Plasma Insulin Levels Research Articles

Acute sub-diaphragmatic anterior vagus nerve stimulation increases peripheral glucose uptake in anaesthetized rats

The sub-diaphragmatic vagus innervates various organs involved in the control of glucose homeostasis including the liver, pancreas and the intestines. In the current study, we investigated the effect of acute electrical stimulation of the anterior trunk of the sub-diaphragmatic vagus on glucose fluxes in anaesthetized adult male rats.After overnight fast, rats underwent either vagus nerve stimulation (VNS+, n = 11; rectangular pulses at 5 Hz, 1.5 mA, 1 msec pulse width) or sham stimulation (VNS-; n = 11) for 120 min under isoflurane anesthesia. Before stimulation, the rats received an i.v. bolus of 1 mL/kg of a sterilized aqueous solution containing 125 mg/mL of D-[6,6-2H2] glucose. Endogenous glucose production (EGP) and glucose clearance rate (GCR) were calculated by kinetic analysis from the wash-out of injected D-[6,6–2H2]glucose from the circulation.VNS+ resulted in lower glucose levels compared to the VNS- group (p < 0.05), with similar insulin levels. EGP was similar in both groups, but the GCR was higher in the VNS+ group compared to the VNS- group (p < 0.001). Circulating levels of the sympathetic transmitter norepinephrine were reduced by VNS+ relative to VNS- treatment (p < 0.01).It is concluded that acute anterior sub-diaphragmatic VNS causes stimulation of peripheral glucose uptake, while plasma insulin levels remained similar, and this is associated with lower activity of the sympathetic nervous system.

Menthol confers neuroprotection through Nrf2/ARE pathway in diabetic encephalopathy

Background: Chronic, long-standing hyperglycemia in diabetes results in diabetic encephalopathy (DE). It is hallmarked by cognitive dysfunction accelerated by hyperglycemia-induced oxidative stress. Objective: This study explored the neuroprotective potency of menthol in experimental diabetes.Methodology: Streptozotocin at a dose of 40 mg/kg body weight was injected into eighteen male Sprague- Dawley rats intraperitoneally to induce diabetes. The animals were kept without treatment for a period of 30 days for the development of DE. The cognitive deficit was confirmed by the Morris water maze test. Menthol (50 mg/kg body weight) was administered orally for 60 days. The behavioral test was conducted after 60 days of treatment. Results obtained were compared to diabetic rats fed with metformin (100 mg/kg body weight). Animals were then sacrificed to get blood and brain tissue for various biochemical examinations.Results:Treatment with menthol improved cognitive performance in diabetic rats. In addition, menthol significantly decreased fasting blood glucose, HbA1c, renal toxicity markers, and lipid peroxidation products. Menthol enhances the levels of plasma insulin and antioxidant enzymes. It also upregulated the mRNA expression of Bcl-2, Nrf2, Glo-1, and γ-GCS while diminishing the expression of Bax, cytochrome c, and caspase-3. Conclusion:Menthol promotes neuroprotection by abating cognitive deficits, attenuating hyperglycemia, regulating oxidative stress, and curtailing apoptosis through Nrf2/ARE signaling. Keywords: Diabetic encephalopathy, Menthol, apoptosis, Nrf2/ARE pathway

Assessment of glucose homeostasis in young adult female β-thalassemia major patients (β-TM) with acquired hypogonadotropic hypogonadism (AHH) never treated with sex steroids compared to eugonadal β-TM patients with spontaneous menstrual cycles.

Acquired ypogonadotropic hypogonadism (AHH) is the most prevalent endocrine complication in thalassemia major (TM). Considering the detrimental effect of estrogen deficiency on glucose metabolism, the ICET-A Network promoted a retrospective study on the long-term effects of estrogen deficiency on glucose homeostasis in female β-TM patients with HH without hormonal replacement therapy (HRT). Seventeen β-TM patients with AHH (4 had arrested puberty; Tanners' breast stage 2-3), never treated with sex steroids, and 11 eugonadal β-TM patients with spontaneous menstrual cycles at the time of referral were studied. A standard 3-h OGTT was performed in the morning, after an overnight fast. Six-point plasma glucose and insulin level determinations, indices of insulin secretion and sensitivity, early-phase insulin insulinogenic index (IGI), HOMA-IR and β-cell function (HOMA-β), oral disposition index (oDI), glucose and insulin areas under the OGTT curves were evaluated. Abnormal glucose tolerance (AGT) or diabetes was observed in 15 (88.2%) of 17 patients with AHH and 6 (54.5%) of 11 patients with eumenorrhea. The difference between the two groups was statistically significant (P: 0.048). However, the group of eugonadal patients was younger compared to AHH patients (26.5 ± 4.8 years vs. 32.6 ± 6.2 years ; P: 0.010). Advanced age, severity of iron overload, splenectomy, increased ALT levels and reduced IGF-1 levels were the main clinical and laboratory risk factors for glucose dysregulation observed in β-TM with AHH compared to eugonadal β-TM patients with spontaneous menstrual cycles. These data further support the indication for an annual assessment of OGTT in patients with β-TM. We believe that a registry of subjects with hypogonadism is necessary for a better understanding of the long-term consequences of this condition and refining treatment options.

