New advances in type 1 diabetes.

Type 1 diabetes is an autoimmune condition resulting in insulin deficiency and eventual loss of pancreatic ß cell function requiring lifelong insulin therapy. Since the discovery of insulin more than 100 years ago, vast advances in treatments have improved care for many people with type 1 diabetes. Ongoing research on the genetics and immunology of type 1 diabetes and on interventions to modify disease course and preserve ß cell function have expanded our broad understanding of this condition. Biomarkers of type 1 diabetes are detectable months to years before development of overt disease, and three stages of diabetes are now recognized. The advent of continuous glucose monitoring and the newer automated insulin delivery systems have changed the landscape of type 1 diabetes management and are associated with improved glycated hemoglobin and decreased hypoglycemia. Adjunctive therapies such as sodium glucose cotransporter-1 inhibitors and glucagon-like peptide 1 receptor agonists may find use in management in the future. Despite these rapid advances in the field, people living in under-resourced parts of the world struggle to obtain necessities such as insulin, syringes, and blood glucose monitoring essential for managing this condition. This review covers recent developments in diagnosis and treatment and future directions in the broad field of type 1 diabetes.

sTREM2 is a plasma biomarker for human NASH and promotes hepatocyte lipid accumulation.

BACKGROUND: Pathogenetic mechanisms of the progression of NAFL to advanced NASH coupled with potential noninvasive biomarkers and novel therapeutic targets are active areas of investigation. The recent finding that increased plasma levels of a protein shed by myeloid cells -soluble Triggering Receptor Expressed on Myeloid cells 2 (sTREM2) -may be a biomarker for NASH has received much interest. We aimed to test sTREM2 as a biomarker for human NASH and investigate the role of sTREM2 in the pathogenesis of NASH. METHODS: We conducted studies in both humans (comparing patients with NASH vs. NAFL) and in mice (comparing different mouse models of NASH) involving measurements of TREM2 gene and protein expression levels in the liver as well as circulating sTREM2 levels in plasma. We investigated the pathogenetic role of sTREM2 in hepatic steatosis using primary hepatocytes and bone marrow derived macrophages. RESULTS: RNA sequencing analysis of livers from patients with NASH or NAFL as well as livers from 2 mouse models of NASH revealed elevated TREM2 expression in patients/mice with NASH as compared with NAFL. Plasma levels of sTREM2 were significantly higher in a well-characterized cohort of patients with biopsy-proven NASH versus NAFL (area under receiver-operating curve 0.807). Mechanistic studies revealed that cocultures of primary hepatocytes and macrophages with an impaired ability to shed sTREM2 resulted in reduced hepatocyte lipid droplet formation on palmitate stimulation, an effect that was counteracted by the addition of exogenous sTREM2 chimeric protein. Conversely, exogenous sTREM2 chimeric protein increased lipid droplet formation, triglyceride content, and expression of the lipid transporter CD36 in hepatocytes. Furthermore, inhibition of CD36 markedly attenuated sTREM2-induced lipid droplet formation in mouse primary hepatocytes. CONCLUSIONS: Elevated levels of sTREM2 due to TREM2 shedding may directly contribute to the pathogenesis of NAFLD by promoting hepatocyte lipid accumulation, as well as serving as a biomarker for distinguishing patients with NASH versus NAFL. Further investigation of sTREM2 as a clinically useful diagnostic biomarker and of the therapeutic effects of targeting sTREM2 in NASH is warranted.

Is Continuous Glucose Monitoring a Tool, an Intervention, or Both?

Studies that investigate use of diabetes technologies such as blood glucose monitoring (BGM) and continuous glucose monitoring (CGM) often report contradictory findings regarding efficacy and clinical utility. Whereas some studies of a given technology have shown no benefit, others have reported significant benefits. These incongruities derive from how the technology is viewed. Is it viewed as a tool, or is it an intervention? In this article, we discuss earlier studies that illustrate the contrast between use of BGM as a tool versus use as an intervention, compare and contrast the roles of BGM and CGM as tools and/or interventions in diabetes management, and suggest that CGM can function effectively as both.

Approach to the Patient With Moderate Hypertriglyceridemia.

