Insulin Response Research Articles

Postprandial glycemic response to a high-protein diabetes-specific nutritional shake compared to isocaloric instant oatmeal in people with type 2 diabetes: a randomized, controlled, crossover trial.

Minimizing postprandial glucose response is an important goal for overall diabetes management. Diabetes-specific nutritional shakes (DSNS) have been clinically shown to minimize postprandial glucose response in people with type 2 diabetes (T2DM) compared to high-glycemic foods. However, it is unknown how a high-protein, low-fat DSNS impacts the GLP-1 response. We tested the postprandial glucose, insulin, and GLP-1 response to a high-protein, low-fat diabetes-specific nutritional shake (DSNS-HP) compared to isocaloric instant oatmeal (IOM) in a randomized, controlled, crossover study in adults with T2DM (n = 24). Participants were randomly selected to receive IOM or DSNS-HP on two test days. Glucose, insulin, and total GLP-1 concentration were measured at baseline and 15, 30, 45, 60, 90, 120, 180, and 240 min postprandially. Compared to IOM, the glucose-positive area under the curve (pAUC) was significantly lower (P = .021). DSNS-HP significantly increased GLP-1 pAUC response by 213% (P <.001) with a corresponding increase in insulin pAUC (P = .033) compared to IOM. A high-protein, low-fat DSNS leads to favorable changes in GLP-1 response and is a suitable option to minimize blood glucose response in people with type 2 diabetes.

Evaluation of glycemic response of ten local meals commonly consumed from Chad

Diabetes mellitus is a metabolic disorder characterized by the presence of chronic hyperglycaemia accompanied by greater or lesser impairment in the metabolism of carbohydrates, lipids and proteins, including defects in either insulin secretion or response. The function of pancreatic cells gradually declines before the onset of clinical hyperglycemia. Its prevalence is increasing everywhere, especially in the developing countries due to the consumption of unknown glycemic index (GI) foods. Thus, the present study aimed to determine the GI of some local meals from Chad. In this purpose, ten meals were investigated and 60 non-diabetic volunteers were recruited in the present study. The proximate composition and the GI of these meals were determined. Results showed that 5 main ingredients (Hibiscus esculentus, Ipomea batata, Hibiscus sabdariffa, Corchorus oletorius and seeds of Parkia biglobosa) differentiate the meals. Soluble sugars and total carbohydrates levels showed a significant (p < 0.05) difference between meals (staples and sauces). The highest value of total carbohydrate of staples was found in Peeled dried sorghum ((BD); 31.80 %) while Cooked rice ((RZ); 19.82 %) has the lowest amount. Then, total carbohydrate content of sauces was in the range of 3.95 % (Leaves of Corchorus oletorius (MLK)) and 8.76 % (Dried okra + Fresh meat (GSV)) while, Sorrel leaves + Smoked fish ((OSP); 2.51 %) and Dried okra + Smoked fish ((GSP); 1.31 %) recorded the highest and lower values of soluble sugars, respectively. Moreover, Peeled dried maize + Dried okra + Fresh meat (MD/GSV) meal showed the highest GI (115.76 %) while the lowest value was found with Cooked rice + Sorrel leaves + Smoked fish (RZ/OZP) meal (31.08 %). The GI of Peeled dried maize + Fresh okra + Fresh meat (MD/GFV) attained a peak of 140 at 40 min while the peak of 130 was obtained with Peeled dried maize + Fresh okra + Smoked fish (MD/GFP) meal at the same time compared to glucose (160 at 40 min). Five meals (OSP/RZ; MD/GFP; MD/GFV; BD/GFP and BD/MLK) were low GI foods and were the best meals for human-being in terms of preventing diabetes mellitus. The consumption of such meals can provide a substantial contribution to the improvement of the Chadian diets.

Effects of acute consumption of a beverage based on extruded whole-grain pearl millet flour on glycemic and insulinemic control, food intake, and appetite sensation in eutrophic adults: A randomized cross-over clinical trial

