Modulation Of Insulin Resistance Research Articles

Maternal selenium status is profoundly involved in metabolic fetal programming by modulating insulin resistance, oxidative balance and energy homeostasis.

High and low levels of selenium (Se) have been related to metabolic disorders in dams and in their offspring. Their relationship to oxidative balance and to AMP-activated protein kinase (AMPK) is some of the mechanisms proposed. The aim of this study is to acquire information about how Se is involved in metabolic programming. Three experimental groups of dam rats were used: control (Se: 0.1ppm), Se supplemented (Se: 0.5ppm) and Se deficient (Se: 0.01ppm). At the end of lactation, the pups' metabolic profile, oxidative balance, Se levels, selenoproteins and IRS-1 hepatic expression, as well as hepatic AMPK activation were measured. The experimental groups present deep changes in Se homeostasis, selenoproteins and IRS-1 hepatic expression, oxidative balance, AMPK activation ratio and insulin levels. They do, however, have different metabolic profiles. High- and low-Se diets are linked to insulin resistance, yet the mechanisms involved are completely opposite.

Impact of weight reduction on insulin resistance, adhesive molecules and adipokines dysregulation among obese type 2 diabetic patients.

Type 2 diabetes mellitus is usually related to vascular problems and is associated with impairment in endothelial function characterized by impaired endothelial-dependent vasodilation and increased platelet adhesion. There is limitation in clinical studies that have addressed the beneficial effects of weight reduction in modulating biomarkers of endothelial dysfunction and adipokines dysregulation for obesity associated with type 2 diabetes mellitus. This study was designed to detect the effects of weight loss on insulin resistance, adhesive molecules and adipokines dysregulation in obese type 2 diabetic patients. Eighty obese patients with type 2 diabetes mellitus, their age ranged from 35-55 years and their body mass index ranged from 31-37 kg/m2 were equally assigned into 2 groups: the weight reduction group received aerobic exercises in addition to diet regimen, where the control group received medical treatment only for 12 weeks. There was a 24.04%, 19.33%, 22.78% ,12.28%, 9.35%, 22.53% & 10.12 % reduction in mean values of Homeostasis Model Assessment-Insulin Resistance Index (HOMA-IR), Leptin, Adiponectin, Resistin, intercellular cell adhesion molecule -1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin & body mass index (BMI) respectively in addition to 26.20% & 24.58% increase in the mean values of adiponectin & the quantitative insulin-sensitivity check index (QUICKI) respectively in group (A) at the end of the study. The mean values of leptin, resistin, insulin, HOMA-IR, ICAM-1, VCAM-1, E-selectin & BMI were significantly decreased in addition to significant increase in the mean values of adiponectin & QUICKI in group (A) those that received aerobic exercise training in addition to diet regimen. While the results of group (B) those that received no treatment intervention were not significant. In addition, there were significant differences between mean levels of the investigated parameters in group (A) and group (B) after treatment (P<0.05). Within the limit of this study, 10% reduction in body mass index modulates insulin resistance, adhesive molecules and adipokines dysregulation among obese type 2 diabetic patients.

Serum Interleukin Levels and Insulin Resistance in Major Depressive Disorder.

Major depressive disorder (MDD) has been associated with inflammatory processes, including increased cytokine levels, even in individuals who are otherwise physically healthy, while some MDD patients may show insulin resistance (IR). However, correlations between cytokines and IR parameters have not been studied extensively in MDD. In the present study, we measured IL-1β, IL-4, IFN-γ, TGF-β1, insulin and glucose in 63 MDD patients and 27 healthy controls. The associations between cytokine levels and IR were examined. The results revealed a significant increase (p<0.05) in serum levels of IL-1β, IL-4, IFN-γ, TGF-β1, insulin, insulin/glucose ratio, and insulin resistance (HOMA2IR) in MDD patients as compared with controls. There was a significant correlation between HOMA2IR with both IFN-γ (ρ=0.289, p<0.05) and TGF-β1 (ρ=0.364, p<0.05). The present study further confirms that MDD is accompanied by activation of the immune system with significant elevations in the levels of four cytokines. These results indicate stimulation of the immune system and increased IR and modulation of IR by increased cytokine levels in MDD. These findings show that immune activation and associated IR are a new drug target in depression.

