Differences In Insulin Resistance Research Articles

Impact of nomenclature as metabolic associated steatotic liver disease on steatotic liver disease prevalence and screening: a prospective population survey in Asians.

The introduction of the latest nomenclature, metabolic associated steatotic liver disease (MASLD), proposed by the multi-society without Asian society consensus statement, aims to redefine the diagnostic criteria for metabolic associated fatty liver disease (MAFLD). However, its effect on the epidemiology in Asia remains unclear. We conducted a population-based cross-sectional survey on fatty liver disease using multistage stratified random sampling of participants from Guangzhou, a representative area in China (ChiCTR2000033376). Demographic, socioeconomic, lifestyle, and laboratory data were collected. Hepatic steatosis and the severity of fibrosis were assessed using FibroScan. A total of 7388 individuals were recruited, the proportion of which meeting the definitions for nonalcoholic fatty liver disease (NAFLD), MAFLD, and MASLD were 2359 (31.9%), 2666 (36.1%), and 2240 (30.3%), respectively. One hundred and twenty (1.6%) patients had cryptogenic SLD, and 537 (7.3%) patients were diagnosed with MetALD. MASLD did not significantly differ from NAFLD and MAFLD, except that MAFLD patients had a lower proportion of males, hypertension, and diabetes and were less likely to consume tea (P<0.05). Both cryptogenic SLD and MASLD non-MAFLD patients exhibited milder hepatic steatosis and a lower frequency of liver injury than NAFLD, MAFLD, or MASLD patients (all P<0.05). An increased HOMA-IR (adjusted OR: 1.33, 95% CI: 1.10-2.03) was associated with higher risk of moderate-to-severe steatosis for MASLD non-MAFLD patients, while consuming more cups of tea (P for trend=0.015) showed inverse associations. Irrespective of terminology used is that fatty liver disease is highly prevalent in the Han Chinese population. Differences in insulin resistance and lifestyle risk factors are associated with redefinition disparities.

Relative Contribution of Metabolic Syndrome Components in Relation to Obesity and Insulin Resistance in Postmenopausal Osteoporosis.

Introduction. Osteoporosis (OP) affects 30% of postmenopausal women, often complicated by metabolic syndrome (MetS) with a still controversial role. We aimed to characterize MetS and its components in relation to bone mineral density (BMD), body mass index (BMI), and insulin resistance. Methods. Patients (n = 188) underwent DEXA scans, spine X-rays, and metabolic and hormonal investigations, including bone biomarkers, muscular strength, and physical performance tests, while insulin resistance was evaluated by the Homeostasis Model Assessment (HOMA-IR). Results. Patients with a normal BMD or osteopenia (n = 68) and with OP (n = 120) displayed 51.5% and 30.8% of MetS, but without differences in insulin resistance. When BMD was studied as a function of the cumulative MetS criteria and centiles of BMI, lower levels of BMD were observed beyond an inflection point of 27.2 kg/m2 for BMI, allowing for further stratification as lean and overweight/obese (OW/OB) subjects. In contrast with lean individuals (n = 74), in OW/OB patients (n = 46), MetS was associated with HbA1c (p < 0.0037, OR 9.6, 95% CI [1.64-55.6]) and insulin resistance (p < 0.0076, OR 6.7, 95% CI [1.49-30.8]) in the context where BMD values were lower than those predicted from BMI in non-OP subjects. In OP patients with fragility fractures (31% of MetS), glycemia also appeared to be the dominant factor for MetS (p < 0.0005, OR 4.1, 95% CI [1.63-10.39]). Conclusions. These data indicate a detrimental effect of insulin resistance in MetS on OP patients, while the prevalence of the syndrome depends on the proportion of obesity. These findings provide new insights into the pathogenic role of MetS and reveal the need to consider different strata of BMI and insulin resistance when studying postmenopausal OP.

Effect of physical activity levels on blood lipids, insulin resistance, and adipokines in children with obesity.

