Insulin Dynamics Research Articles

The influence of fetal sex on antenatal maternal glucose and insulin dynamics

The ‘Developmental Origins of Health and Disease’ (DOHaD) hypothesis postulates that exposures during critical periods of development and growth, including maternal hyperglycemia, can have significant consequences for short- and long-term health in offspring. The influence of fetal status on maternal (patho)physiology is less well understood but gaining attention. Fetal sex specifically may be an independent risk factor for a range of adverse pregnancy outcomes, including increased gestational diabetes mellitus (GDM) frequency with male fetuses in multi-ethnic populations. Fetal sex has been thought to modulate maternal glucose metabolism, including insulin dynamics, through complex genetic and hormonal interactions. Mechanisms have not been fully elucidated, however, but may relate to sexual dimorphism in maternal-fetal-placental interactions. We review current evidence on the potential influence of fetal sex on maternal glucose and insulin dynamics, and fetal outcomes.

Modeling glucose–insulin dynamics to evaluate healthy and diseased population characteristics in type 2 diabetes mellitus

Modeling glucose–insulin dynamics to evaluate healthy and diseased population characteristics in type 2 diabetes mellitus

Effect of Meal Frequency on Insulin Regulation in Athletes: A Cross-Sectional Study

Objective: This study aimed to investigate the effects of meal frequency on total insulin secretion and insulin response in individuals who were engaged in physical activity. Methodology: The research was carried out at the Khyber Medical University, Peshawar, and examined how meal frequency affected the insulin responses in physically active participants (PAP) who were gathered from five sports clubs and four gyms. A sample size of 25 participants was determined based on power analysis. Data collection involved two days of dietary intervention, isocalorie on day one and two meals per day on day two, utilizing blood samples and using Calbiotech ELISAkit at predetermined intervals to test insulin levels. Descriptive statistics and other statistical tests like ANOVO and post HOC analysis were all included as part of the statistical analysis. Result: On day one, insulin levels at 15, 30, and 60 minutes ranged from 15.75 to 25.39 mIU/L, while on day two, particularly in the morning session, insulin levels were signifcantly lower, ranging from 7.23 to 19.51 mIU/L. Significant positive correlation was observed between muscle mass & weight(r=0.632), waist circumference with BMI(r=0.941) and AUC of insulin with age (r=0.554). Conclusion: The significance of personalized dietary strategies for maximizing metabolic conditions in physically active individuals highlights the complex interplay between exercise, meal frequency as well as insulin dynamics. Keywords: Athletes, Blood Glucose, appetite regulations, Insulin

Horses with previous episodes of laminitis have altered insulin responses to seasonal oral sugar testing and grazing compared to horses with no known history of laminitis

Forage is essential for equine health and performance, but intake of elevated pasture nonstructural carbohydrates (NSC) may exacerbate metabolic disorders. This study aimed to investigate the influence of laminitis history on metabolic and morphometric responses in grazing horses. Twelve non-pregnant mares (15 ± 3.4 yrs) were selected based on previous diagnosis of laminitis (PRELAM; n=6) or not (NOLAM; n=6). Horses were maintained on 8.5-ha pasture. Weekly pasture samples were clipped at random for nutrient analysis. Monthly blood samples were collected and analyzed for glucose and insulin concentrations. Body weight (BW), body condition score (BCS), and cresty neck score (CNS) were evaluated monthly. Each month, a modified oral sugar test (OST) was used to assess basal (T0) and 75-minute (T75) insulin dynamics following 0.30 mL/kg BW Karo Light Corn Syrup. Data were analyzed using PROC MIXED with repeated measures (SAS Institute). PRELAM had greater CNS (P < 0.001), BW (P < 0.05), and BCS compared to NOLAM (P < 0.05). Non-fasted glucose was influenced by month (P < 0.001) while non-fasted insulin was affected by group by month (P = 0.004). Fasted insulin concentrations (T0) were affected by month and group (P < 0.001) where PRELAM had greater concentrations. T75 glucose and insulin concentrations were affected by month (P < 0.001 and P = 0.002, respectively) and were higher for PRELAM (P = 0.003). These data suggest horses with greater general and regional adiposity, and previous history of laminitis, often exhibit greater insulin concentrations on pasture and to OST.