High genetic risk scores of SLIT3, PLEKHA5 and PPP2R2C variants increased insulin resistance and interacted with coffee and caffeine consumption in middle-aged adults

Backgrounds and AimsInsulin resistance is a common feature of metabolic syndrome that may be influenced by genetic risk factors. We hypothesized that genetic risk scores (GRS) of SNPs that influence insulin resistance and signaling interact with lifestyles to modulate insulin resistance in Korean adults. Methods and resultsGenome-wide association studies (GWAS) of subjects aged 40–65 years who participated in the Ansung/Ansan cohorts (8842 adults) in Korea revealed 52 genetic variants that influence insulin resistance. The best gene-gene interaction model was explored using the generalized multifactor dimensionality reduction (GMDR) method. GRS from the best model were calculated and the GRS were divided into low, medium and high groups. The best model for representing insulin resistance included SLIT3_rs2974430, PLEKHA5_rs1077044, and PPP2R2C_rs16838853. The odds ratios for insulin resistance were increased by 150% in the High-GRS group compared to the Low-GRS group. However, ORs for insulin secretion capacity, measured by HOMA-B, were not associated with GRS. Coffee and caffeine intake and GRS had an interaction with insulin resistance: In subjects with high coffee (≥10 cups/week) or caffeine intake (≥220 mg caffeine/day), insulin resistance was significantly elevated in the High-GRS group, but not in the Low-GRS. However, alcohol intake, smoking and physical activity did not have an interaction with GRS. Insulin secretion capacity was not significantly influenced by GRS when evaluating the adjusted odds ratios. ConclusionsSubjects with High-GRS may be susceptible to increased insulin resistance by 50% and its risk may be exacerbated by consuming more than 10 cups coffee/week or 220 mg caffeine/day.

Sleep apnea and type 2 diabetes.

The aim of the present review was to clarify the association between obstructive sleep apnea (OSA) and type 2 diabetes, and discuss the therapeutic role of continuous positive airway pressure (CPAP) in type 2 diabetes. OSA patients are more likely than non‐OSA populations to develop type 2 diabetes, while more than half of type 2 diabetes patients suffer from OSA. Similar to Western countries, in the East Asian population, the association between these two disorders has also been reported. CPAP is the primary treatment for OSA, but the effect of CPAP on comorbid diabetes has not been established. CPAP improved glucose metabolism determined by the oral glucose tolerance test in OSA patients, and several studies have shown that CPAP improves insulin resistance, particularly in obese populations undergoing long‐term CPAP. Diabetes is associated with other sleep‐related manifestations as well, such as snoring and excessive daytime sleepiness. Snoring is associated with the development of diabetes, and excessive daytime sleepiness appears to modify insulin resistance. Well‐designed studies are required to clarify the therapeutic effect of CPAP on diabetes. As both diabetes and OSA lead to cardiovascular disease, clinicians and healthcare professionals should be aware of the association between diabetes and OSA, and should take CPAP and health‐related behaviors into consideration when treating patients with diabetes and/or OSA.

THU-460 - Bile acid composition modulate insulin resistance in non-diabetic patients with NAFLD

THU-460 - Bile acid composition modulate insulin resistance in non-diabetic patients with NAFLD

MicroRNA‐190b regulates lipid metabolism and insulin sensitivity by targeting IGF‐1 and ADAMTS9 in non‐alcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is characterized by ectopic lipid accumulation and insulin resistance, yet the underlying molecular mechanisms are poorly understood. MiR-190b is thought to play a role in hepatocellular carcinoma by modulating insulin resistance; however, its role in NAFLD remains unknown. Here, we found that miR-190b expression was significantly increased in the liver tissues of patients with NAFLD, compared to normal tissues. Moreover, miR-190b was upregulated in a high-fat diet NAFLD mouse model and a free fatty acid-induced NAFLD cellular model. Knockdown of miR-190b decreased aspartate transaminase (AST), alanine transaminase (ALT), triglyceride (TG), and total cholesterol (TC). It also reduced expression of the lipogenic genes fatty acid synthase (FAS) and 3-hydroxy-3-methylglutarylCoA reductase (HMGCR), alleviated hepatic steatosis, improved glucose tolerance, elevated insulin sensitivity, and activated insulin receptor substrate (IRS)2/Akt signaling in vivo and/or in vitro. Furthermore, we confirmed that miR-190b directly targeted IGF-1 and ADAMTS9. MiR-190b overexpression suppressed expression of IGF-1 and ADAMTS9, which were increased by miR-190b inhibition. Expression of IGF-1 and ADAMTS9 was inversely correlated with miR-190b in liver tissues of patients with NAFLD, respectively. We also found that IGF-1 or ADAMTS9 inhibition partially reversed the effects of miR-190b on lipid metabolism and insulin signaling in vitro. Taken together, the data reveal that miR-190b inhibition suppressed lipid accumulation and improved insulin sensitivity by targeting IGF-1 and ADAMTS9, suggesting that miR-190b inhibition may be a therapeutic strategy against NAFLD.