Our study was performed to observe children with obesity by using accelerometers and identify their differences in blood lipid levels, insulin resistance, and adipokines based on their physical activity levels. 197 obese children were classified into three groups based on their physical activity levels over a period of 7 days, using the average counts per minute: Sedentary Time (ST), Light Physical Activity (LPA), and Moderate to Vigorous Intensity Physical Activity (MVPA). Blood lipids, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), were analyzed. Insulin resistance was assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) formula. Adipokines, including leptin and resistin, were measured. Our results were obtained through one-way analysis of variance was employed, with Scheffe post-hoc analysis. The statistical significance level was set at p &lt; 0.05 for all analyses. Results showed that the levels of blood lipids (TG: p&lt;0.001, TC: p&lt;0.01, LDL-C: p&lt;0.001, HDL-C: p&lt; 0.05) and adipokines (Leptin, Resistin: p&lt;0.01) of children who had obesity and maintained moderate to vigorous physical activity were healthier than those who engaged in ST or LPA. Specifically, children with obesity engaging in MVPA demonstrated blood lipid and adipokine levels that were normal or close to normal. However, no significant differences in insulin resistance were observed in all groups. In summary, encouraging moderate to vigorous physical activity in children with obesity could help improve obesity indicators, such as blood lipids and adipokines.

Bioinformatics analysis of the diversity of gut microbiota and different microbiota on insulin resistance in diabetes mellitus patients

IntroductionIt aimed to explore the diversity of gut microbiota (GM) and the effect of different microbiota on insulin resistance in diabetes mellitus (DM) patients through bioinformatics analysis. Material and Method: Microarray data were obtained from GEO database. GM samples from DM patients and healthy controls were collected, and 16S rRNA gene sequencing was carried out adopting high-throughput sequencing technology. The differential expression genes were screened using the Qlucore Omics Explorer 3.0 software. Subsequently, online tools such as STRING and DAVID were utilized for bioinformatics analysis of the differential expression genes. The differences in bacterial diversity between DM patients and healthy controls were evaluated by analyzing the diversity indicators of the microbiota, such as Shannon and Chao1 indexes. Differential abundance and functional prediction analysis were adopted to explore the different microbiota and its possible metabolic pathways between DM patients and controls. And differences in insulin resistance in specific bacterial taxa were analyzed. Result: GM diversity between DM patients and controls had significant differences. GM diversity was lower in DM patients compared with controls, as indicated by a decrease in Shannon and Chao1 indexes. The differential abundance analysis showed that there were multiple different bacterial communities between DM patients and controls, including some bacterial communities at the genus-level. Functional prediction analysis also revealed potential metabolic pathways related to GM and insulin resistance in DM patients. HEXB, ZC3H12A, CCR, CXCR3, GBR10, CDK9, TXN, IGFBP3, PDHA1, and NDUFB3 genes may be potential targets for treatment. Conclusion: There are differences in GM diversity between DM patients and healthy controls, and the different microbiota may be related to the occurrence and development of insulin resistance.

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.

