Affect Insulin Sensitivity Research Articles

Interactions of genes with alcohol consumption affect insulin sensitivity and beta cell function.

Alcohol consumption has complex effects on diabetes and metabolic disease, but there is widespread heterogeneity within populations and the specific reasons are unclear. Genetic factors may play a role and warrant exploration. The aim of this study was to elucidate genetic variants modulating the impact of alcohol consumption on insulin sensitivity and pancreatic beta cell function within populations presenting normal glucose tolerance (NGT). We recruited 4194 volunteers in Nanjing, 854 in Jurong and an additional 5833 in Nanjing for Discovery cohorts 1 and 2 and a Validation cohort, respectively. We performed an OGTT on all participants, establishing a stringent NGT group, and then assessed insulin sensitivity and beta cell function. Alcohol consumption was categorised as abstinent, light-to-moderate (<210 g per week) or heavy (≥210 g per week). After excluding ineligible individuals, an exploratory genome-wide association study identified potential variants interacting with alcohol consumption in 1862 NGT individuals. These findings were validated in an additional cohort of 2169 NGT individuals. Cox proportional hazard regression was further employed to evaluate the effect of the interaction between the potential variants and alcohol consumption on the risk of type 2 diabetes within the UK Biobank cohort. A significant correlation was observed between drinking levels and insulin sensitivity, accompanied by a consequent inverse relationship with insulin resistance and beta cell insulin secretion after adjusting for confounding factors in NGT individuals. However, no significant associations were noted in the disposition indexes. The interaction of variant rs56221195 with alcohol intake exhibited a pronounced effect on the liver insulin resistance index (LIRI) in the discovery set, corroborated in the validation set (combined p=1.32 × 10-11). Alcohol consumption did not significantly affect LIRI in rs56221195 wild-type (TT) carriers, but a strong negative association emerged in heterozygous (TA) and homozygous (AA) individuals. The rs56221195 variant also significantly interacts with alcohol consumption, influencing the total insulin secretion index INSR120 (the ratio of the AUC of insulin to glucose from 0 to 120 min) (p=2.06 × 10-9) but not disposition index. In the UK Biobank, we found a significant interaction between rs56221195 and alcohol consumption, which was linked to the risk of type 2 diabetes (HR 0.897, p=0.008). Our findings reveal the effects of the interaction of alcohol and rs56221195 on hepatic insulin sensitivity in NGT individuals. It is imperative to weigh potential benefits and detriments thoughtfully when considering alcohol consumption across diverse genetic backgrounds.

Effect of senolytic drugs in young female mice chemically induced to estropause

AimsThis study aimed to assess metabolic responses and senescent cell burden in young female mice induced to estropause and treated with senolytic drugs. Main methodsEstropause was induced by 4-vinylcyclohexene diepoxide (VCD) injection in two-month-old mice. The senolytics dasatinib and quercetin (D + Q) or fisetin were given by oral gavage once a month from five to 11 months of age. Key findingsVCD-induced estropause led to increased body mass and reduced albumin concentrations compared to untreated cyclic mice, without affecting insulin sensitivity, lipid profile, liver enzymes, or total proteins. Estropause decreased catalase activity in adipose tissue but had no significant effect on other redox parameters in adipose and hepatic tissues. Fisetin treatment reduced ROS levels in the hepatic tissue of estropause mice. Estropause did not influence senescence-associated beta-galactosidase activity in adipose and hepatic tissues but increased senescent cell markers and fibrosis in ovaries. Senolytic treatment did not decrease ovarian cellular senescence induced by estropause. SignificanceOverall, the findings suggest that estropause leads to minor metabolic changes in young females, and the senolytics D + Q and fisetin had no protective effects despite increased ovarian senescence.

Hypertension and insulin resistance in rheumatoid arthritis: unveiling insights with mets-ir index

Aim: Hypertension (HT), together with metabolic dysfunctions and insulin resistance (IR) in its pathophysiology, is a significant risk factor for cardiovascular disease in rheumatoid arthritis (RA) patients. Identifying IR early could enhance HT management, especially in RA patients, where HT prevalence is elevated. The study aimed to assess metabolic indices, particularly the METS-IR, as predictors of HT in RA patients. Material and Methods: This retrospective, cross-sectional study investigated the association between RA, IR, and HT in 80 RA patients and 80 age- and sex-matched controls. Patients with diabetes, pre-diabetes, or other conditions affecting insulin sensitivity were excluded, as were those on glucose-metabolism-affecting medications except low-dose glucocorticoids (

Trefoil Factor 2 Expressed by the Murine Pancreatic Acinar Cells Is Required for the Development of Islets and for β-Cell Function During Aging.

