Increased Plasma Insulin Research Articles

Protective effects of swimming exercises and metformin on cardiac and aortic damage caused by a high-fat diet in obese rats with type 2 diabetes, by regulating the Bcl2/Bax signaling pathway.

Due to the increasing mortality and morbidity rates in diabetes mellitus (DM), which is one of the biggest health problems of our age, many treatment modalities are still being tried. The positive effects of metformin (MET) and physical exercise (EXE) on the pathophysiology of diabetes are well known. In this study, it was aimed to detail these positive effects of MET and EXE in combination on the basis of inflammation, apoptosis mechanisms, and endogen nesfatin-1 (NES-1) synthesis. Twenty-seven type 2 DM (DM-2) male Wistar Albino rats were divided into 4 groups, as the high-fat diet (HFD), MET, EXE, and MET+EXE groups. The total duration of the study was 3 months. At the end of the experiment, blood glucose and lipid profiles were measured. Histopathological evaluation was performed on the cardiac and aortic tissues and apoptotic markers were evaluated immunohistochemically. Inflammatory markers and NES-1 levels were analyzed by enzyme-linked immunosorbent assay. The plasma glucose, homeostatic model evaluation-insulin resistance (HOMA-IR), low-density lipoprotein (LDL) levels increased, and high-density lipoprotein (HDL) levels decreased significantly in the HFD group. In the treatment groups, the glucose, HOMA-IR, LDL, NES-1 levels in the plasma, as well as tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, caspase-3 (Cas-3), Bcl-2-associated X protein (Bax), and histopathological findings of inflammation in tissues were decreased. Additionally, there was an increase in plasma insulin, HDL, and tissue B-cell lymphoma-2 and levels. It was observed that the MET and EXE treatments in the DM-2 model reduced cellular damage mechanisms such as inflammation and apoptosis. The decrease in NES-1 levels was thought to be secondary to this antiinflammatory effect. In conclusion, the results demonstrated the effectiveness of EXE in reducing DM-2 and the NES-1 levels. Further studies are needed to evaluate the effect in different EXE models and treatment durations.

Polymorphisms in insulin pathway genes and cancer risk

Background: Insulin is a big hormone (5808 Da) generally produced with the aid of the pancreas. Insulin receptors (IR) are found in neurons and glial cells. Insulin resistance has been related to increased plasma insulin levels, glucose intolerance, elevated insulin-like growth factor-1 (IGF-I), glucose and free fatty acids, body mass index, and an elevated risk for colorectal cancers. Proinflammatory cytokines, boom components, and hormones secreted by adipocytes play a key role in colorectal cancer etiology. Acetyl-CoA acetyltransferase (ACAT1) mediates insulin-precipitated cell proliferation and metastatic outcomes in colorectal cancer cells. Therefore, miRNAs might serve as a biological connection between metabolic changes linked to obesity and the beginning and progression of Colorectal Cancer Cancer (CRC). Furthermore, these findings shed new light on weight problems as a CRC danger component in which miRNA dysregulation may be involved. The function of IGFs in CRC is investigated by examining the association of two genetic polymorphisms in IGFBP-3 (a G → C single nucleotide polymorphism) and IGF-1 (a cytosine-adenosine dinucleotide repeat) with CRC risk in addition to the possibility of the other interventions, including physical activity, body mass index (BMI), and the use of postmenopausal hormones. These factors can exert their effects by modifying IGF-1 and the related binding proteins (IGFBP). Furthermore, the IGFBP-3 genotype can lead to a substantial effect modifier in the association between CRC and risk factors. It has been found that functional polymorphisms in the pathway of insulin genes, including IGFBPI, INSR, INS, and insulin receptor substrates 1 and 2 (IRS1 and IRS2), can be related to CRC.

RANKL/RANK is required for cytokine-induced beta cell death; osteoprotegerin, a RANKL inhibitor, reverses rodent type 1 diabetes.

Treatment for type 1 diabetes (T1D) requires stimulation of functional β cell regeneration and survival under stress. Previously, we showed that inhibition of the RANKL/RANK [receptor activator of nuclear factor kappa Β (NF-κB) ligand] pathway, by osteoprotegerin and the anti-osteoporotic drug denosumab, induces rodent and human β cell proliferation. We demonstrate that the RANK pathway mediates cytokine-induced rodent and human β cell death through RANK-TRAF6 interaction and induction of NF-κB activation. Osteoprotegerin and denosumab protected β cells against this cytotoxicity. In human immune cells, osteoprotegerin and denosumab reduce proinflammatory cytokines in activated T-cells by inhibiting RANKL-induced activation of monocytes. In vivo, osteoprotegerin reversed recent-onset T1D in nonobese diabetic/Ltj mice, reduced insulitis, improved glucose homeostasis, and increased plasma insulin, β cell proliferation, and mass in these mice. Serum from T1D subjects induced human β cell death and dysfunction, but not α cell death. Osteoprotegerin and denosumab reduced T1D serum-induced β cell cytotoxicity and dysfunction. Inhibiting RANKL/RANK could have therapeutic potential.