Cardiometabolic health in adults born with very low birth weight—a sibling study

BackgroundPreterm survivors have increased risk for impaired cardiometabolic health. We assessed glucose regulation and cardiometabolic biomarkers in adult very low birth weight (VLBW, <1500 g) survivors, using siblings as controls.MethodsVLBW-participants were matched with term-born, same-sex siblings. At mean age 29.2 years (SD 3.9), 74 VLBW-adults and 70 siblings underwent a 2-h 75 g oral glucose tolerance test and blood tests for assessment of cardiometabolic biomarkers.ResultsOf participants, 23 (31%) VLBW and 11 (16%) sibling-controls met World Health Organization criteria for impaired glucose regulation (OR adjusted for age and sex 2.5, 95% CI: 1.1 to 5.8).Adjusting for age and sex, VLBW-participants showed 9.2% higher 2-h glucose (95% CI: 0.4% to 18.8%) than their siblings. Also, fasting (13.4%, −0.3% to 29.0%) and 2-h free fatty acids (15.6%, −2.4% to 36.9%) were higher in VLBW-participants. These differences were statistically significant only after further adjusting for confounders. No statistically significant differences were found regarding other measured biomarkers, including insulin resistance, atherogenic lipid profiles or liver tests.ConclusionsVLBW-adults showed more impaired fatty acid metabolism and glucose regulation. Differences in cardiometabolic biomarkers were smaller than in previous non-sibling studies. This may partly be explained by shared familial, genetic, or environmental factors.ImpactAt young adult age, odds for impaired glucose regulation were 3.4-fold in those born at very low birth weight, compared to same-sex term-born siblings.Taking into consideration possible unmeasured, shared familial confounders, we compared cardiometabolic markers in adults born preterm at very low birth weight with term-born siblings.Prematurity increased risk for impaired glucose regulation, unrelated to current participant characteristics, including body mass index.In contrast to previous studies, differences in insulin resistance were not apparent, suggesting that insulin resistance may partially be explained by factors shared between siblings. Also, common cardiometabolic biomarkers were similar within sibling pairs.

Association of nut consumption with insulin resistance and blood lipid profile in Spanish university students

AimsTo examine whether nut consumption was associated with insulin resistance and blood lipid parameters in a sample of young healthy adults. Material and methodsA cross-sectional study was conducted involving 306 first-year students (aged 18–30 years) from the University of Castilla-La Mancha, Spain. Biochemical variables related to insulin resistance and blood lipid profile (glucose, insulin, HbA1c, total cholesterol (total-c), LDL-c, HDL-c, and triglycerides) were determined from morning fasting blood samples. Nut consumption was estimated using a 137-item Food-Frequency Questionnaire. The associations of walnuts, other nuts and total nut intakes with insulin resistance and lipid profile variables and surrogates were assessed by linear regression analysis. Differences in insulin resistance and lipid profiles between participants meeting or not meeting the nut consumption recommendations were examined by analysis of covariance (ANCOVA). Logistic regressions were used to analyze the likelihood of having higher levels of blood lipids or insulin resistance in participants who met or did not meet the recommended intake of nuts. ResultsThere was no association found between nut consumption, whether walnuts or other nut varieties, and insulin resistance and lipid profile variables. Additionally, there were no significant differences in insulin resistance or blood lipid profile variables between university students meeting or not meeting nut consumption recommendations. Finally, stratified analyses based on sex were consistent and did not substantially modify our estimates in the fully adjusted models. ConclusionsIn conclusion, our results suggest that walnuts, other types of nuts, and total nut consumption did not adversely influence metabolic or lipid profile variables among healthy young adults. Although nuts are recommended among healthy dietary patterns, our findings showed that nut consumption has a null effect on the cardiometabolic risk parameters explored in young healthy adults.

Aldehyde dehydrogenase 2 polymorphism is an important gene for insulin resistance in Japanese patients with type 2 diabetes

BackgroundAldehyde dehydrogenase 2 (ALDH2) is an important enzyme involved in alcohol metabolism. ALDH2 polymorphism has been reported as a risk factor for type 2 diabetes mellitus (T2DM) and is associated with liver insulin resistance due to alcohol consumption in non-diabetic individuals. Herein, we investigated the association between ALDH2 polymorphisms and insulin resistance in patients with T2DM. MethodsWe performed a meal tolerance test and the hyperinsulinemic-euglycemic clamp on 71 Japanese participants: 34 patients with T2DM, and 37 non-diabetic participants. We analyzed the ALDH2 polymorphism (ALDH2 rs67); GG type was defined as the T2DM high-risk group, compared with the low-risk AG and AA groups. ResultsGlucose levels were similar in the high- and low-risk T2DM groups. The high-risk group for T2DM showed a significantly higher BMI (p < 0.005), insulin resistance in HOMA-IR (p < 0.05), and Insulin sensitivity index (p < 0.05); however, there were no significant differences in insulin resistance in the clamp test (p = 0.10). Alcohol consumption did not differ significantly between groups (p = 0.66). Non-diabetic participants also showed higher HOMA-IR insulin resistance in the high-risk group (p < 0.05), but insulin resistance levels in the glucose clamp tests (p = 0.56) and insulin secretion were not significant. ConclusionThe results suggest that ALDH2 is an important gene associated with insulin resistance and obesity in Japanese patients with type 2 diabetes.