Chronic hyperinsulinemia induced miR-27b is linked to adipocyte insulin resistance by targeting insulin receptor.

Defect in insulin signaling leads to the development of insulin resistance followed by type 2 diabetes. Exploiting our previously developed physiological chronic hyperinsulinemia (CI)-mediated insulin resistance (IR) model, we wanted to understand how miRNAs contribute to the development of IR. Amongst the identified and validate miRNAs, the expression of miR-27b was found to be highly upregulated during CI-induced IR in 3T3-L1 adipocytes. We also validated the expression of miR-27b in CI-induced IR in human mesenchymal stem cell (hMSC)-derived adipocytes and in vivo high fat diet (HFD)-induced IR mice model. Bioinformatics target prediction softwares and luciferase reporter assay identified insulin receptor (INSR) as one of a prime target of miR-27b. Lentiviral mediated overexpression of miR-27b impairs insulin signaling by modulating INSR expression that in turn led to decreased glucose uptake in both 3T3-L1 and hMSC-derived adipocytes. Conversely, inhibition of miR-27b reversed CI-mediated suppression of target protein INSR and improved phosphorylation of Akt, a nodal protein of insulin signaling that is impaired by CI treatment. Lentiviral mediated overexpression of miR-27b in in vivo C57BL/6 mice impaired whole body glucose tolerance and adipose tissue insulin sensitivity. Furthermore, inhibition of miR-27b in HFD-induced insulin resistance mice model improved glucose tolerance and adipose tissue insulin sensitivity by increasing the expression of its target gene INSR in eWAT. Thus, our results indicate that miR-27b functions as a prime modulator of CI-induced IR via regulating the expression of INSR. KEY MESSAGES: miR-27b is upregulated in different in vitro and in vivo models of insulin resistance. miR-27b directly suppresses the expression of INSR by targeting 3'UTR of INSR. Modulation of miR-27b expression regulates insulin sensitivity by targeting INSR.

Bile acid composition modulates insulin resistance in non-diabetic patients with NAFLD

Bile acid composition modulates insulin resistance in non-diabetic patients with NAFLD

Vitamin A Improves Hyperglycemia and Glucose-Intolerance through Regulation of Intracellular Signaling Pathways and Glycogen Synthesis in WNIN/GR-Ob Obese Rat Model.

Vitamin A and its metabolites modulate insulin resistance and regulate stearoyl-CoA desaturase 1 (SCD1), which are also known to affect insulin resistance. Here, we tested, whether vitamin A-mediated changes in insulin resistance markers are associated with SCD1 regulation or not. For this purpose, 30-week old male lean and glucose-intolerant obese rats of WNIN/GR-Ob strain were given either a stock or vitamin A-enriched diet, i.e. 2.6 mg or 129 mg vitamin A/kg diet, for 14 weeks. Compared to the stock diet, vitamin A-enriched diet feeding improved hyperglycemia and glucose-clearance rate in obese rats and no such changes were seen in lean rats receiving identical diets. These changes were corroborated with concomitant increase in circulatory insulin and glycogen levels of liver and muscle (whose insulin signaling pathway genes were up-regulated) in obese rats. Further, the observed increase in muscle glycogen content in these obese rats could be explained by increased levels of the active form of glycogen synthase, the key regulator of glycogen synthesis pathway, possibly inactivated through increased phosphorylation of its upstream inhibitor, glycogen synthase kinase. However, the unaltered hepatic SCD1 protein expression (despite decreased mRNA level) and increased muscle-SCD1 expression (both at gene and protein levels) suggest that vitamin A-mediated changes on glucose metabolism are not associated with SCD1 regulation. Chronic consumption of vitamin A-enriched diet improved hyperglycemia and glucose-intolerance, possibly, through the regulation of intracellular signaling and glycogen synthesis pathways of muscle and liver, but not associated with SCD1.