Probiotic Escherichia coli Nissle 1917-derived outer membrane vesicles modulate the intestinal microbiome and host gut-liver metabolome in obese and diabetic mice.

Obesity and diabetes are common chronic metabolic disorders which can cause an imbalance of the intestinal flora and gut-liver metabolism. Several studies have shown that probiotics, including Escherichia coli Nissle 1917 (EcN), promote microbial balance and metabolic health. However, there are no studies on how EcN outer membrane vesicles (EcN-OMVs) influence the intestinal microflora and affect the metabolic disorders of obesity and diabetes. In this study, we evaluated the effects of EcN-OMVs on high-fat diet (HFD)-induced obesity and HFD + streptozotocin (STZ)-induced diabetes. EcN-OMVs could reduce body weight, decrease blood glucose, and increase plasma insulin in obese mice. Similarly, EcN-OMVs treatment could modify the ratio of Firmicutes/Bacteroidetes in the gut, elevate intestinal short-chain fatty acid (SCFA)-producing flora, and influence the SCFA content of the intestine. Furthermore, the intestinal metabolites ornithine and fumaric acid, hepatic ω-6 unsaturated fatty acids, and SCFAs were significantly increased after administering EcN-OMVs. Overall, this study showed that EcN-OMVs might act as post-biotic agents that could modulate gut-liver metabolism and ameliorate the pathophysiology of obesity and diabetes.

Sugar signals from oral glucose transporters elicit cephalic-phase insulin release in mice

Cephalic-phase insulin release (CPIR) occurs before blood glucose increases after a meal. Although glucose is the most plausible cue to induce CPIR, peripheral sensory systems involved are not fully elucidated. We therefore examined roles of sweet sensing by a T1R3-dependent taste receptor and sugar sensing by oral glucose transporters in the oropharyngeal region in inducing CPIR. Spontaneous oral ingestion of glucose significantly increased plasma insulin 5 min later in wild-type (C57BL/6) and T1R3-knockout mice, but intragastric infusion did not. Oral treatment of glucose transporter inhibitors phlorizin and phloretin significantly reduced CPIR after spontaneous oral ingestion. In addition, a rapid increase in plasma insulin was significantly smaller in WT mice with spontaneous oral ingestion of nonmetabolizable glucose analog than in WT mice with spontaneous oral ingestion of glucose. Taken together, the T1R3-dependent receptor is not required for CPIR, but oral glucose transporters greatly contribute to induction of CPIR by sugars.

Effects of creatine supplementation on strength exercise and its optimization through carbohydrates: A review

Nutritional supplements integrated with any physical or sports activity are substances aimed at increasing physical performance, improving physical effort efficiency, enhancing physical recovery processes after intense exertion, enhancing training quality, and facilitating physiological adaptations. Among the most commonly used supplements is creatine (CR), a non-essential nitrogenous compound formed by three amino acids: glycine, arginine, and methionine, whose main benefit lies in improving performance in high-intensity activities. The consumption of CR along with carbohydrate (CHO) sources promotes supplement absorption compared to isolated consumption due to increased plasma insulin levels. The human body can absorb approximately 25% more CR when ingested with a CHO source. This review aimed to provide an expanded outlook on the consumption of CR combined with CHO sources and its relationship with increased CR transport into muscle cells in individuals engaging in strength exercises. Studies have shown that the increase or improvement in CR absorption by muscle cells may be related to increased blood glucose levels and consequent insulin release, which acts in a co-dependent and direct manner on the membrane transporter that regulates the entry of CR together with sodium into the intracellular environment, demonstrating that CHO supplementation is not necessary every time CR is consumed, but instead that this improvement consists of increased serum glucose and insulin release.