Gαi -coupled GPR41 activation increases Ca2+ influx in C2C12 cells and shows a therapeutic effect in diabetic animals.

This study aimed to investigate the possible mechanisms by which orphan G protein-coupled receptor GPR41 activation enhances glucose uptake into C2C12 myotubes using a GPR41-selective agonist, AR420626, and to examine the ability of this agent to improve insulin sensitivity and glucose homeostasis in vivo. Basal and insulin-stimulated glucose uptake and glucose transporter 4 translocations were measured in C2C12 myotubes. Ca2+ influx into cells was measured and GPR41-mediated signaling by AR420626 was examined. An oral glucose tolerance test was performed, and plasma insulin levels were measured in streptozotocin-treated or high-fat diet-fed diabetic mice. The glycogen content was measured in skeletal muscle tissue. AR420626 increased basal and insulin-stimulated glucose uptake, which was reduced by pertussis toxin, an inhibitor of Gαi -mediated signaling, and treatment with small interfering RNA for GPR41 (siGPR41). AR420626 increased intracellular Ca2+ influx and phosphorylated Ca2+ /calmodulin-dependent protein kinase type II, cyclic AMP-responsive element-binding protein, and mitogen-activated protein kinase (p38) in C2C12 myotubes, which were inhibited by treating with pertussis toxin, amlodipine (Ca2+ channel blocker), and siGPR41. AR420626 increased plasma insulin levels and skeletal muscle glycogen content and improved glucose tolerance in streptozotocin- and high-fat diet-induced diabetic mouse models. GPR41 activation with AR420626 increased glucose uptake mediated by Ca2+ signaling via GPR41, improving diabetes mellitus.

Syringic Acid Alleviates Hyperglycemia by Regulating Hepatic Key Enzymes of Carbohydrate Metabolism in Streptozotocin-induced Diabetic Rats

Background: Diabetes mellitus is a complex metabolic disorder characterized by the development of hyperglycemia due to impaired insulin production, insulin action, or both. The persistent hyperglycemia associated with diabetes can lead to an increased risk of developing severe health problems. This study examines whether the bioactive phenolic compound Syringic Acid (SA) mitigates hyperglycemia in streptozotocin-induced diabetic rats. Materials and Methods: A total of 30 male Sprague-Dawley rats were utilized in the investigation, and they were split into five groups: Normal (N), Normal+Syringic Acid (N+SA), Diabetic Control (DC), Diabetic+Syringic Acid (D+SA), and Diabetic+Glimepiride (D+GM). A single dose of streptozotocin (40 mg/kg) injected intraperitoneally was used to induce diabetes. Syringic Acid (SA) was given orally once a day for 60 days at a dose of 50 mg/Kg body weight. The levels of plasma insulin, glucose, glycated haemoglobin, and the activity of carbohydrate metabolizing enzymes were examined. Results were compared with diabetic rats provided with the standard drug glimepiride (0.1 mg/kg). Results: Syringic acid treatment substantially lowered hyperglycemia, enhanced insulin levels, and lowered HbA1c, in diabetic rats when given at a dose of 50 mg/Kg body weight. Additionally, syringic acid exhibited the ability to considerably lower the activities of fructose 1,6-bisphosphatase and glucose-6 phosphatase while significantly increasing the activities of glycolytic enzymes like pyruvate kinase and hexokinase. Conclusion: These results imply that syringic acid could potentially attenuate hyperglycemia in streptozotocin-induced diabetic rats by modulating carbohydrate metabolism.

Insulin Stimulates IL-23 Expression in Human Adipocytes: A Possible Explanation for the Higher Prevalence of Psoriasis in Obesity.

