Elif A. Oral

Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy

Lipodystrophy is a rare disorder that is characterized by selective loss of subcutaneous and visceral fat and is associated with hypertriglyceridemia, hepatomegaly, and disordered glucose metabolism. It has recently been shown that chronic leptin treatment ameliorates these abnormalities. Here we show that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. This improvement in insulin action was associated with a marked reduction in hepatic and muscle triglyceride content. These data suggest that leptin may represent an important new therapy to reverse the severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy.

Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): A 30-year prospective

Abstract: The interaction of insulin with its cell surface receptor is the first step in insulin action and the first identified target of insulin resistance. The insulin resistance in several syndromic forms of extreme insulin resistance has been shown to be caused by mutations in the receptor gene. We studied 8 female patients with the type A form of extreme insulin resistance and 3 patients (2 male and 1 female) with the Rabson-Mendenhall syndrome and followed the natural history of these patients for up to 30 years. The 11 patients ranged in age from 7 to 32 years at presentation. All 11 patients had extreme insulin resistance, acanthosis nigricans, and hyperandrogenism in the female patients, and all but 1 were of normal body weight. This phenotype strongly predicts mutations in the insulin receptor: of the 8 patients studied, 7 were found to have mutations. Similar results from the literature are found in other patients with type A and Rabson-Mendenhall syndromes and leprechaunism. The hyperandrogenic state resulting from hyperinsulinemia and insulin resistance in these patients was extreme: 6 of 8 patients had ovarian surgery to correct the polycystic ovarian syndrome and elevation of serum testosterone. By contrast, a larger group of insulin-resistant patients who were obese with hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN syndrome) did not have a high probability of mutations in the insulin receptor. The morbidity and mortality of these patients were high: 3 of 11 died, 9 of 11 were diabetic and 1 had impaired glucose tolerance, and 7 of 9 patients had 1 or more severe complication of diabetes. Our literature review revealed that the mortality of leprechaunism is so high that the term leprechaunism should be restricted to infants or young children under 2 years of age. Analogous to patients with the common forms of type 2 diabetes, these patients had a heterogeneous course. In 2 patients who were able to maintain extremely high endogenous insulin production, the fasting blood glucose remained normal even though post-glucose-challenge levels were elevated. Most patients, however, required large doses of exogenous insulin to ameliorate the severe hyperglycemia. Preliminary results of a recent study suggest that recombinant leptin administration may benefit these patients with severe insulin resistance.

Predictors of acquired lipodystrophy in juvenile-onset dermatomyositis and a gradient of severity

We describe the clinical features of 28 patients with juvenile dermatomyositis (JDM) and 1 patient with adult-onset dermatomyositis (DM), all of whom developed lipodystrophy (LD) that could be categorized into 1 of 3 phenotypes, generalized, partial, or focal, based on the pattern of fat loss distribution. LD onset was often delayed, beginning a median of 4.6 years after diagnosis of DM. Calcinosis, muscle atrophy, joint contractures, and facial rash were DM disease features found to be associated with LD. Panniculitis was associated with focal lipoatrophy while the anti-p155 autoantibody, a newly described myositis-associated autoantibody, was more associated with generalized LD. Specific LD features such as acanthosis nigricans, hirsutism, fat redistribution, and steatosis/nonalcoholic steatohepatitis were frequent in patients with LD, in a gradient of frequency and severity among the 3 sub-phenotypes. Metabolic studies frequently revealed insulin resistance and hypertriglyceridemia in patients with generalized and partial LD. Regional fat loss from the thighs, with relative sparing of fat loss from the medial thighs, was more frequent in generalized than in partial LD and absent from DM patients without LD. Cytokine polymorphisms, the C3 nephritic factor, insulin receptor antibodies, and lamin mutations did not appear to play a pathogenic role in the development of LD in our patients. LD is an under-recognized sequela of JDM, and certain DM patients with a severe, prolonged clinical course and a high frequency of calcinosis appear to be at greater risk for the development of this complication. High-risk JDM patients should be screened for metabolic abnormalities, which are common in generalized and partial LD and result in much of the LD-associated morbidity. Further study is warranted to investigate the pathogenesis of acquired LD in patients with DM. Abbreviations: CI = confidence interval, CT = computerized tomography, dlk = delta-like, DM= dermatomyositis, DXA = dual-energy X-ray absorptiometry, HDL = high-density lipoprotein, HIV = human immunodeficiency virus, HOMA-IR = homeostasis model assessment of insulin resistance, IL = interleukin, IR = insulin resistance, JDM = juvenile dermatomyositis, LA = lipoatrophy, LD = lipodystrophy, LDL = low-density lipoprotein, LMNA= lamin A, MRI = magnetic resonance imaging, NASH = nonalcoholic steatohepatitis, NIH = National Institutes of Health, OGTT = oral glucose tolerance test, OR = odds ratio, PCR = polymerase chain reaction, TNF = tumor necrosis factor, TTP = tristetraprolin.