Metabolic dysfunctions following chronic oral corticosterone are modified by adolescence and sex in mice

Adolescence is a period of development in which shifts in responses to glucocorticoids is well-documented. Obesity and metabolic syndrome are substantial health issues whose rates continue to rise in both adult and adolescent populations. Though many interacting factors contribute to these dysfunctions, how these shifts in glucocorticoid responses may be related remain unknown. Using a model of oral corticosterone (CORT) exposure in male and female mice, we demonstrate differential responses during adolescence (30–58 days of age) or adulthood (70–98 day of age) in endpoints relevant to metabolic function. Our data indicate that CORT resulted in significant weight gain in adult- and adolescent-exposed females and adult-exposed males, but not adolescent-exposed males. Despite this difference, all animals treated with high levels of CORT showed significant increases in white adipose tissue, indicating a dissociation between weight gain and adiposity in adolescent-treated males. Similarly, all experimental groups showed significant increases in plasma insulin, leptin, and triglyceride levels, further suggesting potential disconnects between overt weight gain, and underlying metabolic dysregulation. Finally, we found age- and dose-dependent changes in the expression of hepatic genes important in glucocorticoid receptor and lipid regulation, which showed different patterns in males and females. Thus, altered transcriptional pathways in the liver might be contributing differentially to the similar metabolic phenotype observed among these experimental groups. We also show that despite little CORT-induced changes in the hypothalamic levels of orexin-A and NPY, we found that food and fluid intake were elevated in adolescent-treated males and females. These data indicate chronic exposure to elevated glucocorticoid levels results in metabolic dysfunction in both males and females, which can be further modulated by developmental stage.

Effect of madecassoside in reducing oxidative stress and blood glucose in streptozotocin-nicotinamide-induced diabetes in rats.

Madecassoside (MAD) is a triterpenoid constituent of Centella asiatica (L.) Urb., an ethnomedical tropical plant, extracts of which were shown to reduce blood glucose in experimental diabetes. This study examines MAD for its anti-hyperglycaemic effects and tests the hypothesis that it reduces the blood glucose in experimentally induced diabetic rats by protecting the β-cells. Diabetes was induced using streptozotocin (60 mg/kg, i.v.) followed by nicotinamide (210 mg/kg, intraperitoneal (i.p.)). MAD (50 mg/kg) was administered orally for 4 weeks, commencing 15 days after induction of diabetes; resveratrol (10 mg/kg) was used as a positive control. Fasting blood glucose, plasma insulin, HbA1c, liver and lipid parameters were measured, along with antioxidant enzymes and malondialdehyde as an index of lipid peroxidation; histological and immunohistochemical studies were also undertaken. MAD normalized the elevated fasting blood glucose levels. This was associated with increased plasma insulin concentrations. MAD alleviated oxidative stress by improving enzymatic antioxidants and reducing lipid peroxidation. Histopathological examination showed significant recovery of islet structural degeneration and an increased area of islets. Immunohistochemical staining showed increased insulin content in islets of MAD-treated rats. The results demonstrate an antidiabetic effect of MAD associated with preservation of β-cell structure and function.

Effect of Glipizide on non-insulin-dependent diabetes mellitus

Type 2 diabetes mellitus, sometimes referred to as non-insulin-dependent diabetes, (NIDDM). The patient was unable to secrete enough insulin, resulting in elevated blood glucose. Complications during a patient's diseases are common in type 2 diabetes patients. Common type 2 diabetes does not have an age or gender difference. Patients with type 2 diabetes or those under treatment are frequently fat and sedentary. Glipizide, a sulfonylurea medication, is prescribed to people with non-insulin-dependent diabetic mellitus. (type 2 diabetes). There are two common types, oral tablets and sustained-release tablets. The common type of oral tablets is fast-acting tablets. Absorption is rapid and the effect is rapid, because oral tablets have a significant effect and may cause short-term hypoglycemia. The body disintegrates the medication and release it. A contributing factor to type 2 diabetes is having high blood glucose levels, as the pancreas produces less insulin, resulting in a residual overall glucose in the blood. These disorders are often caused by genetics or overweight/physical inactivity . The blood glucose levels of patients with type 2 diabetes are greater than those of ordinary healthy individuals since the condition is a chronic metabolic disorder. Glipizide can be used as an insulin secretagogue to stimulate islet β cells to release insulin, thereby increasing plasma insulin concentration. It also serves as an auxiliary hand in diet and exercise. Different regions have different laws for the use of glipizide. Glipizide can be used in combination with other NIDDM drugs in the United States. It can only be used alone or not in the United Kingdom because of the high risk of aggravating hypoglycemia in patients. Patients who have any cardiovascular or renal disease or have a long history do not mind using these drugs. Such agents are likely to worsen the hypoglycemia associated with the disease. Among many drugs, glipizide is one of the most common sulfonylureas and has a moderate price.

