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Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder affecting people worldwide. It is characterized by several key features, including hyperinsulinemia, hyperglycemia, hyperlipidemia, and dysbiosis. Epidemiologic studies have shown that T2DM is closely associated with the development and progression of cancer. T2DM-related hyperinsulinemia, hyperglycemia, and hyperlipidemia contribute to cancer progression through complex signaling pathways. These factors increase drug resistance, apoptosis resistance, and the migration, invasion, and proliferation of cancer cells. Here, we will focus on the role of hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with T2DM in cancer development. Additionally, we will elucidate the potential molecular mechanisms underlying their effects on cancer progression. We aim to identify potential therapeutic targets for T2DM-related malignancies and explore relevant directions for future investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Li, Xue, Li, Gao and Qin.)

Types of fats and oils affect the onset of lifestyle diseases. In this study, we investigated the relationship between the postprandial hyperglycemia and fatty acids content in the skeletal muscle of C57BL/6 mice given 20% lard, palm oil, corn oil, safflower oil, and flaxseed oil for 16 weeks. Lard increased plasma glucose and insulin levels at the end of feeding period, whereas flaxseed oil did not. It was noteworthy that there is a positive correlation between palmitic acid content in the muscle and postprandial hyperglycemia, and a negative correlation between α-linolenic acid content and hyperglycemia. Alternatively, mice were given 30% lard for 16 weeks. When lard was partially substituted with flaxseed oil (10-50% substitution), flaxseed oil dose-dependently prevented lard-induced hyperglycemia and hyperinsulinemia. In conclusion, flaxseed oil prevents the adverse effects of lard through increasing in α-linolenic acid content in the muscle., Competing Interests: No potential conflicts of interest were disclosed., (Copyright © 2024 JCBN.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

In this complex realm of diabetes, hyperinsulinemia is no longer regarded as just a compensatory response to insulin resistance but rather has evolved into an integral feature. This comprehensive review provides a synthesis of the current literature, including various aspects associated with hyperinsulinemia in diabetic complications. Hyperinsulinemia has been shown to be more than just a compensatory mechanism, and the key findings demonstrate how hyperinsulinism affects the development of cardiovascular events as well as microvascular complications. Additionally, recognizing hyperinsulinemia as a modifiable factor, the diabetes management paradigm shifts towards cognitive ones that consider the use of lifestyle modifications in combination with newer pharmacotherapies and precision medicine approaches. These findings have crucial implications for the clinical work, requiring a careful appreciation of hyperinsulinemia's changing aspects as well as incorporation in personalized treatment protocol. In addition, the review focuses on bigger issues related to public health, showing that prevention and early diagnosis will help reduce the burden of complications. Research implications favor longitudinal studies, biomarker discovery, and the study of emerging treatment modalities; clinical practice should adopt global evaluations, patient education, and precision medicine adaptation. Finally, this critical review provides an overview of the underlying processes of hyperinsulinemia in diabetes and its overall health effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To evaluate the effect of hyperinsulinemia (HI) and insulin resistance (IR) on endocrine, metabolic, and reproductive outcomes in women without polycystic ovary syndrome (PCOS) undergoing assisted reproduction.Materials and Methods: The study included 1,104 non-PCOS women undergoing in vitro fertilization/intracytoplasmic sperm injection-fresh embryo transfer. HI was evaluated by serum fasting insulin (FIN), and IR was evaluated by homeostatic model assessment of insulin resistance index (HOMA-IR). In addition, biometric, sex hormone, and metabolic parameters were measured. Independent t-test, linear, and logistic regression examined associations between HI, IR, and endocrine, metabolic, ovarian stimulation characteristics, and reproductive outcomes.Results: Women with HI and IR had lower levels of progesterone, luteinizing hormone, follicle-stimulating hormone, estradiol, high-density lipoproteins, and increased levels of triglycerides low-density lipoproteins. For ovarian stimulation characteristics, those with HI and IR had a longer duration of stimulation, a higher total gonadotropin dose, and a lower peak estradiol level. Linear regression confirmed these associations. For reproductive outcomes, HI and IR were not associated with clinical pregnancy, live birth, and miscarriage.Conclusions: HI and IR did not impair reproductive outcomes in non-PCOS women undergoing assisted reproduction.

Background: There is no study regarding developing a valid index to predict insulin-related disorders in the Iranian population based on their dietary habits and lifestyle. In the current study, we aimed to develop and validate insulinemic potential indices of diet and lifestyle in Iranian adults. Methods: In this cross-sectional study, we analysed data of 1063 men and women aged ≥ 25 years among participants of the examination three of Tehran lipid and glucose study (TLGS) (2006–2008). Dietary intakes were assessed using a valid semi-quantitative food frequency questionnaire. Dietary and lifestyle indices were developed using stepwise linear regression analysis based on dietary intakes, body mass index, and physical activity data. Fasting serum insulin concentration and homeostatic model assessment for insulin resistance (HOMA-IR) were used as biomarkers of hyperinsulinemia (HI) and insulin resistance (IR). Validation analyses were performed in examination four of TLGS. Results: We developed four indices related to insulin homeostasis, including the dietary index for HI (DIH), the dietary index for IR (DIR), the lifestyle index for HI (LIH), and the lifestyle index for IR (LIR). Based on multivariable-adjusted models, the relative values of the biomarker in subjects in the highest quartile of indices were 45% for LIH (95% CI 1.36–1.55, Ptrend < 0.001), 28% for DIR (95% CI 1.13–1.42, Ptrend = 0.019), and 51% for LIR (95% CI 1.41–1.61, Ptrend < 0.001), higher than those in the reference quartile, respectively. Conclusion: We designed and validated indices to determine the insulin potential of diet and lifestyle for the Iranian population, according to Iran's demographic and dietary intake characteristics. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a disease whose diagnosis is based on the detection of hyperandrogenism (HA) and ovulatory dysfunction. Women with PCOS frequently develop insulin resistance (IR), which generates a metabolic condition that involves a decrease in the action of insulin at the cellular level and is linked to compensatory hyperinsulinemia (HI). In PCOS, the ovary remains sensitive to the action of insulin. Additionally, it has been observed that the main effect of insulin in the ovary is the stimulation of androgen synthesis, resulting in HA, one of the fundamental characteristics of the PCOS. In this sense, the excess of androgens favors the development of IR, thus perpetuating the cycle of IR-HI-HA, and therefore PCOS. Moreover, mitochondrial dysfunction is present in PCOS patients and is a common feature in both IR and HA. This review places electron transfer as a key element in HA and IR development, with emphasis on the relationship between androgen biosynthesis and mitochondrial function. Indeed, metformin has been involved in repair mitochondrial dysfunction, decrease of oxidative stress, reduction of androgens levels and the enhancing of insulin sensitivity. Therefore, we propose that treatment with metformin could decrease HI and consequently HA, restoring, at least in part, the metabolic and hormonal disorders of PCOS. [ABSTRACT FROM AUTHOR]

