Insulin and aging - a disappointing relationship.

Experimental studies in animal models of aging such as nematodes, fruit flies or mice have observed that decreased levels of insulin or insulin signaling promotes longevity. In humans, hyperinsulinemia and concomitant insulin resistance are associated with an elevated risk of age-related diseases suggestive of a shortened healthspan. Age-related disorders include neurodegenerative diseases, hypertension, cardiovascular disease, and type 2 diabetes. High ambient insulin concentrations promote increased lipogenesis and fat storage, heightened protein synthesis and accumulation of non-functional polypeptides due to limited turnover capacity. Moreover, there is impaired autophagy activity, and less endothelial NO synthase activity. These changes are associated with mitochondrial dysfunction and oxidative stress. The cellular stress induced by anabolic activity of insulin initiates an adaptive response aiming at maintaining homeostasis, characterized by activation of the transcription factor Nrf2, of AMP activated kinase, and an unfolded protein response. This protective response is more potent in the long-lived human species than in short-lived models of aging research resulting in a stronger pro-aging impact of insulin in nematodes and fruit flies. In humans, resistance to insulin-induced cell stress decreases with age, because of an increase of insulin and insulin resistance levels but less Nrf2 activation. These detrimental changes might be contained by adopting a lifestyle that promotes low insulin/insulin resistance levels and enhances an adaptive response to cellular stress, as observed with dietary restriction or exercise.

Pathophysiological Characteristics Linking Type 2 Diabetes Mellitus and Colorectal Neoplasia.

A substantial body of literature has provided evidence that type 2 diabetes mellitus (T2DM) and colorectal neoplasia share several common factors. Both diseases are among the leading causes of death worldwide and have an increasing incidence. In addition to usual risk factors such as sedentary lifestyle, obesity, and family history, common pathophysiological mechanisms involved in the development of these diseases have been identified. These include changes in glucose metabolism associated with adipose tissue dysfunction including insulin resistance resulting to hyperinsulinemia and chronic hyperglycemia. In addition to altered glucose metabolism, abdominal obesity has been associated with accented carcinogenesis with chronic subclinical inflammation. An increasing number of studies have recently described the role of the gut microbiota in metabolic diseases including T2DM and the development of colorectal cancer (CRC). Due to the interconnectedness of different pathophysiological processes, it is not entirely clear which factor is crucial in the development of carcinogenesis in patients with T2DM. The aim of this work is to review the current knowledge on the pathophysiological mechanisms of colorectal neoplasia development in individuals with T2DM. Here, we review the potential pathophysiological processes involved in the onset and progression of colorectal neoplasia in patients with T2DM. Uncovering common pathophysiological characteristics is essential for understanding the nature of these diseases and may lead to effective treatment and prevention.

A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity.

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.

Time-restricted feeding normalizes hyperinsulinemia to inhibit breast cancer in obese postmenopausal mouse models.

Accumulating evidence indicates that obesity with its associated metabolic dysregulation, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Caloric restriction can ameliorate the harmful metabolic effects of obesity and inhibit cancer progression but is difficult to implement and maintain outside of the clinic. In this study, we aim to test a time-restricted feeding (TRF) approach on mouse models of obesity-driven postmenopausal breast cancer. We show that TRF abrogates the obesity-enhanced mammary tumor growth in two orthotopic models in the absence of calorie restriction or weight loss. TRF also reduces breast cancer metastasis to the lung. Furthermore, TRF delays tumor initiation in a transgenic model of mammary tumorigenesis prior to the onset of obesity. Notably, TRF increases whole-body insulin sensitivity, reduces hyperinsulinemia, restores diurnal gene expression rhythms in the tumor, and attenuates tumor growth and insulin signaling. Importantly, inhibition of insulin secretion with diazoxide mimics TRF whereas artificial elevation of insulin through insulin pumps implantation reverses the effect of TRF, suggesting that TRF acts through modulating hyperinsulinemia. Our data suggest that TRF is likely to be effective in breast cancer prevention and therapy.

Metformin metabolic and vascular effects in normal weight hyperinsulinemic polycystic ovary syndrome patients treated with contraceptive vaginal ring. A pilot study.