Plasma insulin is required for the increase in plasma angiopoietin-like protein 8 in response to nutrient ingestion.

Plasma levels of angiopoietin-like protein 8 (ANGPTL8) are regulated by feeding and they increase following glucose ingestion. Because both plasma glucose and insulin increase following food ingestion, we aimed to determine whether the increase in plasma insulin and glucose or both are responsible for the increase in ANGPTL8 levels. ANGPTL8 levels were measured in 30 subjects, 14 with impaired fasting glucose (IFG), and 16 with normal fasting glucose (NFG); the subjectsreceived 75g glucose oral Glucose tolerance test (OGTT), multistep euglycaemic hyperinsulinemic clamp and hyperglycaemic clamp with pancreatic clamp. Subjects with IFG had significantly higher ANGPTL8 than NGT subjects during the fasting state (p<0.05). During the OGTT, plasma ANGPTL8 concentration increased by 62% above the fasting level (p<0.0001), and the increase above fasting in ANGPTL8 levels was similar in NFG and IFG individuals. During the multistep insulin clamp, there was a dose-dependent increase in plasma ANGPTL8 concentration. During the 2-step hyperglycaemic clamp, the rise in plasma glucose concentration failed to cause any change in the plasma ANGPTL8 concentration from baseline. In response to nutrient ingestion, ANGPTL8 level increased due to increased plasma insulin concentration, not to the rise in plasma glucose. The incremental increase above baseline in plasma ANGLPTL8 during OGTT was comparable between people with normal glucose tolerance and IFG.

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.

Blocking soluble TNF decreases diet‐induced hyperglycemia and modulates immune alterations in 5xFAD animal model of Alzheimer’s disease

AbstractBackgroundRegulatory interactions between the gut and the brain are essential for energy homeostasis across systems. Current evidence indicates high‐fat, high‐carbohydrate diets (HFHC) impact Alzheimer’s disease (AD) pathophysiology, however, the mechanisms underlying this association are poorly understood. We hypothesize that (1) Tumor Necrosis Factor (TNF) mediates metabolic inflammation in an obesogenic environment with impacts across the gut‐brain axis and (2) that HFHC interacts with an AD‐relevant genetic background to promote metabolic and immune dysregulation that accelerates pathological and behavioral dysfunction in an animal model of AD.MethodTo investigate the effects of chronic systemic inflammation on AD‐associated pathology, 2‐month old female 5xFAD mice were fed HFHC or a control diets (CD) for 8 weeks. One month following dietary intervention, the brain‐permeant soluble TNF inhibitor XPro1595 or a brain‐impermeant pan (sol and membrane‐bound) TNF inhibitor Etanercept (Enbrel, Amgen‐Wyeth) or vehicle (saline) were dosed twice weekly for 4 weeks. Behavioral test were performed to assess cognitive parameters. Plasma, brain and gut were collected for evaluation of insulin impairment, metabolic and immune parameters. Cortical tissues were subjected to RNAseq analysis to determine gene pathways modified by interactions between diet, genotype, and TNF inhibition.ResultHFHC promoted metabolic syndrome features associated with increases in adiposity, body weight, and plasma glucose, cholesterol, leptin, and insulin. TNF inhibition did not rescue diet‐induced insulin increases, however XPro specifically reduced plasma glucose, while Enbrel increased HOMA‐IR in HFHC‐fed mice. HFHC diet increased circulating IL‐6, CXCL1, CXCL2 and CCL2 and TNF neutralization with either drug decreased IL‐6 in HFHC‐fed groups. In the colon, HFHC diet decreased CCL3 and TNF blockade increased colonic IL‐15 in HFHC‐fed mice. Ongoing behavioral assessment, cortical transcriptional analysis, and hippocampal protein profiles of insulin signaling and inflammatory markers will determine additional effects of TNF and HFHC in the 5XFAD animal model of AD.ConclusionCollectively, these results suggest that TNF modulates systemic metabolic and inflammatory pathways induced by HFHC consumption and associated with neurodegeneration and neuroinflammation. Blocking soluble TNF decreases hyperglycemia triggered during diet‐induce obesity. Future studies focusing on the impact of TNF on energy homeostasis and inflammation will provide targets for new therapeutics against neurological disease.