Effect of exercise on plasma insulin levels in individuals with type 1 diabetes: A systematic review and meta-analysis.

Current evidence of the impact of acute exercise on insulin levels in individuals with type 1 diabetes remains controversial. Therefore, we conducted a systematic review and meta-analysis to explore exercise-induced changes in insulin levels. We conducted a systematic review (until 05 November 2023) and meta-analysis exploring the effect of exercise on insulin concentration in individuals with type 1 diabetes. We included randomised cross-over studies for rapid-acting insulin and pre- and post-studies for long-acting insulin in individuals with type 1 diabetes performing any type of acute exercise and had a control condition. The exercise-induced change in insulin levels was the outcome of interest. When possible, the mean differences (MDs) in insulin levels were pooled using the DerSimonian and Laird random effect method. Risk of bias was assessed for each included study. Seventeen trials, encompassing 186 participants with type 1 diabetes, were included in the systematic review. Twelve out of 17 studies included participants on rapid-acting insulin regimens and used a cross-over design, whereas five out of 17 single-arm studies included participants on (ultra)long-acting insulin. Seven out of 12 studies on rapid-acting insulins and all the single-arm studies were at high risk of bias. Results suggest a statistically significant, small-to-moderate increase of rapid-acting insulin after 30 min of exercise (MD of 18.44 [95% CI 0.02; 36.86; I2 0%] pmol/L); meanwhile, findings on (ultra)long-acting insulin were inconclusive. A small-to-moderate increase of insulin levels in studies including rapid-acting insulin was found after a bout of physical exercise in individuals with type 1 diabetes. However, current gaps in high-quality evidence challenge our understanding of insulin kinetics around exercise.

Associations Between Relative Lower and Upper Body Strength and Hyperinsulinemia in US Adults: 1999-2002 and 2011-2014 NHANES.

Churilla, JR, Boyer, WR, Richardson, MR, and Williams, CC. Associations between relative lower and upper body strength and hyperinsulinemia in U.S. Adults: NHANES 1999-2002 and 2011-2014. J Strength Cond Res XX(X): 000-000, 2024-Skeletal muscle (SM) is an insulin-sensitive tissue that aids in glucose homeostasis. Insulin resistance leads to chronic hyperglycemia and type 2 diabetes. Previous evidence suggests that greater SM strength and size improve insulin dynamics. The primary aim of this study was to examine the association(s) between relative lower and upper body strength and hyperinsulinemia in a nationally representative sample of US adults. Samples of adult (≥50 years) subjects in the 1999-2002 (N = 1,097) and adults (≥20 years) in the 2011-2014 (N = 2,576) National Health and Nutrition Examination Survey were used in the analyses. Significance was set at p ≤ 0.05 for regression models. Quartiles (Q) of relative lower body strength (RLBS [N·BMI-1]) and relative grip strength (RGS [kg·BMI-1]) were created. Hyperinsulinemia was calculated using the weighted 75th percentile of log-fasted insulin among adults without diabetes. Inverse dose-response relationships were found for decreasing prevalence estimates of hyperinsulinemia by increasing Q of both RLBS and RGS. Similar dose-response associations were revealed for increasing Q of both RLBS and RGS and mean insulin concentrations. Following adjustment for demographic and lifestyle variables, subjects in Q2, Q3, and Q4 of RLBS were found to have significantly lower odds of hyperinsulinemia (OR 0.58 [P = 0.05], OR 0.38, OR 0.22 [p < 0.05 for both], respectively). Subjects in Q2, Q3, and Q4 of RGS were also found to have lower odds of hyperinsulinemia (OR 0.30; OR 0.14; OR 0.05 [p < 0.0001 for all]), respectively. These data suggest RLBS and RGS may both be favorably associated with insulin homeostasis.