PURPOSE: The aim of this longitudinal, controlled, and retrospective pilot study was to assess how metformin, associated with a contraceptive vaginal ring, may influence lipid and carbohydrate metabolism, and surrogate markers of arterial function in normal weight polycystic ovary syndrome patients. MATERIAL AND METHODS: Among 28 lean patients, 15 were treated with vaginal ring plus metformin and 13 women with only vaginal ring. The effects were assessed after six months. The patients were submitted to evaluation of lipid and carbohydrate metabolism; Doppler analysis of ophthalmic artery; brachial artery flow-mediated vasodilatation; and oral glucose tolerance test. RESULTS: After six months, the fasting insulin, glucose/insulin ratio, and homeostatic model assessment estimates for insulin resistance were significantly improved in metformin group. The ophthalmic artery pulsatility index did not significantly improve in either group. The brachial artery vasodilation was better in metformin treated patients. CONCLUSION: Metformin, associated with vaginal ring, improves the insulin and carbohydrate metabolism. This, associated with the significant improvements of surrogate markers of arterial function, may be responsible of a slight possible cardiovascular and cerebrovascular protective effect.

Obesity and esophageal cancer: GERD, Barrett´s esophagus, and molecular carcinogenic pathways.

INTRODUCTION: Increases in the rates of esophageal adenocarcinoma (EAC) have paralleled rises in the prevalence of overweight and obesity. Despite not being fully understood, obesity-related EAC seems to have different carcinogenic pathways. AREAS COVERED: This comprehensive review will thoroughly evaluate the current literature, describing the underlying mechanisms that help understanding the strong association between obesity and esophageal cancer. EXPERT COMMENTARY: The risk of esophageal cancer among obese individuals could be partially explained by several factors: high prevalence of GERD; linear association between central adiposity and Barrett´s esophagus development; low levels of adiponectin and high levels of leptin that alter cell proliferation processes; insulin-resistant state that creates a tumorigenesis environment; and changes in the esophageal microbiota due to unhealthy dietary habits that promote carcinogenesis. In addition, a large proportion of obese patients are undergoing sleeve gastrectomy which can worsen GERD or cause de novo reflux, esophagitis, and Barrett´s metaplasia.

Reduced Insulin Clearance and Insulin-Degrading Enzyme Activity Contribute to Hyperinsulinemia in African Americans.

BACKGROUND: African Americans (AAs) are at a higher risk for developing type 2 diabetes compared with non-Hispanic whites (NHWs). The causal role of ß-cell glucose sensitivity (ß-GS) and insulin clearance in hyperinsulinemia in AA adults is unclear. OBJECTIVE: Using a cross-sectional study design, we compared ß-cell function and insulin clearance in nondiabetic AAs (n = 36) and NHWs (n = 47) after a mixed meal test (MMT). METHODS: Insulin secretion rate, glucose sensitivity, rate sensitivity, and insulin sensitivity during MMT were derived from a mathematical model. Levels of insulin-degrading enzyme (IDE) and carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1), key players in insulin clearance, were measured (by enzyme-linked immunosorbent assay) in hepatic cytosolic fractions from age-, sex-, and body mass index-matched AA and NHW cadaveric donors (n = 10). RESULTS: Fasting and mean postprandial plasma glucose levels were similar in both ethnic groups. AAs had significantly higher fasting and mean postprandial plasma insulin levels. However, fasting ISR, total insulin output, and insulin sensitivity during MMT were not different between the groups. ß-GS and rate sensitivity were higher in AAs. Fasting and meal plasma insulin clearance were lower in AAs. Hepatic levels of IDE and CEACAM-1 were similar in AAs and NHWs. Hepatic IDE activity was significantly lower in AAs. CONCLUSIONS: In this study, lower insulin clearance contributes to higher plasma insulin levels in AAs. Reduced insulin clearance may be explained by lower IDE activity levels in AAs. Further confirmatory studies are needed to investigate diminished insulin clearance in AAs as a result of lower IDE activity levels.

Increased cancer risk in polycystic ovary syndrome: An (un)sympathetic connection?

Women with polycystic ovary syndrome (PCOS) have been shown to have a higher incidence of cancer. It is suggested that several factors, including hyperinsulinemia, dyslipidemia, raised estrogen levels, chronic inflammation, and reduced apoptosis are responsible for this association. However, in this paper we propose the hypothesis that increased sympathetic activity may represent an important factor that interconnects PCOS and cancer. This hypothesis is based on two facts: a) in women with PCOS is found sympathetic hyperactivity and b) recent data showing a stimulatory effect of the sympathetic system on cancer initiation, progression, and development of metastases. If our hypothesis is correct, then new preventive approaches might be used to reduce cancer risk in women with PCOS.