Abomasal infusion of oleic acid and exogenous emulsifier alter fatty acid digestibility and production responses of lactating dairy cows

We evaluated the effects of abomasal infusion of cis-9 C18:1 (oleic acid) and an exogenous emulsifier (polysorbate-C18:1) on fatty acid (FA) digestibility and production responses of dairy cows. Eight rumen-cannulated multiparous cows (96 ± 23 d in milk) were assigned to a 2 × 2 factorial arrangement of treatments in 4 × 4 Latin squares with 18-d periods consisting of 7 d of washout and 11 d of infusion. Treatments were abomasal infusions of water carrier only (CON), 45 g/d oleic acid (OA), 20 g/d polysorbate-C18:1 (T80), or both 45 g/d OA and 20 g/d T80 (OA+T80). The OA treatments were dissolved in ethanol and the T80 treatments in water. To deliver the daily dose for each treatment, the infusate solution was divided into 4 equal infusions per day, occurring every 6 h. Cows were fed the same diet, which contained [% of dry matter (DM)] 30.3% neutral detergent fiber (NDF), 16.3% crude protein, 30% starch, and 3.2% FA (including 1.8% DM from a FA supplement containing 34.4% C16:0 and 47.7% C18:0). Infusion of T80 increased NDF digestibility compared with all other treatments (3.57 percentage units), whereas OA+T80 decreased NDF digestibility compared with CON (3.30 percentage units). Compared with CON, OA (4.90 percentage units) and T80 (3.40 percentage units) increased total FA digestibility, whereas OA+T80 had no effect on total FA digestibility. We did not observe differences between OA and T80 for total FA digestibility. Infusion of OA (3.90 percentage units) and T80 (2.80 percentage units) increased 16-carbon FA digestibility compared with CON. Digestibility of 16-carbon FA did not differ between OA and T80 or between CON and OA+T80. Compared with CON, OA increased (5.60 percentage units) and T80 tended to increase 18-carbon FA digestibility. Digestibility of 18-carbon FA did not differ between OA and T80 or between CON and OA+T80. Compared with CON, all treatments increased or tended to increase the absorption of total and 18-carbon FA. Infusion of OA and T80 increased the yields of milk fat (both increased 0.10 kg/d), 3.5% fat-corrected milk (1.90 and 2.50 kg/d), and energy-corrected milk (1.80 and 2.60 kg/d) compared with CON. We did not observe differences between OA and T80 or between CON and OA+T80 for yields of milk fat, 3.5% fat-corrected milk, or energy-corrected milk. Infusing OA tended to increase plasma insulin concentration compared with CON. Compared with the other treatments, OA+T80 decreased the yield of de novo milk FA (31.3 g/d). Compared with CON, OA tended to increase the yield of de novo milk FA. Compared with OA+T80, CON and OA tended to increase the yield of mixed milk FA, whereas T80 increased it (83 g/d). Compared with CON, all emulsifier treatments increased the yield of preformed milk FA (52.7 g/d). In conclusion, abomasally infusing either 45 g of OA or 20 g of T80 improved digestibility and similarly favored the production parameters of dairy cows. In contrast, providing both (45 g of OA + 20 g of T80) had no additional benefits and moderated the positive responses observed in the individual treatments with OA and T80.

The SGLT2 inhibitor, empagliflozin reduces early progressive proteinuria in obese SS rats

Childhood/prepubertal obesity (PPO) is a world-wide epidemic and is considered a risk factor for renal injury. Therefore, there is a need to control this trend to decrease the future risk of chronic kidney disease. Recently, we reported that the SS LepR mutant rat is a novel model to study the mechanisms of renal injury associated with PPO. The SS LepR mutant rat develops progressive renal injury in the absence of hyperglycemia before puberty. SGLT2 inhibitors have been demonstrated to exert renoprotective effects independent of lowering blood glucose. Therefore, the objective of this study was to determine the effects of SGLT2 blockade with empagliflozin on the early progression of proteinuria in SS LepR mutant rats, during PPO. Four-week-old SS and SS LepR mutant rats (n = 5/group) were either treated with vehicle (diet) or empagliflozin (30 mg/kg/day, orally) for four weeks. While the SS LepR mutant rats had significantly higher body weights vs SS rats, there were no detectable differences in body weight or blood glucose levels in response to empagliflozin treatment in SS LepR mutant rats. We observed a significant increase in plasma insulin in control SS LepR mutant rats vs SS rats (7±1 vs 1±0.3 ng/mL, respectively, p&lt;0.05), and treatment with empagliflozin did not have any effect on plasma insulin in SS LepR mutant rats (8±2 ng/mL). At baseline, we did not observe any significant difference in urine flow rate between control SS LepR mutant vs SS rats. After two weeks of treatment, while there was no observed difference in urine flow rate between SS LepR mutant and SS rats (17±3 ml/day vs 18±2 ml/day, respectively), empagliflozin significantly increased urine flow rate in SS LepR mutant rats (29±4 ml/day, p&lt;0.05), but not in SS rats (17±3 ml/day). At baseline, we observed a difference in proteinuria between control SS LepR mutant vs SS rats (68±11 vs 6±3 mg/day, respectively, p&lt;0.05), which remained elevated over the course of the study (471±75 vs 32±5 mg/day, respectively, p&lt;0.05). Treatment with empagliflozin significantly decreased proteinuria in SS LepR mutant rats (223±52 mg/day, p&lt;0.05) without affecting SS rats (27±8 mg/day). At the end of the study, we observed a significant increase in GFR in control SS LepR mutant rats vs SS rats (2.4±0.6 vs 0.5 mL/min/gkwt, respectively, p&lt;0.05). Treatment with empagliflozin only significantly reduced GFR in SS LepR mutant rats (0.9±0.2 mL/min/gkwt, p&lt;0.05). In conclusion, these data suggest that empagliflozin attenuates renal hyperfiltration and confers renoprotective effects during the early progression of renal disease associated with PPO. DK109133 and HL151407 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.