Elevations in plasma glucagon are associated with reduced insulin clearance after ingestion of a mixed-macronutrient meal in people with and without type 2 diabetes

Aims/hypothesisThe temporal suppression of insulin clearance after glucose ingestion is a key determinant of glucose tolerance for people without type 2 diabetes. Whether similar adaptations are observed after the ingestion of a mixed-macronutrient meal is unclear.MethodsIn a secondary analysis of data derived from two randomised, controlled trials, we studied the temporal responses of insulin clearance after the ingestion of a standardised breakfast meal consisting of cereal and milk in lean normoglycaemic individuals (n=12; Lean-NGT), normoglycaemic individuals with central obesity (n=11; Obese-NGT) and in people with type 2 diabetes (n=19). Pre-hepatic insulin secretion rates were determined by the deconvolution of C-peptide, and insulin clearance was calculated using a single-pool model. Insulin sensitivity was measured by an oral minimal model.ResultsThere were divergent time course changes in insulin clearance between groups. In the Lean-NGT group, there was an immediate post-meal increase in insulin clearance compared with pre-meal values (p<0.05), whereas insulin clearance remained stable at baseline values in Obese-NGT or declined slightly in the type 2 diabetes group (p<0.05). The mean AUC for insulin clearance during the test was ~40% lower in the Obese-NGT (1.3 ± 0.4 l min−1 m−2) and type 2 diabetes (1.4 ± 0.7 l min−1 m−2) groups compared with Lean-NGT (1.9 ± 0.5 l min−1 m−2; p<0.01), with no difference between the Obese-NGT and type 2 diabetes groups. HOMA-IR and glucagon AUC emerged as predictors of insulin clearance AUC, independent of BMI, age or insulin sensitivity (adjusted R2=0.670). Individuals with increased glucagon AUC had a 40% reduction in insulin clearance AUC (~ −0.75 l min−1 m−2; p<0.001).Conclusions/interpretationThe ingestion of a mixed-macronutrient meal augments differing temporal profiles in insulin clearance among individuals without type 2 diabetes, which is associated with HOMA-IR and the secretion of glucagon. Further research investigating the role of hepatic glucagon signalling in postprandial insulin kinetics is warranted.Trial registrationISRCTN17563146 and ISRCTN95281775Graphical

Associations of adipose insulin resistance index with pancreatic β cell function (inverse) and glucose excursion (positive) in young Japanese women

The relationship of adipose tissue insulin resistance (AT-IR, a product of fasting insulin and free fatty acids) and homeostasis-model assessment-insulin resistance (HOMA-IR) to β-cell function was studied cross-sectionally in the setting of subtle glucose dysregulation. Associations of AT-IR and HOMA-IR with fasting and post-glucose glycemia and β-cell function inferred from serum insulin kinetics during a 75 g oral glucose tolerance test were studied in 168 young female Japanese students. β-cell function was evaluated by disposition index calculated as a product of the insulinogenic index (IGI) and Matsuda index. AT-IR, not HOMA-IR, showed positive associations with post-glucose glycemia and area under the glucose response curve although both indices were associated with fasting glycemia. HOMA-IR, not AT-IR, was associated positively with log IGI whereas both indices were inversely associated with Matsuda index. AT-IR, not HOMA-IR, showed inverse associations with log disposition index. Associations of adipose tissue insulin resistance with β-cell function (inverse) and glucose excursion in young Japanese women may suggest that lipotoxicity to pancreatic β-cells for decades may be associated with β cell dysfunction found in Japanese patients with type 2 diabetes. Positive association of HOMA-IR with insulinogenic index may be associated with compensatory increased insulin secretion.

Low muscle mass is associated with low insulin sensitivity, impaired pancreatic β cell function, and high glucose excursion in nondiabetic nonobese Japanese women