Hyperinsulinemia is commonly viewed as a compensatory response to insulin resistance, yet studies have demonstrated that chronically elevated insulin may also drive insulin resistance. The molecular mechanisms underpinning this potentially cyclic process remain poorly defined, especially on a transcriptome‐wide level. Transcriptomic meta‐analysis in >450 human samples demonstrated that fasting insulin reliably and negatively correlated with INSR mRNA in skeletal muscle. To establish causality and study the direct effects of prolonged exposure to excess insulin in muscle cells, we incubated C2C12 myotubes with elevated insulin for 16 h, followed by 6 h of serum starvation, and established that acute AKT and ERK signaling were attenuated in this model of in vitro hyperinsulinemia. Global RNA‐sequencing of cells both before and after nutrient withdrawal highlighted genes in the insulin receptor (INSR) signaling, FOXO signaling, and glucose metabolism pathways indicative of ‘hyperinsulinemia’ and ‘starvation’ programs. Consistently, we observed that hyperinsulinemia led to a substantial reduction in Insr gene expression, and subsequently a reduced surface INSR and total INSR protein, both in vitro and in vivo. Bioinformatic modeling combined with RNAi identified SIN3A as a negative regulator of Insr mRNA (and JUND, MAX, and MXI as positive regulators of Irs2 mRNA). Together, our analysis identifies mechanisms which may explain the cyclic processes underlying hyperinsulinemia‐induced insulin resistance in muscle, a process directly relevant to the etiology and disease progression of type 2 diabetes. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) expressed in the hypothalamus are capable of regulating energy balance and peripheral metabolism by inhibiting translation of target messenger RNAs (mRNAs). Hypothalamic insulin resistance is known to precede that in the periphery, thus a critical unanswered question is whether central insulin resistance creates a specific hypothalamic miRNA signature that can be identified and targeted. Here we show that miR-1983, a unique miRNA, is upregulated in vitro in 2 insulin-resistant immortalized hypothalamic neuronal neuropeptide Y-expressing models, and in vivo in hyperinsulinemic mice, with a concomitant decrease of insulin receptor β subunit protein, a target of miR-1983. Importantly, we demonstrate that miR-1983 is detectable in human blood serum and that its levels significantly correlate with blood insulin and the homeostatic model assessment of insulin resistance. Levels of miR-1983 are normalized with metformin exposure in mouse hypothalamic neuronal cell culture. Our findings provide evidence for miR-1983 as a unique biomarker of cellular insulin resistance, and a potential therapeutic target for prevention of human metabolic disease. [ABSTRACT FROM AUTHOR]

Aluminum phosphide (AlP) is commonly used as a powerful suicidal tool. The exact mechanism of acute toxicity has not been well defined despite high mortality rates as well as its supportive treatment including rapid decontamination and institution of resuscitative measures. The current study aimed to investigate a new combination therapy using trimetazidine, N‐acetyl cysteine, vitamin C, and hyperinsulinemia–euglycemia to manage acute AlP poisoning. Acute AlP‐induced cardiotoxicity, hemodynamic changes, and hepatotoxicity were evaluated using electrocardiogram, creatinine kinase MB iso‐enzyme, troponin‐1, blood pressure, random blood glucose level, liver function tests, and histopathological changes in both the heart and liver in a rabbit model of AlP poisoning. The results showed that the new regimen therapy ameliorates the toxic effect of AlP with significant improvement in survival, cardiovascular and hemodynamic parameters in addition to histopathological changes. These results highlight the strong cardioprotective, antioxidant, hepatoprotective effects of the new combined therapy along with correction of hemodynamic changes and hyperglycemia as a potential target in the management of acute AlP poisoning. [ABSTRACT FROM AUTHOR]

Intoxication from calcium channel blockers exhibits almost 50% mortality rates. Amlodipine is a long-acting dihydropyridine and inappropriate dosage poses a great threat for profound vasodilation, hypotension, and refractory vasopressor-resistant shock. A 72-year-old woman with unremarkable medical history presented to the emergency department due to amlodipine overdose after a suicide attempt attributed to COVID-19 pandemic severe anxiety disorder. Vital signs at presentation: heart rate 82 beats/ min, arterial pressure 72/55 mmHg, and oxygen saturation 98%. Resuscitation was initiated with intravenous infusion of normal saline 0,9%, noradrenaline, and calcium chloride, while activated charcoal was orally administrated; however, blood pressure remained at 70/45 mmHg. Abruptly, she experienced acute pulmonary edema and was finally intubated. We commenced high-dose insulin infusion with Dextrose 10% infusion to maintain euglycemic hyperinsulinemia. Hemodynamic improvement occurred after 30 min, systolic blood pressure raised to 95 mmHg, and decongestion was achieved with intravenous furosemide. Insulin effect was dose-dependent and patient's hemodynamic status improved after insulin uptitration. Eight days later, the patient was weaned from the mechanical ventilation and she was successfully discharged after 14 days. High-dose intravenous infusion of insulin up to 10 units/kg per hour appears as an inotropic agent possibly through alterations in myocardial metabolism of fatty acids and augmentation of insulin secretion and uptake. This regimen possibly exhibits additional vasotropic properties. We conclude that euglycemic hyperinsulinemia is a potentially advantageous treatment in CCB toxicity. [ABSTRACT FROM AUTHOR]

Calcium‐channel blockers (CCBs) are widely used in people and animals. Overdose can result in cardiovascular collapse and death. Hyperinsulinemia/euglycemia therapy (HIET) and intralipid therapy (ILT) are reported treatment options in people. This is the first report describing HIET and ILT as treatments for amlodipine toxicosis in a cat. [ABSTRACT FROM AUTHOR]

Preadipocyte factor-1 (Pref-1) is made as a transmembrane protein containing EGF-repeats at the extracellular domain that can be cleaved to generate a biologically active soluble form. Pref-1 is found in islet β-cells and its level has been reported to increase in neonatal rat islets upon growth hormone treatment. We found here that Pref-1 can promote growth of pancreatic tumor derived AR42J cells. To examine Pref-1 function in pancreatic islets in vivo, we generated transgenic mouse lines overexpressing the Pref-1/hFc in islet β-cells using rat insulin II promoter (RIP). These transgenic mice exhibit an increase in islet mass with higher proportion of larger islets in pancreas compared to wild-type littermates. This is in contrast to pancreas from Pref-1 null mice that show higher proportion of smaller islets. Insulin expression and insulin secretion from pancreatic islets from RIP-Pref-1/hFc transgenic mice are increased also. Thus, RIP-Pref-1/hFc transgenic mice show normal glucose levels but with higher plasma insulin levels in both fasting and fed conditions. These mice show improved glucose tolerance. Taken together, we conclude Pref-1 as a positive regulator of islet β-cells and insulin production.