ObjectivesWhole-grain pearl millet is a nutritious cereal source of dietary fiber, vitamins, minerals, and bioactive compounds. It offers health benefits such as glycemic control and satiety. Extrusion cooking for diverse formulations, including beverages, can alter its chemical composition, impacting the nutritional value. This study aimed to evaluate the sensory acceptability of an extruded millet flour beverage and its acute effects on glycemic index (GI), glycemic and insulinemic response, food intake, and subjective appetite sensations in euglycemic and eutrophic adults. MethodsThis is an acute, single-blind, randomized, controlled, cross-over clinical study comprising 14 euglycemic and eutrophic adults. Initially, beverages based on whole extruded millet flour were developed, and sensorially and chemically analyzed. Next, a clinical trial was conducted with participants undergoing four sessions and consuming one of the following options: extruded millet beverage, a maltodextrin control beverage, or a glucose solution administered in two separate sessions. Blood glucose, insulin, and appetite responses were assessed over a 2-h period, in addition to determining the GI of the beverages and analyzing food intake in the 24 h following each session. ResultsThe extruded millet flour strawberry-flavored beverage had the best sensory acceptance and was classified as having as high GI. Consumption of the extruded millet beverage showed similar glycemic and insulinemic responses, as well as appetite control and food intake of the subjects, when compared with consumption of the maltodextrin control beverage. ConclusionsIntake of the extruded millet beverage maintained glycemic and insulinemic responses, appetite control, and food intake in euglycemic and eutrophic subjects.

Effect of polymethoxylated flavonoids on glucose and lipid metabolism in rat model of obesity induced by a high-fat diet

This study established a rat model of obesity by using a high-fat diet(HFD) to explore the effect of polymethoxylated flavonoids on glucose and lipid metabolism in the model rats and decipher the role and mechanism of polymethoxylated flavonoids in mitigating obesity. Thirty normal SD rats were selected and randomized into normal, model, ezetimibe(0.1 mg·kg~(-1)), and polymethoxylated flavonoids(62.5 mg·kg~(-1) and 125 mg·kg~(-1)) groups based on the body weight. Except the normal group receiving a conventional diet, the other groups received a HFD. Rats were administrated with corresponding doses of drugs by gavage. During the administration period, the body weight of each group of rats was regularly weighed, and the serum lipid and glucose levels were measured by a fully automated biochemical analyzer. Islet homeostasis and serum levels of obesity factors were measured by ELISA. The 16S rRNA high-throughput sequencing was employed to study the gut microbiota. Hematoxylin-eosin staining was employed to observe the histomorphology of white fat, brown fat, and pancreas. After the wet weights of white fat and brown fat were measured, the organ index was calculated. Immunohistochemistry and Western blot were employed to determine the protein levels. The results showed that polymethoxylated flavonoids reduced the body weight and Lee's index and improved blood lipid levels of the model rats. Polymethoxylated flavonoids reduced blood glucose and insulin secretion, increased insulin responsiveness, and alleviated insulin resistance. In addition, polymethoxylated flavonoids regulated the serum levels of obesity factors and reduced the weights and indexes of white fat and brown fat, the diameter of white adipocytes, and the number of fat vacuoles in brown fat and pancreatic islet cells. The intervention with polymethoxylated flavonoids increased the diversity of gut microbiota in the model rats, increasing the beneficial bacteria associated with glucose and lipid metabolism and reduced the harmful bacteria at the genus level. In addition, polymethoxylated flavonoids up-regulated the protein levels of glucose transporter 4(GLUT4), phosphorylated AMP-activated protein kinase(p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α), and uncoupling protein 1(UCP1). In summary, polymethoxylated flavonoids may increase the body utilization of glucose and lipids by regulating the homeostasis of insulin, the serum levels of obesity factors, the diversity of gut microbiota, and the expression of mitochondrial metabolism-related proteins in brown adipocytes, thereby mitigating obesity in rats.

Regulatory Role of Fatty Acid Metabolism on Glucose-Induced Changes in Insulin and Glucagon Secretion by Pancreatic Islet Cells.