Exocrine-to-endocrine crosstalk in the pancreas is crucial to maintain beta cell function. However, the molecular mechanisms underlying this crosstalk are largely undefined. Trefoil factor 2 (Tff2) is a secreted factor known to promote the proliferation of beta cells in vitro, but its physiological role in vivo in the pancreas is unknown. Also, it remains unclear which pancreatic cell type expresses Tff2 protein. We therefore created a mouse model with a conditional knockout of Tff2 in the murine pancreas. We find that the Tff2 protein is preferentially expressed in acinar but not ductal or endocrine cells. Tff2 deficiency in the pancreas reduces beta cell mass on embryonic day 16.5. However, homozygous mutant mice are born without a reduction of beta cells and with acinar Tff3 compensation by day 7. When mice are aged to 1 year, both male and female homozygous and male heterozygous mutants develop impaired glucose tolerance without affected insulin sensitivity. Perifusion analysis reveals that the second phase of glucose-stimulated insulin secretion from islets is reduced in aged homozygous mutant compared to controls. Collectively, these results demonstrate a previously unknown role of Tff2 as an exocrine acinar cell-derived protein required for maintaining functional endocrine beta cells in mice.

Hypothalamic POMC neuron-specific knockout of MC4R affects insulin sensitivity by regulating Kir2.1

BackgroundImbalance in energy regulation is a major cause of insulin resistance and diabetes. Melanocortin-4 receptor (MC4R) signaling at specific sites in the central nervous system has synergistic but non-overlapping functions. However, the mechanism by which MC4R in the arcuate nucleus (ARC) region regulates energy balance and insulin resistance remains unclear.MethodsThe MC4Rflox/flox mice with proopiomelanocortin (POMC) -Cre mice were crossed to generate the POMC-MC4Rflox/+ mice. Then POMC-MC4Rflox/+ mice were further mated with MC4Rflox/flox mice to generate the POMC-MC4Rflox/flox mice in which MC4R is selectively deleted in POMC neurons. Bilateral injections of 200 nl of AAV-sh-Kir2.1 (AAV-sh-NC was used as control) were made into the ARC of the hypothalamus. Oxygen consumption, carbon dioxide production, respiratory exchange ratio and energy expenditure were measured by using the CLAMS; Total, visceral and subcutaneous fat was analyzed using micro-CT. Co-immunoprecipitation assays (Co-IP) were used to analyze the interaction between MC4R and Kir2.1 in GT1-7 cells.ResultsPOMC neuron-specific ablation of MC4R in the ARC region promoted food intake, impaired energy expenditure, leading to increased weight gain and impaired systemic glucose homeostasis. Additionally, MC4R ablation reduced the activation of POMC neuron, and is not tissue-specific for peripheral regulation, suggesting the importance of its central regulation. Mechanistically, sequencing analysis and Co-IP assay demonstrated a direct interaction of MC4R with Kir2.1. Knockdown of Kir2.1 in POMC neuron-specific ablation of MC4R restored the effect of MC4R ablation on energy expenditure and systemic glucose homeostasis, indicating by reduced body weight and ameliorated insulin resistance.ConclusionHypothalamic POMC neuron-specific knockout of MC4R affects energy balance and insulin sensitivity by regulating Kir2.1. Kir2.1 represents a new target and pathway that could be targeted in obesity.

Differential effects of fish-oil and cocoa-butter based high-fat/high-sucrose diets on endocrine pancreas morphology and function in mice.

A high-fat/high-sucrose diet leads to adverse metabolic changes that affect insulin sensitivity, function, and secretion. The source of fat in the diet might inhibit or increase this adverse effect. Fish oil and cocoa butter are a significant part of our diets. Yet comparisons of these commonly used fat sources with high sucrose on pancreas morphology and function are not made. This study investigated the comparative effects of a fish oil-based high-fat/high-sucrose diet (Fish-HFDS) versus a cocoa butter-based high-fat/high-sucrose diet (Cocoa-HFDS) on endocrine pancreas morphology and function in mice. C57BL/6 male mice (n=12) were randomly assigned to dietary intervention either Fish-HFDS (n=6) or Cocoa-HFDS (n=6) for 22 weeks. Intraperitoneal glucose and insulin tolerance tests (IP-GTT and IP-ITT) were performed after 20-21 weeks of dietary intervention. Plasma concentrations of c-peptide, insulin, glucagon, GLP-1, and leptin were measured by Milliplex kit. Pancreatic tissues were collected for immunohistochemistry to measure islet number and composition. Tissues were multi-labelled with antibodies against insulin and glucagon, also including expression on Pdx1-positive cells. Fish-HFDS-fed mice showed significantly reduced food intake and body weight gain compared to Cocoa-HFDS-fed mice. Fish-HFDS group had lower fasting blood glucose concentration and area under the curve (AUC) for both GTT and ITT. Plasma c-peptide, insulin, glucagon, and GLP-1 concentrations were increased in the Fish-HFDS group. Interestingly, mice fed the Fish-HFDS diet displayed higher plasma leptin concentration. Histochemical analysis revealed a significant increase in endocrine pancreas β-cells and islet numbers in mice fed Fish-HFDS compared to the Cocoa-HFDS group. Taken together, these findings suggest that in a high-fat/high-sucrose dietary setting, the source of the fat, especially fish oil, can ameliorate the effect of sucrose on glucose homeostasis and endocrine pancreas morphology and function.