Abstract Calcium‐channel blockers (CCBs) are widely used in people and animals. Overdose can result in cardiovascular collapse and death. Hyperinsulinemia/euglycemia therapy (HIET) and intralipid therapy (ILT) are reported treatment options in people. This is the first report describing HIET and ILT as treatments for amlodipine toxicosis in a cat.

Type 2 Diabetes Mellitus (T2DM) is characterized by chronically elevated blood glucose (hyperglycemia) and elevated blood insulin (hyperinsulinemia). When the blood glucose concentration is 100 milligrams/deciliter the bloodstream of an average adult contains about 5–10 grams of glucose. Carbohydrate-restricted diets have been used effectively to treat obesity and T2DM for over 100 years, and their effectiveness may simply be due to lowering the dietary contribution to glucose and insulin levels, which then leads to improvements in hyperglycemia and hyperinsulinemia. Treatments for T2DM that lead to improvements in glycemic control and reductions in blood insulin levels are sensible based on this pathophysiologic perspective. In this article, a pathophysiological argument for using carbohydrate restriction to treat T2DM will be made.

Background: Long-term administration of dexamethasone induces adverse effects such as muscle catabolism, hyperplasia, increased adiposity, and insulin resistance (IR). In view of these data, many authors tried to induce IR with different individual dose ranges with a varied induction periods. In this study, dexamethasone was used to find the dose to induce maximum insulin resistance in rodents. Materials and methods: A sum of 42 healthy male Wistar albino rats were categorized into six groups of dexamethasone treatment and one control group (n=6/group). In a 6-day study period, all treatment groups received respective graded doses of dexamethasone starting from low - (0.5 mg/kg and 1 mg/kg), intermediate - (2 mg/kg and 4 mg/kg) and high-dose (8 mg/kg and 16 mg/kg). Results: Graded doses of dexamethasone treatment for 6 days produced hyperglycemia and hyperinsulinemia in a dose-dependent manner and the maximum effect was noted with high doses of dexamethasone compared to intermediate and low (p<0.05). The profound reduction in insulin sensitivity was caused by high-doses of dexamethasone treatment evidenced by sustained elevation of homeostatic model assessment of insulin resistance (HOMA-IR) which was strongly associated with a declined homeostatic model assessment of insulin sensitivity (HOMA-IS), The peripheral sensitivity indices, Gutt and Matsuda, were markedly elevated in high dexamethasone groups compared to intermediate- and low-dose groups (p<0.05). Serum lipids and creatinine (p<0.05), whereas high-density lipoprotein cholesterol (HDL-CH) was markedly reduced and resulted in the subsequent rise in the atherogenic index (AGI) (p<0.05). Moderate to severe glycosuria and ketonuria were noted in intermediate- and high-dose treatment groups only. However, there is no significant difference in metabolic effects between 8 mg/kg and 16 mg/kg treatments (p>0.05). Conclusion: Administration of 8 mg/kg dexamethasone for 6 days would be sufficient for the induction of maximum insulin resistance in Wistar albino rats. [ABSTRACT FROM AUTHOR]

Hyperinsulinemia increases the risk factor of diabetes and infertility at a manifold. Lactobacillus plantarum has several medical significances with limited reports. Hence, this study assessed the effect of L. plantarum on sexual-reproductive functions and distribution of insulin receptors in the hypothalamic-pituitary-testicular axis of hyperinsulinemic mice. Forty male adult mice were divided into five groups as follows: control, high-fat diet (HFD) + streptozotocin (STZ), therapeutic, co-administration group type 1 (CO-AD) and probiotics. They were either simultaneously exposed to an HFD and L. plantarum treatment for 28 days with a dose of STZ injection to induce hyperinsulinemia on day 28 or treated with L. plantarum for 14 days, and following induction of hyperinsulinemia. Mice were subjected to a sexual behavioural test and thereafter sacrificed under euthanasia condition. Blood, brain and testes were collected for biochemical and immunohistochemical assays. Treatment with L. plantarum ameliorated reproductive hormones activity disruption, sexual behavioural defects, antioxidant imbalance, insulin dysregulation and lipid metabolism dysfunction following exposure to HFD + STZ when compared to the hyperinsulinemic untreated mice. Taken together, data from this study reveal that L. plantarum abrogated hyperinsulinemia-induced male sexual and reproductive deficits by modulating antioxidant status, lipid metabolism and insulin signalling in the hypothalamic-pituitary-testicular axis of mice. [ABSTRACT FROM AUTHOR]

Immunoglobulin A (IgA) is a major antibody in the gut. We previously observed that a high-fat diet (HFD) reduces IgA reactivity to gut microbiota, but the physiological implications have yet to be elucidated. We hypothesized that a reduction of IgA reactivity to gut microbiota induced by a HFD may contribute to development of gut dysbiosis and inflammation that accompanies HFD feeding. To test our hypothesis, we used Aicda deficient mice, which have a deficiency in IgA production. Aicda deficient mice and wild-type mice were fed normal-fat diet or HFD for 12 weeks. We found that HFD feeding but not Aicda deficiency altered the fecal microbiota composition. Meanwhile, Aicda deficiency significantly increased gene expression of inflammatory cytokines in the ileum, but not in the colon despite no significant difference between diets. These results suggest that a reduction of IgA reactivity to gut microbiota induced by HFD partly contributes to development of inflammation in the ileum, but not to gut dysbiosis. We also found that the fasting blood insulin level was significantly increased by Aicda deficiency only under HFD feeding. Furthermore, the gene expression of monocyte chemoattractant protein1, a major chemokine responsible for the onset of hyperinsulinemia, in the liver was significantly increased by HFD feeding and tended to be increased by Aicda deficiency. These findings suggest that a reduction of IgA reactivity to gut microbiota induced by HFD contributes to hyperinsulinemia partly via increasing monocyte chemoattractant protein-1 expression in the liver. [ABSTRACT FROM AUTHOR]