A detailed study of palmitate metabolism in pancreatic islets subject to different experimental conditions, like varying concentrations of glucose, as well as fed or starved conditions, has allowed us to explore the interaction between the two main plasma nutrients and its consequences on hormone secretion. Palmitate potentiates glucose-induced insulin secretion in a concentration-dependent manner, in a physiological range of both palmitate (0-2 mM) and glucose (6-20 mM) concentrations; at glucose concentrations lower than 6 mM, no metabolic interaction with palmitate was apparent. Starvation (48 h) increased islet palmitate oxidation two-fold, and the effect was resistant to its inhibition by glucose (6-20 mM). Consequently, labelled palmitate and glucose incorporation into complex lipids were strongly suppressed, as well as glucose-induced insulin secretion and its potentiation by palmitate. 2-bromostearate, a palmitate oxidation inhibitor, fully recovered the synthesis of complex lipids and insulin secretion. We concluded that palmitate potentiation of the insulin response to glucose is not attributable to its catabolic mitochondrial oxidation but to its anabolism to complex lipids: islet lipid biosynthesis is dependent on the uptake of plasma fatty acids and the supply of α-glycerol phosphate from glycolysis. Islet secretion of glucagon and somatostatin showed a similar dependence on palmitate anabolism as insulin. The possible mechanisms implicated in the metabolic coupling between glucose and palmitate were commented on. Moreover, possible mechanisms responsible for islet gluco- or lipotoxicity after a long-term stimulation of insulin secretion were also discussed. Our own data on the simultaneous stimulation of insulin, glucagon, and somatostatin by glucose, as well as their modification by 2-bromostearate in perifused rat islets, give support to the conclusion that increased FFA anabolism, rather than its mitochondrial oxidation, results in a potentiation of their stimulated release. Starvation, besides suppressing glucose stimulation of insulin secretion, also blocks the inhibitory effect of glucose on glucagon secretion: this suggests that glucagon inhibition might be an indirect or direct effect of insulin, but not of glucose. In summary, there seems to exist three mechanisms of glucagon secretion stimulation: 1. glucagon stimulation through the same secretion coupling mechanism as insulin, but in a different range of glucose concentrations (0 to 5 mM). 2. Direct or indirect inhibition by secreted insulin in response to glucose (5-20 mM). 3. Stimulation by increased FFA anabolism in glucose intolerance or diabetes in the context of hyperlipidemia, hyperglycemia, and hypo-insulinemia. These conclusions were discussed and compared with previous published data in the literature. Specially, we discussed the mechanism for inhibition of glucagon release by glucose, which was apparently contradictory with the secretion coupling mechanism of its stimulation.

Understanding the Impact of Different Doses of Reducose® Mulberry Leaf Extract on Blood Glucose and Insulin Responses after Eating a Complex Meal: Results from a Double-Blind, Randomised, Crossover Trial.

Non-communicable diseases (NCDs) are becoming an increasingly important health concern due to a rapidly ageing global population. The fastest growing NCD, type 2 diabetes mellitus (T2DM), is responsible for over 2 million deaths annually. Lifestyle changes, including dietary changes to low glycemic response (GR) foods, have been shown to reduce the risk of developing T2DM. The aim of this study was to investigate whether three different doses of Reducose®, a mulberry leaf extract, could lower the GR and insulinemic responses (IR) to a full meal challenge in healthy individuals. A double-blind, randomised, placebo-controlled, repeat-measure, crossover design trial was conducted by the Oxford Brookes Centre for Nutrition and Health; 37 healthy individuals completed the study. Participants consumed capsules containing either 200 mg, 225 mg, 250 mg Reducose® or placebo before a test meal consisting of 150 g white bread and egg mayo filler. Capillary blood samples were collected at 15-min intervals in the first hour and at 30-min intervals over the second and third hours to determine glucose and plasma insulin levels. The consumption of all three doses of Reducose® resulted in significantly lower blood glucose and plasma insulin levels compared to placebo. All three doses of Reducose® (200 mg, 225 mg, 250 mg) significantly lowered glucose iAUC 120 by 30% (p = 0.003), 33% (p = 0.001) and 32% (p = 0.002), respectively, compared with placebo. All three doses of Reducose® (200 mg, 225 mg, 250 mg) significantly lowered the plasma insulin iAUC 120 by 31% (p = 0.024), 34% (p = 0.004) and 38% (p < 0.001), respectively. The study demonstrates that the recommended dose (250 mg) and two lower doses (200 mg, 225 mg) of Reducose® can be used to help lower the GR and IR of a full meal containing carbohydrates, fats and proteins.

The effect of statin treatment on glucose homeostasis in prediabetic individuals: A prospective, randomized, controlled trial.

This study aimed to evaluate the effects of rosuvastatin and pravastatin on glucose homeostasis and other biomarkers in individuals at high risk of developing diabetes. This prospective, randomized, open-labeled, and controlled trial included prediabetic individuals with impaired fasting glucose and impaired glucose tolerance. The participants were randomized into three groups: rosuvastatin (10 mg), pravastatin (40 mg), or control. Biomarkers of diabetes and glucose and insulin responses to oral glucose tolerance tests were assessed at baseline and after 6 months of treatment. The primary outcomes were comparisons of glucose homeostasis and biomarkers of diabetes among groups at baseline and after 6 months of treatment. A total of 141 subjects with impaired fasting glucose (IFG) were screened and 41 participants were recruited. Twenty-two subjects were randomized to either the rosuvastatin or pravastatin group and 19 subjects were assigned to the control group. After 6 months of treatment, all groups had similar cholesterol and triglyceride levels. Likewise, HbA1c levels, glucose, and insulin excursions during oral glucose tolerance test, were similar among the three groups. However, compared to the other groups, the rosuvastatin group had higher homeostasis model assessment for insulin resistance (HOMA-IR) (insulin resistance) and a lower Matsuda index (insulin sensitivity). Among prediabetic individuals with IFG, rosuvastatin treatment was associated with increased insulin resistance and decreased insulin sensitivity compared to pravastatin and control groups. Further research is needed to elucidate the underlying mechanisms and clinical implications of these findings.