Impaired Endothelium-Dependent Hyperpolarization Underlies Endothelial Dysfunction during Early Metabolic Challenge: Increased ROS Generation and Possible Interference with NO Function.

Endothelial dysfunction is a hallmark of diabetic vasculopathies. Although hyperglycemia is believed to be the culprit causing endothelial damage, the mechanism underlying early endothelial insult in prediabetes remains obscure. We used a nonobese high-calorie (HC)-fed rat model with hyperinsulinemia, hypercholesterolemia, and delayed development of hyperglycemia to unravel this mechanism. Compared with aortic rings from control rats, HC-fed rat rings displayed attenuated acetylcholine-mediated relaxation. While sensitive to nitric oxide synthase (NOS) inhibition, aortic relaxation in HC-rat tissues was not affected by blocking the inward-rectifier potassium (Kir) channels using BaCl2 Although Kir channel expression was reduced in HC-rat aorta, Kir expression, endothelium-dependent relaxation, and the BaCl2-sensitive component improved in HC rats treated with atorvastatin to reduce serum cholesterol. Remarkably, HC tissues demonstrated increased reactive species (ROS) in smooth muscle cells, which was reversed in rats receiving atorvastatin. In vitro ROS reduction, with superoxide dismutase, improved endothelium-dependent relaxation in HC-rat tissues. Significantly, connexin-43 expression increased in HC aortic tissues, possibly allowing ROS movement into the endothelium and reduction of eNOS activity. In this context, gap junction blockade with 18-ß-glycyrrhetinic acid reduced vascular tone in HC rat tissues but not in controls. This reduction was sensitive to NOS inhibition and SOD treatment, possibly as an outcome of reduced ROS influence, and emerged in BaCl2-treated control tissues. In conclusion, our results suggest that early metabolic challenge leads to reduced Kir-mediated endothelium-dependent hyperpolarization, increased vascular ROS potentially impairing NO synthesis and highlight these channels as a possible target for early intervention with vascular dysfunction in metabolic disease. SIGNIFICANCE STATEMENT: The present study examines early endothelial dysfunction in metabolic disease. Our results suggest that reduced inward-rectifier potassium channel function underlies a defective endothelium-mediated relaxation possibly through alteration of nitric oxide synthase activity. This study provides a possible mechanism for the augmentation of relatively small changes in one endothelium-mediated relaxation pathway to affect overall endothelial response and highlights the potential role of inward-rectifier potassium channel function as a therapeutic target to treat vascular dysfunction early in the course of metabolic disease.

Hyperinsulinemia restrains endometrial angiogenesis during decidualization in early pregnancy.

Previous research on the role of insulin has focused on metabolism. This study investigated the effect of insulin on angiogenesis in endometrial decidualization. High insulin-treated mouse model was constructed by subcutaneous injection of insulin. Venous blood glucose, serum insulin, P4, E2, FSH and LH levels in the pregnant mice were detected by ELISA. Decidual markers, angiogenesis factors and decidual vascular network were detected during decidualization in the pregnant mouse model and an artificially induced decidualization mouse model. Tube formation ability and angiogenesis factors expression were also detected in high insulin-treated HUVECS cells. To confirm whether autophagy participates in hyperinsulinemia-impaired decidual angiogenesis, autophagy was detected in vivo and in vitro. During decidualization, in the condition of high insulin, serum insulin and blood glucose were significantly higher, while ovarian steroid hormones were also disordered (P < 0.05), decidual markers BMP2 and PRL were significantly lower (P < 0.05). Uterine CD34 staining showed that the size of the vascular sinus was significantly smaller than that in control. Endometrial VEGFA was significantly decreased after treatment with high insulin in vivo and in vitro (P < 0.05), whereas ANG-1 and TIE2 expression was significantly increased (P < 0.05). In addition, aberrant expression of autophagy markers revealed that autophagy participates in endometrial angiogenesis during decidualization (P < 0.05). After treatment with the autophagy inhibitor 3-MA in HUVEC, the originally damaged cell tube formation ability and VEGFA expression were repaired. This study suggests that endometrial angiogenesis during decidualization was impaired by hyperinsulinemia in early pregnant mice.