The well-balanced secretion between insulin and growth hormone (GH) is essential in regulating substrate metabolism, energy metabolism, and body composition. High insulin and low GH levels are often observed in obesity, contributing to reduced energy expenditure and further fat accumulation. Although suppression of hyperinsulinemia is proposed as a treatment for obesity, changes in GH secretion and energy metabolism following this treatment are not thoroughly studied. This leaves unexplained observations, such as unchanged lean mass following insulin reduction. In this study, high-fat diet-induced obese (DIO) and normal chow-fed lean mice on a C57BL/6J background were treated for 7 weeks with diazoxide (1250 mg/kg in food), a KATP channel opener that suppressed insulin secretion. Diazoxide treatment f or 10 days was sufficient to increase pulsatile GH secretion in DIO mice before any signi ficant body weight change. The restored insulin-GH balance in DIO mice was followed by improvement in substrate and energy metabolism in a prolonged treatment period (4-6 weeks), including reduced fat mass, increased lipid oxidation and energy expenditure, as well as improved insulin sensitivity and metabolic flexibility. These metabolic benefits o ccurred along with the changes in the expression level of genes regulated by the insulin-GH balance. When applying diazoxide to normal chow-fed normoinsulinemic lean mice, none of the above metabolic effects was observed, suggesting that the metabolic ch anges following diazoxide treatment were mediated through the suppression of hyperinsulinemia. These results suggest that suppression of hyperinsulinemia by diazoxide restores GH secretion and improves substrate and energy metabolism in DIO mice. [ABSTRACT FROM AUTHOR]

Insulin resistance engenders a compensatory increase in plasma insulin. Inadequate compensation is a primary element in the pathogenesis of type 2 diabetes. The signal that heralds developing insulin resistance and initiates hyperinsulinemic compensation is not known. It has often been assumed to be increased glucose. We tested this assumption by determining whether development of fasting and/or glucose-stimulated hyperinsulinemia with diet-induced insulin resistance occurs because of concomitant elevation of glycemia. Male dogs (n = 58) were fed a hypercaloric, fat-supplemented diet for 6 weeks. Dogs underwent magnetic resonance imaging to quantify total and regional (visceral, subcutaneous) adiposity as well as euglycemic hyperinsulinemic clamps. A subset of animals also underwent an insulin-modified intravenous glucose tolerance test to assess insulin sensitivity, acute insulin response (AIRg), and glucose effectiveness. Fat feeding caused modest weight gain, increased visceral and subcutaneous fat, and insulin resistance at both peripheral and hepatic levels. Hyperinsulinemic compensation was observed in fasting levels as well as increased AIRg. However, we observed absolutely no increase in carefully measured fasting, evening (6 to 8 pm) or nocturnal glycemia (2 to 4 am). Insulin resistance and hyperinsulinemia occurred despite no elevation in 24-hour glucose. Compensatory development of hyperinsulinemia during diet-induced insulin resistance occurs without elevated fasting or 24-hour glycemia. These data refute the idea that glucose itself is a requisite signal for β-cell upregulation. Alternative feedback mechanisms need to be identified. [ABSTRACT FROM AUTHOR]

Context: Sleep loss in men increases cortisol and decreases testosterone, and sleep restriction by 3 to 4 hours/night induces insulin resistance.Objective: We clamped cortisol and testosterone and determined the effect on insulin resistance.Methods: This was a randomized double-blind, in-laboratory crossover study in which 34 healthy young men underwent 4 nights of sleep restriction of 4 hours/night under 2 treatment conditions in random order: dual hormone clamp (cortisol and testosterone fixed), or matching placebo (cortisol and testosterone not fixed). Fasting blood samples, and an additional 23 samples for a 3-hour oral glucose tolerance test (OGTT), were collected before and after sleep restriction under both treatment conditions. Cytokines and hormones were measured from the fasting samples. Overall insulin sensitivity was determined from the OGTT by combining complementary measures: homeostasis model assessment of insulin resistance of the fasting state; Matsuda index of the absorptive state; and minimal model of both fasting and absorptive states.Results: Sleep restriction alone induced hyperinsulinemia, hyperglycemia, and overall insulin resistance (P < 0.001 for each). Clamping cortisol and testosterone alleviated the development of overall insulin resistance (P = 0.046) and hyperinsulinemia (P = 0.014) by 50%. Interleukin-6, high-sensitivity C-reactive protein, peptide YY, and ghrelin did not change, whereas tumor necrosis factor-α and leptin changed in directions that would have mitigated insulin resistance with sleep restriction alone.Conclusion: Fixing cortisol-testosterone exposure mitigates the development of insulin resistance and hyperinsulinemia, but not hyperglycemia, from sustained sleep restriction in men. The interplay between cortisol and testosterone may be important as a mechanism by which sleep restriction impairs metabolic health. [ABSTRACT FROM AUTHOR]

Objective: To study the reprometabolic syndrome in normal-weight, eumenorrheic women by infusing a combination of insulin and lipid. Women with obesity have been shown to have reduced gonadotropins and impaired luteinizing hormone (LH) and follicle-stimulating hormone (FSH) response to gonadotropin-releasing hormone (GnRH).Design: Randomized crossover.Setting: Academic medical center.Participant(s): Fifteen women, median age 32 (interquartile ranged [IQR] 26, 36) years and body mass index 21.9 (IQR 20.2, 22.9) kg/m2 were recruited.Intervention(s): Early follicular phase, 6-hour infusions of insulin (20-40 mU/m2 per minute) and lipid (Intralipid)-insulin/lipid infusion; or saline infusion (controls). The first 4 hours of each study assessed endogenous gonadotropins; at 4 hours, GnRH (75 ng/kg) bolus was administered and sampling continued until 6 hours.Main Outcome Measure(s): Linear mixed model analysis was used to determine differences between insulin/lipid and saline influence on endogenous LH pulse amplitude (primary outcome), mean FSH, and area under the curve (AUC) response to GnRH (secondary outcomes).Result(s): Twelve women completed both intended studies and an additional 3 women completed only 1 of the 2 studies. LH pulse amplitude, mean FSH, and both AUC responses to GnRH were reduced by insulin/lipid, mean FSH and AUC for LH were at or near statistical significance. LH response to GnRH was significantly reduced when 1 participant with very high LH and antimullerian hormone levels was excluded.Conclusion(s): Acute infusion of insulin/lipid to eumenorrheic, normal-weight women recapitulated the reprometabolic syndrome of obesity. These findings imply that specific circulating factors in obese women contribute to their subfertility and thus may be amenable to discovery and treatment.Clinical Trial Registration Number: NCT02653092. [ABSTRACT FROM AUTHOR]