Psoriasis is a chronic systemic inflammatory disease involving the production of many pro-inflammatory cytokines derived from immune cells and interacting with different tissues leading to the typical skin lesions. Psoriasis shows a higher prevalence and a worse progression in obese than in lean subjects. The IL-23/IL-17 immune axis has a pivotal role in the pathogenesis of psoriasis and anti-IL-23 monoclonal antibodies are highly effective in its treatment. Since obesity in frequently associated with elevated insulin plasma levels, we have investigated the ability of in vitro differentiated human adipocytes to produce IL-23 at basal conditions and after insulin stimulation. In vitro differentiated human adipocytes were incubated in the absence and presence of different insulin concentrations and the expression of IL-23 was analyzed by real-time PCR and Western blotting. The results of this study show that in vitro differentiated human adipocytes spontaneously express IL-23 mRNA and protein being stimulated by insulin in a dose-dependent manner. The stimulatory effects of insulin on IL-23 expression were specific since it did not stimulate the expression of other well-known cytokines involved in psoriasis pathogenesis such as Il-22 nor LL-37. Furthermore, lipopolysaccharide did not stimulate IL-23 expression in human adipocytes, thus highlightening the specific effects of insulin in the stimulation of IL-23 expression in human adipocytes. Here we show that human adipocytes spontaneously express IL-23 and that insulin stimulates IL-23 production by these cells in a specific manner as other stimuli, known to be involved in psoriasis pathophysiology, are ineffective. These observations could explain the association between psoriasis and obesity, a condition frequently characterized by a state of insulin hypersecretion.

Risk of Developing Insulin Resistance in Adult Subjects with Phenylketonuria: Machine Learning Model Reveals an Association with Phenylalanine Concentrations in Dried Blood Spots.

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism where high phenylalanine (Phe) concentrations cause irreversible intellectual disability that can be prevented by newborn screening and early treatment. Evidence suggests that PKU subjects not adherent to treatment could be at risk of insulin resistance (IR). We studied how Phe concentrations (PheCs) relate to IR using machine learning (ML) and derived potential biomarkers. In our cross-sectional study, we analyzed subjects with neonatal diagnoses of PKU, grouped as follows: 10 subjects who adhered to treatment (G1); 14 subjects who suspended treatment (G2); and 24 control subjects (G3). We analyzed plasma biochemical variables, as well as profiles of amino acids and acylcarnitines in dried blood spots (DBSs). Higher PheCs and plasma insulin levels were observed in the G2 group compared to the other groups. Additionally, a positive correlation between the PheCs and homeostatic measurement assessments (HOMA-IRs) was found, as well as a negative correlation between the HOMA-Sensitivity (%) and quantitative insulin sensitivity check index (QUICKI) scores. An ML model was then trained to predict abnormal HOMA-IRs using the panel of metabolites measured from DBSs. Notably, ranking the features' importance placed PheCs as the second most important feature after BMI for predicting abnormal HOMA-IRs. Our results indicate that low adherence to PKU treatment could affect insulin signaling, decrease glucose utilization, and lead to IR.

Nocturnal melatonin increases glucose uptake via insulin-independent action in the goldfish brain.

Melatonin, a neurohormone nocturnally produced by the pineal gland, is known to regulate the circadian rhythm. It has been recently reported that variants of melatonin receptors are associated with an increased risk of hyperglycemia and type 2 diabetes, suggesting that melatonin may be involved in the regulation of glucose homeostasis. Insulin is a key hormone that regulates circulating glucose levels and cellular metabolism after food intake in many tissues, including the brain. Although cells actively uptake glucose even during sleep and without food, little is known regarding the physiological effects of nocturnal melatonin on glucose homeostasis. Therefore, we presume the involvement of melatonin in the diurnal rhythm of glucose metabolism, independent of insulin action after food intake. In the present study, goldfish (Carassius auratus) was used as an animal model, since this species has no insulin-dependent glucose transporter type 4 (GLUT4). We found that in fasted individuals, plasma melatonin levels were significantly higher and insulin levels were significantly lower during the night. Furthermore, glucose uptake in the brain, liver, and muscle tissues also significantly increased at night. After intraperitoneal administration of melatonin, glucose uptake by the brain and liver showed significantly greater increases than in the control group. The administration of melatonin also significantly decreased plasma glucose levels in hyperglycemic goldfish, but failed to alter insulin mRNA expression in Brockmann body and plasma insulin levels. Using an insulin-free medium, we demonstrated that melatonin treatment increased glucose uptake in a dose-dependent manner in primary cell cultures of goldfish brain and liver cells. Moreover, the addition of a melatonin receptor antagonist decreased glucose uptake in hepatocytes, but not in brain cells. Next, treatment with N1-acetyl-5-methoxykynuramine (AMK), a melatonin metabolite in the brain, directly increased glucose uptake in cultured brain cells. Taken together, these findings suggest that melatonin is a possible circadian regulator of glucose homeostasis, whereas insulin acquires its effect on glucose metabolism following food intake.

Insulin secretory actions of ethanolic extract of Acacia arabica bark in high fat-fed diet-induced obese Type 2 diabetic rats.