Glucose volume of distribution affects insulin sensitivity measured by intravenous glucose tolerance test.

To determine whether glucose volume of distribution (VdGLUCOSE ) affects the diagnosis of impaired insulin sensitivity (IS) when using an intravenous glucose tolerance test (IVGTT). Individuals with distinct levels of IS underwent IVGTT after an overnight fast. The prediabetic group (Prediab; n = 33) differed from the healthy group (Healthy; n = 14) in their larger glycosylated hemoglobin (HbA1c of 5.9 ± 0.3 vs. 5.4 ± 0.1%; 41 ± 4 vs. 36 ± 1 mmol/mol; p < 0.001), percent body fat (37 ± 6 vs. 24 ± 3%; p < 0.001) and cardiovascular fitness level (VO2MAX 22 ± 5 vs. 44 ± 5 mL of O2 ·kg-1 ·min-1 ; p < 0.001). Ten minutes after intravenous infusion of the glucose bolus (i.e., 35 g in a 30% solution), VdGLUCOSE was assessed from the increases in plasma glucose concentration. IS was calculated during the next 50 min using the slope of glucose disappearance and the insulin time-response curve. VdGLUCOSE was higher in Healthy than in Prediab (230 ± 49 vs. 185 ± 21 mL·kg-1 ; p < 0.001). VdGLUCOSE was a strong predictor of IS (β standardized coefficient 0.362; p = 0.004). VO2MAX was associated with VdGLUCOSE and IS (Pearson r = 0.582 and 0.704, respectively; p < 0.001). However, body fat was inversely associated with VdGLUCOSE and IS (r = -0.548 and -0.555, respectively; p < 0.001). Since fat mass is inversely related to VdGLUCOSE and in turn, VdGLUCOSE affects the calculations of IS, the IV glucose bolus dose should be calculated based on fat-free mass rather than body weight for a more accurate diagnosis of impaired IS.

Effect of Vitamin D on Retinoblastoma Protein in Prediabetic Individuals.

About 50.8 million people were diagnosed with diabetes in 2011; the count has increased by 10 million in the last five years. Type-1 diabetes could occur at any age, but predominantly in children and young adults. The risk of developing type II diabetes mellitus in the offspring of parents with DM II is 40% if one parent has DM II and approaches 70% if both parents have DM II. The process of developing diabetes from normal glucose tolerance is continuous, with insulin resistance being the first stage. As prediabetes progresses slowly to DM II, it may take approximately 15-20 years for an individual to become diabetic. This progression can be prevented or delayed by taking some precautions and making some lifestyle amendments, e.g., reducing weight by 5-7% of total body weight if obese, etc. Retinoblastoma protein is one of the pocket proteins that act as crucial gatekeepers during the G1/S transition in the cell cycle. A loss or defect in single- cell cycle activators (especially CDK4 and CDK6) leads to cell failure. In diabetic or stress conditions, p53 becomes a transcription factor, resulting in the transactivation of CKIs, which leads to cell cycle arrest, cell senescence, or cell apoptosis. Vitamin D affects insulin sensitivity by increasing insulin receptors or the sensitivity of insulin receptors to insulin. It also affects peroxisome proliferator-activated receptors (PPAR) and extracellular calcium. These influence both insulin resistance and secretion mechanisms, undertaking the pathogenesis of type II diabetes. The study confines a marked decrement in the levels of random and fasting blood glucose levels upon regular vitamin D intake, along with a significant elevation of retinoblastoma protein levels in the circulatory system. The most critical risk factor for the occurrence of the condition came out to be family history, showing that patients with first-degree relatives with diabetes are more susceptible. Factors such as physical inactivity or comorbid conditions further aggravate the risk of developing the disease. The increase in pRB levels caused by vitamin D therapy in prediabetic patients directly influences blood glucose levels. pRB is supposed to play a role in maintaining blood sugar levels. The results of this study could be used for further studies to evaluate the role of vitamin D and pRB in regeneration therapy for beta cells in prediabetics.