Context: Insulin resistance (IR) is associated with polycystic ovaries and hyperandrogenism, but underpinning mechanisms are poorly understood and therapeutic options are limited.Objective: To characterize hyperandrogenemia and ovarian pathology in primary severe IR (SIR), using IR of defined molecular etiology to interrogate disease mechanism. To extend evaluation of gonadotropin-releasing hormone (GnRH) analogue therapy in SIR.Methods: Retrospective case note review in 2 SIR national referral centers. Female patients with SIR with documented serum total testosterone (TT) concentration.Results: Among 185 patients with lipodystrophy, 65 with primary insulin signaling disorders, and 29 with idiopathic SIR, serum TT ranged from undetectable to 1562 ng/dL (54.2 nmol/L; median 40.3 ng/dL [1.40 nmol/L]; n = 279) and free testosterone (FT) from undetectable to 18.0 ng/dL (0.625 nmol/L; median 0.705 ng/dL [0.0244 nmol/L]; n = 233). Higher TT but not FT in the insulin signaling subgroup was attributable to higher serum sex hormone-binding globulin (SHBG) concentration. Insulin correlated positively with SHBG in the insulin signaling subgroup, but negatively in lipodystrophy. In 8/9 patients with available ovarian tissue, histology was consistent with polycystic ovary syndrome (PCOS). In 6/6 patients treated with GnRH analogue therapy, gonadotropin suppression improved hyperandrogenic symptoms and reduced serum TT irrespective of SIR etiology.Conclusion: SIR causes severe hyperandrogenemia and PCOS-like ovarian changes whether due to proximal insulin signaling or adipose development defects. A distinct relationship between IR and FT between the groups is mediated by SHBG. GnRH analogues are beneficial in a range of SIR subphenotypes. [ABSTRACT FROM AUTHOR]

Hyperandrogenic disorders, such as polycystic ovary syndrome, are often associated with metabolic disruptions such as insulin resistance and hyperinsulinemia. Studies in sheep, a precocial model of translational relevance, provide evidence that in utero exposure to excess testosterone during days 30–90 of gestation (the sexually dimorphic window where males naturally experience elevated androgens) programs insulin resistance and hyperinsulinemia in female offspring. Extending earlier findings that adverse effects of testosterone excess are evident in fetal day 90 pancreas, the end of testosterone treatment, the present study provides evidence that transcriptomic and phenotypic effects of in utero testosterone excess on female pancreas persist after cessation of treatment, suggesting lasting organizational changes, and induce a male-like phenotype in female pancreas. These findings demonstrate that the female pancreas is susceptible to programmed masculinization during the sexually dimorphic window of fetal development and shed light on underlying connections between hyperandrogenism and metabolic homeostasis. • Exposure to excess testosterone programs masculinization of female sheep pancreas. • Programming of beta-cell phenotype parallels transcriptomic masculinization. • Pancreatic alpha-cell phenotype is inconsistent with masculinization. • Fetal beta- and alpha-cell changes may underlie adverse adult pancreatic phenotype. [ABSTRACT FROM AUTHOR]

Context: Hyperinsulinemia is the most common metabolic change associated with cochleovestibular diseases. Aim: We aimed to investigate the auditory functions in hyperinsulinemic individuals. Settings and Design: A total of 164 patients were included in this case-control study. While 76 patients with insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] of ≥2.5) constituted the case group, 88 patients with HOMA-IR values of

Hyperinsulinemia is the hallmark of the development of insulin resistance and precedes the diagnosis of type 2 diabetes. Here we evaluated the effects of prolonged exposure (≥4 days) to high insulin doses (150 nM) in vitro in two adipose cell types, mouse 3T3-L1 and human SGBS. Chronic insulin treatment significantly decreased lipid droplet size, insulin signalling and insulin-stimulated glucose uptake. 3T3-L1 displayed an increased basal glucose internalization following chronic insulin treatment, which was associated with increased GLUT1 expression. In addition, both cells showed increased basal lipolysis. In conclusion, we report the effects of prolonged hyperinsulinemia in 3T3-L1 and SGBS, highlighting similarities and discrepancies between the cell types, to be considered when using these cells to model insulin-induced insulin resistance.

Vivian Soetikno,1 Andriyani Murwantara,2 Prisma Andini,2 Fabrian Charlie,2 Gilbert Lazarus,3 Melva Louisa,1 Wawaimuli Arozal1 1Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia; 2Graduate Course, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia; 3Undergraduate Course, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, IndonesiaCorrespondence: Vivian Soetikno Tel +62 21 31930481Email vivian.soetikno@ui.ac.idPurpose: The aim of present study was to analyze the effect of alpha-mangostin on cardiac hypertrophy and fibrosis and biochemical parameters in high-fat/high-glucose diet and low-dose streptozotocin injection (HF/HG/STZ)-induced type 2 diabetic rats.Methods: Diabetes was induced in male Wistar rats by giving a combination of high-fat/high-glucose (HF/HG) diet for 3 weeks and followed by low-dose streptozotocin intraperitoneal injection (STZ; 35 mg/kg) at Week-3 and the HF/HG diet was continued until 8 weeks. The diabetic rats were then divided into four groups (each, n=6): untreated diabetic group (HF/HG/STZ); diabetic group treated with metformin 200 mg/kg/day (HF/HG/STZ+Metformin); diabetic group treated with alpha-mangostin 100 mg/kg/day (HF/HG/STZ+AM100); and diabetic group treated with alpha-mangostin 200 mg/kg/day (HF/HG/STZ+AM200) and all were given by oral gavage for 8 weeks. We also included a control group (C) treated with AM200 (C+AM200). The role of alpha-mangostin was assessed through its effect on blood glucose levels, HOMA-IR, blood pressure, body weight, pro-inflammatory cytokines in cardiac tissue, serum aminotransferases (ALT and AST), lipid profiles (cholesterol and triglyceride), blood urea nitrogen (BUN), uric acid, cardiac hypertrophy and fibrosis.Results: Diabetic rats treated with alpha-mangostin in both doses for 8 weeks showed decrease in blood glucose levels, HOMA-IR, and blood pressure. Alpha-mangostin treatment also prevented HF/HG/STZ-induced changes in the activities of ALT, AST, BUN, uric acid, lipid profiles, and pro-inflammatory cytokines, which were comparable with the standard drug metformin, while alpha-mangostin did not show any significant effects on control rats (p> 0.05). The cardiac hypertrophy and fibrosis were also attenuated in diabetic rats treated with alpha-mangostin in both doses.Conclusion: These data suggest that administration of alpha-mangostin can effectively attenuate diabetes-induced alteration in cardiac hypertrophy and fibrosis as well as biochemical parameters in HF/HG/STZ rats.Keywords: insulin resistance, diabetes mellitus, hyperinsulinemia, hyperglycemia, cardiomyopathy, dietary fats