Intersections and Clinical Translations of Diabetes Mellitus with Cancer Promotion, Progression and Prognosis.

The association between cancer and dysglycemia has been well documented. It is underappreciated, however, that sustained dysglycemia could potentially be a catalyst toward a pro-cancer physiologic milieu and/or increase the burden of cancer. Hyperglycemia, hyperinsulinemia and energy metabolism at large impact a cascade of growth pathways, epi/genetic modifications, and mitochondrial changes that could feasibly link to tumor processes. Oxidative stress is a recurring motif in cell dysfunction: in diabetes, oxidative stress and reactive oxygen species (ROS) feature prominently in the damage and demise of pancreatic beta cells, as well as cell damage contributing to diabetes-related complications. Oxidative stress may be one intersection at which metabolic and oncogenic processes cross paths with deleterious results in the development of precancer, cancer, and cancer progression. This would augur for tight glucose control. Regrettably, some medical societies have recently relaxed hemoglobin A1c targets. A framework for the hyperglycemic state is presented that helps account and translate the full scope of effects of dysglycemia to ultimately improve clinical best practices.

Effect of hyperinsulinaemia and insulin resistance on endocrine, metabolic and fertility outcomes in women with polycystic ovary syndrome undergoing ovulation induction.

OBJECTIVE: The aim of this study was to evaluate the effects of hyperinsulinaemia and insulin resistance (IR) on reproductive and metabolic disorders and fertility in women with polycystic ovary syndrome (PCOS). DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: This was a multicenter, randomized controlled trial involving a total of 1000 women diagnosed with PCOS according to the modified Rotterdam criteria at 21 sites (27 hospitals). We evaluated the effects of serum insulin levels and HOMA-IR on parameters and outcomes. The main outcome measures were anthropometric, biometric and ultrasound parameters at baseline and the clinical outcomes of ovulation, conception, pregnancy, live birth and pregnancy loss. RESULTS: The relevant analysis between hyperinsulinaemia and IR and clinical characteristics showed that weight, waist and hip circumference, BMI, waist-to-hip ratio, acanthosis nigricans score and menstrual period were significantly correlated with fasting insulin (FIN) and HOMA-IR. There was no significant correlation between the hirsutism score or acne score with FIN or HOMA-IR. The relevant analysis between hyperinsulinaemia and IR and circulating sex steroids and gonadotrophins showed that FAI was significantly correlated with FIN and HOMA-IR (r = 0.240, P < 0.001 and r = 0.191, P < 0.001, respectively). Free testosterone was significantly correlated with FIN after adjusting for the influence of age. LH and LH/FSH were not related to FIN or HOMA-IR after statistical correction for differences in BMI. The relevant analysis between hyperinsulinaemia and IR and metabolic profile showed that FIN and HOMA-IR were positively associated with fasting glucose, cholesterol, triglycerides, low-density lipoprotein, Apo B, and the incidence of metabolic syndrome and were negatively associated with high-density lipoprotein. The predictive analysis between hyperinsulinaemia and IR with fertility showed that the levels of FIN and HOMA-IR were related to the fertility outcome (ovulation, pregnancy, conception or live birth) in patients with PCOS. After adjustments for age, total testosterone and free testosterone, increasing serum insulin levels and HOMA-IR were significantly associated with decreased cycle ovulation, conception, pregnancy and live birth rates. CONCLUSIONS: Hyperinsulinaemia and IR are associated with reproductive and metabolic disorders and can predict the fertility outcomes in PCOS patients.

Metformin metabolic and vascular effects in overweight/moderately obese hyperinsulinemic PCOS patients treated with contraceptive vaginal ring: a pilot study.

The aim of this pilot study was to assess how metformin, associated with a contraceptive vaginal ring, may influence lipid and carbohydrate metabolism, fat distribution, and surrogate markers of arterial function. Among 62 patients, 25 were treated with vaginal ring plus metformin and 37 women with only vaginal ring. The effects were assessed after 6 months. The patients were submitted to evaluation of lipid and carbohydrate metabolism; extended view ultrasonographic evaluation of fat distribution; Doppler analysis of ophthalmic artery; brachial artery flow-mediated vasodilatation; oral glucose tolerance test. After 6 months, the body mass index and waist/hip ratio resulted significantly better in patients who associated metformin to vaginal ring. The fasting glucose, insulin, and glucose/insulin ratio, HOMA-IR, glucose, and insulin AUC 120 were significantly improved in metformin group. The ultrasonographic fat analysis resulted significantly better after metformin. The ophthalmic artery PI significantly improved in metformin group. The brachial artery vasodilation was better in metformin treated patients. In conclusion, metformin, associated with vaginal ring, improves the insulin and carbohydrate metabolism, reduces the body weight and android fat distribution. This, associated with the significant improvements of surrogate markers of arterial function, may be responsible of possible cardiovascular and cerebrovascular protective effects.