Effect of metformin adjunct therapy on cardiometabolic parameters in Indian adolescents with type 1 diabetes: a randomized controlled trial.

Insulin resistance is being increasingly reported in type-1 Diabetes (T1D) and is known to accelerate microvascular complications. The Asian Indian population has a higher risk of double diabetes development compared to Caucasians. Hence, we studied the effect of adding Metformin to standard insulin therapy on glycemic control, insulin sensitivity (IS), cardiometabolic parameters and body composition in Indian adolescents with T1D. A Randomized controlled trial was conducted spanning 9 months (Registration number:CTRI/2019/11/022126). Inclusion: Age 10-19 years, T1D duration>1year, HbA1c>8% Exclusion: Uncontrolled vascular complications/comorbidities, Metformin intolerance, concomitant drugs affecting insulin sensitivity. Participants were randomized to Metformin/Placebo (n=41 each) groups and age, sex, duration-matched. Assessments were performed at baseline, 3 and 9 months. 82 participants aged 14.7 ± 3years (40 females) were enrolled, with a mean diabetes duration of 5.2 ± 2.3 years. Over 9 months, HbA1c decreased significantly by 0.8 (95% confidence interval: -1.2 to -0.3) from 9.8 ± 1.8% to 9.1 ± 1.7% on Metformin but remained largely unchanged (difference of 0.2, 95% confidence interval: -0.7 to 0.2) i.e. 9.9 ± 1.6% and 9.7 ± 2.2% on placebo. HbA1c improvement correlated negatively with baseline IS (EGDR:r= -0.3;SEARCH:r = -0.24, p<0.05) implying better HbA1c-lowering in those with decreased initial IS. CGM-based glycemic variability (standard deviation) reduced by 6.3 mg/dL (95% confidence interval: -12.9 to 0.2) from 100.2 ± 19.1 mg/dL to 93.7 ± 19.9 mg/dL in those on Metformin (p=0.05) but not placebo (94.0 ± 20.5; 90.0 ± 22.6 mg/dL). Insulin sensitivity: CACTIexa & SEARCH scores demonstrated no change with Metformin but significant worsening on placebo. Significant increase in LDL-C(42%), total cholesterol(133.6 to 151.1 mg/dL), triglyceride (60.0 to 88.0 mg/dL) and carotid intima-media thickness was noted on placebo but not Metformin. Weight, BMI, fat Z-scores increased significantly on placebo but not Metformin. Adverse events (AE) were minor; AE, compliance and safety parameters were similar between the two groups. Metformin as an adjunct to insulin in Asian Indian adolescents with T1D demonstrated beneficial effect on glycemic control, glycemic variability, IS, lipid profile, vascular function, weight and body fat, with a good safety profile when administered for 9 months.

The Relationship Between Pain, Daily Function, and Sleep Quality in Diabetic Neuropathy

Background and Aims: Poor sleep quality affects insulin sensitivity and glucose metabolism. There were limited information about sleep quality in individuals with diabetic peripheral neuropathy. The Pittsburgh Sleep Quality Index was used in this study to measure sleep quality and determine how sleep quality and pain were related in patients with diabetic peripheral neuropathy. Methods: This is a secondary analysis of an aerobic exercise research study in patients with diabetic peripheral neuropathy. Participants performed the Pain Inventory and the Pittsburgh Sleep Quality Index at baseline to measure clinical pain and sleep quality, respectively. Pain Inventory consists of two com¬ponents including The Pain Severity Index and the Pain Interference Index. The relationship between pain and sleep quality was evaluated using Pearson’s correlations. Results: The study showed that 77.8% of the subjects had low sleep quality (i.e., Pittsburgh Sleep Quality Index scores &gt; 5) (mean score of Pittsburgh Sleep Quality Index scores was 9.94±4.35). The mean scores of the Pain Interference Index and Pain Severity Index were 3.54±2.90 and 3.36±2.21, respectively. Both Pittsburgh Sleep Quality Index and Brief Pain Inventory-Pain severity index had positive relationship (r= 0.642, p = 0.004). In addition, there were positive relationship between Pittsburgh Sleep Quality Index and Brief Pain Inventory-Pain interference index (r= 0.591, p = 0.01). Conclusions: The majority of patient with diabetic peripheral neuropathy had low sleep quality. A higher pain intensity and more interference with daily activities were both strongly linked with poor sleep quality. The item of sleep discomfort in everyday activity was highly influenced in patients with diabetic peripheral neuropathy. Future studies are needed to determine if addressing poor sleep quality would impact perception of pain as well as diabetes management.