Role for insulin sensitivity in the cerebrovascular response to hyperinsulinemia in young adults

Objective: Cerebral blood flow is highly regulated and cerebrovascular responsiveness to vasodilatory stimuli is predictive of brain health. In preclinical animal models, insulin elicits cerebrovascular dilation and subsequent increases in cerebral blood flow. Contrary to this, preliminary data from our group in a large cohort of healthy humans indicate surrogate measures of cerebral blood flow remain at baseline levels during hyperinsulinemia – although responses were highly variable. In the peripheral circulation, insulin-stimulated vasodilation is closely associated with markers of insulin sensitivity (e.g., elevated fasting glucose, insulin, HOMA-IR); whether these associations translate to the cerebral circulation remains unclear. With this information in mind, we hypothesized the degree of insulin-mediated increases in cerebral blood flow would correlate with indices of peripheral insulin sensitivity.Methods: Middle cerebral artery blood velocity (MCAv) was measured with transcranial Doppler ultrasound in 17 adults (11M/6F, 28±2 yrs, 24±1 kg/m 2 ) at baseline and following a 60-min hyperinsulinemic (40 mU/m 2 body surface area/min), euglycemic infusion. Correlations between MCAv and indices of peripheral insulin sensitivity [i.e., fasting glucose, insulin, HOMA-IR, glucose infusion rate, weight, body mass index (BMI), age, physical activity] were determined. Results: Intravenous insulin infusion increased plasma insulin concentrations (6±1 to 49±3 μIU/mL, p&lt;0.001) with blood glucose maintained (73±4 to 82±6 mg/dL, p=0.196). There was no net change in MCAv during hyperinsulinemia (60±4 to 60±4 cm/s, p=0.930). We observed negative associations between the change in MCAv during hyperinsulinemia (Δ=Insulin–Baseline) and both body weight (R=-0.49, p=0.047) and BMI (R=-0.50, p=0.040). No correlations between ΔMCAv and fasting glucose (p=0.435), insulin (p=0.733), HOMA-IR (p=0.960), age (p=0.132), physical activity (p=0.179), or glucose infusion rate (p=0.599) were observed. Conclusions: As previously shown in these participants, hyperinsulinemia in young adults elicits no net change in MCAv. Any increases in MCAv during hyperinsulinemia occur primarily in individuals with lower body weight and lower BMI. Future studies are needed to translate results to disease states (e.g., diabetes). Margaret W. Mangel Faculty Research Catalyst Fund (JP, JKL), NIH HL137769 (JP), NIH HL130339 (JKL) 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.

Potential impact of Novel Polyherbal Formulations on Streptozotocin-Nicotinamide Induced Diabetic wistar rats