Meta‐Analysis of 19,005 Individuals Identifies Interplay Between Dietary Saturated Fats and Genetic Variants of the NLRP3 Inflammasome, to Modulate Insulin Resistance and Diabetes Risk

Type 2 Diabetes (T2D) is a multi‐factorial disease, caused by a complex interaction of environmental and genetic factors. Dietary fats represent an important environmental factor. Our previous research has demonstrated that the ‘nod like receptor pyrin domain containing‐3’ (NLRP3) inflammasome plays a critical role in obesity associated insulin resistance (IR) and has a specific sensitivity to saturated fatty acids (SFA) (*Finucane et al, 2014). We investigated genetic variants related to NLRP3 and potential interactions with SFA, which may modulate T2D risk.Using METAL software, a cross‐sectional meta‐analyses of 6 Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=19,005), tested interactions (linear regression effects) between dietary saturated fats and candidate NLRP3 related SNP's, to determine if these interactions could modulate three glycemic traits, fasting insulin, fasting glucose and Homeostasis Model Assessment of IR (HOMA‐IR).NLRP3 variant rs12143966 interacted with SFA intake (β ± SE = 0.0068 ± 0.002, p= 0.001), suggesting that each 1% increase SFA intake, in the presence of the minor A allele (MAF 0.38), increased fasting insulin by 0.0068 units. Olfactory Receptor Family 2, Subfamily B member 11 (OR2B11) variant rs4925663, minor allele T (MAF 0.4), also interacted with SFA (β ± SE = −0.0068 ± 0.002, p= 0.0001), suggesting a 0.0068 uIU/ml reduction in fasting insulin with each additional 1% SFA intake. Both SNP's are located on Chromosome 1 q44. In Silico functional analysis describes OR2B11 variant rs4925663 as a non‐synonymous missense SNP with highly significant eQTL hits with NLRP3 expression in whole blood and liver tissue.Two inflammatory SNPs show a novel interaction with dietary SFA to modulate fasting insulin. Altering SFA intake may modulate T2D risk depending on the genotype of inflammasome related variants.Support or Funding InformationScience Foundation Ireland Principal Investigator Programme awarded to Prof Helen Roche (11/PI/1119)

Associations of objective physical activity with insulin sensitivity and circulating adipokine profile: the Framingham Heart Study.

The purpose of this study was to explore the relation of physical activity (PA) and sedentary time (SED) to insulin sensitivity and adipokines. We assessed PA and SED using Actical accelerometers and insulin resistance (HOMA-IR) in 2109 participants (free of type 1 and 2 diabetes mellitus) from Framingham Generation 3 and Omni 2 cohorts (mean age 46 years, 54% women). Systemic inflammation (C-reactive protein [CRP]) and circulating adipokines were measured 6 years earlier. Steps per day, moderate-to-vigorous PA (MVPA) and SED per wear time (%SED) were predictor variables in multivariable regression analyses, with HOMA-IR, CRP and circulating adipokines as outcome measures. We reported that higher MVPA and more steps per day were associated with lower HOMA-IR, adjusting for %SED (β = -0.036, P = 0.002; β = -0.041, P = 0.005). Steps were inversely associated with CRP, but were directly associated with insulin-like growth factor (IGF)-1 levels (β = -0.111, P = 0.002; β = 3.293, P = 0.007). %SED was positively associated with HOMA-IR (β = 0.033, P < 0.0001), but non-significant after adjusting for MVPA (P = 0.13). %SED was associated with higher ratio of leptin/leptin receptor (sOB-R) and higher adipocyte fatty acid-binding protein (FABP)4 (β = 0.096, P < 0.0001; β = 0.593, P = 0.002). Our findings suggest differential influences of PA vs. SED on metabolic pathways, with PA modulating insulin resistance and inflammation, whereas SED influences FABPs.

Vitamin D and diabetes mellitus: Causal or casual association?

The incidence of both type 2 and type 1 diabetes mellitus has been increasing worldwide. Vitamin D deficiency, or the awareness of its prevalence, has also been increasing. Vitamin D may have a role in the pathogenic mechanisms predisposing to type 2 diabetes by modulating insulin resistance and/or pancreatic β-cell function. Vitamin D status or elements involved in its activation or transport may also be involved in the development of type 1 diabetes mellitus through immunomodulatory role . Based on these observations a potential association between vitamin D and diabetes has been hypothesized. In this review we discuss up to date evidence linking vitamin D with the development of diabetes. Moreover, the role of vitamin D supplementation in the prevention of both types of diabetes is analysed together with its role in improving glycemic control in diabetic patients. We also address the potential role of vitamin D deficiency in the development of macro- and microvascular complications in diabetes. Finally, we provide recommendation for Vitamin D therapy in diabetes in view of current evidence and highlight areas for potential future research in this area.

