Elevated Plasma Insulin Levels Research Articles

Modulation of GABA by sodium butyrate ameliorates hypothalamic inflammation in experimental model of PCOS

Polycystic ovarian syndrome (PCOS) is a known endocrine disorder that has affected many women of childbearing age, and is accompanied by various neurodegenerative conditions. Hence, this study investigates the impact of butyrate in reversing hypothalamic-related disorder, possibly through γ aminobutyric acid (GABA) in a rat model of PCOS. Eight-week-old female Wistar rats were allotted into four groups (n = 5), which include control, butyrate, letrozole, and letrozole + butyrate groups. PCOS was induced by administering 1 mg/kg of letrozole (oral gavage) for 21 days. After confirmation of PCOS, 200 mg/kg of butyrate (oral gavage) was administered for 6 weeks. Rats with PCOS were characterized by elevated levels of plasma insulin and testosterone. Increases in plasma and hypothalamic triglyceride levels, inflammatory biomarker (SDF-1), apoptotic marker (caspase-6), and decreased plasma GnRH were observed. Additionally, a decrease in hypothalamic GABA was revealed. Nevertheless, the administration of butyrate attenuated these alterations. The present study suggests that butyrate ameliorates hypothalamic inflammation in an experimental model of PCOS, a beneficial effect that is accompanied by enhanced GABA production.

Naringenin protects pancreatic β cells in diabetic rat through activation of estrogen receptor β

Naringenin is a citrus flavonoid that potently improves metabolic parameters in animal models of metabolic disorders, such as type 2 diabetes. Estrogen receptor (ER) activation promotes β cell function and survival, thereby improving systemic glucose metabolism. In this study, we used a luciferase reporter assay, isolated rat islets and a diabetic rat model to investigate the effects of naringenin on ER signaling and the underlying mechanism of naringenin-mediated improvement of islet function in diabetes. Naringenin specifically activated ERβ without affecting the activity of ERα, G protein-coupled estrogen receptor (GPER) or estrogen-related receptor (ERR) α/β/γ. Additionally, treatment with naringenin enhanced glucose-stimulated insulin secretion in isolated rat islets. This effect was abrogated by PHTPP, an ERβ antagonist. Transcriptomic analysis revealed that naringenin upregulated the expression of genes, such as Pdx1 and Mafa, which are closely linked to improved β-cell function. In consistence, single administration of naringenin to normal rats elevated plasma insulin levels and improved glucose responses. These beneficial effects were blocked by PHTPP. In streptozocin-nicotinamide induced diabetic rats, treatment for 2 weeks with naringenin alone, but not in combination with PHTPP, significantly restored pancreatic β cell mass and improved glucose metabolism. Collectively, these data support that naringenin specifically activate ERβ to improve insulin secretion in the primary rat islets. Furthermore, naringenin administration also protected β cell function and reversed glucose dysregulation in diabetic rats. These beneficial effects are at least partially dependent on the ERβ pathway.

The Effect of Plant-Derived Low-Ratio Linoleic Acid/α-Linolenic Acid on Markers of Glucose Controls: A Systematic Review and Meta-Analysis.

The objective of this meta-analysis was to examine the impact of a low-ratio linoleic acid/α-linolenic acid (LA/ALA) diet on the glycemic profile of adults. A comprehensive search was performed across four databases (Web of Science, Scopus, Embase, and PubMed) to evaluate the influence of the low-ratio LA/ALA. Relevant references were screened up until February 2023. Intervention effects were analyzed by calculating change values as weighted mean differences (WMD) and 95% confidence intervals (CI) using fixed-effects models. Additionally, subgroup analysis and meta-regression were employed to investigate potential sources of heterogeneity. Twenty-one randomized controlled trials (RCTs) were included, and the low-ratio LA/ALA diet had no significant effect on fasting blood sugar (FBS, WMD: 0.00 mmol/L, 95% CI: -0.06, 0.06, p = 0.989, I2 = 0.0%), insulin levels (WMD: 0.20 μIU/mL, 95% CI: -0.23, 0.63, p = 0.360, I2 = 3.2%), homeostatic model assessment insulin resistance (HOMA-IR, WMD: 0.09, 95% CI: -0.06, 0.23, p = 0.243, I2 = 0.0%), and hemoglobin A1c (HbA1c, WMD: -0.01%, 95% CI: -0.07, 0.06, p = 0.836, I2 = 0.0%). Based on subgroup analyses, it was observed that the impact of a low-ratio LA/ALA diet on elevated plasma insulin (WMD: 1.31 μIU/mL, 95% CI: 0.08, 2.54, p = 0.037, I2 = 32.0%) and HOMA-IR (WMD: 0.47, 95% CI: 0.10, 0.84, p = 0.012, I2 = 0.0%) levels exhibited greater prominence in North America compared to Asian and European countries. Publication bias was not detected for FBS, insulin, HOMA-IR, and HbA1c levels according to the Begg and Egger tests. Furthermore, the conducted sensitivity analyses indicated stability, as the effects of the low-ratio LA/ALA diet on various glycemic and related metrics remained unchanged even after removing individual studies. Overall, based on the available studies, it can be concluded that the low-ratio LA/ALA diet has limited impact on blood glucose-related biomarker levels.