Single-cell transcriptome analysis reveals the regulatory functions of islet exocrine cells after short-time obesogenic diet.

This study aims to investigate the functions of exocrine islet cell subtypes in the early stage of obesity induced by high-fat diet (HFD), which is accompanied with deterioration of the systemic insulin response and islet subpopulation abnormalities. In this study, we analyzed published islet single-cell RNA sequencing (scRNA-seq) datasets from the early stage induced by HFD feeding. Bioinformatics tools such as findMarkers, Cellchat, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and Gene Ontology (GO) terms were applied to identify the different functions of exocrine cell clusters. A total of 26 cell clusters were obtained were identified from this dietary intervention model. Most proportions of cell subtypes were consistent between high-fat diet (HFD) and low-fat diet (LFD) groups, except for partial endocrine islet clusters and exocrine clusters. Most differentiated expression of genes in the HFD group was found in exocrine cluster. And we also found that the cell-cell interactions between ductal and endothelial cells were reduced in the HFD group, with the significant alteration in C17 (ductal) cluster. By further analyzing the co-expression regulatory network of transcription in the C17 cluster, we speculate that differentially expressed transcription factors affected the function of duct cells by affecting the expression of related genes in intercellular interaction networks, thereby promoting insulin resistance (IR) development. Our results provide a reference for the function and regulatory mechanisms of exocrine cells in the obesity induced by HFD and probably influence the process of following insulin resistance.

Association between insulin sensitivity and lean mass loss during weight loss.

The study objective was to assess the relationship between insulin sensitivity and changes in total lean mass (LM) and appendicular LM (ALM) during weight loss. Individuals were randomly assigned to either a standard or a moderately reduced carbohydrate diet for 16 weeks. Body composition was assessed using dual-energy x-ray absorptiometry and insulin sensitivity index (SI) using an intravenous glucose tolerance test. Multiple linear regression was used to determine whether baseline SI was predictive of changes in total LM and ALM. Participants (n = 57; baseline BMI 32.1 ± 3.8 kg/m2) lost an average of 6.8 ± 3.2 kg of body weight (p < 0.001), with 1.5 ± 2.6 kg coming from LM (p < 0.05) and 0.5 ± 0.73 kg from ALM (p < 0.05). Multiple regression analysis demonstrated that SI was inversely associated with changes in total LM (kilograms; β = 0.481, p < 0.001), after adjusting for baseline LM, fat mass, acute insulin response to glucose, and weight loss. Similar results were seen when assessing ALM loss (β = 0.359, p < 0.05). Identifying individuals with low insulin sensitivity prior to weight loss interventions may allow for a personalized approach aiming at minimizing LM loss.

Hypothalamic sex-specific metabolic shift by canagliflozin during aging

The hypothalamus undergoes significant changes with aging and plays crucial roles in age-related metabolic alterations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are anti-diabetic agents that promote glucose excretion, and metabolic homeostasis. Recent studies have shown that a SGLT2i, Canagliflozin (Cana), can extend the median survival of genetically heterogeneous UM-HET3 male mice and improve central metabolic control via increases in hypothalamic insulin responsiveness in aged males, as well as reduced age-associated hypothalamic inflammation. We studied the long- and short-term effects of Cana on hypothalamic metabolic control in UM-HET3 mice. Starting the treatment from 7 months of age, we show that 4 weeks of Cana treatment significantly reduced body weight and fat mass in male but not female mice that was associated with enhanced glucose tolerance and insulin sensitivity observed by 12 months. Indirect calorimetry showed that Cana treatment increased energy expenditure in male, but not female mice, at 12 months of age. Long-term Cana treatment increased metabolic rates in both sexes, and markedly increasing formation of both orexigenic and anorexigenic projections to the paraventricular nucleus of the hypothalamus (PVH) mostly in females by 25 months. Hypothalamic RNA-sequencing analysis revealed increased sex-specific genes and signaling pathways related to insulin signaling, glycogen catabolic pathway, neuropeptide signaling, and mitochondrial function upregulated by Cana, with males showing a more pronounced and sustained effect on metabolic pathways at both age groups. Overall, our data provide critical evidence for sex-specific mechanisms that are affected by Cana during aging suggesting key targets of hypothalamic Cana-induced neuroprotection for metabolic control.