Hypertriglyceridemia is a common lipid disorder encountered in clinical practice. Plasma triglycerides are a marker for the concentration of triglycerides carried in chylomicrons and very low-density lipoprotein particles. A fasting triglyceride level <150 mg/dL is accepted widely as the upper limit of normal range. Guidelines for hypertriglyceridemia are variable without a global consensus on classification and goals for triglyceride levels. A general classification of hypertriglyceridemia is mild < 200 mg/dL, moderate = 200 to 500 mg/dL, moderate to severe = 500 to 1000 mg/dL, and severe > 1000 mg/dL. Because moderate hypertriglyceridemia does increase atherosclerotic cardiovascular disease risk, it is important to determine the underlying etiology to guide appropriate and timely management. This article provides stepwise recommendations on the diagnosis and management of moderate hypertriglyceridemia, based on 3 common scenarios encountered in clinical practice. Initial steps in management include evaluating for secondary contributors, especially diabetes mellitus. Based on patient characteristics, appropriate management decisions include lifestyle adjustments aimed at weight loss and decreasing alcohol consumption and use of statin and nonstatin therapies.

Evolving Use of Continuous Glucose Monitoring Beyond Intensive Insulin Treatment.

Numerous studies have demonstrated the clinical benefits of continuous glucose monitoring (CGM) use in individuals with type 1 diabetes and type 2 diabetes (T2D) who are treated with intensive insulin therapy. A growing body of evidence suggests that CGM use may also confer similar glycemic benefits in T2D individuals who are treated with less-intensive therapies. Investigators are also exploring the potential use of CGM as an aid in weight management. This article reviews the continuing evolution of CGM, focusing on how CGM may be used to improve glycemic control and promote adoption of desired health behaviors within broader T2D and prediabetes populations.

Glycation of HDL blunts its anti-inflammatory and cholesterol efflux capacities in vitro, but has no effect in poorly controlled type 1 diabetes subjects.

BACKGROUND: High-density lipoproteins (HDL) modified by glycation have been reported to be dysfunctional. Little is known regarding the anti-inflammatory effects on adipocytes of glycated HDL. AIMS: We tested whether modification of HDL in vitro by glycolaldehyde (GAD), malondialdehyde (MDA) or glucose affected HDL's anti-inflammatory properties and ability to promote cholesterol efflux. To determine whether similar changes occur in vivo, we examined modifications of apolipoprotein A1 (APOA1) and APOA2 and anti-inflammatory and cholesterol efflux properties of HDL isolated from subjects with type 1 diabetes in poor glycemic control. RESULTS: In vitro modification with both GAD and MDA blunted HDL's ability to inhibit palmitate-induced inflammation and cholesterol efflux in adipocytes. Modification of HDL by glucose had little impact on HDL function, like the response using HDL isolated from subjects with diabetes. Mass spectrophotometric analysis revealed that lysine residues in APOA1 and APOA2 of HDL modified by GAD and MDA in vitro differed from those modified by glucose, which resembled that seen with HDL from patients with type1 diabetes. CONCLUSIONS: Modification of lysine residues in HDL by GAD and MDA in vitro does not mirror the HDL glycation in vivo in patients with diabetes, but resembles HDL modified in vitro by glucose.

Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline.

OBJECTIVE: This guideline will provide the practicing endocrinologist with an approach to the assessment and treatment of dyslipidemia in patients with endocrine diseases, with the objective of preventing cardiovascular (CV) events and triglyceride-induced pancreatitis. The guideline reviews data on dyslipidemia and atherosclerotic cardiovascular disease (ASCVD) risk in patients with endocrine disorders and discusses the evidence for the correction of dyslipidemia by treatment of the endocrine disease. The guideline also addresses whether treatment of the endocrine disease reduces ASCVD risk. CONCLUSION: This guideline focuses on lipid and lipoprotein abnormalities associated with endocrine diseases, including diabetes mellitus, and whether treatment of the endocrine disorder improves not only the lipid abnormalities, but also CV outcomes. Based on the available evidence, recommendations are made for the assessment and management of dyslipidemia in patients with endocrine diseases.

Adipocyte-Derived Versican and Macrophage-Derived Biglycan Control Adipose Tissue Inflammation in Obesity.