Adipose tissue function and insulin sensitivity in syndromic obesity of Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive syndromic obesity of childhood onset among many other features. To date, the excess risk of metabolic complications of severe early-onset obesity in BBS remains controversial. In-depth investigation of adipose tissue structure and function with detailed metabolic phenotype has not been investigated yet. To investigate adipose tissue function in BBS. A prospective cross-sectional study. To determine if there are differences in insulin resistance, metabolic profile, adipose tissue function and gene expression in patients with BBS compared to BMI-matched polygenic obese controls. 9 adults with BBS and 10 controls were recruited from the national centre for BBS, Birmingham, UK. An in-depth study of adipose tissue structure and function along with insulin sensitivity was performed using hyperinsulinemic-euglycemic clamp studies, adipose tissue microdialysis, histology and RNA sequencing, and measurement of circulating adipokines and inflammatory biomarkers. Adipose tissue structure, gene expression and in vivo functional analysis between BBS and polygenic obesity cohorts were similar. Using hyperinsulinemic-euglycemic clamp and surrogate markers of insulin resistance, we found no significant differences in insulin sensitivity between BBS and obese controls. Furthermore, no significant changes were noted in an array of adipokines, cytokines, pro-inflammatory markers and adipose tissue RNA transcriptomic. Although childhood-onset extreme obesity is a feature of BBS, detailed studies of insulin sensitivity and adipose tissue structure and function are similar to common polygenic obesity. This study adds to the literature by suggesting that it is the quality and quantity of adiposity not the duration that drives the metabolic phenotype.

Significance of pancreatic duodenal homeobox-1 (PDX-1) genetic polymorphism in insulin secretion in Japanese patients with type 2 diabetes

IntroductionPancreatic and duodenal homeobox factor-1 (PDX-1) is an imperative gene for insulin secretion in maturity-onset diabetes of the young 4. PDX-1 gene polymorphism was associated with lower first-phase insulin secretion...

Association Between Visceral Adiposity Index and Insulin Resistance: A Cross-Sectional Study Based on US Adults.

BackgroundVisceral obesity index (VAI) is an empirical mathematical model used to evaluate the distribution and function of fat. Some studies have shown that VAI may be associated with the development of insulin resistance. In view of the differences in insulin resistance among different ethnic groups, this study attempts to analyze the special relationship between VAI and insulin resistance in American adults.MethodsWe conducted a cross-sectional study through NHANES database. A total of 27309 patients over the age of 18 from the United States took part in the survey. It was divided into two groups: the IR-positive group and the IR-negative group. The association of VAI with IR was evaluated by logistic regression analyses mainly, including univariate analysis, multivariate regression analysis, curve fitting analysis and subgroup analysis.ResultsThe results showed that in the full-adjusted model, there is a strong positive association between VAI level and insulin resistance (OR: 1.28 (1.2~1.37), P<0.001) and there is a threshold effect.ConclusionsThis study suggests that higher VAI levels are associated with insulin resistance. VAI index may be used as a predictor of insulin resistance.

Improvement of glycemic indices by a hypocaloric legume-based DASH diet in adults with type 2 diabetes: a randomized controlled trial.