Diabetes is a chronic and group of metabolic disease which might lead to severe associated complications. Many synthetic anti-diabetic drugs used in first line treatment does not significantly control nor protect other organs from diabetes associated damage, but it increases the risk of developing complications due to their adverse effects. Hence, present research was designed to develop and evaluate polyherbal anti-diabetic formulations for the management of diabetes and its complications associated with liver, kidney and hematological parameters. Ethanolic extracts (50%) of four plants including calyx of Hibiscus sabdariffa (H), leaves of Annona squamosa (A), stem bark of Ficus religiosa (F) and leaves of Aegle marmelos (A), i.e., HAFA, were used for development of formulations by using geometrical dilution methods, which were named HAFA 1 to HAFA 24. To identify the most effective formulations, they were evaluated using oral glucose tolerance test (OGTT) in normal rats. Four most effective HAFA formulations selected were subjected to hypoglycemic study in normal rats, acute and sub-acute anti-hyperglycemic activity in streptozotocin-nicotinamide induced diabetic rats. HAFA formulations were further evaluated for the parameters like body weight change, food and water intake and biochemical parameters like lipid profile, cardiovascular risk and complete blood count using standard parameters. From the hypoglycemic studies of four most effective HAFA formulation, it was revealed that a single dose of HAFA 2, 4, 8 and 10 did not reduced the blood glucose below the normal level, whereas glibenclamide did and caused hypoglycemia. Streptozotocin-nicotinamide induced anti-hyperglycemic studies revealed that HAFA potentially reduced and maintained blood glucose level to near normal. Out of four formulations, HAFA 4 not only showed significant result in hypoglycemic study, but it also showed significant activities in both acute and sub acute anti-hyperglycemic study. In acute study HAFA 4 reduced fasting blood glucose by 48.96%, in sub-acute study reduction was observed 75.34% followed by HAFA 10, 2 and 8. Apart from that HAFA 4 significantly reversed and improved body weight change by 23% and water and food intake by 45 and 58%. HAFA 4 formulation significantly acted on biochemical parameters and increased plasma insulin by approx 117%, decreased HOMA-IR by 42%, HbA1c by 58% and significantly reversed the alteration of complete blood count, thus prevented from anemia. HAFA 4 significantly reverted the altered lipid profile to near normal. Thus, by research study it was concluded that, HAFA 4 formulations significantly improved glucose tolerance and effectively controlled blood glucose, without causing hypoglycemia. It significantly improved mean body weight, normalized food and water intake, corrected diabetes induced anemia, and reversed the altered lipid profile to near normal after 28 days of continuous treatment. Thus HAFA 4 was considered to be safer and effective antidiabetic with potential to prevent development of other associated complications.

Soluble insulin receptor and metabolic syndrome.

The metabolic syndrome describes a group of signs that increase the likelihood for developing type 2 diabetes mellitus, cardiovascular diseases and some types of cancer. The action of insulin depends on its binding to membrane receptors on its target cells. We wonder if blood insulin could travel bound to proteins and if, in the presence of hyperinsulinemia, a soluble insulin receptor might be generated. We used young adult Wistar rats (which have no predisposition to obesity or diabetes), whose drinking water was added 20 % of sugar and that were fed a standard diet ad libitum for two and six months. They were compared with control rats under the same conditions, but that had running water for consumption. At two months, the rats developed central obesity, moderate hypertension, high triglyceride levels, hyperinsulinemia, glucose intolerance and insulin resistance, i.e., metabolic syndrome. Electrophoresis of the rats' plasma proteins was performed, followed by Western Blot (WB) for insulin and for the outer portion of the insulin receptor. The bands corresponding to insulin and to the receptor external part were at the same molecular weight level, 25-fold higher than that of free insulin. We demonstrated that insulin, both in control animals and in those with hyperinsulinemia, travels bound to the receptor outer portion (ectodomain), which we called soluble insulin receptor, and that is released al higher amounts in response to plasma insulin increase; in rats with metabolic syndrome and hyperinsulinemia, plasma levels are much higher than in controls. Soluble insulin receptor increase in blood might be an early sign of metabolic syndrome.

The Protective Effect of 11-Keto-β-Boswellic Acid against Diabetic Cardiomyopathy in Rats Entails Activation of AMPK

This study examined the protective effect of 11-keto-β-boswellic acid (AKBA) against streptozotocin (STZ)-induced diabetic cardiomyopathy (DC) in rats and examined the possible mechanisms of action. Male rats were divided into 5 groups (n = 8/each): (1) control, AKBA (10 mg/kg, orally), STZ (65 mg/kg, i.p.), STZ + AKBA (10 mg/kg, orally), and STZ + AKBA + compound C (CC/an AMPK inhibitor, 0.2 mg/kg, i.p.). AKBA improved the structure and the systolic and diastolic functions of the left ventricles (LVs) of STZ rats. It also attenuated the increase in plasma glucose, plasma insulin, and serum and hepatic levels of triglycerides (TGs), cholesterol (CHOL), and free fatty acids (FFAs) in these diabetic rats. AKBA stimulated the ventricular activities of phosphofructokinase (PFK), pyruvate dehydrogenase (PDH), and acetyl CoA carboxylase (ACC); increased levels of malonyl CoA; and reduced levels of carnitine palmitoyltransferase I (CPT1), indicating improvement in glucose and FA oxidation. It also reduced levels of malondialdehyde (MDA); increased mitochondria efficiency and ATP production; stimulated mRNA, total, and nuclear levels of Nrf2; increased levels of glutathione (GSH), heme oxygenase (HO-1), superoxide dismutase (SOD), and catalase (CAT); but reduced the expression and nuclear translocation of NF-κB and levels of tumor-necrosis factor-α (TNF-α) and interleukin-6 (IL-6). These effects were concomitant with increased activities of AMPK in the LVs of the control and STZ-diabetic rats. Treatment with CC abolished all these protective effects of AKBA. In conclusion, AKBA protects against DC in rats, mainly by activating the AMPK-dependent control of insulin release, cardiac metabolism, and antioxidant and anti-inflammatory effects.