Is testing for postprandial hyperinsulinemic hypoglycemia after gastric bypass necessary?

INTRODUCTION: Postprandial hyperinsulinemic hypoglycemia (pHH) is an increasingly reported complication after Roux-en-Y gastric bypass (RYGB). As pHH can cause life-threatening emergencies if occurring without warning symptoms, challenge testing may detect patients at risk. The study objective was to determine the frequency of occurrence of pHH with or without symptoms of hypoglycemia after RYGB. METHODS: We undertook an observational cohort study of consecutive, unselected patients approximately one year after uncomplicated RYGB. To simulate normal habits, all patients received a standardized carbohydrate-rich solid mixed meal. Plasma glucose and insulin were measured at 30, 60, 90, 120, and 150 min thereafter. Symptoms were classified as autonomous or neuroglycopenic. Patients with hypoglycemia (plasma glucose <3.0 mmol/L [55 mg/dL]), were tested a second time with a protein-rich solid mixed meal. RESULTS: 113 patients were included. Total weight loss at the first follow-up check (14 ± 0.4 months) was 33.97 ± 9.3%. After the carbohydrate-rich meal, glucose dropped to <3.0 mmol/L in 13.2% (n = 15) of patients vs no drop to <3.0 mmol/L after a protein-rich meal. The pHH occurred in 11.5% (n = 13) of patients. Asymptomatic patients (5.3%, n = 6) carried an increased risk (p = 0.008) for pHH. One patient needed emergency treatment after sudden loss of consciousness after the carbohydrate-rich meal. CONCLUSIONS: The occurrence of pHH was quite high in our study population with 11.5% thereof 5.3% asymptomatic. We therefore suggest that detection of these patients warrants a screening of patients after RYGB. At-risk patients should than be adequately advised to avoid carbohydrate-rich meals in order to optimize risk management.

Anti-diabetic effect of S-adenosylmethionine and α-glycerophosphocholine in KK-Ay mice.

Six-week-old male KK-Ay mice received drinking water with S-adenosylmethionine (SAM), α-glycerophosphocholine (GPC), or SAM+GPC for 10 weeks. The serum glucose of SAM+GPC at 15 weeks old, total cholesterol of GPC at 12 weeks old, and triglyceride of GPC at 15 weeks old and of SAM at 16 weeks old were reduced. SAM+GPC reduced serum leptin and food intake. Abbreviations: SAM: S-adenosylmethionine; GPC: α-glycerophosphocholine.

Insulin and incretin responses to grazing in insulin-dysregulated and healthy ponies.

BACKGROUND: Supraphysiological insulin and incretin responses to a cereal-based diet have been described in horses and ponies with insulin dysregulation (ID). However, the hormonal responses to grazing have not yet been described. OBJECTIVES: To determine if there is a difference in the insulin and incretin responses to grazing pasture between insulin-dysregulated and healthy ponies. ANIMALS: A cohort of 16 ponies comprising 5 with normal insulin regulation (NIR), 6 with moderate ID (MID), and 5 with severe ID (SID). METHODS: In this case-control study, an oral glucose test (OGT) was used to determine the insulin responsiveness of each pony to PO carbohydrate before grazing pasture (4 hours) for 3 consecutive days. Serial blood samples collected during grazing were analyzed for glucose, insulin, glucose-dependent insulinotropic peptide (GIP) and active glucagon-like peptide-1 (aGLP-1), and compared among pony groups and day of pasture access. RESULTS: The area under the insulin curve when grazing increased with ID severity (P < .03). The median (range) maximal insulin concentration was greater in the MID (72.5 [129] µIU/mL) and SID (255 [338.5] µIU/mL) groups, compared to the NIR (11.7 [24.9] µIU/mL) group (P < .03) and occurred within 2-4 hours of grazing. Postprandial OGT insulin concentration was positively correlated with 2 hours post-grazing insulin across all 3 grazing days (P ≤ .03). The aGLP-1 and GIP concentrations increased in response to grazing but did not differ among groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Grazing pasture provoked an increased insulin and incretin response in insulin-dysregulated ponies within 4 hours of grazing. The pasture and OGT insulin concentrations were correlated.