Obesity is characterized by adipose tissue inflammation. Because proteoglycans regulate inflammation, here we investigate their role in adipose tissue inflammation in obesity. We find that adipose tissue versican and biglycan increase in obesity. Versican is produced mainly by adipocytes and biglycan by adipose tissue macrophages. Both proteoglycans are also present in adipose tissue from obese human subjects undergoing gastric bypass surgery. Deletion of adipocyte-specific versican or macrophage-specific biglycan in mice reduces macrophage accumulation and chemokine and cytokine expression, although only adipocyte-specific versican deletion leads to sustained improvement in glucose tolerance. Macrophage-derived biglycan activates inflammatory genes in adipocytes. Versican expression increases in cultured adipocytes exposed to excess glucose, and adipocyte-conditioned medium stimulates inflammation in resident peritoneal macrophages, in part because of a versican breakdown product, versikine. These findings provide insights into the role of adipocyte- and macrophage-derived proteoglycans in adipose tissue inflammation in obesity.

Safety of Sodium-Glucose Co-Transporter 2 Inhibitors.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have a well-defined safety profile based on data obtained from numerous clinical trials, including cardiovascular outcomes trials (CVOTs) and postmarketing pharmacovigilance reporting. Adverse events including risk of genital mycotic infection and volume depletion-related events are consistent with the mechanism of action of this drug class. However, several emergent (albeit infrequent) serious safety issues have also been reported. In their respective CVOTs, the proportion of patients with reported diabetic ketoacidosis was similar in empagliflozin or canagliflozin compared with their placebo groups, but it was higher for dapagliflozin. Canagliflozin may be associated with an increased risk of bone fracture and lower limb amputation; however, data are inconclusive. There is no evidence linking SGLT2 inhibitors with an increased risk of cancer, but these agents, particularly dapagliflozin, should be used with caution in patients with hematuria or a history of bladder cancer. Postmarketing reports of acute kidney injury have occurred in patients receiving SGLT2 inhibitors, and cases identified in recent CVOTs occurred with similar frequency in SGLT2 inhibitor and placebo groups. Common adverse events associated with SGLT2 inhibitors (such as genital infections or volume depletion) are generally mild and manageable by patients or by primary care physicians, and the risk of rare events (such as ketoacidosis) can be minimized by appropriate patient selection and early recognition of symptoms. When selecting treatment, it is important that clinicians weigh the known risks of SGLT2 inhibitors against their proven benefits, including the reduction of adverse cardiovascular and renal outcomes.

10,12 Conjugated Linoleic Acid-Driven Weight Loss Is Protective against Atherosclerosis in Mice and Is Associated with Alternative Macrophage Enrichment in Perivascular Adipose Tissue.

The dietary fatty acid 10,12 conjugated linoleic acid (10,12 CLA) promotes weight loss by increasing fat oxidation, but its effects on atherosclerosis are less clear. We recently showed that weight loss induced by 10,12 CLA in an atherosclerosis-susceptible mouse model with characteristics similar to human metabolic syndrome is accompanied by accumulation of alternatively activated macrophages within subcutaneous adipose tissue. The objective of this study was to evaluate whether 10,12 CLA-mediated weight loss was associated with an atheroprotective phenotype. Male low-density lipoprotein receptor deficient (Ldlr-/-) mice were made obese with 12 weeks of a high-fat, high-sucrose diet feeding (HFHS: 36% fat, 36% sucrose, 0.15% added cholesterol), then either continued on the HFHS diet with or without caloric restriction (CR), or switched to a diet with 1% of the lard replaced by either 9,11 CLA or 10,12 CLA for 8 weeks. Atherosclerosis and lipid levels were quantified at sacrifice. Weight loss in mice following 10,12 CLA supplementation or CR as a weight-matched control group had improved cholesterol and triglyceride levels, yet only the 10,12 CLA-treated mice had improved en face and aortic sinus atherosclerosis. 10,12 CLA-supplemented mice had increased lesion macrophage content, with enrichment of surrounding perivascular adipose tissue (PVAT) alternative macrophages, which may contribute to the anti-atherosclerotic effect of 10,12 CLA.

Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat.