Acacia arabica commonly known as 'babul' has been widely used for the treatment of numerous diseases, including diabetes due to their potential pharmacological actions. The aim of the present study was to investigate the insulinotropic and antidiabetic properties of ethanol extract of Acacia arabica (EEAA) bark through in vitro and in vivo studies in high fat-fed (HFF) rats. EEAA at 40-5000 µg/ml significantly increased (P<0.05-0.001) insulin secretion with 5.6 and 16.7 mM glucose, respectively, from clonal pancreatic BRIN BD11 β-cells. Similarly, EEAA at 10-40 µg/ml demonstrated a substantial (P<0.05-0.001) insulin secretory effect with 16.7 mM glucose from isolated mouse islets, with a magnitude comparable to 1 µM glucagon-like peptide-1 (GLP-1). Diazoxide, verapamil, and calcium-free conditions decreased insulin secretion by 25-26%. The insulin secretory effect was further potentiated (P<0.05-0.01) with 200 µM isobutylmethylxanthine (IBMX; 1.5-fold), 200 µM tolbutamide (1.4-fold), and 30 mM KCl (1.4-fold). EEAA at 40 µg/ml, induced membrane depolarization and elevated intracellular Ca2+ as well as increased (P<0.05-0.001) glucose uptake in 3T3L1 cells and inhibited starch digestion, glucose diffusion, dipeptidyl peptidase-IV (DPP-IV) enzyme activity, and protein glycation by 15-38%, 11-29%, 15-64%, and 21-38% (P<0.05, 0.001), respectively. In HFF rats, EEAA (250 mg/5 ml/kg) improved glucose tolerance, plasma insulin, and GLP-1 levels, and lowered DPP-IV enzyme activity. Phytochemical screening of EEAA revealed the presence of flavonoids, tannins and anthraquinone. These naturally occurring phytoconstituents may contribute to the potential antidiabetic actions of EEAA. Thus, our finding suggests that EEAA, as a good source of antidiabetic constituents, would be beneficial for Type 2 diabetes patients.

Associations of healthful and unhealthful plant-based diets with plasma markers of cardiometabolic risk.

Plant-based diets, particularly when rich in healthy plant foods, have been associated with a lower risk of type 2 diabetes and cardiovascular disease. However, the impact of plant-based diets that distinguish between healthy and unhealthy plant foods on cardiometabolic biomarkers remains unclear. Dietary information was collected by two 24-h recalls among 34,785 adults from a nationwide cross-sectional study. Plasma levels of insulin, C-peptide, glucose, C-reactive protein (CRP), white blood cell (WBC) count, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) were measured. Linear regression was used to evaluate the percentage difference in plasma marker concentrations by three plant-based diet indices, namely the overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI). Greater hPDI-adherence scores (comparing extreme quartiles) were associated with lower levels of insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), TG/HDL-C ratio, CRP, WBC count, and TG, and higher levels of HDL-C, with the percentage differences of - 14.55, - 15.72, - 11.57, - 14.95, - 5.26, - 7.10, and 5.01, respectively (all Ptrend ≤ 0.001). Conversely, uPDI was associated with higher levels of insulin, C-peptide, HOMA-IR, TG/HDL-C ratio, CRP, WBC count, and TG, but lower HDL-C, with the percentage differences of 13.71, 14.00, 14.10, 10.43, 3.32, 8.00, and - 4.98 (all Ptrend ≤ 0.001), respectively. Overall PDI was only associated with lower levels of CRP and WBC count (all Ptrend ≤ 0.001). Our findings suggest that hPDI may have positive, whereas uPDI may have negative impacts on multiple cardiometabolic risk markers, and underscore the need to consider the quality of plant foods in future PDI studies.

Hepatic glycogenolysis and hypometabolism induced by chemogenetic stimulation of C1 neurons.