Stimulatory effect of imeglimin on incretin secretion.

Imeglimin is a new antidiabetic drug structurally related to metformin. Despite this structural similarity, only imeglimin augments glucose-stimulated insulin secretion (GSIS), with the mechanism underlying this effect remaining unclear. Given that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) also enhance GSIS, we examined whether these incretin hormones might contribute to the pharmacological actions of imeglimin. Blood glucose and plasma insulin, GIP, and GLP-1 concentrations were measured during an oral glucose tolerance test (OGTT) performed in C57BL/6JJcl (C57BL/6) or KK-Ay/TaJcl (KK-Ay) mice after administration of a single dose of imeglimin with or without the dipeptidyl peptidase-4 inhibitor sitagliptin or the GLP-1 receptor antagonist exendin-9. The effects of imeglimin, with or without GIP or GLP-1, on GSIS were examined in C57BL/6 mouse islets. Imeglimin lowered blood glucose and increased plasma insulin levels during an OGTT in both C57BL/6 and KK-Ay mice, whereas it also increased the plasma levels of GIP and GLP-1 in KK-Ay mice and the GLP-1 levels in C57BL/6 mice. The combination of imeglimin and sitagliptin increased plasma insulin and GLP-1 levels during the OGTT in KK-Ay mice to a markedly greater extent than did either drug alone. Imeglimin enhanced GSIS in an additive manner with GLP-1, but not with GIP, in mouse islets. Exendin-9 had only a minor inhibitory effect on the glucose-lowering action of imeglimin during the OGTT in KK-Ay mice. Our data suggest that the imeglimin-induced increase in plasma GLP-1 levels likely contributes at least in part to its stimulatory effect on insulin secretion.

Cannabidiol treatment improves metabolic profile and decreases hypothalamic inflammation caused by maternal obesity.

The implications of maternal overnutrition on offspring metabolic and neuroimmune development are well-known. Increasing evidence now suggests that maternal obesity and poor dietary habits during pregnancy and lactation can increase the risk of central and peripheral metabolic dysregulation in the offspring, but the mechanisms are not sufficiently established. Furthermore, despite many studies addressing preventive measures targeted at the mother, very few propose practical approaches to treat the damages when they are already installed. Here we investigated the potential of cannabidiol (CBD) treatment to attenuate the effects of maternal obesity induced by a cafeteria diet on hypothalamic inflammation and the peripheral metabolic profile of the offspring in Wistar rats. We have observed that maternal obesity induced a range of metabolic imbalances in the offspring in a sex-dependant manner, with higher deposition of visceral white adipose tissue, increased plasma fasting glucose and lipopolysaccharides (LPS) levels in both sexes, but the increase in serum cholesterol and triglycerides only occurred in females, while the increase in plasma insulin and the homeostatic model assessment index (HOMA-IR) was only observed in male offspring. We also found an overexpression of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNFα), interleukin (IL) 6, and interleukin (IL) 1β in the hypothalamus, a trademark of neuroinflammation. Interestingly, the expression of GFAP, a marker for astrogliosis, was reduced in the offspring of obese mothers, indicating an adaptive mechanism to in utero neuroinflammation. Treatment with 50 mg/kg CBD oil by oral gavage was able to reduce white adipose tissue and revert insulin resistance in males, reduce plasma triglycerides in females, and attenuate plasma LPS levels and overexpression of TNFα and IL6 in the hypothalamus of both sexes. Together, these results indicate an intricate interplay between peripheral and central counterparts in both the pathogenicity of maternal obesity and the therapeutic effects of CBD. In this context, the impairment of internal hypothalamic circuitry caused by neuroinflammation runs in tandem with the disruptions of important metabolic processes, which can be attenuated by CBD treatment in both ends.