The current study aimed to investigate the effects of legumes inclusion in the hypocaloric dietary approaches to stop hypertension (DASH) diet on fasting plasma glucose (FPG) and cardiometabolic risk factors in overweight and obese patients with type 2 diabetes over 16weeks. Also, the modulatory effects of rs7903146 variant in the transcription factor 7 like 2 (TCF7L2) gene that is associated with the risk of diabetes, were assessed on these cardiometabolic risk factors. This study was a randomized controlled trial. Three-hundred participants, aged 30-65years, whose TCF7L2 rs7903146 genotype was determined, were studied. The participants were randomly assigned to receive either the hypocaloric DASH diet or a hypocaloric legume-based DASH diet. The primary outcome was the difference in FPG change from baseline until the 16-week follow-up between the two dietary interventions. The secondary outcomes were differences in insulin resistance and lipid profile changes between the dietary intervention diets. A reduction in FPG, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), triglyceride, total cholesterol, and low-density lipoproteincholesterol (LDL-C) was observed at week 16 in both hypocaloric dietary interventions. Compared to the DASH diet, the legume-based DASH diet decreased the FPG and HOMA-IR. There is no interaction between rs7903146 and intervention diets on glycemic parameters. The DASH diet, enrich in legumes, could improve the glycemic parameters in participants with type 2 diabetes, regardless of having rs7903146 risk or non-risk allele. Iranian Registry of Clinical Trials (IRCT) (code: IRCT20090203001640N17).

Hormonal and metabolic profiles of obese and nonobese type 2 diabetes patients: implications of plasma insulin, ghrelin, and vitamin D levels.

BackgroundType 2 diabetes (T2D) is associated with obesity whereas loss of weight is a feature of the disease; however, the two states are not mutually exclusive. Obesity is linked with changes in hormonal activity and overall body metabolism.Materials and methodsIn this study, 408 T2D patients were recruited in three distinct studies conducted in Bahrain, Saudi Arabia, and Kuwait in three different intervals between 2001 and 2019. In addition to demographics, glycemic and lipid profiles were obtained in all studies, whereas plasma insulin and HOMA-IR, vitamin D, and ghrelin were analyzed in Saudi Arabia. Different techniques such as chemical auto-analyzer, ELISA, chemiluminescent immunoassay, radioimmunoassay were used.ResultsThe obese (BMI ≥ 30 kg/m2) compared with nonobese (BMI 18.5 to <30) patients with diabetes were more likely to be women (P < 0.001), smaller in age (P = 0.028), and with shorter disease duration (P = 0.018). Unexpectedly, the glycemic and lipid profiles were consistently comparable between the two groups in the three sites. Furthermore, vitamin D was strikingly lower in obese patients with diabetes (P = 0.007). Finally, plasma ghrelin (P = 0.163), insulin (P = 0.063), and HOMA-IR (P = 0.166) were comparable between obese and nonobese patients with diabetes.ConclusionDiabetic obesity was significantly associated with female sex, young age, short disease duration, and noticeably low vitamin D, and a trend of high insulin levels. However, the obese and nonobese patients had comparable metabolic profiles with no differences in insulin resistance and ghrelin levels. Further studies, especially at a molecular level, are needed to explore this topic which is barely investigated.

Effect of 6 weeks Pilates training along with dill supplementation on serum concentrations of nesfatin-1, lipocalin-2, and insulin resistance in females with overweight and obesity: A randomized controlled trial.