AimWe tested whether skeletal muscle mass is associated with insulin sensitivity, pancreatic β-cell function, and postglucose glycemia. MethodsAppendicular skeletal muscle mass (ASM) (relative to body size, %ASM) by DXA, surrogate measures of insulin sensitivity, insulin secretion and the disposition index (insulin sensitivity adjusted insulin secretion: a product of the insulinogenic index and Matsuda insulin sensitivity index) inferred from serum insulin kinetics during a 75 g oral glucose tolerance test (OGTT) were evaluated in 168 young and 65 middle-aged women, whose BMI averaged <23.0 kg/m2 and HbA1c ≦ 5.5 %. ResultsIn two groups of women, %ASM was associated negatively with homeostasis model assessment insulin resistance (HOMA-IR) and 2-h insulin (both p < 0.01 or less). In middle-aged women not in young women, %ASM was associated inversely with the Matsuda index (p < 0.001). In middle-aged women only, it also showed a positive association with the disposition index (p = 0.02) and inverse associations with 1-h and 2-h glucose (both p < 0.01) and area under the glucose concentration curve during OGTT (p = 0.006). On multivariate linear regression analyses, 2-h insulin emerged as a determinant of %ASM independently of HOMA-IR in young women (standardized β: 0.287, p < 0.001, R2 = 0.077). In middle-aged women, the Matsuda index emerged as a determinant of %ASM (standardized β: 0.476, p < 0.001) independently of HOMA-IR, log ODI and AUCg and explained 21.3 % of %ASM variability. Post-glucose glycemia and AUCg were higher and log ODI was lower in middle-aged women with low compared with high %ASM. ConclusionLow skeletal muscle mass (relative to body size) was associated with low insulin sensitivity in young and middle-aged Japanese women who were neither obese nor diabetic. Middle-aged women with low muscle mass had low disposition index, an early marker of inadequate pancreatic β-cell compensation, and hence high glucose excursion. Low skeletal muscle mass may be associated with the development of type 2 diabetes at a much lower BMI in Japanese people.

Insulin Dynamics and Pathophysiology in Youth-Onset Type 2 Diabetes.

Youth-onset type 2 diabetes (T2D) is increasing around the globe. The mounting disease burden of youth-onset T2D portends substantial consequences for the health outcomes of young people and for health care systems. The pathophysiology of this condition is characterized by insulin resistance and initial insulin hypersecretion ± an inherent insulin secretory defect, with progressive loss of stimulated insulin secretion leading to pancreatic β-cell failure. Research studies focusing on youth-onset T2D have illuminated key differences for youth- vs adult-onset T2D, with youth having more profound insulin resistance and quicker progression to loss of sufficient insulin secretion to maintain euglycemia. There is a need for therapies that are targeted to improve both insulin resistance and, importantly, maintain sufficient insulin secretory function over the lifespan in youth-onset T2D.

In Vitro Investigation of Insulin Dynamics During 4 Hours of Simulated Cardiopulmonary Bypass.

Hyperglycemia is common in patients undergoing cardiovascular surgery with cardiopulmonary bypass. We hypothesize that intraoperative hyperglycemia may be, at least partially, attributable to insulin loss due to adhesion on artificial surfaces and/or degradation by hemolysis. Thus, our primary aim was to investigate the loss of insulin in 2 different isolated extracorporeal circulation circuits (ECCs), that is, a conventional ECC (cECC) with a roller pump, and a mini-ECC (MiECC) system with a centrifugal pump. The secondary aim was to assess and compare the relationship between changes in insulin concentration and the degree of hemolysis in our 2 ECC models. Six cECC and 6 MiECC systems were primed with red packed blood cells and thawed fresh-frozen plasma (1:1). Four additional experiments were performed in cECC using only thawed fresh-frozen plasma. Human insulin (Actrapid) was added, targeting a plasma insulin concentration of 400 mU/L. Insulin concentration and hemolysis index were measured at baseline and hourly thereafter. The end points were the change in insulin level after 4 hours compared to baseline and hemolysis index after 4 hours. The insulin concentration and hemolysis index were analyzed by means of a saturated linear mixed-effect regression model with a random offset for each experiment to account for the repeated measure design of the study, resulting in mean estimates and 95% confidence intervals (CIs) of the primary end points as well as of pairwise contrasts with respect to ECC type. Insulin concentration decreased by 63% (95% CI, 48%-77%) in the MiECC and 92% (95% CI, 77%-106%) in the cECC system that contained red blood cells. Insulin loss was significantly higher in the cECC system compared to the MiECC (P = .022). In the cECC with only plasma, insulin did not significantly decrease (-4%; 95% CI, -21% to 14%). Hemolysis index in MiECC increased from 68 (95% CI, 46-91) to 76 (95% CI, 54-98) after 4 hours, in cECC from 81 (95% CI, 59-103) to 121 (95% CI, 99-143). Hemolysis index and percent change of insulin showed an excellent relationship (r = -0.99, P < .01). Our data showed that insulin levels substantially decreased during 4 hours of simulated cardiopulmonary bypass only in the ECC that contained hemoglobin. The decrease was more pronounced in the cECC, which also exhibited a greater degree of hemolysis. Our results suggest that insulin degradation by hemolysis products may be a stronger contributor to insulin loss than adhesion of insulin molecules to circuit surfaces.