Association between Altered Thyroid Function and Prediabetes in Diet-Induced Prediabetic Male Sprague Dawley Rats

There is a correlation between the existence of type 2 diabetes mellitus (T2DM) and the development of thyroid disorders. Prediabetes is a progressive state of moderate insulin resistance that often precedes the onset of T2DM. However, the association between prediabetes and thyroid function is unknown. This study assessed changes in markers of thyroid function in diet-induced prediabetes. Twelve male Sprague Dawley rats (n = 12) were randomly assigned into two groups. Rats in the non-prediabetic (NPD) group were fed a standard rat diet, while rats in the prediabetic (PD) were fed a high-fat high-carbohydrate diet for 20 weeks to induce prediabetes. Thereafter, fasting blood glucose levels were measured. Plasma samples were assessed for triiodothyronine (T3), thyroxine (T4), thyroxine peroxidase (TPO) antibody, insulin, and glycated hemoglobin (HbA1c) concentrations. The elevated blood glucose, HbA1c, and plasma insulin levels coincided with increased T3 and reduced T4 levels in the PD group when compared to the NPD group. There was also an increase in the concentration of TPO antibodies in the PD group. Additionally, there was a significant correlation between the thyroid hormone concentrations and HbA1c levels. In conclusion, these results indicated that there is a positive association between thyroid dysfunction and diet-induced prediabetes in rats.

Menthol Attenuates Cholinergic Dysfunction and Neurotransmitter Imbalance in Experimental Diabetes

One of the most predominant enduring consequences of Diabetes Mellitus (DM) is Diabetic Encephalopathy (DE), which has neither a reliable treatment nor an effective preventive strategy. Cognitive dysfunction is the primary problem allied with DE. The current inquiry aims to determine the potency of menthol in reducing the risk of brain complications induced by Streptozotocin (STZ) in diabetic rats. A single STZ intraperitoneal injection (40 mg/kg body weight) was employed to induce DM in Sprague-Dawley male rats and animals were held without treatment for 30 days to develop DE. The Morris water maze test, followed by the supplementation of menthol and metformin for 60 days at 50 and 100 mg/kg body weight dosages, verified the cognitive deficit in diabetic rats. After 60 days of therapy, rats were sacrificed to obtain blood and brain tissues for biochemical investigation. Oral delivery of menthol enhanced cognitive function in DE rats. Furthermore, menthol markedly reduced fasting blood sugar, glycosylated Hemoglobin (HbA1c), and elevated plasma insulin levels. In the brain, menthol increases neurotransmitter levels and choline acetyltransferase activity while decreasing AChE activity. Menthol also downregulated the expressions of monoamine oxidase A and B. Thus, the study indicates that menthol was effective in attenuating the neurodegenerative alterations in DE rats. It had a therapeutic potential and could be effectively utilized as a dietary supplement for regulating complications associated with encephalopathy.

Chronic Glucocorticoid Exposure Induced an S1PR2-RORγ Axis to Enhance Hepatic Gluconeogenesis in Male Mice.

It is well-established that chronic glucocorticoid exposure causes hyperglycemia. While glucocorticoid receptor (GR) stimulates hepatic gluconeogenic gene transcription, additional mechanisms are activated by chronic glucocorticoid exposure to enhance gluconeogenesis. We found that chronic glucocorticoid treatment activated sphingosine-1-phosphate (S1P)-mediated signaling. Hepatic knockdown of hepatic S1P receptor 1 (S1PR1) had no effect on chronic glucocorticoid-induced glucose intolerance but elevated fasting plasma insulin levels. In contrast, hepatic S1PR3 knockdown exacerbated chronic glucocorticoid-induced glucose intolerance without affecting fasting plasma insulin levels. Finally, hepatic S1PR2 knockdown attenuated chronic glucocorticoid-induced glucose intolerance and reduced fasting plasma insulin levels. Here we focused on dissecting the role of S1PR2 signaling in chronic glucocorticoid response on glucose homeostasis. We found that chronic glucocorticoid-induced hepatic gluconeogenesis, gluconeogenic gene expression, and GR recruitment to the glucocorticoid response elements (GREs) of gluconeogenic genes were all reduced in hepatic S1PR2 knockdown male mice. Hepatic S1PR2 knockdown also enhanced glucocorticoid suppression of RAR-related orphan receptor gamma (RORγ) expression. Hepatic RORγ overexpression in hepatic S1PR2 knockdown mice restored glucocorticoid-induced glucose intolerance, gluconeogenic gene expression, and GR recruitment to their GREs. Conversely, RORγ antagonist and the reduction of hepatic RORγ expression attenuated such glucocorticoid effects. Thus, chronic glucocorticoid exposure induces a S1PR2-RORγ axis to cooperate with GR to enhance hepatic gluconeogenesis. Overall, this work provides novel mechanisms of and pharmaceutical targets against steroid-induced hyperglycemia.