This study aimed to investigate the effect of 6 weeks' pilates training along with dill supplementation on serum concentrations of nesfatin-1, lipocaline-2, and insulin resistance in females with overweight and obesity. In this randomized controlled trial study, 45 overweight and obese females are randomly assigned to four groups: Pilates training + dill group (PDG) (n = 12), pilates training + placebo group (PPG) (n = 11), dill supplementation group (DG) (n = 11), and placebo group (PG) (n = 11). Participants of PDG and PPG performed pilates training for 6 weeks (60 min, 3 sessions per week). PDG and DG received dill tablet (three times a day, 6 weeks). Anthropometric measurements, glycemic markers, and blood samples were assessed before (pretest) and after (posttest) 6 weeks of intervention. Results showed a significant increase in serum concentrations of nesfatin-1 in PDG compared to pretest (P = 0.001). Differences in the serum concentrations of nesfatin-1 in PDG were greater than PPG, DG, and PG (P = 0.01). Furthermore, results found in significant reduction in serum concentrations of lipocalin-2, body mass index (BMI), and waist-hip ratio (WHR) in PDG, PPG, and DG as compared to pretest (P > 0.05). Fasting glucose plasma (FGP) was significantly decreased in all three intervention groups PDG (P < 0.001), PPG (P < 0.001), and DG (P < 0.001) as compared to pretest. Differences in FGP were significantly higher in PDG than PPG, DG, and PG (P = 0.001). A significant reduction was found for insulin only in PDG after 6 weeks of intervention as compared to pretest (P = 0.03). Insulin resistance significantly decreased in PDG (P = 0.03) and PPG (P = 0.04) as compared to pretest. Body fat percent (BFP) was significantly decreased in PDG (P = 0.003), PPG (P = 0.006), and DG (P = 0.01). However, there were no significant inter-group differences in insulin resistance, insulin, serum concentrations of lipocalin-2, BMI, BFP, and WHR after 6 weeks of Pilates training along with dill supplementation (P > 0.05). We concluded that 6 weeks of Pilates training along with dill may be beneficial for improvements in serum concentrations of nesfatin-1 and FGP.

Autonomic Nervous System Function in Newly Diagnosed Multiple Sclerosis: Association With Lipid Levels and Insulin Resistance.

Autonomic nervous system (ANS) disorders are common in multiple sclerosis (MS). Previous studies showed differences in insulin resistance (IR) and lipoprotein levels in MS subjects compared to controls. Lipolysis caused by increased sympathetic activity could be one of the possible linking mechanisms leading to dyslipidemia in MS. Our study aimed to evaluate ANS activity in the context of glucose and lipid metabolism in people with MS. We prospectively measured short-term heart rate variability (HRV), fasting lipoprotein concentrations, and calculated IR indices based on plasma glucose and insulin levels during oral glucose tolerance test (oGTT) in 32 patients with MS and 29 healthy controls matched for age, sex and body mass index in our study. There was no significant difference in HRV parameters and lipoprotein levels between MS and controls. A significant positive correlation was found between low/high-frequency power ratio (LF/HF) and triglycerides (r=0.413, p=0.021) in MS subjects but not in controls. A significantly lower whole-body insulin sensitivity index (ISIMat) was found in patients with MS compared to the control group (7.3±3.7 vs. 9.8±5.6, p=0.041). No significant correlations were found between LF/HF and IR parameters. In MS subjects, the positive correlation of LF/HF with triglycerides could reflect the effects of sympathetic activity on lipolysis. Positive correlations of sympathetic activity with increased lipoprotein levels could rather reflect processes associated with immune system activation/inflammation, than processes involved in glucose homeostasis maintenance.

Association of Insulin Resistance and Higher Oncotype DX™ Recurrence Score.

Black women with breast cancer have a worse overall survival compared with White women; however, no difference in Oncotype DX™ (ODX) recurrence scores has been observed to explain this health disparity. Black women are also disproportionately affected by insulin resistance. We evaluated whether insulin resistance is associated with a higher ODX recurrence score and whether there is a difference between White and Black women to explain disparate clinical outcomes. A subgroup analysis of patients in a multi-institutional cross-sectional study evaluating differences in insulin resistance between White and Black women was performed. Women diagnosed with a new hormone receptor-positive, HER2/neu-negative breast cancer with an ODX recurrence score were identified. Fasting blood glucose and insulin measurements were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) score, a method for assessing insulin resistance, and compared against ODX scores. Overall, 412 women (358 White women, 54 Black women) were identified. Compared with White women, Black women had a higher body mass index (30 vs. 26kg/m2, p<0.0001), higher HOMA-IR score (2.4 vs. 1.4, p=0.004), and more high-grade tumors (30% vs. 16%, p=0.01). There was a direct positive association with an increasing ODX score and HOMA-IR (p=0.014). On subset analysis, this relationship was seen in White women (p=0.005), but not in Black women (p=0.55). In women with newly diagnosed breast cancer, increasing insulin resistance is associated with a higher recurrence score; however, this association was not present in Black women. This lack of association may be due to the small number of Black women in the cohort, or possibly a reflection of a different biological disease process of the patient's tumor.