BCG Vaccination Suppresses Glucose Intolerance Progression in High-Fat-Diet-Fed C57BL/6 Mice.

Background and Objectives: Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccine administration has been suggested to prevent glucose metabolism abnormalities and fatty liver in genetically obese ob/ob mice; however, it is not clear whether the beneficial effects of BCG are also observed in the progression of glucose intolerance induced by a high-fat diet (HFD). Therefore, the effects of BCG vaccination on changes in glucose tolerance and insulin response were investigated in HFD-fed C57BL/6 mice. Materials and Methods: We used the BCG Tokyo 172 strain to determine effects on abnormalities in glucose metabolism. For vaccination, five-week-old male mice were injected intraperitoneally with BCG and maintained on a HFD for three weeks. The mice were regularly subjected to intraperitoneal glucose tolerance and insulin tolerance tests (IGTTs and ITTs). These tests were also performed in mice transplanted with bone marrow cells from BCG-vaccinated donor mice. Results: Significant effects of BCG vaccination on blood glucose levels in the IGTTs and ITTs were observed from week 12 of the experiment. BCG vaccination significantly improved changes in fasting glucose and insulin levels, insulin resistance indexes, and glucagon-to-insulin ratios in conjunction with the HFD at the end of the experiment. Significant inhibitory effects in the IGTTs and ITTs on glucose intolerance were also observed with transplantation with bone marrow cells derived from BCG-vaccinated donor mice. Conclusions: BCG vaccination significantly delayed glucose intolerance progression, suggesting a beneficial effect of BCG on the pathogenesis of type 2 diabetes. It has also been suggested that the effects of BCG vaccination may be at least partially due to an immune memory (trained immunity) for hematopoietic stem and progenitor cells of the bone marrow.

Hepatic WDR23 proteostasis mediates insulin homeostasis by regulating insulin-degrading enzyme capacity

Maintaining insulin homeostasis is critical for cellular and organismal metabolism. In the liver, insulin is degraded by the activity of the insulin-degrading enzyme (IDE). Here, we establish a hepatic regulatory axis for IDE through WDR23-proteostasis. Wdr23KO mice have increased IDE expression, reduced circulating insulin, and defective insulin responses. Genetically engineered human cell models lacking WDR23 also increase IDE expression and display dysregulated phosphorylation of insulin signaling cascade proteins, IRS-1, AKT2, MAPK, FoxO, and mTOR, similar to cells treated with insulin, which can be mitigated by chemical inhibition of IDE. Mechanistically, the cytoprotective transcription factor NRF2, a direct target of WDR23-Cul4 proteostasis, mediates the enhanced transcriptional expression of IDE when WDR23 is ablated. Moreover, an analysis of human genetic variation in WDR23 across a large naturally aging human cohort in the US Health and Retirement Study reveals a significant association of WDR23 with altered hemoglobin A1C (HbA1c) levels in older adults, supporting the use of WDR23 as a new molecular determinant of metabolic health in humans.

Effect of Obstructive Sleep Apnea during Pregnancy on Fetal Development: Gene Expression Profile of Cord Blood.

Obstructive sleep apnea (OSA) is quite prevalent during pregnancy and is associated with adverse perinatal outcomes, but its potential influence on fetal development remains unclear. This study investigated maternal OSA impact on the fetus by analyzing gene expression profiles in whole cord blood (WCB). Ten women in the third trimester of pregnancy were included, five OSA and five non-OSA cases. WCB RNA expression was analyzed by microarray technology to identify differentially expressed genes (DEGs) under OSA conditions. After data normalization, 3238 genes showed significant differential expression under OSA conditions, with 2690 upregulated genes and 548 downregulated genes. Functional enrichment was conducted using gene set enrichment analysis (GSEA) applied to Gene Ontology annotations. Key biological processes involved in OSA were identified, including response to oxidative stress and hypoxia, apoptosis, insulin response and secretion, and placental development. Moreover, DEGs were confirmed through qPCR analyses in additional WCB samples (7 with OSA and 13 without OSA). This highlighted differential expression of several genes in OSA (EGR1, PFN1 and PRKAR1A), with distinct gene expression profiles observed during rapid eye movement (REM)-OSA in pregnancy (PFN1, UBA52, EGR1, STX4, MYC, JUNB, and MAPKAP). These findings suggest that OSA, particularly during REM sleep, may negatively impact various biological processes during fetal development.