Oral magnesium supplementation does not affect insulin sensitivity in people with insulin-treated type 2 diabetes and a low serum magnesium: a randomised controlled trial

Aims/hypothesisHypomagnesaemia has been associated with insulin resistance and an increased risk of type 2 diabetes. Whether magnesium supplementation improves insulin sensitivity in people with type 2 diabetes and a low serum magnesium level is unknown.MethodsUsing a randomised, double-blind (both participants and investigators were blinded to the participants’ treatment sequences), placebo-controlled, crossover study design, we compared the effect of oral magnesium supplementation (15 mmol/day) for 6 weeks with that of matched placebo in individuals with insulin-treated type 2 diabetes (age ≥18 years, BMI 18–40 kg/m2, HbA1c <100 mmol/mol [11.3%], serum magnesium ≤0.79 mmol/l). Participants were recruited from the outpatient clinic and through advertisements. Randomisation to a treatment sequence order was done using a randomisation list. We used block randomisation and the two possible treatment sequences were evenly distributed among the trial population. The primary outcome was the mean glucose infusion rate during the final 30 min of a hyperinsulinaemic–euglycaemic clamp (i.e. M value). Secondary outcomes included variables of glucose control, insulin need, BP, lipid profile and hypomagnesaemia-related symptoms during follow-up.ResultsWe recruited 14 participants (50% women, 100% White, mean ± SD age 67±6 years, BMI 31±5 kg/m2, HbA1c 58±9 mmol/mol [7.4±0.9%]) with insulin-treated type 2 diabetes. Magnesium supplementation increased both mean ± SEM serum magnesium level (0.75±0.02 vs 0.70±0.02 mmol/l, p=0.016) and urinary magnesium excretion (magnesium/creatinine ratio, 0.23±0.02 vs 0.15±0.02, p=0.005), as compared with placebo. The M value of the glucose clamp did not differ between the magnesium and placebo study arms (4.6±0.5 vs 4.4±0.6 mg kg−1 min−1, p=0.108). During the 6 weeks of treatment, continuous glucose monitoring outcomes, HbA1c, insulin dose, lipid profile and BP also did not differ, except for a lower HDL-cholesterol concentration after magnesium compared with placebo (1.14±0.08 vs 1.20±0.09 mmol/l, p=0.026). Symptoms potentially related to hypomagnesaemia were similar for both treatment arms.Conclusions/interpretationDespite an albeit modest increase in serum magnesium concentration, oral magnesium supplementation does not improve insulin sensitivity in people with insulin-treated type 2 diabetes and low magnesium levels.Trial registrationEudraCT number 2021-001243-27.FundingThis study was supported by a grant from the Dutch Diabetes Research Foundation (2017–81–014).Graphical

BEVA primary care clinical guidelines: Diagnosis and management of equine pituitary pars intermedia dysfunction.

BEVA primary care clinical guidelines: Diagnosis and management of equine pituitary pars intermedia dysfunction.

FRI417 An Interdisciplinary Program Promoting The Adoption Of A Healthy Lifestyle Increases Insulin Sensitivity In Women With Obesity And Infertility

Abstract Disclosure: A. Forget-Renaud: None. M. Belan: None. F. Jean-Denis: None. M. Pesant: None. J. Baillargeon: Grant Recipient; Self; Ferring Pharmaceuticals, JPB received an unrestricted investigator-initiated grant from Ferring Canada, which was not for the reported study. Introduction Obesity increases the risk of ovulatory and anovulatory infertility in women, mainly through the development of polycystic ovary syndrome (PCOS). Insulin resistance contributes to the pathogenesis of PCOS and may play a role in the infertility of PCOS and non-PCOS women with overweight or obesity. Lifestyle modifications are recommended as a first-line therapy in women with PCOS or those with obesity and infertility, as it was associated with improvement in menstrual pattern and fertility outcomes. We therefore hypothesized that a lifestyle intervention may increase insulin sensitivity in women with obesity and infertility. Methods Women with obesity and infertility were randomly allocated to usual fertility care (control group, CG) or to an interdisciplinary intervention promoting the adoption of a healthy lifestyle (LSG) alone for 6 months and then combined with usual care. Insulin resistance was estimated during fasting (HOMA-IR) and a 75-g oral glucose test (Matsuda Insulin Sensitivity Index, ISI(M)), and β-cell function was estimated using the Insulin Secretion-Sensitivity Index (ISSI-2) in women not taking medication affecting insulin sensitivity (except metformin). Data were collected at baseline, 6, 12 and 18 months, and as soon as possible when the participant knew she was pregnant. We estimated the integrated change in insulin sensitivity during follow-up using the incremental area-under-the-curve of ISI(M) divided by time (iAUC-ISI(M)/time). Results Among 130 randomized participants, 105 had available data (LSG=51, CG=54). PCOS was diagnosed using the Rotterdam criteria in 63.2% of participants, equally distributed between the groups. As compared to CG, women in the LSG improved significantly more their ISI(M) after 6 months (+0.24 [IQR: -0.48 - +0.94] vs 0.16 [-1.32 - +0.53], p=0.039, n=90), as well as their iAUC-ISI(M)/time during follow-up (+0.18±0.84 vs -0.21±0,93, p=0.035, n=104). All these results remained statistically significant after correction for baseline BMI, age and use of folic acid. Increases in iAUC-ISI(M)/time in the intervention vs control groups were significantly more important (p for interaction=0.045) in participants with baseline ISI(M) above the median (LSG: +0.10±1.13, n=24, vs CG: -0.62±1.13, n=27, p=0.028) than in those below the median (LSG: +0.26±0.48, n=27, vs CG: +0.21±0.35, n=26, p=0.71). Interactions with PCOS status and other subgroups were not statistically significant. There was no impact on HOMA-IR or ISSI-2. Conclusion An interdisciplinary program promoting the adoption of a healthy lifestyle significantly increases whole-body insulin sensitivity in women with infertility and obesity, mainly in those with higher baseline insulin sensitivity. It may be explained in part by the weight loss associated with the intervention and may have a role in improving fertility in this population. Presentation: Friday, June 16, 2023