First person – Sarah Elzinga

ABSTRACTFirst Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Sarah Elzinga is first author on ‘Sex differences in insulin resistance, but not peripheral neuropathy, in a diet-induced prediabetes mouse model’, published in DMM. Sarah is a postdoc in the lab of Eva Feldman at the University of Michigan, Ann Arbor, MI, USA, investigating immune-mediated mechanisms that promote neurodegeneration in obesity, metabolic syndrome, prediabetes and type 2 diabetes.

Sex differences in insulin resistance, but not peripheral neuropathy, in a diet-induced prediabetes mouse model.

ABSTRACTPeripheral neuropathy (PN) is a common complication of prediabetes and diabetes and is an increasing problem worldwide. Existing PN treatments rely solely on glycemic control, which is effective in type 1 but not type 2 diabetes. Sex differences in response to anti-diabetic drugs further complicate the identification of effective PN therapies. Preclinical research has been primarily carried out in males, highlighting the need for increased sex consideration in PN models. We previously reported PN sex dimorphism in obese leptin-deficient ob/ob mice. This genetic model is inherently limited, however, owing to leptin's role in metabolism. Therefore, the current study goal was to examine PN and insulin resistance in male and female C57BL6/J mice fed a high-fat diet (HFD), an established murine model of human prediabetes lacking genetic mutations. HFD mice of both sexes underwent longitudinal phenotyping and exhibited expected metabolic and PN dysfunction compared to standard diet (SD)-fed animals. Hindpaw thermal latencies to heat were shorter in HFD females versus HFD males, as well as SD females versus males. Compared to HFD males, female HFD mice exhibited delayed insulin resistance, yet still developed the same trajectory of nerve conduction deficits and intraepidermal nerve fiber density loss. Subtle differences in adipokine levels were also noted by sex and obesity status. Collectively, our results indicate that although females retain early insulin sensitivity upon HFD challenge, this does not protect them from developing the same degree of PN as their male counterparts.This article has an associated First Person interview with the first author of the paper.

Oral minimal model-based estimates of insulin sensitivity in obese youth depend on oral glucose tolerance test protocol duration

IntroductionThe Oral Minimal Model (OMM), a differential-equations based mathematical model of glucose-insulin dynamics, utilizes data from a frequently sampled oral glucose tolerance test (OGTT) to quantify insulin sensitivity (SI). OMM-based estimates of SI can detect differences in insulin resistance (IR) across population groups and quantify effects of clinical or behavioral interventions. These estimates of SI have been validated in healthy adults using data from OGTTs with durations from 2 to 7 h. However, data demonstrating how protocol duration affects SI estimates in highly IR populations such as adolescents with obesity are limited. MethodsA 6-h frequently sampled OGTT was performed in adolescent females with obesity. Two, 3-, and 4- hour implementations of OMM assuming an exponentially-decaying rate of glucose appearance beyond measured glucose concentrations were compared to the 6-h implementation. A 4- hour OMM implementation with truncated data (4h Tr) was also considered. ResultsData from 68 participants were included (age 15.8 ± 1.2 years, BMI 35.4 ± 5.6 kg/m2). Although SI values were highly correlated for all implementations, they varied with protocol duration (2h: 2.86 ± 3.31, 3h: 2.55 ± 2.62, 4h: 2.81 ± 2.59, 4h tr: 3.13 ± 3.14, 6h: 3.06 ± 2.85 x 10-4 dl/kg/min per U/ml). SI estimates based on 2 or 3 h of data underestimated SI values, whereas 4-h SI estimates more closely approximated 6-h SI values. DiscussionThese results suggest that OGTT protocol duration should be considered when implementing OMM to estimate SI in adolescents with obesity and other IR populations.