Association of postabsorptive glucose and acetate metabolism with feed intake, growth, and efficiency in finishing beef heifers

The objective of this experiment was to determine whether acetate and glucose metabolism and insulin response to glucose are associated with the growth, feed intake, and feed efficiency of finishing heifers. Charolais heifers ( n = 18; initial body weight = 415.7 ± 45.17 kg) were acclimated to restraint with a halter and fed a finishing diet ad libitum using an Insentec feeding system. Following a 12 h fast, a jugular catheter was inserted, and an acetate clearance test was performed followed by a glucose clearance test. Four days after the metabolic tests, heifers began an 84-day DMI and ADG test period. Heifers gained 1.69 ± 0.03 kg/day and consumed 10.4 ± 0.19 kg/day. Acetate and glucose clearance rates were not associated with any production trait ( P ≥ 0.40). Insulin time to peak concentration after the glucose challenge was associated ( r = 0.69; P = 0.003) with G:F, but not peak concentration ( P = 0.45). The increased time to insulin peak could indicate that efficient heifers have pancreatic β-cell dysfunction, which is a contributor to insulin resistance. These data indicate that insulin resistance early in the finishing period could be related to improved feed efficiency in finishing heifers.

Impact of chickpea hummus on postprandial blood glucose, insulin and gut hormones in healthy humans combined with mechanistic studies of food structure, rheology and digestion kinetics

Slowing the rate of carbohydrate digestion leads to low postprandial glucose and insulin responses, which are associated with reduced risk of type 2 diabetes. There is increasing evidence that food structure plays a crucial role in influencing the bioaccessibility and digestion kinetics of macronutrients. The aims of this study were to compare the effects of two hummus meals, with different degrees of cell wall integrity, on postprandial metabolic responses in relation to the microstructural and rheological characteristics of the meals. A randomised crossover trial in 15 healthy participants was designed to compare the acute effect of 27 g of starch, provided as hummus made from either intact chickpea cells (ICC) or ruptured chickpea cells (RCC), on postprandial metabolic responses. In vitro starch digestibility, microstructural and rheological experiments were also conducted to evaluate differences between the two chickpea hummus meals. Blood insulin and GIP concentrations were significantly lower (P < 0.02, P < 0.03) after the consumption of the ICC meal than the meal containing RCC. In vitro starch digestion for 90 min was slower in ICC than in RCC. Microscopic examination of hummus samples digested in vitro for 90 min revealed more intact chickpea cells in ICC compared to the RCC sample. Rheological experiments showed that fracture for ICC hummus samples occurred at smaller strains compared to RCC samples. However, the storage modulus for ICC was higher than RCC, which may be explained by the presence of intact cells in ICC. Food structure can affect the rate and extent of starch bioaccessibility and digestion and may explain the difference in the time course of metabolic responses between meals. The rheological properties were measured on the two types of meals before ingestion, showing significant differences that may point to different breakdown mechanisms during subsequent digestion.This trial was registered at clinicaltrial.gov as NCT03424187.

239 Variation in muscle protein synthesis in growing gilts is partially associated with insulin resistance and sensitivity

Abstract Pigs with similar body weight (BW), same genetic background and sex vary in protein deposition (PD) overgrowth. We aimed to study metabolic factors influencing PD in 65 kg BW gilts. Gilts were fed ad libitum a diet balanced to maximize PD. Dual X-rays were conducted to estimate body protein mass on d 1 and 21, allowing calculation of PD by difference. On d 23, the gilts were categorized into Low (157 g/d) and High (219 ± 9.97 g/d) PD groups. In each group, eight pigs underwent jugular vein cannulation. After a 48-h recovery period, where they were fed at 90% of the measured feed intake, they were fasted for 8 h. All pigs were then given a 300 g meal at time 0, and blood samples were collected at 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 150, 178, and 178 min, to study insulin and glucose responses. At 180 min post-meal, a solution of L-13C valine was administered i.v. (18 ape – flooding dose), and liver, duodenum, and longissimus dorsi muscle samples were collected within 5 minutes of slaughter. The fractional synthesis rate (FSR, %/d), absolute synthesis rate (ASR, g/d), ribosomal capacity for protein synthesis (Cs), and the efficiency of protein synthesis (KRNA) based on total RNA concentration in skeletal muscle were calculated. The insulin resistance index (HOMA-B) and insulin sensitivity index (QUICKI) were also determined. The difference between Low and High PD gilts was compared using a F-test. The longissimus dorsi muscle exhibited a 31% greater (P = 0.01) FSR in High compared with Low PD group. No significant differences were observed in the FSR of the jejunum and liver. High PD gilts showed a 55% greater ASR in whole-body muscles (P = 0.003) and 42% greater ASR in the liver (P = 0.04) compared with Low PD gilts, with no difference for the ASR in the jejunum. The KRNA in the longissimus dorsi was 48% greater in High PD gilts (P = 0.01), with no differences in KRNA for the jejunum or liver. Cs did not differ between Low and High PD gilts. The QUICKI index tended to be greater in High PD gilts (P = 0.10). Spearman’s correlation revealed that longissimus dorsi FSR was negatively correlated with the HOMA-B index (r = -0.53; P = 0.04). Increases in the HOMA-B index tended to be associated with greater KRNA (r = -0.49; P = 0.06). These correlations highlight the complex interplay of metabolic and hormonal factors involved in the observed differences in protein synthesis and efficiency in growing gilts. Insulin resistance and sensitivity may play a role in influencing skeletal muscle PD variations.