Detection of early Alzheimer's disease-like molecular alterations in a mouse model expressing human ApoE4.

The E4 allele of apolipoprotein E (ApoE4) is a key genetic risk factor for late-onset Alzheimer's disease (AD), increasing the risk of developing the disease by up to three-fold. However, the mechanisms by which ApoE4 contributes to AD pathogenesis are poorly understood. Here, we utilize a mouse model expressing either human ApoE3 or human ApoE4 to examine the effects of the E4 allele on a wide range of genetic and molecular pathways that are altered in early AD pathology. We demonstrate that ApoE4-expressing mice begin to show early differential expression of multiple genes, leading to alterations in downstream pathways related to neural cell maintenance, insulin signaling, amyloid processing and clearance, and synaptic plasticity. These alterations may result in the earlier accumulation of pathological proteins such as β-amyloid that may build up within cells, leading to the accelerated degeneration of neurons and astrocytes as observed in ApoE4-positive individuals. We also examine the metabolic effects associated with a high-fat diet (HFD) in male ApoE4-expressing mice compared with regular chow diet (RD) fed mice at different ages. We found that young ApoE4-expressing mice fed HFD developed metabolic disturbances, such as elevated weight gain, blood glucose, and plasma insulin levels that cumulatively have been observed to increase the risk of AD in humans. Taken together, our results reveal early pathways that could mediate ApoE4-related AD risk and may help identify more tractable therapeutic targets for treating ApoE4-associated AD.

Preoperative administration of branched-chain amino acids reduces postoperative insulin resistance in rats by reducing liver gluconeogenesis

BackgroundPostoperative insulin resistance (PIR) represents an important characteristic of metabolic response following surgical injury. Clinical outcomes are negatively correlated to postoperative insulin resistance and hyperglycemia, indicating a novel treatment for reducing postoperative insulin resistance is urgently needed. The current work aimed to assess the protective effects of branched-chain amino acids (BCAA) on glucose metabolism disorders induced surgically in a rat model, and to explore the underpinning mechanism.Methods and resultsRats were randomly assigned to 2 groups, including the control and BCAA groups. Rats were given a compulsory oral 3 mL load by gavage two hours before surgery. The results showed that BCAA remarkably reduced glycemia by suppressing liver gluconeogenesis via reduction of cAMP-response element-binding protein-regulated transcription coactivator 2 (CRTC2) and glucose-6-phosphatase (G6PC) gene and protein expression levels (all Ps < 0.05).ConclusionsThis study revealed that BCAA lower blood glucose levels by reducing liver gluconeogenesis without significant elevation of plasma insulin levels. We anticipate that preoperative BCAA supplementation may be a means for preventing postoperative insulin resistance.

PSUN278 Factitious hypoglycemia, diagnostic delay due to insulin assay failure to detect insulin analogues.