NEW FINDINGS: What is the central question of this study? Whether chronic oral rapamycin promotes beneficial effects on glucose/lipid metabolism and energy balance when administered to mice with an obesogenic diet rich in saturated fat and sucrose has not been explored. What is the main finding and its importance? Chronic oral rapamycin reduces body weight and fat gain, improves insulin sensitivity and reduces hepatic steatosis when administered to mice with a high-fat, high-sucrose diet. In addition, we make the new observation that there appear to be tissue-specific effects of rapamycin. Although rapamycin appears to impart its effects mainly on visceral adipose tissue, its effects on insulin sensitivity are mediated by subcutaneous adipose tissue. ABSTRACT: Excess adiposity is commonly associated with insulin resistance, which can increase the risk of cardiovascular disease. However, the exact molecular mechanisms by which obesity results in insulin resistance are yet to be understood clearly. The intracellular nutrient-sensing protein, mechanistic target of rapamycin (mTOR), is a crucial signalling component in the development of obesity-associated insulin resistance. Given that increased tissue activation of mTOR complex-1 (mTORC1) occurs in obesity, diabetes and ageing, we hypothesized that pharmacological inhibition of mTORC1 would improve metabolic dysregulation in diet-induced obesity. We administered continuous rapamycin, a specific mTORC1 inhibitor, orally to C57BL/6J mice concurrently with a high-fat, high-sucrose (HFHS) diet for 20 weeks. The control group received placebo microcapsules. Rapamycin-treated mice showed significantly reduced weight gain and adiposity (33.6 ± 4.9 versus 40.4 ± 3.0% body fat, P < 0.001, n = 8 mice per group), despite increased or equivalent food intake compared with the placebo group. The rapamycin-fed mice also demonstrated reduced plasma glucose (252 ± 57 versus 297 ± 67 mg dl-1 , P < 0.001) and improved insulin sensitivity during insulin and glucose tolerance testing. Rapamycin-treated mice also had lower plasma triglycerides (48 ± 13 versus 67 ± 11 mg/dL, P < 0.01) and hepatic triglyceride content (89 ± 15 versus 110 ± 19 mg/g liver, P < 0.05) compared with the placebo group. A moderately low dose of rapamycin decreased adiposity and improved the metabolic profile in a model of diet-induced obesity. These data suggest that low-grade chronic mTORC1 inhibition might be a potential strategy for anti-obesity therapies.

Diabetic Kidney Disease: Is There a Role for Glycemic Variability?

PURPOSE OF REVIEW: Diabetes is the leading cause of kidney disease globally. Diabetic kidney disease (DKD) is a heterogeneous disorder manifested as albuminuria and/or decreasing GFR. Hyperglycemic burden is the major contributor to the development of DKD. In this article, we review the evidence for the contribution of glycemic variability and the pitfalls associated with use of hemoglobin A1c (A1C), the gold standard for assessment of glucose control, in the setting of DKD. RECENT FINDINGS: Glycemic variability, characterized by swings in blood glucose levels, can result in generation of mitochondrial reactive oxygen species, a putative inciting factor for hyperglycemia-induced alterations in intracellular metabolic pathways. While there is indirect evidence supporting the role of glycemic variability in the pathogenesis of DKD, definitive data are lacking. A1C has many limitations and is a particularly suboptimal measure in patients with kidney disease, because its accuracy is compromised by variables affecting RBC survival and other factors. Continuous glucose monitoring (CGM) technology has the potential to enable us to use glucose as a more important clinical tool, for a more definitive understanding of glucose variability and its role in DKD. Glycemic variability may be a factor in the development of DKD, but definitive evidence is lacking. Currently, all available glycemic biomarkers, including A1C, have limitations and in the setting of DKD and should be used cautiously. Emerging data suggest that personal and professional CGM will play an important role in managing diabetes in patients with DKD, where risk of hypoglycemia is high.

Deficiency of Invariant Natural Killer T Cells Does Not Protect Against Obesity but Exacerbates Atherosclerosis in Ldlr-/- Mice.