The impact of eosinophilia on high fat diet-induced obesity and airway hyperresponsiveness

Hypothesis/Rationale: Eosinophils contribute to both adipose tissue metabolic homeostasis in obesity and airway hyperresponsiveness in asthma, but the role of eosinophils in obesity-related airway hyperresponsiveness is not understood. Considering that metabolic disorders increase the susceptibility to airway hyperresponsiveness in obese individuals, we investigated whether adipose eosinophils play a protective role in obesity-related airway hyperresponsiveness. Methods: Wild type (WT) and transgenic mice that overexpress interleukin 5 in peripheral T cells (+IL5T) were fed a high fat (61.6% fat) or normal chow (13.6% fat) diet for 19 weeks. Body weight, body fat, fasting glucose and insulin, and bronchoconstriction in response to inhaled serotonin were measured. The number of eosinophils were counted using flow cytometry in lung, adipose, and blood from transgenic WT and +IL5T mice with GFP-expressing eosinophils. Data: High fat diet significantly increased body weight and body fat in both WT and +IL5T mice, however +IL5T mice gained less weight and body fat than the WT mice. High fat diet increased fasting glucose, fasting insulin, and nerve-mediated airway responsiveness to inhaled serotonin in only the WT mice. On a normal chow diet, +IL5T mice had significantly more eosinophils in lung, blood, and adipose, and high fat diet further increased eosinophils in +IL5T adipose tissue. Acute administration of 1.29 U/kg (i.p.) insulin to a WT mouse on a normal chow diet significantly potentiated airway hyperresponsiveness to inhaled serotonin. Summary of results: Eosinophils in adipose tissue prevented high fat diet increases in circulating glucose and insulin, resulting in less body weight and body fat. This reduction in insulin by eosinophils in adipose tissue prevented obesity-related airway hyperresponsiveness. Conclusions: Insulin is a key modulator of obesity-related airway hyperresponsiveness. Eosinophils in adipose tissue play an important role in preventing obesity-related airway hyperresponsiveness by modulating insulin levels. Funding: NIH HL164474, NIH HL163087. This is the full abstract presented at the American Physiology Summit 2024 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.

The association of insulin responses and insulin sensitivity with cognition in adults with pre-diabetes: The Diabetes Prevention Program Outcomes Study

ObjectiveDysglycemia is a significant risk factor for cognitive impairment. However, which pathophysiologic determinant(s) of dysglycemia, impaired insulin sensitivity (ISens) or the islet β-cell's response (IResp), contribute to poorer cognitive function, independent of dysglycemia is not established. Among 1052 adults with pre-diabetes from the Diabetes Prevention Program Outcomes Study (DPPOS), we investigated the relationship between IResp, ISens and cognitive function. Research design and methodsIResp was estimated by the insulinogenic index (IGI; pmol/mmol) and ISens as 1/fasting insulin from repeated annual oral glucose tolerance tests. The mean IResp and mean ISens were calculated over approximately 12 years of follow-up. Verbal learning (Spanish-English Verbal Learning Test [SEVLT]) and executive function (Digital Symbol Substitution Test [DSST]) were assessed at the end of the follow-up period. Linear regression models were run for each cognitive outcome and were adjusted for dysglycemia and other factors. ResultsHigher IResp was associated with poorer performance on the DSST (−0.69 points per 100 unit increase in IGI, 95 % CI: −1.37, −0.01). ISens was not associated with DSST, nor were IResp or ISens associated with performance on the SEVLT. ConclusionsThese results suggest that a greater β-cell response in people at high risk for type 2 diabetes is associated with poorer executive function, independent of dysglycemia and ISens.

Deletion of CD44 promotes adipogenesis by regulating PPARγ and cell cycle-related pathways.