Abstract Factitious hypoglycemia may be difficult to diagnose clinically. Hypoglycemia due to insulin self-administration is established by the presence of a low c-peptide and elevated plasma insulin levels. Commercial insulin assays often fail to detect insulin analogs and can create confusion among providers investigating causes of hypoglycemia. A 20 year old female with no significant past medical history presented to an Emergency Room (ER) with hypoglycemia. She was treated with a single dose of octreotide 150 mcg, dexamethasone 10 mg PO and started on a D10W drip at 100ml/hr prior to transfer. Laboratory studies on transfer reported plasma glucose 52ng/dL (RR: 70-100), low C-peptide 0.02 (RR: 0.78-5.19), low insulin level &amp;lt;0.087 uIU/mL, normal IGF-I level 122 ng/mL (RR: 85-370). Normal IGF-II level 401 ng/mL (RR: 333-967), and low Pro-insulin level 1.8 pmol/L (RR: 3.6-22 pmol/L). Sulfonylurea Screen was negative. The patient and her mother both denied exogenous insulin use. The patient and her mother both work in healthcare. The patient's boyfriend has type 1 diabetes mellitus and the patient stated she keeps insulin in her purse for him. The patient was admitted for a 72 hour fast and remained normoglycemic. An aliquot of the admission ER insulin blood sample was sent to second laboratory utilizing an assay able to detect analog insulins. The patient's sample previously reporting an undetectable insulin level (&amp;lt;0.087 uIU/mL) now reported an insulin level 8 uIU/mL. Factitious hypoglycemia is a challenging clinical diagnosis. The term factitious implies an attempt to deceive and creates mistrust between the physician and patient. However, hypoglycemia may be the result of medication errors or administered by a second party with the intent to harm. Analog insulins (glargine, aspart, lispro, glulisine, etc) are genetically modified insulins developed to mimic the physiologic pattern of pancreatic beta cell insulin secretion. The amino acid modifications in analog insulins result in structural variations which alters the ability of highly specific commercial automated immunoassays to accurately quantitate these analog insulins. The variation in lab assay detection may cause confusion when interpreting the results. The DiaSorin Liaison XL platform in our hospital utilizes a chemiluminescence immunoassay which does not detect insulin analogs, but detects regular and NPH insulin as they are structurally identical to endogenous human insulin. The second laboratory uses the Siemens Advia Centaur platform, an immunoassay which reacts with insulin analogs "on a nearly equimolar basis with the analogs insulin aspart, insulin glargine, and insulin lispro. Insulin detemir exhibits approximately 50 percent cross-reactivity. Test reactivity with insulin glulisine is negligible (&amp;lt; 3 percent)". Many commercial insulin assays do not detect analog insulins and none qualitatively distinguish between different insulins. Failure to recognize this detection flaw may result in misdiagnosis, patient safety issues and costly unneeded additional studies Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Obese female mice do not exhibit overt hyperuricemia despite hepatic steatosis and impaired glucose tolerance

Recent reports have clearly demonstrated a tight correlation between obesity and elevated circulating uric acid levels (hyperuricemia). However, nearly all preclinical work in this area has been completed with male mice, leaving the field with a considerable gap in knowledge regarding female responses to obesity and hyperuricemia. This deficiency in sex as a biological variable extends beyond unknowns regarding uric acid (UA) to several important comorbidities associated with obesity including nonalcoholic fatty liver disease (NAFLD). To attempt to address this issue, herein we describe both phenotypic and metabolic responses to diet-induced obesity (DIO) in female mice. Six-week-old female C57BL/6J mice were fed a high-fat diet (60% calories derived from fat) for 32 weeks. The DIO female mice had significant weight gain over the course of the study, higher fasting blood glucose, impaired glucose tolerance, and elevated plasma insulin levels compared to age-matched on normal chow. While these classic indices of DIO and NAFLD were observed such as increased circulating levels of ALT and AST, there was no difference in circulating UA levels. Obese female mice also demonstrated increased hepatic triglyceride (TG), cholesterol, and cholesteryl ester. In addition, several markers of hepatic inflammation were significantly increased. Also, alterations in the expression of redox-related enzymes were observed in obese mice compared to lean controls including increases in extracellular superoxide dismutase (Sod3), heme oxygenase (Ho)-1, and xanthine dehydrogenase (Xdh). Interestingly, hepatic UA levels were significantly elevated (∼2-fold) in obese mice compared to their lean counterparts. These data demonstrate female mice assume a similar metabolic profile to that reported in several male models of obesity in the context of alterations in glucose tolerance, hepatic steatosis, and elevated transaminases (ALT and AST) in the absence of hyperuricemia affirming the need for further study.

Starch and Fiber Contents of Purified Control Diets Differentially Affect Hepatic Lipid Homeostasis and Gut Microbiota Composition.

BackgroundInterpretation of results from diet-induced-obesity (DIO) studies critically depends on control conditions. Grain-based chows are optimized for rodent nutrition but do not match the defined composition of purified diets used for DIO, severely limiting the comparability. Purified control diets are recommended but often contain high starch and only minor fiber amounts. It is unknown whether this composition leads to metabolic alterations compared with chow and whether the addition of refined fibers at the expense of starch affects these changes.MethodsIn this experiment, 6-week-old C57BL/6N mice were fed (i) a conventional purified control diet (high-starch, low-fiber; Puri-starch), (ii) an alternative, custom-made purified control diet containing pectin and inulin (medium-starch, higher-fiber; Puri-fiber), or (iii) grain-based chow for 30 weeks (N = 8–10).ResultsPuri-starch feeding resulted in significantly elevated levels of plasma insulin (p = 0.004), cholesterol (p < 0.001), and transaminases (AST p = 0.002, ALT p = 0.001), hepatic de novo lipogenesis and liver steatosis, and an altered gut microbiota composition compared with chow-fed mice. In contrast, Puri-fiber exerted only minor effects on systemic parameters and liver lipid homeostasis, and promoted a distinct gut microbiota composition.ConclusionCarbohydrate-rich purified diets trigger a metabolic status possibly masking pathological effects of nutrients under study, restricting its use as control condition. The addition of refined fibers is suited to create purified, yet physiological control diets for DIO research.