Polycystic ovary syndrome (PCOS) and the accompanying disorders of glucose homeostasis among girls at the time of puberty.

Polycystic ovary syndrome (PCOS) usually arises during puberty and is marked by insulin resistance, hyperinsulinemia, and hyperandrogenism. The principle is that the diagnosis of PCOS must be based on the presence of at least two of the following three criteria: chronic anovulation, hyperandrogenism (clinical or biological), and polycystic ovaries. The diagnosis of PCOS in adolescents is particularly difficult due to developmental problems in this group. Many symptoms of PCOS, including acne, menstrual irregularities, and hyperinsulinemia, are common in normal puberty. Adolescents with PCOS are at an increased risk of developing health problems later on in life, such as diabetes, cardiovascular disease, and infertility. One should reckon with the frequent occurrence of the PCOS in type 1 diabetes, when the ovaries and the adrenals are exposed to excessive insulin concentrations. Ovarian hyperandrogenism is common in adolescent girls with type 1 diabetes. Methods of treatment for an adolescent with PCOS include diet and exercise. Metformin is commonly used in young girls and adolescents with PCOS as first-line monotherapy or in combination with anti-androgen medications.

T2DM inhibition of endothelial miR-342-3p facilitates angiogenic dysfunction via repression of FGF11 signaling.

Understanding the function and molecular relevance of distinct miRNAs in endothelial cells (ECs) paves avenues for possible therapeutic intervention by targeting epigenetic mechanisms in vascular endothelial dysfunction, one of the major complications of type 2 diabetes mellitus (T2DM). MiR-342-3p, an obesity-associated miRNA, has recently been shown to be significantly upregulated in human angiosarcoma compared to benign hemangioma, indicating its potential involvement as a proangiogenic factor. Herein, we show that endothelial miR-342-3p expression was significantly compromised in T2DM organisms and this inhibition powerfully blocked vasculogenesis in vivo by repressing endothelial proliferation and migration. From a mechanistic standpoint, miR-342-3p promoted the transactivation of fibroblast growth factor 11 (FGF11) by directly targeting its 3' untranslated regions (3'UTRs). Functionally, overexpression of exogenous FGF11 successfully rescued miR-342-3p deficiency-impaired endothelial proliferation and migration. Thus, perturbation of miR-342-3p/FGF11 cascade by hyperinsulinemia plays a causative role in the induction of vascular dysfunction in T2DM. Overall, the current study underscore an endothelial facet of miR-342-3p, which may operate as a novel epigenetic integrator linking adipogenic homeostasis and angiogenesis.

Effect of infliximab and tocilizumab on fructose-induced hyperinsulinemia and hypertension in rats.

Fructose administration can induce hypertension, insulin resistance and hypertriglyceridemia. Here, we investigated the possible protective effect of infliximab (IFX), a tumor necrosis factor alpha (TNF-α) inhibitor, or tocilizumab (TOC), an interleukin-6 (IL6) inhibitor, on fructose-induced increase in blood pressure, insulin resistance and hyperlipidemia in rats. The animals were fed a 60% fructose diet in the absence or presence of IFX (5 mg/kg, i.p., once weekly) or TOC (8 mg/kg, i.p., once every two weeks). Fructose significantly increased blood pressure, heart rate and homeostatic model assessment of insulin resistance (HOMA-IR). Fructose also significantly raised the concentrations of fasting plasma insulin, triglycerides, total cholesterol, uric acid, tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), malondialdhyde (MDA) and nitric oxide. Fructose also significantly decreased plasma superoxide dismutase (SOD) and catalase activities. In addition, fructose significantly increased aortic endothelin and nitric oxide concentrations. Both IFX and TOC attenuated the fructose-induced increase in blood pressure, insulin resistance, and the concentrations of uric acid, MDA and IL-6. TOC significantly reduced fructose-induced increase in triglycerides and cholesterol. In addition, IFX increased plasma SOD and catalase activities. Our results showed that both IFX and TOC were partially successful in reversing fructose - induced changes.