The precise regulation of blood glucose levels is indispensable for maintaining physiological functions. C1 neurons determine the outflow of the autonomic nervous and endocrine systems to maintain blood glucose levels in the body. In contrast, activation of C1 neurons induces a decrease in activity, suggesting that hypoactivity also participates in maintaining blood glucose levels. To examine this, we evaluated both glycogenolysis and hypometabolism induced by the selective activation of C1 neurons. We used DbhCre/0 mice expressing receptors for chemogenetic tools in C1 neurons, owing to microinjection of the viral vector. C1 neurons were activated by intraperitoneal injection of clozapine N-oxide (CNO). The chemogenetic activation of C1 neurons significantly decreased body temperature, oxygen consumption, and carbon dioxide production. On the other hand, the blood glucose level was increased by the activation of C1 neurons 2 h after CNO administration, even in the fasting state. In this situation, an increase in glucagon and corticosterone levels was observed, while hepatic glycogen content decreased significantly. Plasma insulin level was not changed by the activation of C1 neurons despite the blood glucose level increased. Furthermore, adrenal sympathetic nerve activity was significantly increased by the activation of C1 neurons, and plasma catecholamine levels increased significantly. In conclusion, the selective activation of C1 neurons using chemogenetic tools induced an increase in blood glucose level, probably because of hepatic glycogenolysis and hypometabolism. KEY POINTS: Chemogenetic activation of C1 neurons in medulla oblongata decreased body temperature. Oxygen consumption and carbon dioxide production were decreased by chemogenetic activation of C1 neurons in medulla oblongata. Blood glucose level was increased by chemogenetic activation of C1 neurons in medulla oblongata. Chemogenetic activation of C1 neurons in medulla oblongata increased glucagon, corticosterone, and catecholamine levels in plasma. Increase in blood glucose level by activation of C1 neurons occurred due to combined effect of hepatic glycogenolysis and hypometabolism. Abstract figure legend We investigated the effects of selectively activating C1 neurons using chemogenetic tools on blood glucose levels. The activation of C1 neurons resulted in an increase in blood glucose levels. This increase is due to the activation of hepatic glycogenolysis through the release of humoral factors, including adrenaline, glucagon, and corticosterone. Additionally, the decrease in energy expenditure, as evidenced by a reduction in body temperature, oxygen consumption, and carbon dioxide production, suggests that activation of C1 neurons may induce hypometabolism, which could also contribute to an increase in blood glucose levels. These responses indicate that C1 neurons may serve as a switch for energy conservation to maintain blood glucose levels, presumably by being activated in a stressful situation. This article is protected by copyright. All rights reserved.

Nicotinamide mononucleotide (NMN) intake increases plasma NMN and insulin levels in healthy subjects

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme of the NAD+-dependent protein deacetylase sirtuin-1 (SIRT1). An increase in NAD+ concentration induces SIRT1 activation that results in various health benefits. Since nicotinamide mononucleotide (NMN) is a precursor of NAD+, NMN ingestion is expected to have multiple health benefits such as alleviation of aging, lifestyle-related and neurodegenerative diseases, through the activation of SIRT1. In this study, we aimed to determine the effects of daily NMN ingestion on plasma levels of NMN and NAD+. Healthy volunteers received 250mg of NMN once a day in the morning (n=11) for 12 weeks, and the plasma concentrations of NMN and NAD+ were measured monthly. Physiological and laboratory tests were performed within 2h after lunch (at 2 pm) before and during NMN administration. Oral administration of NMN increased the plasma concentrations of NMN and NAD+, and the postprandial serum insulin levels. The elevation levels of NMN and insulin varied widely among individuals. No adverse symptoms were observed in the participants. Oral administration of NMN elevates plasma levels of NMN and NAD+, and postprandial serum insulin levels.

Diallyl disulfide alleviates hypercholesterolemia induced by a western diet by suppressing endoplasmic reticulum stress in apolipoprotein E-deficient mice

BackgroundThe endoplasmic reticulum (ER) plays a pivotal role in maintaining cellular metabolic homeostasis. ER stress refers to the accumulation of misfolded proteins, which can trigger an unfolded protein response for survival or death in the cells. Diallyl disulfide (DADS), a major active compound in garlic, has many health benefits for patients with metabolic diseases, especially cardiovascular or fatty liver diseases. However, its role in attenuating hypercholesterolemia by suppressing ER stress remains unknown. Therefore, in this study, we determined whether DADS supplementation could reduce ER stress in apolipoprotein E-deficient (ApoE−/−) mice fed a Western-type diet (WD).MethodsApoE−/− mice were fed either a WD alone or a WD supplemented with 0.1% DADS for 12 weeks (n = 10). Levels of plasma total cholesterol, triglyceride, leptin, and insulin were determined. Western blotting was performed to measure protein levels involved in ER stress markers. Histology and Immunostaining were performed on aortic root sections to confirm the effect of DADS on histology and expression of ER chaperone protein GRP78.ResultsThe metabolic parameters showed that increases in fat weight, leptin resistance, and hypercholesterolemia were reversed in DADS-supplemented mice (p < 0.05). In addition, DADS ameliorated not only the protein of ER stress markers, phospho-eukaryotic initiation factor 2 subunit alpha and C/EBP homologous protein in the liver (p < 0.05) but also glucose-related protein 78 localization in the aorta.ConclusionsThis indicates that DADS inhibits diet-induced hypercholesterolemia, at least in parts by regulating ER stress markers. DADS may be a good candidate for treating individuals with diet-induced hypercholesterolemia.