Pro-α-cell-derived β-cells contribute to β-cell neogenesis induced by antagonistic glucagon receptor antibody in type 2 diabetic mice

SummaryThe deficiency of pancreatic β-cells is the key pathogenesis of diabetes, while glucagon-secreting α-cells are another player in the development of diabetes. Here, we aimed to investigate the effects of glucagon receptor (GCGR) antagonism on β-cell neogenesis in type 2 diabetic (T2D) mice and explore the origins of the neogenic β-cells. We showed that GCGR monoclonal antibody (mAb) elevated plasma insulin level and increased β-cell mass in T2D mice. By using α-cell lineage-tracing (glucagon-cre-β-gal) mice and inducible Ngn3+ pancreatic endocrine progenitor lineage-tracing (Ngn3-CreERT2-tdTomato) mice, we found that GCGR mAb treatment promoted α-cell regression to progenitors, and induced Ngn3+ progenitor reactivation and differentiation toward β-cells. Besides, GCGR mAb upregulated the expression levels of β-cell regeneration-associated genes and promoted insulin secretion in primary mouse islets, indicative of a direct effect on β-cell identity. Our findings suggest that GCGR antagonism not only increases insulin secretion but also promotes pro-α-cell-derived β-cell neogenesis in T2D mice.

Early-life determinants of childhood plasma insulin levels: implications for primordial prevention of diabetes.

We earlier reported prematurity as an independent risk factor for elevated insulin levels. Investigation is still lacking on the influence of prenatal and perinatal factors on childhood insulin levels. In this secondary analysis of a prospective birth cohort, plasma insulin levels were measured at birth and early childhood. Regression models identified early-life factors associated with the primary outcome: log-transformed childhood plasma insulin levels. One thousand one hundred and nine children had insulin levels at birth and 825 at both time points. Compared to term, preterm infants had higher plasma insulin levels (geometric mean) at birth (612, 95% CI 552-679 vs. 372, 95% CI 345-402 pmol/ml) and in early childhood (547, 95% CI 494-605 vs. 445, 95% CI 417-475 pmol/ml). Factors associated with higher early childhood insulin levels included higher insulin level at birth, black race, female sex, maternal smoking during pregnancy, maternal perceived stress, in utero drug exposure, maternal pregestational diabetes mellitus, and maternal preconception overweight and obesity. In this high-risk US birth cohort, we identified multiple prenatal and perinatal risk factors for higher early childhood insulin levels, in addition to prematurity. These findings lend support to primordial preventive strategies for diabetes mellitus. In this secondary analysis of a large prospective study from a high-risk racially diverse cohort, we identify biological and social factors that contribute to elevated levels of plasma insulin in early childhood. Our study also investigates factors affecting plasma insulin in preterm infants along with comorbidities commonly seen during the neonatal intensive care stay. Our work reaffirms the importance of Developmental Origins of Health and Disease with regards to in utero programming of insulin levels. Our work supports the possibility that primordial preventive strategies for diabetes mellitus in high-risk populations may need to begin as early as the prenatal period.

IDF21-0029 Maternal separation aggravated pancreatic oxidative and inflammatory damage in chronic socially defeated adult male rats