OR31-05 Long-Term Effects Of Gender Affirming Hormone Therapy On Insulin Sensitivity, Insulin Secretion, And Glucose Tolerance

Abstract Disclosure: S. Pinkson: None. J. Trejo: None. A. Mendoza: None. L. Gondin Hernandez: None. S. Chen: None. S. ahuja: None. D. Tripathy: None. Over the past 15 years, transgender veterans seeking Gender Affirming Hormone Therapy (GAHT) have increased significantly. The metabolic effects of long-term GAHT have been controversial possibly because of multiple confounding factors and different methodologies. We examined long-term effects of estradiol and testosterone on insulin sensitivity and insulin secretion in nondiabetic transwomen and transmen. A total of 4 groups (i) 7 transwomen (age 50 ± 4 yr, BMI 31 ± 2 kg/m2) (ii) 6 transmen (age 38 ± 4yr, BMI 33 ± 2 mg/m2) followed for 52 ± 9 months and as a control group (iii) six cisgender men (age 36 ± 4 yrs, BMI 32 ± 2 kg/m2) and (iv) 8 cisgender women (age 39 ± 4 yr, BMI 28 ± 2 kg/m2) participated in an OGTT and Botnia clamp (IV glucose tolerance test: IVGTT followed by hyperinsulinemic (80 mU.m2/min euglycemic clamp). Total testosterone (by equilibration dialysis method), estradiol, sex hormone binding globulin (SHBG) and lipid profile was measured in all subjects. Insulin, and C-peptide were measured every 30 min during the OGTT. Insulin sensitivity was measured as the M-value form last 30 minutes of insulin clamp and as Matsuda index of insulin sensitivity from the OGTT. Indices of insulin secretion (data pending) was calculated as the first phase insulin response from IVGTT (FPIR: 2-10min) and as indices of beta cell function from OGTT: Insulin secretion/insulin resistance index (Insulin 0-120/Glucose 0-120 X Matsuda index). Plasma estradiol in transwomen was 209 ± 92 pg/ml vs. 32 ± 6 pg/ml in cisgender men. Similarly, the total testosterone level in transmen was 319 ± 57 vs. 19 ± 4 ng/dl in cisgender women. There was no difference in SHBG levels between the groups. The body fat content was not different between trans or cis men (36 ± 3 vs 35 ± 1.4 % ) while it was higher in trans vs cis women (40 ± 0.8 vs 30 ± 3%). There was no difference in HbA1c (5.4 ± 0.2 vs 5.2 ± 0.2%, p=ns) between transwomen and cismen and (5.6 ± 0.1 vs 5.5 ± 0.1, p=ns) transmen and ciswomen. The glucose AUC was higher in transmen vs cisgender women (5,487 ± 994 vs. 3,420 ± 533; P &amp;lt; 0.05). There was no difference in glucose AUC between the transwomen and cismen. There was no difference in insulin sensitivity (M-value) between transwomen and cisgender men (6.9 ± 1.2 vs 7.0 ± 1.4 mg.kg/min, p=ns), while it tended to be worse in transmen compared to cisgender women ( 6.03 ± 1.0 vs 7.7± 0.6 mg.kg/min, p=0.1). In both groups M-Value was inversely related to BMI (r=-0.59; p&amp;lt;0.05). There was no relationship between insulin sensitivity and plasma total testosterone level. HDL cholesterol was lower in transmen (41 ± 2.5 vs 55 ± 4 mg/dL, p&amp;lt;0.05) versus cisgender women though there was no difference in triglyceride, total or LDL cholesterol between the groups. In conclusion long-term GAHT therapy does not adversely affect insulin sensitivity in trans men or women and the mildly altered glucose tolerance is likely a result of higher BMI in transmen. Presentation: Sunday, June 18, 2023