Abstract #1412446: Pseudohypoglycemia in a Patient with Scleroderma with Minimal Skin Involvement

Point-of-care (POC) glucose monitor is often used in hospitalized patients and is a valuable tool for deciding therapy in cases of abnormal glucose levels. However, it has limitations in conditions such as Raynaud’s phenomenon, monoclonal gammopathies, leukemia, and peripheral hypoperfusion. (1). Here, we describe a patient whose results of POC were unreliable, resulting in overtreatment of hypoglycemia. A 76-year-old African American woman with a history of scleroderma, diagnosed after a skin biopsy was admitted for hypoglycemia. Her symptoms of scleroderma include significant esophageal dysmotility but minimal skin involvement. She was initially treated with hydroxychloroquine which improved her symptoms but discontinued after a few months when it was suspected of causing hypoglycemia. While in rehab for a pubic rami fracture, she was diagnosed with recurrent hypoglycemia and started on Diazoxide. She was transferred to our facility because of persistent hypoglycemia requiring a dextrose drip and multiple infusions of 25g of 50 percent glucose. Despite being on Diazoxide, she had remained hypoglycemic with POC blood glucose readings as low as 30-50 mg/dl. A 72-hour fast was initiated, and Diazoxide was stopped. A fasting blood sugar test off Diazoxide for four days showed discordant fingerstick and plasma blood glucose levels of 59 mg/dl and 138 mg/dl, respectively. Plasma levels of insulin (<1 uU/ml), proinsulin (1.6 pmol/L), and C-peptide (0.4 ng/ml) were appropriately low in the setting of a fast. Records from inpatient rehab showed three episodes of hypoglycemia measured by POC. However, all values of low glucose seen on POC testing had a corresponding normal plasma glucose level. We could not find an episode of hypoglycemia confirmed by a plasma glucose test. She had insulin and C-peptide levels checked several times, and none of them elevated in the setting of normal plasma glucose. Insulin levels ranged from 2.2-13.0 [2.6-24.9 uU/ml], and C-peptide levels ranged from 1.2-2.0 [1.1-4.4 ng/ml], all within normal limits. Additional workup for other etiologies of hypoglycemia showed normal cortisol stimulation test, low IGF-2, and elevated chromogranin A. This patient was diagnosed with hypoglycemia based on POC glucose levels only. If plasma glucose had been used to confirm hypoglycemia this patient could have been diagnosed with pseudohypoglycemia sooner and avoided unnecessary testing and medications. She was also treated for hypoglycemia with dextrose-containing intravenous fluids and Diazoxide. Treating hypoglycemia reflexively is understandable, given the significant risks of withholding treatment. However, Diazoxide likely contributed to this patient’s symptoms of nausea and anorexia already caused by her esophageal dysmotility. It is likely that the minimal skin involvement of her disease minimized the suspicion of psudohypoglycemia. It is worth mentioning that hydroxychloroquine, used for scleroderma management, was stopped for the presumed hypoglycemia. This case highlights the importance of confirming POC testing and evaluating for potential causes of discordant results.

Effect of Rebreathing-Induced Intermittent Hypoxia on Glucose Tolerance in Adults with Type 2 Diabetes

Hypoxia stimulates glucose uptake through an insulin-independent pathway. The aim of this study was to examine the acute effect of rebreathing-induced hypoxia on plasma glucose and insulin levels in adults with type 2 diabetes. We hypothesized that rebreathing-induced hypoxia would attenuate the increase in glucose and insulin levels during an oral glucose tolerance test. Nine individuals with type 2 diabetes (5 men, age: 53±10 years, body mass index: 35±7 kg/m2, HbA1c: 7.1±0.5%) visited the laboratory on two occasions. On both visits, a 2-hour, 75 g oral glucose tolerance test was conducted while simultaneously performing a rebreathing-induced hypoxia protocol (RIH) or breathing room air (Norm). Venous blood samples were collected 0, 30, 60, 90, and 120 min following ingestion of the high-glucose drink to measure plasma glucose and insulin levels. The rebreathing-induced hypoxia protocol consisted of two series of five 2-min rebreathing bouts in a low-volume, closed circuit system interspersed with two minutes of breathing room air. The first and second series of rebreathing bouts were performed within the first 30 min and 30-60 min after ingestion of the high-glucose drink, respectively. Rebreathing-induced hypoxia resulted in a nadir oxygen saturation of 88±4 % and a nadir fraction of inspired oxygen of 12±5%. Plasma glucose responses to the oral glucose tolerance test were not different between conditions, however, insulin levels were lower during rebreathing-induced hypoxia than normoxia (RIH vs. Norm: 0: 17±13 vs. 21 ±14; 30: 37 ±28 vs. 42±26; 60: 57±32 vs. 77±52; 90: 88±67 vs. 116±81; and 120: 114±96 vs. 136 ±111 ulU/ml, p=0.03), suggesting an acutely improved insulin sensitivity. Accordingly, the insulin area under the curve was lower during rebreathing-induced hypoxia than normoxia (124±84 vs. 157±102, p=0.02). In conclusion, exposure to short and intermittent rebreathing-induced hypoxia following the ingestion of a high-glucose drink acutely improves insulin sensitivity in adults with type 2 diabetes. Rebreathing-induced hypoxia could therefore represent a novel and simple strategy to improve glycemic control in individuals living with type 2 diabetes. College of Education Small Grants Program This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Plasma Insulin level have linkage with neurodegeneration in patients with type 2 DM