Background: It is believed that psychosocial stress as one of the main sources of stress in humans may play an essential role in developing chronic degenerative metabolic diseases. Early life adverse experiences were supposed to affect the response to stress in later life. Aim: This research was done to test the effect of maternal separation on the metabolic response to chronic social defeat stress (CSDS) at young adulthood. In this respect, the possible contribution of oxidative stress and inflammatory damage to the pancreas along with insulin resistance in response to CSDS exposure in young adult male rats who experienced early life maternal separation was explored. Method: During the first 2 weeks of life, male Wistar rats were exposed to either maternal separation (MS) or left undisturbed with their mothers (Std). Starting on postnatal date 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent chronic social defeat stress (CSDS) for 3 weeks. Thus, totally there were 4 groups (n=6/group). Then, fasting plasma corticosterone, insulin, and glucose levels were measured and insulin resistance was calculated. Pancreatic Catalase (CAT) activity, reduced Glutathione (GSH), Malondialdehyde (MDA) and interleukin-1 beta contents were measured. Results: In this study, MS-CSDS animals showed an elevated fasting plasma corticosterone and insulin levels along with insulin resistance in comparison with standard-reared controls (Std-Con); however, neither early nor adult life adversity affected fasting glucose levels. Likewise, CAT activity, MDA, and Il-1β contents of pancreatic tissue were increased only in MS-CSDS rats compared to Std-Cons. Discussion: The finding of this study shows that maternal separation intensifies vulnerability to develop HPA axis over-activation, insulin resistance, pancreatic oxidative and inflammatory damage associated with chronic exposure to social defeat stress in young adult male rats, which could play an important role in mediating the effects of chronic stress‐related risk of diabetes mellitus. Abnormal responses to stress in adults, who were exposed to stress in early life, almost occurred because of increasing basal tone of central CRFergic activity and coincident intensified HPA axis responsiveness. It may be secondary to facilitation of noradrenergic neurocircuits, central glucocorticoid resistance, and/or dampened regional GABAergic tone that have been observed to happen in response to maternal separation stress. Elevated levels of circulating glucocorticoid have been reported to influence the insulin signaling cascade at the level of insulin receptor and insulin-sensitive glucose transporter 4 (GLUT4) functionality, which may contribute to insulin resistance. In the face of insulin resistance, the β cells adapt by increasing insulin secretion, leading to peripheral compensatory hyperinsulinemia as a protective measure to maintain normal glucose concentrations without hypoglycemia. Augmented pancreatic oxidative stress in MS-CSDS animals may exceeded the increased compensatory antioxidant mechanisms, as evidenced by excessive peroxidation of cell membrane lipids. Based on the central role of IL-1β in the destruction of pancreatic β cells, raised pancreatic IL-1β content could be related to oxidative stress-mediated β cell damage and development of diabetes in response to CSDS exposure in young adult rats who underwent early life maternal separation.

Insulin-Related Liver Pathways and the Therapeutic Effects of Aerobic Training, Green Coffee, and Chlorogenic Acid Supplementation in Prediabetic Mice.

Background The liver controls blood glucose levels via regulation of anabolic (glycogen synthesis and gluconeogenesis) and catabolic (glycolysis and glycogenolysis) processes through activation of the PI3K-AKT signalling pathway. The aim of this study was to assess the effect of aerobic training, green coffee, and chlorogenic acid supplementation on glucose metabolism-regulating pathways in prediabetic mice. Methods C57BL/6 mice were exposed to a high-fat diet and physical activity limitation to induce a state of prediabetes. After 12 weeks, mice were fed a high-fat diet compared to the control mice. The prediabetic mice were further treated with either green coffee, chlorogenic acid, or training or combinations of the same for 10 weeks. At the end of the experimental period, metabolic data (FBG, GTT, HOMA for IR, plasma level of insulinfrom systematic, AST, and ALT assessed into blood), histopathologic, and analysis of gene and protein expressions were obtained for target tissues. Results Training along with green coffee and chlorogenic acid supplementation improved complications of prediabetes including weight gain and elevated fasting blood glucose and plasma insulin levels. These effects were associated with the changes in mRNA levels of genes important in hepatic glycogen synthesis (GYS2), glucogenesis (PCK and G6PC2), and glycolysis (GK, PK, and PFKL). Conclusion The training in conjunction with green coffee or chlorogenic acid is effective in the prevention of prediabetes in mice. As these interventions are relatively inexpensive and safe application to individuals with prediabetes appears warranted.

Morphological alteration of the pancreatic islet in ovariectomized rats fed a high-fat high-fructose diet.

Diabetes and its complications are major causes of mortality worldwide. Type 2 diabetes coexists with insulin resistance and β-cell dysfunction, which are aggravated by overconsumption and estrogen-deprived conditions. However, the morphology of pancreatic islets in a combined condition of excessive caloric intake and estrogen deficiency has never been described. Herein, we examined morphological changes in the pancreatic islets of ovariectomized (OVX) rats fed a high-fat high-fructose diet (HFFD) for 12weeks. The histological changes in the size and number of pancreatic islets were assessed by hematoxylin-eosin and immunohistochemical staining. Enlarged pancreatic islets with fat deposition in OVX rats were accompanied by whole-body insulin resistance and hyperglycemia. The addition of a HFFD to OVX rats (OVX + HFFD) further aggravated insulin resistance, with a substantial increase in the density of enlarged pancreatic islets and fat accumulation. The augmented number of enlarged islets was correlated with elevated plasma glucose and insulin levels. Intriguingly, unlike the HFFD and OVX alone, the OVX + HFFD markedly expanded the area of insulin-producing β-cells and glucagon-producing α-cells. Importantly, enlarged islets, pancreatic fat deposits, and diabetic states developing in OVX + HFFD conditions were resolved by estrogen replacement. Collectively, the morphological characteristics of pancreatic islets were influenced in an insulin-resistant state caused by estrogen deficiency and HFFD consumption and were distinct from each factor alone. A combination of estrogen deficiency with HFFD consumption worsened the integrity of pancreatic islets, ultimately resulting in disease progression. These findings expand our understanding of the causal relationship between pancreatic morphology and diabetes development and suggest therapeutic strategies.