Association of fatty acid binding protein-4 (FABP-4) T87C and rs8192688 gene polymorphisms and FABP-4 level with cardiovascular disease susceptibility in type 2 diabetic patients

Type 2 Diabetes Mellitus (T2DM) is known to cause dyslipidemia and increase the risk of cardiovascular disease (CVD). Fatty acid binding protein (FABP)-4 plays a significant role in various stages of T2DM and CVD. Although it has been demonstrated that genetic variations of the FABP-4 gene can affect insulin sensitivity, the results obtained so far are controversial. The aim of this study was to investigate the possible association between T87C and rs8192688 polymorphisms and serum levels of FABP-4 with CVD susceptibility in T2DM patients. The study included 70 healthy controls, 70 individuals with T2DM, and 70 T2DM patients with CVD. Genomic DNA was extracted, and FABP-4 T87C and rs8192688 gene polymorphic sites were amplified using the ARMS-PCR method. Lipid profile and FABP-4 serum levels were significantly higher in T2DM patients with CVD compared to those with only T2DM (p < 0.05). Additionally, FABP-4 T87C gene polymorphism (TC genotypes) and dominant model (TT vs. TC + CC) were significantly associated with a decreased risk of both T2DM and T2DM with CVD patients (p < 0.05). Patients carrying TC + CC genotypes had significantly lower levels of triglyceride and FABP-4 compared to those carrying the TT genotype (p < 0.05). There was no significant association between FABP-4 rs8192688 polymorphism and either T2DM or CVD disease. It appears that FABP-4 T87C polymorphism decreases FABP-4 levels leading to decreased serum TG levels. Since both T2DM and CVD have inflammatory backgrounds, reducing inflammation can improve insulin sensitivity and lower TG levels in these patients.

Folic acid supplementation in a mouse model of diabetes in pregnancy alters insulin sensitivity in female mice and beta cell mass in offspring.

Epidemiological studies have reported discrepant findings on the relationship between folic acid intake during pregnancy and risk for gestational diabetes mellitus (GDM). To begin to understand how folic acid impacts metabolic health during pregnancy, we determined the effects of excess folic acid supplementation (5× recommendation) on maternal and fetal offspring metabolic health. Using a mouse (female C57BL/6J) model of diet-induced diabetes in pregnancy (western diet) and control mice, we show that folic acid supplementation improved insulin sensitivity in the female mice fed the western diet and worsened insulin sensitivity in control mice. We found no unmetabolized folic acid in liver from supplemented mice suggesting the metabolic effects of folic acid supplementation are not due to unmetabolized folic acid. Male fetal (gestational day 18.5) offspring from folic acid supplemented dams (western and control) had greater beta cell mass and density than those from unsupplemented dams; this was not observed in female offspring. Differential sex-specific hepatic gene expression profiles were observed in the fetal offspring from supplemented dams but this differed between western and controls. Our findings suggest that folic acid supplementation affects insulin sensitivity in female mice, but is dependent on their metabolic phenotype and has sex-specific effects on offspring pancreas and liver.

Gender Differences in Insulin Resistance: New Knowledge and Perspectives.

Insulin resistance is the main mechanism in a whole series of pathological conditions, which are not only of metabolic interest but also of a systemic type. This phenomenon means that the body's cells become less sensitive to the hormone insulin, leading to higher levels of insulin in the blood. Insulin resistance is a phenomenon that can be found in both men and women and in particular, in the latter, it is found mainly after menopause. Premenopause, hormonal fluctuations during the menstrual cycle, and the presence of estrogen can affect insulin sensitivity. Androgens, such as testosterone, are typically higher in men and can contribute to insulin resistance. In both sexes, different human body types affect the distribution and location of body fat, also influencing the development of diabetes and cardiovascular disease. Insulin resistance is also associated with some neurological and neurogenerative disorders, polycystic ovary syndrome, atherosclerosis, and some of the main neoplastic pathologies. A healthy lifestyle, including regular physical activity, a balanced diet, and self-maintenance, can help to prevent the onset of insulin resistance, regardless of gender, although the different habits between men and women greatly affect the implementation of preventative guidelines that help in fighting the manifestations of this metabolic disorder. This review may help to shed light on gender differences in metabolic diseases by placing a necessary focus on personalized medical management and by inspiring differentiated therapeutic approaches.

Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in Cyp2c70-/- Mice with a Human-like Bile Acid Composition.

Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated Cyp2c70-/- (KO) mice that were not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possessed a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with the development of liver fibrosis. The aim of this study was to determine whether BA sequestration modulates liver pathology in Western type-diet (WTD)-fed KO mice. The BA sequestrant colesevelam was mixed into the WTD (2% w/w) of male Cyp2c70+/+ (WT) and KO mice and the effects were evaluated after 3 weeks of treatment. Colesevelam increased fecal BA excretion in WT and KO mice and reduced the hydrophobicity of biliary BAs in KO mice. Colesevelam ameliorated diet-induced hepatic steatosis in WT mice, whereas KO mice were resistant to diet-induced steatosis and BA sequestration had no additional effects on liver fat content. Total cholesterol concentrations in livers of colesevelam-treated WT and KO mice were significantly lower than those of untreated controls. Of particular note, colesevelam treatment normalized plasma levels of liver damage markers in KO mice and markedly decreased hepatic mRNA levels of fibrogenesis-related genes in KO mice. Lastly, colesevelam did not affect glucose excursions and insulin sensitivity in WT or KO mice. Our data show that BA sequestration ameliorates liver pathology in Cyp2c70-/- mice with a human-like bile acid composition without affecting insulin sensitivity.

Auto adaptation of closed-loop insulin delivery system using continuous reward functions and incremental discretization

Several closed or hybrid loop controllers for Blood Glucose (BG) regulation, which are also known as Artificial Pancreas (AP) Systems or Automated Insulin Delivery systems (AIDs), are in development worldwide. Most AIDs are designed and evaluated for short-term performance, with a particular emphasis on the post-meal period. However, if controllers are not adapted properly to account for variations in physiology that affect Insulin Sensitivity (IS), the AIDs may perform inadequately. In this work, the performance of two Reinforcement Learning (RL) agents trained under both piecewise and continuous reward functions is evaluated in-silico for long-term adaptation of a Fully Automated Insulin Delivery (fAID) system. An automatic adaptive discretization scheme that expands the state space as needed is also implemented to avoid disproportionate state space exploration. The proposed agents are evaluated for long-term adaptation of the Automatic Regulation of Glucose (ARG) algorithm, considering variations in IS. Results show that both RL agents have improved performance compared to a rule-based decision-making approach and the baseline controller for the majority of the adult population. Moreover, the use of a continuous shaped reward function proves to enhance the performance of the agents further than a piecewise one.

Impact of saturated compared with unsaturated dietary fat on insulin sensitivity, pancreatic β-cell function and glucose tolerance: a systematic review and meta-analysis of randomized, controlled trials

BackgroundThe impact of the dietary fat type on type 2 diabetes (T2D) remains unclear. ObjectivesWe aimed to evaluate the effects of replacing dietary saturated fatty acids (SFA) with mono- or poly-unsaturated fatty acids (MUFA and PUFA, respectively) on insulin sensitivity, pancreatic β-cell function, and glucose tolerance, as surrogate endpoints for T2D. MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials that replaced ≥5% of total energy intake provided by SFA with MUFA or PUFA and reported indexes of insulin sensitivity, β-cell function, and/or glucose tolerance. We searched MEDLINE, Scopus, and the Cochrane Library (CENTRAL) up to 9 January, 2023. Eligible interventions had to be isocaloric, with no significant difference in other macronutrients. Data were synthesized using random-effects model meta-analysis. ResultsOf 6355 records identified, 10 parallel and 20 crossover trials with 1586 participants were included. The mean age of the participants was 42 years, 47% were male, mean body mass index (BMI; in kg/m2) was 26.8, median baseline fasting glucose was 5.13 mmol/L, and the median duration of interventions was 5 weeks. Replacing SFA with MUFA or PUFA had no significant effects on insulin sensitivity [standardized mean difference (SMD) SFA compared with MUFA: 0.01, 95% confidence interval (CI): −0.06 to 0.09, I2 = 0% and SMD SFA compared with PUFA: 0, 95% CI: −0.15 to 0.14, I2 = 0%]. Replacing SFA with MUFA did not significantly impact the β-cell function, evaluated by the disposition index (mean difference: −12, 95% CI: −158 to 133, I2=0%). Evidence on glucose tolerance (SFA compared with MUFA or PUFA) and on β-cell function when SFA were replaced with PUFA was scant. ConclusionsShort-term substitution of saturated with unsaturated fat does not significantly affect insulin sensitivity nor β-cell function (the latter in the SFA compared with MUFA comparison). Future studies are needed to elucidate longer term effects of dietary fat saturation on glucose homeostasis. This trial was registered at PROSPERO as CRD42020178382.