Obesity is a chronic inflammatory state characterized by altered levels of adipose tissue immune cell populations. Natural killer T (NKT) cells are CD1d restricted lymphocyte subsets that recognize lipid antigens whose level decreases in obese adipose tissue. However, studies in mice with deficiency or increased levels of NKT cells have yielded contradictory results, so the exact role of these cells in obesity and adipose tissue inflammation is not yet established. We previously showed that Ldlr-/- mice with excess invariant NKT (iNKT) cells demonstrate significant weight gain, adiposity, metabolic abnormalities, and atherosclerosis. The current study evaluates the effects of NKT cell deficiency on obesity, associated metabolic changes, and atherosclerosis in Jα18-/-Ldlr-/- (lacking iNKT cells) and Cd1d-/-Ldlr-/- (lacking invariant and type II NKT cells) mice, and control mice were fed an obesogenic diet (high fat, sucrose, cholesterol) for 16 weeks. Contrary to expectations, Ja18-/-Ldlr-/- mice gained significantly more weight than Ldlr-/- or Cd1d-/-Ldlr-/- mice, developed hypertriglyceridemia, and had worsened adipose tissue inflammation. All the mice developed insulin resistance and hepatic triglyceride accumulation. Ja18-/-Ldlr-/- mice also had increased atherosclerotic lesion area. Our findings suggest that iNKT cells exacerbates the metabolic, inflammatory, and atherosclerotic features of diet-induced obesity. Further work is required to unravel the paradox of an apparently similar effect of iNKT cell surplus and depletion on obesity.

Intensive Diabetes Treatment and Cardiovascular Outcomes in Type 1 Diabetes Mellitus: Implications of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study 30-Year Follow-up.

Type 1 diabetes mellitus, an autoimmune disorder characterized by beta-cell destruction and absolute insulin deficiency, is associated with significantly increased cardiovascular disease risk but the mechanisms underlying this enhanced risk are unclear. Results of the pivotal Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study have shown that compared to conventional therapy, intensive glycemic control results in decreased cardiovascular morbidity and mortality. Evidence from this study also revealed contributions of blood pressure, renal disease, body weight, and lipids to cardiovascular disease in type 1 diabetes mellitus. Extrapolating from existing evidence, this article addresses clinical strategies to mitigate cardiovascular risks.

Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH.

We recently reported that cholesterol crystals form in hepatocyte lipid droplets (LDs) in human and experimental nonalcoholic steatohepatitis. Herein, we assigned WT C57BL/6J mice to a high-fat (15%) diet for 6 months, supplemented with 0%, 0.25%, 0.5%, 0.75%, or 1% dietary cholesterol. Increasing dietary cholesterol led to cholesterol loading of the liver, but not of adipose tissue, resulting in fibrosing steatohepatitis at a dietary cholesterol concentration of ≥0.5%, whereas mice on lower-cholesterol diets developed only simple steatosis. Hepatic cholesterol crystals and crown-like structures also developed at a dietary cholesterol concentration ≥0.5%. Crown-like structures consisted of activated Kupffer cells (KCs) staining positive for NLRP3 and activated caspase 1, which surrounded and processed cholesterol crystal-containing remnant LDs of dead hepatocytes. The KCs processed LDs at the center of crown-like structures in the extracellular space by lysosomal enzymes, ultimately transforming into lipid-laden foam cells. When HepG2 cells were exposed to LDL cholesterol, they developed cholesterol crystals in LD membranes, which caused activation of THP1 cells (macrophages) grown in coculture; upregulation of TNF-alpha, NLRP3, and interleukin 1beta (IL1ß) mRNA; and secretion of IL-1beta. In conclusion, cholesterol crystals form on the LD membrane of hepatocytes and cause activation and cholesterol loading of KCs that surround and process these LDs by lysosomal enzymes.

Metabolically distinct weight loss by 10,12 CLA and caloric restriction highlight the importance of subcutaneous white adipose tissue for glucose homeostasis in mice.