Investigation of the effects of maternal separation on the pancreatic oxidative and inflammatory damages along with metabolic impairment in response to chronic social defeat stress in young adult male rats.

Chronic glucocorticoid release during the stress response has been proposed to initiate certain damages, which in turn produce metabolic disorders. The present study is the first work to test whether maternal separation (MS) would impact the metabolic alterations associated with pancreatic oxidative and inflammatory damages under chronic exposure to social defeat stress (CSDS) in adulthood. During the first 2weeks of life, male Wistar rats were exposed to MS or left undisturbed with their mothers (Std). Starting on postnatal day 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent CSDS for 3weeks. Thus, there were 4 groups (n = 7/group): Std-Con, Ms-Con, Std-CSDS, MS-CSDS. Each animal was weighed and then decapitated so that we could collect trunk blood for assessment of fasting plasma corticosterone, insulin, glucose, lipid profile, and insulin resistance. Plasma and pancreatic catalase activity, reduced glutathione (GSH), malondialdehyde levels and pancreatic interleukin-1 beta (IL-1β) content were also measured. MS-CSDS animals showed elevated plasma corticosterone and insulin levels (P < 0.01) along with insulin resistance (P < 0.05). According to one-way ANOVA results, chronic exposure to early or adult life adversity decreased body weight (P < 0.0001), Catalase activity and GSH levels (P < 0.0001) and increased malondialdehyde level (P = 0.0006) in plasma. Pancreatic MDA and IL-1β contents elevated just in MS-CSDS rats (P < 0.05). Maternal separation shapes vulnerability to develop corticosterone hypersecretion, insulin resistance, pancreatic oxidative, and inflammatory damages associated with chronic exposure to later social challenges, which could potentially trigger metabolic disorders. The online version contains supplementary material available at 10.1007/s40200-021-00902-3.

115-LB: Liver-Derived FGF21 Mediates the Promoting Effect of Glucagon Receptor Antagonism on Beta-Cell Regeneration in Type 2 Diabetic Mice

Objective: Based on the clear role for glucagon in the pathogenesis of diabetes, glucagon-blocking therapies have been pursued as a therapeutic strategy for this disease. Here, we used REMD 2.59, a human antagonistic glucagon receptor (GCGR) monoclonal antibody (mAb), to clarify the effects of GCGR mAb in promoting pancreatic β cell regeneration in type 2 diabetes (T2D), and its potential mechanism. Methods: GCGR mAb was administrated weekly for 4 weeks in db/db mice and HFD/STZ-induced T2D mice, including different lineage-tracing mice. The plasma insulin and glucagon were determined by using ELISA. The evaluation of islet morphology was performed with immunofluorescent analysis. GCGR mAb was also treated in the systemic Fgf21 gene knockout (Fgf21-/-) and hepatocyte-specific Fgf21 gene knockout (Fgf21Hep-/-) T2D mice. Results: Treatment with GCGR mAb lowered blood glucose, improved glucose tolerance, and elevated plasma glucagon and insulin levels in both db/db mice and HFD/STZ-induced T2D mice. The β cell dedifferentiation as indicated by β cell lineage-tracing was blocked by GCGR mAb. The β cell proliferation as indicated by insulin+ and BrdU+ cells was boosted by GCGR mAb. The α-to-β cell conversion, as evaluated by glucagon+ insulin+ cells and confirmed by α cell lineage-tracing, was facilitated by GCGR mAb. After GCGR mAb treatment, some insulin+ cells were located in the duct region or even colocalized with duct cell markers, suggestive of duct-derived β cell neogenesis that was also verified by Ngn3+ cell lineage-tracing. Notably, GCGR mAb could still improve glucose tolerance and increase β cell mass, but these effects were attenuated in Fgf21-/- and Fgf21Hep-/- T2D mice compared with WT T2D mice. Conclusions: GCGR mAb promotes β cell regeneration via inhibiting β cell dedifferentiation and promoting β cell self-replication, α-to-β cell conversion and duct-derived β cell neogenesis in T2D mice, which is partly mediated by liver-derived FGF21. Disclosure X. Cui: None. T. Wei: None. J. Feng: None. J. Yang: None. H. Yan: Board Member; Self; REMD Biotherapeutics, Other Relationship; Spouse/Partner; REMD Biotherapeutics. R. Wei: None. T. Hong: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Sanofi. Funding National Natural Science Foundation of China (81830022)

