usually occurs in 2 pathological situations: the most frequent is insulinoma and, secondly, nesidioblastosis or also known as non-insulinoma pancreatic hypoglycemic syndrome. Nesidioblastosis is a rare cause of hyperinsulinic hypoglycemia in adults. We present the clinical case of an adult patient with recurrent hypoglycemia secondary to nesidioblastosis.

La hipoglucemia por hiperinsulinismo endógeno suele presentarse en dos situaciones patológicas: la más frecuente es el insulinoma y, en segundo lugar, la nesidioblastosis o síndrome hipoglucémico pancreático no insulinoma. La nesidioblastosis es una causa poco frecuente de hipoglucemia por hiperinsulinismo en adultos. Presentamos el caso de un paciente adulto con cuadros recurrentes de hipoglucemia secundarios a nesidioblastosis.

Metformin prevents airway hyperreactivity in rats with dietary obesity.

Increased insulin is associated with obesity-related airway hyperreactivity and asthma. We tested whether the use of metformin, an antidiabetic drug used to reduce insulin resistance, can reduce circulating insulin, thereby preventing airway hyperreactivity in rats with dietary obesity. Male and female rats were fed a high- or low-fat diet for 5 wk. Some male rats were simultaneously treated with metformin (100 mg/kg orally). In separate experiments, after 5 wk of a high-fat diet, some rats were switched to a low-fat diet, whereas others continued a high-fat diet for an additional 5 wk. Bronchoconstriction and bradycardia in response to bilateral electrical vagus nerve stimulation or to inhaled methacholine were measured in anesthetized and vagotomized rats. Body weight, body fat, caloric intake, fasting glucose, and insulin were measured. Vagally induced bronchoconstriction was potentiated only in male rats on a high-fat diet. Males gained more body weight, body fat, and had increased levels of fasting insulin compared with females. Metformin prevented development of vagally induced airway hyperreactivity in male rats on high-fat diet, in addition to inhibiting weight gain, fat gain, and increased insulin. In contrast, switching rats to a low-fat diet for 5 wk reduced body weight and body fat, but it did not reverse fasting glucose, fasting insulin, or potentiation of vagally induced airway hyperreactivity. These data suggest that medications that target insulin may be effective treatment for obesity-related asthma.

What Regulates Basal Insulin Secretion and Causes Hyperinsulinemia?

We hypothesize that basal hyperinsulinemia is synergistically mediated by an interplay between increased oxidative stress and excess lipid in the form of reactive oxygen species (ROS) and long-chain acyl-CoA esters (LC-CoA). In addition, ROS production may increase in response to inflammatory cytokines and certain exogenous environmental toxins that mislead ß-cells into perceiving nutrient excess when none exists. Thus, basal hyperinsulinemia is envisioned as an adaptation to sustained real or perceived nutrient excess that only manifests as a disease when the excess demand can no longer be met by an overworked ß-cell. In this article we will present a testable hypothetical mechanism to explain the role of lipids and ROS in basal hyperinsulinemia and how they differ from glucose-stimulated insulin secretion (GSIS). The model centers on redox regulation, via ROS, and S-acylation-mediated trafficking via LC-CoA. These pathways are well established in neural systems but not ß-cells. During GSIS, these signals rise and fall in an oscillatory pattern, together with the other well-established signals derived from glucose metabolism; however, their precise roles have not been defined. We propose that failure to either increase or decrease ROS or LC-CoA appropriately will disturb ß-cell function.

Dietary citrate acutely induces insulin resistance and markers of liver inflammation in mice.

Citrate is widely used as a food additive being part of virtually all processed foods. Although considered inert by most of the regulatory agencies in the world, plasma citrate has been proposed to play immunometabolic functions in multiple tissues through altering a plethora of cellular pathways. Here, we used a short-term alimentary intervention (24 hours) with standard chow supplemented with citrate in amount corresponding to that found in processed foods to evaluate its effects on glucose homeostasis and liver physiology in C57BL/6J mice. Animals supplemented with dietary citrate showed glucose intolerance and insulin resistance as revealed by glucose and insulin tolerance tests. Moreover, animals supplemented with citrate in their food displayed fed and fasted hyperinsulinemia and enhanced insulin secretion during an oral glucose tolerance test. Citrate treatment also amplified glucose-induced insulin secretion in vitro in INS1-E cells. Citrate supplemented animals had increased liver PKCα activity and altered phosphorylation at serine or threonine residues of components of insulin signaling including IRS-1, Akt, GSK-3 and FoxO1. Furthermore, citrate supplementation enhanced the hepatic expression of lipogenic genes suggesting increased de novo lipogenesis, a finding that was reproduced after citrate treatment of hepatic FAO cells. Finally, liver inflammation markers were higher in citrate supplemented animals. Overall, the results demonstrate that dietary citrate supplementation in mice causes hyperinsulinemia and insulin resistance both in vivo and in vitro, and therefore call for a note of caution on the use of citrate as a food additive given its potential role in metabolic dysregulation.

Anti-Müllerian Hormone Accelerates Pathological Process of Insulin Resistance in Polycystic Ovary Syndrome Patients.

Insulin resistance (IR) is one of the most common features of polycystic ovary syndrome (PCOS), which is related to obesity. Whether increased anti-Müllerian hormone (AMH) levels in PCOS are involved in the pathogenesis of insulin resistance remains unclear. We investigated serum levels of leptin and AMH along with basic clinical and metabolic parameters in 114 PCOS patients and 181 non-PCOS women. PCOS patients presented higher fasting blood glucose, insulin concentrations and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in addition to body mass index (BMI), lipids profiles and hormone levels. HOMA-IR showed a positive correlation with BMI, AMH, leptin, and low-density lipoprotein-cholesterol (LDL-c) levels. Interestingly, AMH is strongly positively correlated with HOMA-IR and insulin concentrations for 1st and 2nd hours of glucose treatment after fasting. Among PCOS women with BMI≥25 kg/m2, high AMH level group showed an increased HOMA-IR when compared to normal AMH level. However, among PCOS women with normal BMI, women with high AMH presented an elevated fasting insulin levels but not HOMA-IR when compared to normal AMH group. In vitro treatment of isolated islet cells with high concentration of leptin (200 ng/ml) or high leptin plus high concentration of AMH (1 ng/ml) significantly enhanced insulin secretion. Importantly, co-treatment of AMH plus leptin upregulates the expression of pro-apoptotic proteins, such as Bax, caspase-3, and caspase-8 after incubating with a high level of glucose. These results suggest that AMH may involve in the pathological process of pancreatic ß-cells in obese PCOS women.