Introduction: Type 2 Diabetes Mellitus (DM2) viewed as a major cause for neurodegenerative and cognitive abnormalities. One of the possible reason for that should be insulin resistance and hyperinsulinemia two main clinical future of DM2. The mechanism relationship between insulin and development of diabetic neuropathy and encephalopathy not clear yet. Material and methods: In 51 DM2 patients in age between 42 and 64 years old, without neurologic complications or with presence of different stages of neuropathy/encephalopathy were observed clinically and diagnosis confirmed by neurologist. Patients divided into two groups according to presence of mild and severe neuropathy or encephalopathy. For lab study cubital venous blood plasma taken for measure of plasma insulin level by ELISA. Results: Neuropathy/encephalopathy were registered in 71% of DM2 patients. HbA1c level were higher than healthy subjects and were comparable in both groups with severe neuropathy/encephalopathy and without. Blood plasma insulin level were between 14 and 21,7 μU/ml, significantly higher than normal ranges (0,7 – 9,07 μU/ml). Plasma insulin level were decreased according to severity of neuropathy/encephalopathy, and suggested about linkage between functional activity of beta-cells and neurodegeneration. Index HOMA-B indicates decreasing of beta-cells functional activity. Index Caro (glucose to insulin ratio) also been decreased and suggested about insulin resistance in these patients. When we analysed blood plasma insulin level according to presence and severity of diabetic neuropathy and encephalopathy there was significant Conclusion: Neurodegeneration is a frequent future of DM2 and were found in 71% cases. Presence and severity of neurodegeneration in DM2 have negative linkage with plasma insulin level and suggest about involvement of insulin resistance into pathogenesis of neurodegeneration. no funding or grants This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Thermoneutral housing increases the obesogenic phenotype of mice, while some effects of exercise are reduced

Introduction: Mice are extensively used to investigate the molecular foundations of obesity and the beneficial effect of exercise training (ET). Mice are most often housed at ambient temperature, ~22°C, which is below their thermoneutral environment (~30°C). Mild cold stress at ambient temperature accelerates mouse metabolic rate and may confound translation of results to humans. Aiming to determine the metabolic adaptations of ET in an obesogenic environment, we hypothesized that thermoneutral housing would increase adiposity during high-fat feeding. Moreover, thermoneutral housing would blunt the effects of ET by relieving the added cold stress. Methods: After temperature acclimatization (3 weeks, 22°C vs. 30°C), C57BL/6J mice (n=68, ♀, Age: 11 weeks) were dual-housed for 8 weeks receiving a chow diet or a 60%E high-fat diet (HFD). HFD mice were then separated into two additional groups with access to voluntary wheel running for another 8 weeks. Metabolic parameters were measured using magnetic resonance imaging, indirect calorimetry, glucose tolerance tests, and maximal running capacity on treadmill. Brown and white adipose tissues and gastrocnemius muscle mRNA and protein content were analyzed using qPCR and immunoblotting analyses, respectively. Results: In chow-fed mice, thermoneutral housing decreased metabolic rate (VO2), fasting plasma glucose, and thermogenic genes in adipose tissue depots, without changes in skeletal muscle mitochondrial protein content compared to 22°C. In HFD mice, thermoneutral housing increased fat mass, induced glucose intolerance, and fasting plasma insulin levels compared to 22°C housing. This was despite decreased food intake and metabolic rate compared to HFD mice housed at 22°C. ET mice improved the exercise capacity and glucose tolerance independent of housing temperature. Interestingly, while ET at 30°C prevented further fat gain during the intervention, ET at 22°C decreased fat mass. Moreover, only ET at 22°C increased the metabolic rate during the active phase. Gene expression responded similarly to ET independent of housing temperature in adipose tissue depots. ET induced GLUT4, peroxiredoxin 2 and pyruvate dehydrogenase protein content to a lesser extent in muscle at 30°C housing. Conclusion: Adaptations to diet-induced obesity and ET in mice critically depend upon housing temperature. Our findings underscore housing temperature as a key consideration in research related the beneficial effect of exercise in an obesogenic environment. Disclosure of funding: SHR is supported by the Lundbeck Foundation and Independent Research Fund Denmark. LS and EAR are supported by the Novo Nordisk Foundation and Independent Research Fund Denmark. IK is supported by the Novo Nordisk Foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