The Expression of Genes Encoding ABCA1 and ABCG1 Transporters and PPARγ, LXRβ, and RORα Transcriptional Factors in Subcutaneous and Visceral Adipose Tissue in Women with Metabolic Syndrome

The study aimed to investigate tissue-specific gene expression of ABCA1 and ABCG1, encoding cholesterol transporters, as well as PPARG, LXRβ (NR1H2), and RORA, encoding the most important transcriptional regulators of lipid metabolism, in subcutaneous and visceral adipose tissue (SAT and VAT) in women with metabolic syndrome. It was shown that the ABCG1 mRNA SAT/VAT ratio decreases with age and correlates with the development of metabolic syndrome. After age adjustment, women have reduced chances of metabolic syndrome development when ABCG1 gene expression in SAT is higher relative to VAT than women with VAT ABCG1 gene expression higher or comparable to SAT: OR = 0.15 (95% CI 0.03-0.76), p = 0.023. The ABCA1 mRNA SAT/VAT ratio positively correlated with HDL cholesterol levels (after age adjustment β = 0.350, p = 0.046), therefore individuals with higher ABCA1 mRNA level in SAT relative to VAT had elevated HDL levels. The ABCA1 mRNA level in SAT was decreased in smokers (p = 0.001). There was a negative correlation between the PPARG mRNA level in SAT with body mass index and waist circumference in the general sample (β = -0.602, p = 0.003 and β = -0.642, p = 0.001, respectively, after age adjustment). A decrease of the PPARG mRNA SAT/VAT ratio was associated with elevated plasma insulin level and the insulin resistance index HOMA-IR β = -0.819, p = 0.004 and β = -1.053, p = 0.008, respectively, after age adjustment). Thus, the study has shown that the ratio of ABCA1, ABCG1, and PPARG genes expression in different types of adipose tissue (SAT/VAT) could be a significant factor that predicts the development of atherogenic dyslipidemia, metabolic syndrome, and insulin resistance in obesity.

Bozulmuş glukoz ve lipid metabolizması ve anormal karaciğer enzim düzeylerinin multipl akrokordonların oluşumundaki rolü: Bir olgu kontrol çalışması

Background Acrochordons, one of skin tumors, are protrusions of the loose fibrous tissue. In various studies, they have found to be associated with abnormal lipid profile, diabetes, cardiovascular disease, obesity, abnormal liver enzymes and genetic factors. In our case-control study, we aimed to determine possible associations of multiple acrochordons with obesity, impaired glucose and lipid metabolism, thyroid disorders, anemia and liver enzymes abnormalities.Methods Sixty-five patients (32 male, 33 female) with at least 8 skin tags and age- and gender-matched 60 controls without skin tags (30 male, 30 female) were enrolled to the study. We noted patients’ and controls’ age, height, weight, body mass index (BMI) and detailed medical history. Locations of acrochordons were recorded for the patient group. We recorded values of fasting plasma glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR), total cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), free T3 (fT3), free T4 (fT4), thyroid-stimulating hormone (TSH), hemoglobin, ferritin, vitamin B12, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP).Results Our study has shown a genetic predisposition to the development of multiple skin tags (P=0.0001). The mean BMI was statistically significant between the patients and controls (P&amp;lt;0.0001). In addition, we have found that when fasting plasma glucose, AST and GGT levels increase, the possibility of the forming of multiple acrochordons also increases (P=0.048, P=0.003, P=0.013). We determined that increasing of BMI is a risk factor for both genders (P=0.003, P&amp;lt;0.0001, respectively). We found that elevated fasting plasma glucose, insulin, HOMA-IR, total cholesterol, triglyceride, AST, ALT and GGT levels increase possibility of the forming of multiple acrochordons in females (P=0.037, P=0.022, P=0.013, P=0.03, P=0.007, P&amp;lt;0.0001, P=0.015, P=0.005, respectively).Conclusion Our results show that multiple acrochordons may be the cutaneous signs of abnormal glucose and lipid metabolism and liver enzyme abnormalities. Thus, we suggest that clinicians should see appropriate bloodtests for patients with multiple skin tags and manage them accordingly.