Disturbances in dynamics of glucose, insulin and C-peptide in blood after a normalized intake of mixed meal in obesity and type 2 diabetes mellitus

The aim of the study is to investigate the dynamics of venous blood glucose, insulin, and C-peptide in response to intake a meal normalized to body mass in obese patients without and with type 2 diabetes mellitus. Venous blood samples were taken from 7 healthy subjects, 9 obese patients, and 10 obese patients with type 2 diabetes mellitus (mean period of diagnosed diabetes 7 years) before and 30, 60, 90, 120, and 180 min after a mixed meal (6 kcal/kg of body mass); additionally, 9 patients with obesity and type 2 diabetes mellitus and 3 healthy volunteers completed a hyperinsulinemic euglycemic clamp test. In patient groups the energy content of food did not differ, but was 1.8 times higher than in the control. An increase in glucose level one hour after a meal was maximal in patients with type 2 diabetes, but an increase in insulin and C-peptide — in obese patients, that related to impairment of insulin-dependent glucose uptake by tissues and of the rate of insulin secretion (dysfunction of â-cells) in patients. At the same time, an increase in the total area under the curve “C-peptide–time” shows that the maximum secretory response of â-cells is comparable in obese patients without and with type 2 diabetes mellitus. The absolute blood glucose level 90 minutes after a meal was closely correlated with the M-index — the marker of systemic sensitivity to insulin (rs = –0.82, p = 0.002). Our results characterize the features in the regulation of carbohydrate metabolism after intake a mixed meal, normalized to body mass, in people with the varying severity of metabolic disorders, and open up prospects for a wider application of this test in practice.

Artificial intelligence powered glucose monitoring and controlling system: Pumping module.

Diabetes, a globally escalating health concern, necessitates innovative solutions for efficient detection and management. Blood glucose control is an essential aspect of managing diabetes and finding the most effective ways to control it. The latest findings suggest that a basal insulin administration rate and a single, high-concentration injection before a meal may not be sufficient to maintain healthy blood glucose levels. While the basal insulin rate treatment can stabilize blood glucose levels over the long term, it may not be enough to bring the levels below the post-meal limit after 60 min. The short-term impacts of meals can be greatly reduced by high-concentration injections, which can help stabilize blood glucose levels. Unfortunately, they cannot provide long-term stability to satisfy the post-meal or pre-meal restrictions. However, proportional-integral-derivative (PID) control with basal dose maintains the blood glucose levels within the range for a longer period. To develop a closed-loop electronic system to pump required insulin into the patient's body automatically in synchronization with glucose sensor readings. The proposed system integrates a glucose sensor, decision unit, and pumping module to specifically address the pumping of insulin and enhance system effectiveness. Serving as the intelligence hub, the decision unit analyzes data from the glucose sensor to determine the optimal insulin dosage, guided by a pre-existing glucose and insulin level table. The artificial intelligence detection block processes this information, providing decision instructions to the pumping module. Equipped with communication antennas, the glucose sensor and micropump operate in a feedback loop, creating a closed-loop system that eliminates the need for manual intervention. The incorporation of a PID controller to assess and regulate blood glucose and insulin levels in individuals with diabetes introduces a sophisticated and dynamic element to diabetes management. The simulation not only allows visualization of how the body responds to different inputs but also offers a valuable tool for predicting and testing the effects of various interventions over time. The PID controller's role in adjusting insulin dosage based on the discrepancy between desired setpoints and actual measurements showcases a proactive strategy for maintaining blood glucose levels within a healthy range. This dynamic feedback loop not only delays the onset of steady-state conditions but also effectively counteracts post-meal spikes in blood glucose. The WiFi-controlled voltage controller and the PID controller simulation collectively underscore the ongoing efforts to enhance efficiency, safety, and personalized care within the realm of diabetes management. These technological advancements not only contribute to the optimization of insulin delivery systems but also have the potential to reshape our understanding of glucose and insulin dynamics, fostering a new era of precision medicine in the treatment of diabetes.