Posttraumatic stress disorder (PTSD) is associated with a 2–4 fold increased risk of developing Type 2 diabetes mellitus. However, detailed assessments of glucose metabolism and insulin secretion in a study designed to minimize confounders are lacking. Furthermore, few studies examine potential mechanisms involved. We analyzed data from a case–control study of medically healthy, medication-free adults to determine whether individuals with PTSD had abnormal glucose or insulin response to oral glucose tolerance test (OGTT) compared to controls. Secondarily, we assessed potential mediators such as sleep, cortisol and adiponectin. Data was analyzed from 92 age and gender-matched subjects (44 PTSD, 48 controls). Chronic PTSD was diagnosed using the Structured Clinical Interview for DSM-IV and Clinician Administered PTSD Scale. Subjects underwent 75-g OGTT, actigraphy and sleep diary (to quantify sleep duration), polysomnography (to assess slow wave sleep [SWS] and delta power), and overnight blood sampling (for cortisol and adiponectin). At baseline, individuals with PTSD had mildly increased insulin levels (by 19%, compared to controls, p = 0.048) that was mediated primarily by weight. In response to OGTT, the PTSD group had higher levels of insulin at 120 min (by 44%, p = 0.03) and insulin AUC (by 43%, p = 0.015) compared to controls, after adjusting for confounders. Glucose levels were similar in the two groups. Although self-reported sleep duration, SWS, and delta power differed between PTSD subjects and controls, they did not mediate the effects of PTSD status on insulin response.Posttraumatic stress disorder (PTSD) is associated with a 2–4 fold increased risk of developing Type 2 diabetes mellitus. However, detailed assessments of glucose metabolism and insulin secretion in a study designed to minimize confounders are lacking. Furthermore, few studies examine potential mechanisms involved. We analyzed data from a case–control study of medically healthy, medication-free adults to determine whether individuals with PTSD had abnormal glucose or insulin response to oral glucose tolerance test (OGTT) compared to controls. Secondarily, we assessed potential mediators such as sleep, cortisol and adiponectin. Data was analyzed from 92 age and gender-matched subjects (44 PTSD, 48 controls). Chronic PTSD was diagnosed using the Structured Clinical Interview for DSM-IV and Clinician Administered PTSD Scale. Subjects underwent 75-g OGTT, actigraphy and sleep diary (to quantify sleep duration), polysomnography (to assess slow wave sleep [SWS] and delta power), and overnight blood sampling (for cortisol and adiponectin). At baseline, individuals with PTSD had mildly increased insulin levels (by 19%, compared to controls, p = 0.048) that was mediated primarily by weight. In response to OGTT, the PTSD group had higher levels of insulin at 120 min (by 44%, p = 0.03) and insulin AUC (by 43%, p = 0.015) compared to controls, after adjusting for confounders. Glucose levels were similar in the two groups. Although self-reported sleep duration, SWS, and delta power differed between PTSD subjects and controls, they did not mediate the effects of PTSD status on insulin response.In this case–control study, individuals with PTSD had a hyperinsulinemic response to oral glucose challenge compared to controls, suggestive of insulin resistance.

Abstract Background Type A insulin resistance syndrome, one type of the hereditary insulin resistance syndromes, is a rare disorder. Patients with type A insulin resistance syndrome are nonobese and demonstrate severe hyperinsulinemia, hyperandrogenism, and acanthosis nigricans. The clinical features are more severe in affected females than in males, and they mostly become apparent at the age of puberty. In many cases, when severe insulin resistance is covered up by other signs or symptoms of type A insulin resistance syndrome, patients are often easily misdiagnosed with other diseases, such as polycystic ovary syndrome. Case presentation Our patient was a 27-year-old Han Chinese woman who sought treatment because of a menstrual disorder and hirsutism. Tests showed that her levels of insulin and testosterone were elevated, and gynecological color Doppler ultrasound suggested multiple cystic changes in the bilateral ovaries. After a diagnosis of polycystic ovary syndrome was made, pulsatile gonadotropin-releasing hormone therapy and metformin were administered, but the patient’s symptoms did not improve in 1 year of follow-up. Considering that the previous diagnosis might have been incorrect, venous blood samples were collected from the patient and her relatives for genetic analysis. Subsequently, using Illumina sequencing, it was found that the proband, her father, and two brothers all had the c.3601C>T heterozygous missense mutation in exon 20 of the insulin receptor gene. The diagnosis was corrected to type A insulin resistance syndrome, and the patient’s treatment was modified. Conclusion We report a case of a young woman with type A insulin resistance syndrome that was misdiagnosed as polycystic ovary syndrome. We discuss the causes, clinical features, diagnosis, and treatment of type A insulin resistance syndrome to improve the recognition of the disease and reduce its misdiagnosis. Female patients with high androgen levels and severe hyperinsulinemia should be considered for the possibility of hereditary insulin resistance syndromes (such as type A insulin resistance syndrome). Gene sequencing helps in making an early diagnosis and developing a targeted treatment strategy.