CD44, a cell surface adhesion receptor and stem cell biomarker, is recently implicated in chronic metabolic diseases. Ablation of CD44 ameliorates adipose tissue inflammation and insulin resistance in obesity. Here, we investigated cell type-specific CD44 expression in human and mouse adipose tissue and further studied how CD44 in preadipocytes regulates adipocyte function. Using Crispr Cas9-mdediated gene deletion and lentivirus-mediated gene re-expression, we discovered that deletion of CD44 promotes adipocyte differentiation and adipogenesis, whereas re-expression of CD44 abolishes this effect and decreases insulin responsiveness and adiponectin secretion in 3T3-L1 cells. Mechanistically, CD44 does so via suppressing Pparg expression. Using quantitative proteomics analysis, we further discovered that cell cycle-regulated pathways were mostly decreased by deletion of CD44. Indeed, re-expression of CD44 moderately restored expression of proteins involved in all phases of the cell cycle. These data were further supported by increased preadipocyte proliferation rates in CD44-deficient cells and re-expression of CD44 diminished this effect. Our data suggest that CD44 plays a crucial role in regulating adipogenesis and adipocyte function possibly through regulating PPARγ and cell cycle-related pathways. This study provides evidence for the first time that CD44 expressed in preadipocytes plays key roles in regulating adipocyte function outside immune cells where CD44 is primarily expressed. Therefore, targeting CD44 in (pre)adipocytes may provide therapeutic potential to treat obesity-associated metabolic complications.

Investigating molecular interactions between SARS-CoV-2 spike protein variants and glucose metabolic dysregulation in beta-cells

The severity of COVID-19 disease onset is strongly linked to co-morbidities such as diabetes, with hyperglycemia an independent risk factor for mortality. Additionally, hyperglycemia alters intracellular mechanisms to induce oxidative stress and subsequently dysregulate glucose metabolic pathways such as the hexosamine biosynthetic pathway (HBP) and the formation of advanced glycation end-products (AGEs). The emergence of new-onset hyperglycemia following SARS-CoV-2 infection is a cause for concern. One possible explanation is the direct infection of the pancreas leading to damage of β-cells. Binding of SARS-CoV-2 spike (S)-protein to its primary receptor, ACE2, can be enhanced via glycosylation and/or glycation of the receptor, rendering it more susceptible to S-protein interactions. The interplay between hyperglycemia and SARS-CoV-2 infection, however, remains to be fully elucidated. The primary objective of this study is therefore to investigate the effects of hyperglycemia and SARS-CoV-2 binding on pancreatic β-cells. More specifically, we aim to determine the role(s) of AGE production and HBP-mediated O-GlcNAcylation in modulation of SARS-CoV-2 entry and accessory proteins, S-protein binding, and downstream molecular effects in cultured INS-1 β-cells under hyperglycemic conditions. We hypothesize that hyperglycemia primes host cells for SARS-CoV-2 S-protein variants via glycation (AGE) and O-GlcNAcylation (HBP) pathways to promote binding to INS-1 β-cells. INS-1 cells were exposed to 1) high glucose, glucosamine (increases HBP), and methylglyoxal (AGE precursor) and 2) recombinant S-protein (Wild type, β and δ-variants) in separate experiments. Metabolic activity (WST-1 assays) and Western blot analyses were performed to assess markers of mitochondrial oxidative phosphorylation, the AGE (RAGE) and HBP (OGT and O-GlcNAc), SARS-CoV-2 entry (ACE2, DPP4, Basigin, EEA1, VCP) and accessory proteins (TMPRSS2, ADAM10, ADAM17, Cathepsin B, CD13). Glucose-stimulated insulin response was determined using an insulin ELISA. Metabolic activity was increased by high glucose (p&lt;0.0001), glucosamine (p&lt;0.0001) and methylglyoxal (p&lt;0.05) versus controls. Recombinant S-protein variants increased metabolic activity in a time, concentration and variant-dependent manner. Here, the lower (10 ng/ml) concentration showed a &gt;4-fold increase for the β- and δ-variants (p&lt;0.0001 versus control, respectively), while the wild type had a similar response with higher concentrations (100 and 1000 ng/ml). The endosomal protein EEA1 was significantly increased (p&lt;0.05 versus control) in response to AGE modulation. We conclude that hyperglycemia and modulation of the HBP and AGE pathways exert differential β-cell metabolic effects and AGE induction may prime endosomal entry mechanisms for SARS-CoV-2 spike protein. The spike variants significantly stimulate metabolic activity, modulating β-cell function in an acute manner. This project is funded by the National Research Foundation (NRF) of South Africa and the South African Medical Research Council (SAMRC). This is the full abstract presented at the American Physiology Summit 2024 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.