Caveolin 1 Modulates Aldosterone‐Mediated Pathways of Glucose and Lipid Homeostasis

BackgroundOveractivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav‐1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav‐1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav‐1–null mice and humans with a prevalent variant in the CAV1 gene.Methods and ResultsIn mouse studies, cav‐1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high‐ to low‐density lipoprotein (all P<0.001 versus wild type). Moreover, cav‐1 knockout mice displayed hypertriglyceridemia and higher mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia (P<0.01), total cholesterol (P<0.05), resistin (P<0.05), and described enzymes, with no effect on insulin or triglycerides. In the human study, we analyzed the CAV1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40–3.64]) and low high‐density lipoprotein (odds ratio 1.54 [95% CI 1.01–3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high‐density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav‐1 expression in adipose tissues by the rs926198 minor allele.ConclusionsOur findings in mice and humans suggested that decreased cav‐1 expression may activate the effect of aldosterone/MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MR‐independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype‐mediated cav‐1 deficiency.

Interaction of an S100A9 gene variant with saturated fat and carbohydrates to modulate insulin resistance in 3 populations of different ancestries1–3

S100 calcium-binding protein A9 (S100A9) has previously been identified as a type 2 diabetes (T2D) gene. However, this finding requires independent validation and more in-depth analyses in other populations and ancestries. We aimed to replicate the associations between an S100A9 variant and insulin resistance and T2D and to initiate an investigation of potential interactions with the habitual diet in several independent populations. We investigated the association of the S100A9 variant rs3014866 with insulin resistance and T2D risk and its interactions with diet in 3 diverse populations as follows: the CORDIOPREV (Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention; n = 711), which consisted of Spanish white adults; the GOLDN (Genetics of Lipids Lowering Drugs and Diet Network; n = 818), which involved North American non-Hispanic white adults; and Hispanic adults who participated in the BPRHS (Boston Puerto Rican Health Study; n = 1155). Meta-analysis indicated that T carriers presented a lower risk of T2D than CC carriers (pooled OR: 0.714; 95% CI: 0.584, 0.845; P = 0.002). In all 3 populations (CORDIOPREV, GOLDN, and BPRHS), we showed a significant interaction between the rs3014866 single nucleotide polymorphism and dietary SFA:carbohydrate ratio intake for the homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.028, P = 0.017, and P = 0.026, respectively). CC carriers had a significantly higher HOMA-IR only when SFA:carbohydrate intake was high (P = 0.045 for the CORDIOPREV, P = 0.033 for the GOLDN, and P = 0.046 for the BPRHS) but not when SFA:carbohydrate ratio intake was low. The minor allele (T) of the S100A9 variant rs3014866 is associated with lower T2D risk in 3 populations of different ancestries. Note that individuals with the high-risk CC genotype may be more likely to benefit from a low SFA:carbohydrate ratio intake to improve insulin resistance as evaluated with the use of the HOMA-IR. These trials were registered at clinicaltrials.gov as NCT00924937 (CORDIOPREV), NCT00083369 (GOLDN), and NCT01231958 (BPRHS).

Biochemical parameters response to weight loss in patients with non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that is capable of progressing to end-stage liver disease, but generally has a benign course. Non-alcoholic steatohepatitis (NASH) is a growing public health problem with no approved therapy. NASH projected to be the leading cause of liver transplantation in the United States by 2020. Obesity, non-insulin-dependent diabetes mellitus and hyperlipidaemia are the most common associations of the disease. Global prevalence of NASH is 10-24% amongst general population but increases to 25-75% in obese diabetic individuals. There is an urgent need for efficient therapeutic options as there is still no approved medication. The aim of this study was to detect changes in biochemical parameters including insulin resistance, cytokines, blood lipid profile and liver enzymes following weight loss in patients with non-alcoholic steatohepatitis. One hundred obese patients with NASH, their age between 35-50 years, body mass index (BMI) from 30 to 35 Kg/m(2) were included in the study in two subgroups; the first group (A) received moderate aerobic exercise training in addition to diet regimen , where the second group (B) received no treatment intervention. The mean values of leptin, TNF-α, IL6, IL8, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Homeostasis Model Assessment-Insulin Resistance- index (HOMA-IR), Total Cholesterol (TC), Low Density Lipoprotein Cholesterol (LDL-c) , Triglycerides (TG) and BMI were significantly decreased in group (A), where the mean value of Adiponectin and High Density Lipoprotein Cholesterol (HDL-c) were significantly increased, while there were no significant changes in group (B). Also, there was a significant difference between both groups at the end of the study. Weight loss modulates insulin resistance, adiponectin, leptin, inflammatory cytokine levels and markers of hepatic function in patients with nonalcoholic steatohepatitis.