Background: Hyperinsulinemia associated with equine metabolic syndrome (EMS) and pituitary pars intermedia dysfunction (PPID) is a risk factor for laminitis. Research in other species has shown elevated body iron levels as both a predictor and consequence of insulin resistance. In humans this is known as dysmetabolic hyperferritinemia. Aim: To explore the relationship between equine hyperinsulinemia and body iron levels. Methods: We reviewed case histories and laboratory results from an open access database maintained by the Equine Cushings and Insulin Resistance Group Inc. (ECIR). We identified 33 horses with confirmed hyperinsulinemia and laboratory results for serum iron, TIBC, and ferritin. Pearson correlation was used to test the relationship between insulin and iron indices. Additionally, we performed a secondary analysis of a previously reported controlled trial that was originally designed to test the correlation between iron status and the insulin response in horses. Here we used a t-test to compare the mean values of insulin and ferritin between horses we categorized as normal or hyperinsulinemic based on their response to an oral challenge. Results: Serum ferritin exceeded published reference range in 100% of the horses identified from the ECIR database. There were no statistically significant associations between insulin indices (RISQI, log insulin) and iron indices (log serum iron, log TSI%, log ferritin). There were trends for a negative association between RISQI and log iron (r(31) = -0.33, p = .058) and a positive association between age and ferritin, (r(30) = 0.34, p = .054). From the secondary data analysis of published data, we found significantly elevated ferritin (P = .05) in horses considered hyperinsulinemic by dynamic insulin testing compared to horses with a normal response. Conclusion: These results suggest the potential for iron overload in hyperinsulinemic horses, a feature documented in other species, and should stimulate further study into the relationship between insulin and iron dysregulation in the horse.

Background: Insulin resistance is a pathological condition in which physiological levels of insulin produce only subnormal biological responses. In such instances, â cells of the pancreas produce more insulin but the cells in other body tissues are resistant to insulin leading to hyperinsulinemia, and subsequent hyperglycemia further results in metabolic syndrome. Aim and Objectives: This study was aimed to evaluate the hydro-alcoholic extract of Enicostemma littorale (ELE) in preventing dexamethasone 8mg/kg induced insulin resistance. Materials and Methods: Thirty-six male Wistar rats were categorized into Group I plain control that received distilled water, Group II dexa control that received dexamethasone 8mg/kg. Group III and Group IV received dexamethasone 8 mg/kg along with Metformin 500 mg/kg and 1g/kg respectively. Group V and VI received dexamethasone along with ELE 2.5 g/kg and 3.5 g/kg respectively. At the end, the fasting and repeated blood samples were collected at 30, 60 and 120 min for the estimation of post Intraperitoneal Glucose Tolerance Test (IPGTT), serum glucose and insulin. Data were utilized for the assessment of the homeostasis model of assessment for insulin resistance and sensitivity, Gutt, Matsuda, fasting glucose to insulin ratio and disposition indices. Results: All insulin sensitivity indices were worsened in dexa control group as compared to plain control (P

Abstract Background Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. Results MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. Conclusions These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.

Purpose Acanthosis nigricans (AN) is a hyperpigmented dermatosis associated with obesity and insulin resistance (IR). There is no consensus whether AN extension scoring offers added value to the clinical estimation of IR. In this study we aimed to assess and score AN using both a short and an extended version of the scale proposed by Burke et al. and analyze the relationships of both versions with hyperinsulinemia and IR. Methods We analyzed data from 139 overweight adolescents (body mass index ≥85th percentile) aged 12–18 with (n=67) or without (n=72) AN who were followed at a pediatric obesity clinic. Results Adolescents with AN had higher levels of insulin (d=0.56, P=0.003) and HOMA-IR (d=0.55, P=0.003) compared to those without. Neither the short nor the extended versions of AN scores explained either hyperinsulinemia (β=1.10, P=0.316; β=1.15, P=0.251) or IR (β=1.07, P=0.422; β=1.10, P=0.374). The presence of AN alone predicted hyperinsulinemia and the presence of IR in 7.3% (β=2.68, P=0.008) and 7.1% (β=2.59, P=0.009) of adolescents, respectively. Conclusions Screening for AN at the neck and axilla is a noninvasive and cost-effective way to identify asymptomatic overweight adolescents with or at risk of developing IR.

Abstract Background Endocrinopathic laminitis is common in horses and ponies, but the recurrence rate of the disease is poorly defined. Objectives To determine the incidence of, and risk factors for, the recurrence of endocrinopathic laminitis. Animals Privately owned horses and ponies with acute laminitis (n = 317, of which 276 cases with endocrinopathic laminitis were followed up to study completion). Methods This prospective cohort study collected data on veterinary‐diagnosed cases of acute laminitis for 2 years. Each case was classified on acceptance to the study as endocrinopathic or non‐endocrinopathic using data collected in a questionnaire completed by the animal's veterinarian. Follow‐up data were collected at regular intervals to determine whether the laminitis recurred in the 2‐year period after diagnosis. Results The recurrence rate for endocrinopathic laminitis was 34.1%. The risk of recurrence during the 2‐year study period increased with basal, fasted serum insulin concentration (P ≤ .05), with the probability of recurrence increasing markedly as the insulin concentration increased beyond the normal range (0‐20 μIU/mL) to over the threshold for normal (up to approximately 45 μIU/mL). Being previously diagnosed with laminitis (before the study; P = .05) was also a risk factor for recurrent laminitis. Cases with a higher Obel grade of laminitis were likely (P = .05) to recur sooner. Conclusions and clinical importance Knowing that hyperinsulinemia and being previously diagnosed with laminitis are significant risk factors for recurrence will enable clinicians to proactively address these factors, thereby potentially reducing the risk of recurrence of laminitis.

Background Equine endocrinopathic laminitis is common and can be associated with an underlying endocrinopathy, such as equine metabolic syndrome (EMS), pituitary pars intermedia dysfunction (PPID), pasture consumption, or any combination of these factors. Objectives The aim of the study was to improve the risk assessment capabilities of clinicians, and to inform management strategies, for acute endocrinopathic laminitis by prospectively examining the phenotypic, hormonal, and clinical characteristics of the disease in a large cohort. Animals Privately owned horses and ponies (n = 301) of any age, sex, or breed diagnosed with laminitis by a veterinarian. A history of laminitis was acceptable. Methods This was a prospective cohort study. Veterinarians provided information on each case via an online questionnaire after informed consent from the animal's owner, and all data were de‐identified before analysis. Serum insulin and plasma adrenocorticotrophic hormone concentrations were measured in each case. Results Most cases were recruited in spring (109/301; 36.2%). Concurrent EMS and PPID resulted in higher basal insulin concentrations (49 [21.5‐141]; P