HMC Ameliorates Hyperglycemia via Acting PI3K/AKT Pathway and Improving FOXO1 Pathway in ob/ob Mice

Type 2 diabetes is a disease characterized by hyperglycemia and is a growing health problem worldwide. Since many known diabetes drugs are side effects, it is necessary to develop natural substances with guaranteed safety. HM-chromanone isolated from Portulaca oleracea L. is a homoisoflavonoid compound. We investigated the effects of HM-chromanone on hyperglycemia and its mechanism in C57BL/6J ob/ob mice. C57BL/6J-Jms Slc mice were used as the control group, and C57BL/6J-ob/ob mice were divided into three groups: ob/ob (control), metformin (Met; positive control), and HM-chromanone (HMC). Fasting blood glucose was lower in the HMC group than those in the ob/ob group. Insulin resistance was improved by reducing HbA1c, plasma insulin, and HOMA-IR levels in the HMC group. HMC administration decreased the phosphorylation of IRS-1ser307 and increased the phosphorylation of IRS-1tyr612, PI3K, phosphorylation of AKTser473, and PM-GLUT4 in the skeletal muscles of ob/ob mice, indicating improved insulin signaling. HMC administration also increased the phosphorylation of FOXO1 in the liver of ob/ob mice. This inhibited PEPCK and G6pase involved in gluconeogenesis and regulated phosphorylation of glycogen synthase kinase 3β and glycogen synthase involved in glycogen synthesis. In conclusion, HM-chromanone ameliorates hyperglycemia by PI3K/AKT and improves the FOXO1 in ob/ob mice.

Effect of Tinospora cordifolia on gestational diabetes mellitus and its complications

ABSTRACT Ayurvedic system of medicine uses giloy or guduchi, also known as Tinospora cordifolia (TC), to treat diabetes and related diseases like hyperglycemia and hyperlipididemia. However, its usage in gestational diabetes mellitus (GDM) is not well studied. The primary objective of the study was to examine the effects of water extract of TC called satva, essential oil, and hydroalcoholic (HA) extract on GDM and its complications and to explore their mechanism of action using mice model. We used streptozotocin-induced diabetes in pregnant mice as murine model and tested TC preparations for anti-GDM activities. Blood glucose, insulin, litter size, and placental weight were assessed. ELISA method was used to measure plasma insulin level to compute homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and homeostatic model assessment for assessing beta cell function (HOMA-Beta) levels to estimate insulin resistance, insulin sensitivity, and beta cell function respectively. TC-treated groups had significantly higher serum insulin levels, QUICKI, average litter size, and lower placental weight (p < .001). TC oil and HA extract increased pancreatic beta cell activity according to the level of HOMA-Beta. TC lowered placenta weight and increased litter size significantly compared to control group. Our findings suggest that TC preparations preserve pancreatic beta cells, increase insulin production, decrease insulin resistance, and improve beta cell function, hence preventing GDM. TC preparations also reduced placental weight and increased litter size in mice. Based on these results, we recommend the clinical trial and testing of TC preparations for management of GDM and associated complications. Refer graphical abstract (Figure S1).

Plasma Insulin Concentration in Newborns and Children and Age at Menarche.

To investigate the association of plasma insulin levels and their trajectories from birth to childhood with the timing of menarche. This prospective study included 458 girls recruited at birth between 1998 and 2011 and followed prospectively at the Boston Medical Center. Plasma nonfasting insulin concentrations were measured at two time points: at birth (cord blood) and in childhood (age 0.5-5 years). Age at menarche was obtained from a pubertal developmental questionnaire or abstracted from electronic medical records. Three hundred six (67%) of the girls had reached menarche. The median (range) age at menarche was 12.4 (9-15) years. Elevated plasma insulin concentrations at birth (n = 391) and in childhood (n = 335) were each associated with an earlier mean age at menarche: approximately 2 months earlier per doubling of insulin concentration (mean shift, -1.95 months, 95% CI, -0.33 to -3.53, and -2.07 months, 95% CI, -0.48 to -3.65, respectively). Girls with overweight or obesity in addition to elevated insulin attained menarche about 11-17 months earlier, on average, than those with normal weight and low insulin. Considering longitudinal trajectories (n = 268), having high insulin levels both at birth and in childhood was associated with a roughly 6 months earlier mean age at menarche (mean shift, -6.25 months, 95% CI, -0.38 to -11.88), compared with having consistently low insulin levels at both time points. Our data showed that elevated insulin concentrations in early life, especially in conjunction with overweight or obesity, contribute to the earlier onset of menarche, suggesting the need for early screening and intervention.