BACKGROUND: Widely used as a weight loss supplement, trans-10,cis-12 conjugated linoleic acid (10,12 CLA) promotes fat loss in obese mice and humans, but has also been associated with insulin resistance. OBJECTIVE: We therefore sought to directly compare weight loss by 10,12 CLA versus caloric restriction (CR, 15-25%), an acceptable healthy method of weight loss, to determine how 10,12 CLA-mediated weight loss fails to improve glucose metabolism. METHODS: Obese mice with characteristics of human metabolic syndrome were either supplemented with 10,12 CLA or subjected to CR to promote weight loss. Metabolic endpoints such as energy expenditure, glucose and insulin tolerance testing, and trunk fat distribution were measured. RESULTS: By design, 10,12 CLA and CR caused equivalent weight loss, with greater fat loss by 10,12 CLA accompanied by increased energy expenditure, reduced respiratory quotient, increased fat oxidation, accumulation of alternatively activated macrophages, and browning of subcutaneous white adipose tissue (WAT). Moreover, 10,12 CLA-supplemented mice better defended their body temperature against a cold challenge. However, 10,12 CLA concurrently induced the detrimental loss of subcutaneous WAT without reducing visceral WAT, promoted reduced plasma and WAT adipokine levels, worsened hepatic steatosis, and failed to improve glucose metabolism. Obese mice undergoing CR were protected from subcutaneous-specific fat loss, had improved hepatic steatosis, and subsequently showed the expected improvements in WAT adipokines, glucose metabolism and WAT inflammation. CONCLUSIONS: These results suggest that 10,12 CLA mediates the preferential loss of subcutaneous fat that likely contributes to hepatic steatosis and maintained insulin resistance, despite significant weight loss and WAT browning in mice. Collectively, we have shown that weight loss due to 10,12 CLA supplementation or CR results in dramatically different metabolic phenotypes, with the latter promoting a healthier form of weight loss.

Serum amyloid A impairs the antiinflammatory properties of HDL.

HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO3 fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO3-injected mice lacking Saa1.1 and Saa2.1 exhibited a partial restoration of antiinflammatory and cholesterol efflux properties in adipocytes. Conversely, incorporation of SAA into HDL preparations reduced antiinflammatory properties but not to the same extent as HDL from AgNO3-injected mice. SAA-enriched HDL colocalized with cell surface-associated extracellular matrix (ECM) of adipocytes, suggesting impaired access to the plasma membrane. Enzymatic digestion of proteoglycans in the ECM restored the ability of SAA-containing HDL to inhibit palmitate-induced inflammation and cholesterol efflux. Collectively, these findings indicate that inflammation results in a loss of the antiinflammatory properties of HDL on adipocytes, which appears to partially result from the SAA component of HDL binding to cell-surface proteoglycans, thereby preventing access of HDL to the plasma membrane.

Polybrominated diphenyl ether congener, BDE-47, impairs insulin sensitivity in mice with liver-specific Pten deficiency.

BACKGROUND: The potential health effects of polybrominated diphenyl ethers (PBDEs) that are widely used as flame-retardants in consumer products have been attributed, in part, to their endocrine disrupting properties. The purpose of this study is to examine the in vivo effects of an early exposure to PBDEs on the development of insulin resistance in mice. RESULTS: The metabolic consequences of BDE-47 in mice with varying insulin sensitivities secondary to liver-specific activation of Akt (Pten (fl/fl);Alb (Cre)) and mTORC1 (Tsc1 (fl/fl);Alb (Cre)) as well as wild-type littermates, were studied. BDE-47, a dominant congener of PBDE, was given daily (1 mg/kg/day) for six weeks by oral gavage in young mice following weaning. At the end of the exposure, there were no significant differences in total body, liver, or white adipose tissue weights between the BDE-47-treated vs. DMSO-treated mice for each respective genotype. Metabolic studies revealed significant impairment in insulin sensitivity in the BDE-47-treated Pten (fl/fl);Alb (Cre) mice, but not in wild-type or Tsc1 (fl/fl);Alb (Cre) mice. This was not accompanied by significant alterations in plasma insulin levels or hepatic triglyceride accumulation in the Pten (fl/fl);Alb (Cre) mice. The mean plasma BDE-47 level in the wild-type mice was 11.7 ± 2.9 ng/g (wet weight). CONCLUSIONS: Our findings indicate that BDE-47 exposure during the early post-natal period induces a mild disturbance in glucose metabolism in susceptible mice with increased baseline insulin sensitivity. These results suggest an interaction between BDE-47 and genetic factors that regulate insulin signaling, which may result in long-term consequences.