CrossTalk proposal: Intramyocellular ceramide accumulation does modulate insulin resistance.

CrossTalk proposal: Intramyocellular ceramide accumulation does modulate insulin resistance.

CrossTalk opposing view: Intramyocellular ceramide accumulation does not modulate insulin resistance.

CrossTalk opposing view: Intramyocellular ceramide accumulation does not modulate insulin resistance.

New-onset diabetes after renal transplantation.

Transplantation medicine has grown to be an important element of medical practice, and with the development of modern immunosuppression agents and protocols, the occurrence of diabetes as renal transplantation is recognized as one of the metabolic consequences of therapy with these agents. New-onset diabetes after transplantation can be defined as diabetes mellitus developing in any patient without history of diabetes before transplantation, who has sustained hyperglycemia that meets the current diagnostic criteria by the American Diabetes Association or by the World Health Organization. New-onset diabetes after transplantation has been associated with the following risk factors: age, non-white ethnicity, hepatitis C infection, glucocorticoid therapy for rejection, and chronic immunosuppression with cyclosporine and tacrolimus. The observation that current immunosuppression using tacrolimus is one of the most important single risk factor for the development of new-onset diabetes after transplantation has been made. The pathophysiology of this condition resembles that of type 2 diabetes mellitus. There is conclusive evidence that pretransplantation end-stage renal disease is an insulin-resistant state, and after transplantation, glucocorticoids induce further peripheral insulin insensitivity. The "second hit" seems to be an acquired (yet reversible) insulin secretion defect caused by the calcineurin inhibitors cyclosporine but more pronounced with tacrolimus. Future directions include pretransplantation and posttransplantation testing using glucose measurements and other techniques to identify high-risk individuals and possibly develop treatment strategies aimed to modify insulin resistance as well as to preserve beta cell function.

Insulin Resistance is Associated with Higher Cerebrospinal Fluid Tau Levels in Asymptomatic APOEɛ4 Carriers.

Insulin resistance (IR) is linked with the occurrence of pathological features observed in Alzheimer's disease (AD), including neurofibrillary tangles and amyloid plaques. However, the extent to which IR is associated with AD pathology in the cognitively asymptomatic stages of preclinical AD remains unclear. To determine the extent to which IR is linked with amyloid and tau pathology in late-middle-age. Cerebrospinal fluid (CSF) samples collected from 113 participants enrolled in the Wisconsin Registry for Alzheimer's Prevention study (mean age = 60.6 years), were assayed for AD-related markers of interest: Aβ₄₂, P-Tau181, and T-Tau. IR was determined using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Linear regression was used to test the effect of IR, and APOEɛ4, on tau and amyloid pathology. We hypothesized that greater IR would be associated with higher CSF P-Tau181 and T-Tau, and lower CSF Aβ₄₂. No significant main effects of HOMA-IR on P-Tau181, T-Tau, or Aβ₄₂ were observed; however, significant interactions were observed between HOMA-IR and APOEɛ4 on CSF markers related to tau. Among APOEɛ4 carriers, higher HOMA-IR was associated with higher P-Tau181 and T-Tau. Among APOEɛ4 non-carriers, HOMA-IR was negatively associated with P-Tau181 and T-Tau. We found no effects of IR on Aβ₄₂ levels in CSF. IR among asymptomatic APOEɛ4 carriers was associated with higher P-Tau181 and T-Tau in late-middle age. The results suggest that IR may contribute to tau-related neurodegeneration in preclinical AD. The findings may have implications for developing prevention strategies aimed at modifying IR in mid-life.