A novel optimized fractional order system for tuning biological parameters

AbstractIn contemporary biological research and applications, control systems have become indispensable for understanding and managing the intricate dynamics of the human biological system. Given the critical role of components such as the pancreas structure, protein formation, insulin and glucose regulation, and the genetic regulatory network (GRN), any disturbances in these systems can lead to severe health issues. To overcome these issues, to introduced a novel hybrid controller called the fuzzy lion‐based optimized fractional order system (FL‐OFOS) for evaluating the performance of the system. This controller aims to efficiently govern and regulate key components of the human biological system, including insulin dynamics, protein synthesis, pancreas functionality, and GRN management. The controller is specifically tailored to regulate insulin, protein synthesis, pancreas function, and GRN dynamics within the human biological system. The optimization of biological parameter values is achieved through the incorporation of the fuzzy lion function. The results of this study highlight the efficacy of the FL‐OFOS controller in optimizing and regulating various biological parameters. The system demonstrates minimal error rates, rapid response times, reduced overshoot, and high control precision and accuracy. The proposed controller achieves a minimal error rate of 0.98%, with only minor overshoot occurring in the outcomes. As a result, the FL‐OFOS controller offers substantial gains and delivers optimal results in the realm of biological systems.

Kinetics of insulin and C-peptide and estimation of prehepatic insulin secretion rates after intravenous glucose stimulation using arterial versus venous blood sampling in healthy males

An intravenous glucose-infusion of 0.3 g glucose per Kg body weight was administered over 1 min in nine healthy males with simultaneous blood sampling from the hepatic vein, femoral artery and a peripheral vein. Insulin secretion rates (ISR) were determined by the Eaton method and the ISEC method using C-peptide concentrations from arterial and peripheral venous blood. First phase (0–10 min), second phase (10–60 min), and total insulin secretion (0–60 min) were calculated as the incremental areas (iAUC) above baseline. The primary endpoint was first phase insulin response. The first phase insulin response in artery and venous blood did not differ with the Eaton method (p = 0.25), but was significantly greater with the ISEC method in arterial compared with venous blood (p < 0.05). The first phase insulin responses did not differ between methods in artery (p = 0.73) or venous blood (p = 0.73). The first phase responses of insulin and C-peptide were significant higher in the hepatic vein compared with those in the artery (p < 0.05) and peripheral vein (p < 0.05) but did not differ significantly between the artery compared with the peripheral vein for insulin (p = 0.09) or C-peptide (p = 0.26). Prehepatic insulin secretion rates did not differ between the Eaton and ISEC methods, but with the ISEC method the first phase insulin response was significantly greater in arterial compared with venous blood. The first phase insulin response differs when calculated from plasma insulin or C-peptide and depends on sample sites.

Design of PD Controllers with Input Saturation for Postprandial Blood Glucose Regulation

An Artificial pancreas system regulates blood glucose in people with type 1 diabetes by automating the appropriate insulin infusion rate calculation. Insulin cannot be removed once injected, and thus, the control input is constrained to be positive. Controllers designed without taking this constraint into consideration often deliver an excessive insulin dose after a meal intake (postprandial period), which may cause hypoglycemia, a condition related to harmful complications. The non-negativeness is usually handled indirectly through additional control structures that compensate for the saturation by cutting of the insulin flow in advance. The few approaches that consider the non-negativeness of insulin in the controller design process end up with high-order controllers, which are difficult to analyze. In this work, the design of a input-constrained PD controller for regulating postprandial glucose is explored. The set of feasible controller parameters is computed and related to the meal and insulin dynamics.

Identification of PK-PD Insulin Models using Experimental GIR Data

We present a method to estimate parameters in pharmacokinetic (PK) and pharmacodynamic (PD) models for glucose insulin dynamics in humans. The method combines 1) experimental glucose infusion rate (GIR) data from glucose clamp studies and 2) a PK-PD model to estimate parameters such that the model fits the data. Assuming that the glucose clamp is perfect, we do not need to know the details of the controller in the clamp, and the GIR can be computed directly from the PK-PD model. To illustrate the procedure, we use the glucoregulatory model developed by Hovorka and modify it to have a smooth non-negative endogeneous glucose production (EGP) term. We estimate PK-PD parameters for rapid-acting insulin analogs (Fiasp and NovoRapid). We use these PK-PD parameters to illustrate GIR for insulin analogs with 30% and 50% faster absorption time than currently available rapid-acting insulin analogs. We discuss the role of system identification using GIR data from glucose clamp studies and how such identified models can be used in automated insulin dosing (AID) systems with ultra rapid-acting insulin.