Reduced Insulin Sensitivity in Patients with Myeloid Malignancies and Clonal Hematopoiesis Mutations

Cancer survivors are at increased risk for insulin resistance, which can lead to diabetes mellitus, dyslipidemia, and cardiovascular disease. Whether susceptibility to insulin resistance is due to shared onco-metabolic risk factors, like obesity and older age, or if it originates from malignancy and its treatment is unknown. We investigated metabolic and malignancy-associated risk factors and their effect on insulin sensitivity in patients with treated hematological malignancies. Due to previous glucocorticoid exposure, we hypothesized that patients with lymphoid malignancies would be less insulin sensitive. Nineteen adult patients with treated hematological malignancies but without diabetes mellitus were evaluated with a 2-hour, 75-gram, oral glucose tolerance test (OGTT) and a hyperinsulinemic-euglycemic clamp. Hyperinsulinemic-euglycemic clamps were performed to measure steady-state glucose infusion rate (M-value) as an indicator of whole-body glucose utilization during high-dose insulin stimulation. Decreasing M-values reflect increasing insulin resistance. Patient characteristics were analyzed and compared with OGTT and clamp results. The majority of individuals had myeloid malignancies [MDS/AML (n=7) and CML/MPN (n = 4)]. The remainder were diagnosed with NHL (n=7) and CML lymphoid blast crisis (n=1). All patients were treated before metabolic testing. Sixteen individuals (84%) received cytotoxic chemotherapy and 3 (16%) were administered only tyrosine kinase inhibitors. Median lines of systemic treatment were 2 (range, 1-6), and median time from cancer diagnosis to metabolic testing was 10 months (range, 3-132). Immediately before OGTTs and clamps, 10 (53%) patients were in a complete response, and 9 (47%) had persistent/stable disease. During OGTTs, impaired fasting glucose (plasma glucose 100-125 mg/dL) and impaired glucose tolerance (2-hour plasma glucose 140-199 mg/dL) were respectively observed in 5 (26%) and 6 (32%) patients. M-values were decreased in patients with impaired glucose tolerance. Overweight and obese cancer patients also had lower M-values than individuals with normal body mass indices (BMI) (Table 1). There were otherwise no differences in insulin resistance per age, sex, performance status, ethnicity, or diabetes family history. Differences in insulin resistance were not observed based on exposure to cytotoxic chemotherapy, non-cranial irradiation, numbers of lines of treatment, response, or malignancy duration. Previous glucocorticoid exposure did not impact insulin sensitivity. Surprisingly, patients with myeloid malignancies demonstrated lower M-values (6.92 + 0.54 vs. 12.11 + 1.89; p=0.026) than did those with lymphoid cancers. Acquired mutations involved with myeloid malignancies and clonal hematopoiesis (CH) can increase the risk for atherosclerosis and cardiovascular disease, which are sequelae of insulin resistance. Accordingly, insulin resistance was increased in patients with both a myeloid malignancy and mutations involving either DNMT3A, TET2, ASXL1, or JAK2 compared to myeloid malignancies with unknown/absent CH mutations or lymphoid cancers (6.71 + 0.77 vs. 7.28 + 0.72 vs. 12.11 + 1.89; p=0.031). After adjustment for interaction effect in linear regression modeling, both myeloid malignancy and elevated BMI continued to predict lower insulin sensitivity (Table 2). Pre-diabetes was diagnosed by fasting glucose or OGTT in 26-32% of patients with treated hematological cancers, more than double the prevalence of impaired fasting glucose or impaired glucose tolerance reported by the National Health and Nutrition Examination Survey III. Contrary to our hypothesis, lymphoid cancers and short-term steroids did not contribute to insulin resistance. Instead, myeloid malignancies and CH mutations were associated with reduced insulin sensitivity. Interventions targeting energy balance and obesity will be needed to prevent the harmful sequelae of insulin resistance in long-term cancer survivors. Alternatively, elimination of CH mutations could prove to be a novel treatment of insulin resistance. Disclosures Dholaria: bms: Research Funding; Poseida: Research Funding; Angiocrine: Research Funding; Takeda: Research Funding; J&amp;J: Research Funding.