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that develops in 10–15% of reproductive aged women. Over the past two decades, the inositol effectiveness in normalizing the clinical and hormonal disorders associated with PCOS has been actively studied. Inositol and its stereoisomers are classified as insulin sensitizers and act as a second conductor for insulin transmission routes. Myo-inositol and D-chiro-inositol are two of the nine existing stereoisomers the most studied currently, which play an important role in the PCOS physiology and treatment. The aim of the study was to study the Protalis effectiveness in patients with PCOS. 40 women with PCOS (mean age 24.4 ± 0.8 years) who were resistant to previous treatment with clomiphene citrate were examined. Protalis was administered for three months, after the end of the drug intake clomiphene citrate was used according to the standard regimen to restore fertility. The levels of luteinizing hormone, follicle-stimulating hormone, sex hormone binding globulin, total testosterone, antiMullerian hormone, homocysteine, folic acid were determined, and free androgen index was calculated. Fasting insulin was tested in serum and 120 minutes after the glucose load, the HOMA-IR was calculated, and lipid metabolism parameters were studied. Monotherapy with Protalis normalized the menstrual cycle in 52.5%, restore ovulation in 40%, contributed to the pregnancy in 7.5% patients with PCOS, in combination with clomiphene citrate in 27.5% women previously resistant to clomiphene. No changes in body mass index, waist circumference/hip circumference or hirsutism were found. A decrease in hyperandrogenism due to a testosterone decrease and an sex hormone binding globulin increase was found, the carbohydrate, lipid metabolism, and folate status improved. Protalis monotherapy can be recommended for patients with PCOS as a preliminary preparation, potentiating the clomiphene citrate effects, on the background insulin resistance. It is advisable to consider the Protalis use in combination with drugs for standard treatment of PCOS.

Background. It is proved that patients with diabetes mellitus (DM) have an increased risk of cancer. The main factors of oncogenesis in DM are obesity, cytokine imbalance, hyperinsulinemia (HI), hyperglycemia. These disorders cause dysfunction of the intracellular regulatory signaling pathways, the main of which is PI3K/Akt/mTOR. The purpose of the work was to study the role of phosphorylated Akt-protein kinase (phospho-Akt) in the oncogenesis processes in patients with type 2 DM. Materials and methods. Seventy-five people were examined. Patients were divided into groups: І — healthy, ІІ — persons with DM type 2, ІІІ — patients with cancer, IV — patients with cancer and DM type 2. Patients with breast, endometrial, pancreatic and intestinal cancer were included in the study. The levels of insulin, insulin-like growth factor 1 (IGF-1) and phospho-Akt were determined. Results. Patients of groups II and IV had a decompensated DM with HbA1c level > 8.0 %. Reliable HI was found in patients with DM in groups II and IV (p

Ranjit I Kylat Division of Neonatal-Perinatal Medicine and Developmental Biology, Department of Pediatrics, The University of Arizona, College of Medicine, Tucson, AZ, USA Abstract: Pharmacologic modulation to open the KATP channels with diazoxide is useful in treating hyperinsulinemia. Diazoxide is being used more often in neonates with hyperinsulinemic hypoglycemia. This report highlights a case of severe pulmonary hypertension (PH) with re-opening of ductus arteriosus in an extremely premature infant after the use of diazoxide. The rapid onset of PH with respiratory failure was completely reversible. This case emphasizes the need for extreme caution with use of diazoxide in the premature infant population, especially those with chronic lung disease of prematurity. In addition, the use of diazoxide should be limited to the persistent form of congenital hyperinsulinism, after adequate work up has been completed to evaluate for other causes of hypoglycemia. It is postulated that development of PH could be related to KATP agonsim. Keywords: hypoglycemia, hyperinsulinemia, pulmonary hypertension, diazoxide, KATP channels, ductus arteriosus

Abstract Background Obesity is a chronic and multifactorial disease characterized by increased adipose tissue. In females, obesity leads to reduced ovulation and lower chances of conception in diseases like polycystic ovary syndrome, making it important to characterize complementary medicine to attenuate such deleterious effects. Therefore, the aim of this study was to assess the effects of a hydroethanolic extract from Syzigium cumini leaves in female reproductive impairments present in the obesity model of neonatal L-monosodium glutamate injection. Methods Newborn Wistar rats received saline (CTRL) or L-monosodium glutamate 4 mg/g BW (MSG). At 90 days of age, CTRL and some MSG rats received saline, while others received hydroethanolic extract of S. cumini leaves (HESc 500 mg/kg/day, MSG-Syz group) for 30 consecutive days. Estrous cycle was determined by daily vaginal washes. On days 26 and 28 of treatment, oral glucose tolerance test and blood collection were performed for biochemical assessment. At the end, animals were euthanized during estrous phase; blood was collected to measure sex hormones and organs collected for weighing and histological evaluation. Results MSG-Syz showed reduced Lee Index, retroperitoneal fat pads and restored gluco-insulin axis. Moreover, HESc treatment reduced serum cholesterol levels when compared to MSG. Treatment with HESc did not restore the oligociclicity observed in obese animals, though MSG-Syz reestablished ovarian follicle health back to CTRL levels, with proliferating primordial follicles – these effects were followed by a decrease on periovarian adipocyte area. Conclusions This is the first report to show the reversibility of the reproductive dysfunctions seen in MSG female rats through ethnopharmacological treatment. Moreover, it expands the use of HESc as a prominent tool to treat metabolic and reproductive disorders. Finally, we provide novel evidence that, without a functioning hypothalamus-pituitary-gonads axis, metabolic improvement is ineffective for estrous cyclicity, but critical for ovarian follicle health.

Regular exercise involves daily muscle contractions helping metabolize up to 70% of daily ingested glucose. Skeletal muscle increases glucose uptake through two distinct pathways: insulin signaling pathway and muscle contraction mediated AMPK pathway. People with paralysis are unable to contract their muscles which atrophy, transform into insulin resistant glycolytic muscle, and develop osteoporosis. Our goal is to determine if low force electrically induced exercise (LFE) will modulate the post prandial insulin and glucose response in people with and without spinal cord injury (SCI). 18 people with SCI and 23 without SCI (Non-SCI) participated in an assessment of metabolic biomarkers during passive sitting (CTL) and a bout of LFE delivered to the quadriceps/hamstring muscle groups after a glucose challenge. Baseline fasting insulin (p = 0.003) and lactate (p = 0.033) levels were higher in people with SCI, but glucose levels (p = 0.888) were similar compared to the non-SCI population. After 1-h of muscle contractions using LFE, heart rate increased (p < 0.001), capillary glucose decreased (p = 0.004), insulin decreased (p < 0.001), and lactate increased (p = 0.001) in the SCI population. These findings support that LFE attenuates certain metabolic blood biomarkers during a glucose challenge and may offer a lifestyle strategy to regulate metabolic responses after eating among people with SCI.