Disturbances in Dynamics of Glucose, Insulin, and C-Peptide in Blood after a Normalized Intake of a Mixed Meal in Obesity and Type 2 Diabetes Mellitus

Disturbances in Dynamics of Glucose, Insulin, and C-Peptide in Blood after a Normalized Intake of a Mixed Meal in Obesity and Type 2 Diabetes Mellitus

The generation of senescent-like CD4+ EMRA T cells in T2D and their contribution to poor COVID-19 vaccine responses

Abstract CD4+ T cells are essential for protection from viral pathogens, such as SARS-CoV-2. However, an increase in the dysfunction CD4+ EMRA subset is likely to hinder the immune response towards viruses. We show here that CD4+ EMRAs are increased with elevated blood glucose, such as people living with T2D, which alters mitochondrial function and causes the differentiation of CD4+ T cells, reducing the immune response to COVID-19 vaccination. CD4+ T cells were examined for senescence, their insulin dynamics, and mitochondrial function after in vitro culture of high and low glucose media, with or without rotenone or mitoQ. Serum samples were used to assess circulating inflammation and IgG antibodies to SARS-CoV-2. People living with T2D had increased expression of CD4+ EMRA T cells, the appearance of which correlated with increasing blood glucose values. The T2D cohort showed a reduced mitochondrial membrane potential and increased mtROS production. These results were mimicked using high glucose media which accelerated CD4+ T cell differentiation and reduced MMP. People living with T2D (non-hyperglycaemic and hyperglycaemic) had altered expression of inflammatory mediators. CD4+ EMRA cells did not respond to COVID-19 peptides, and people with T2D had a reduced T cell and antibody response to SARS-CoV-2 S1 spike protein. We have shown that senescent-like CD4+ EMRA influence the viral response in SARS-CoV-2 and that CD4+ EMRAs may arise from faulty mitochondrial dynamics due to increased environmental glucose. Further study is required to determine the direct link increased glucose has with CD4+ EMRA formation.

Associations of Alanine Aminotransferase/Aspartate Aminotransferase, a Marker of Hepatosteatosis, with Adipose Tissue Insulin Resistance Index and Leptin/Adiponectin Ratio in Japanese Women.

Objective: We assessed whether alanine aminotransferase/aspartate aminotransferase (ALT/AST), a marker of hepatic steatosis, may be associated with adipose tissue dysfunction more closely than hepatic and muscle insulin resistance (IR). Methods: Associations with adipose tissue IR index (AT-IR) calculated as a product of fasting insulin and free fatty acids, leptin/adiponectin ratio, a proxy of adipocyte dysfunction, homeostasis model assessment IR (HOMA-IR), hepatic and muscle IR inferred from plasma insulin kinetics during a 75 grams oral glucose tolerance test (OGTT) were studied in nondiabetic 307 young and 148 middle-aged Japanese women, whose body mass index averaged 20 and 22 kilograms/m2, respectively. Results: On multivariate linear regression analysis in young women, ALT/AST was associated with trunk/leg fat ratio (standardized β = 0.202, P = 0.007), a marker of abdominal fat accumulation, and AT-IR (standardized β = 0.185, P = 0.003) independently of HOMA-IR and Matsuda index (R2 = 0.07). In middle-aged women, leptin/adiponectin ratio (standardized β = 0.446, P < 0.001) and AT-IR (standardized β = 0.292, P = 0.009) emerged as determinants of ALT/AST independently of trunk/leg fat ratio, OGTT-derived hepatic IR, leptin, and adiponectin (R2 = 0.34). Conclusions: ALT/AST was associated with AT-IR and adipocyte dysfunction more closely than hepatic and muscle IR even in nondiabetic lean Japanese women.