Hemodynamic, autonomic, and vascular effects of exposure to coarse particulate matter air pollution from a rural location

Background: Fine particulate matter (PM) air pollution is associated with numerous adverse health effects, including increased blood pressure (BP) and vascular dysfunction. Coarse PM substantially contributes to global air pollution, yet differs in characteristics from fine particles and is currently not regulated. However, the cardiovascular (CV) impacts of coarse PM exposure remain largely unknown. Objectives: Our goal was to elucidate whether coarse PM, like fine PM, is itself capable of eliciting adverse CV responses. Methods: We performed a randomized double-blind crossover study in which 32 healthy adults (25.9 ± 6.6 years of age) were exposed to concentrated ambient coarse particles (CAP; 76.2 ± 51.5 μg/m3) in a rural location and filtered air (FA) for 2 hr. We measured CV outcomes during, immediately after, and 2 hr postexposures. Results: Both systolic (mean difference = 0.32 mmHg; 95% CI: 0.05, 0.58; p = 0.021) and diastolic BP (0.27 mmHg; 95% CI: 0.003, 0.53; p = 0.05) linearly increased per 10 min of exposure during the inhalation of coarse CAP when compared with changes during FA exposure. Heart rate was on average higher (4.1 bpm; 95% CI: 3.06, 5.12; p < 0.0001) and the ratio of low-to-high frequency heart rate variability increased (0.24; 95% CI: 0.07, 0.41; p = 0.007) during coarse particle versus FA exposure. Other outcomes (brachial flow-mediated dilatation, microvascular reactive hyperemia index, aortic hemodynamics, pulse wave velocity) were not differentially altered by the exposures. Conclusions: Inhalation of coarse PM from a rural location is associated with a rapid elevation in BP and heart rate during exposure, likely due to the triggering of autonomic imbalance. These findings add mechanistic evidence supporting the biological plausibility that coarse particles could contribute to the triggering of acute CV events. Citation: Brook RD, Bard RL, Morishita M, Dvonch JT, Wang L, Yang HY, Spino C, Mukherjee B, Kaplan MJ, Yalavarthi S, Oral EA, Ajluni N, Sun Q, Brook JR, Harkema J, Rajagopalan S. 2014. Hemodynamic, autonomic, and vascular effects of exposure to coarse particulate matter air pollution from a rural location. Environ Health Perspect 122:624–630; http://dx.doi.org/10.1289/ehp.1306595

Insufficient sensitivity of hemoglobin A1C determination in diagnosis or screening of early diabetic states

An International Expert Committee made recommendations for using the hemoglobin A(₁C) (A1C) assay as the preferred method for the diagnosis of diabetes in nonpregnant individuals. A concentration of at least 6.5% was considered as diagnostic. It is the aim of this study to compare the sensitivity of A1C with that of plasma glucose concentrations in subjects with early diabetes or impaired glucose tolerance (IGT). We chose 2 groups of subjects who had A1C not exceeding 6.4%. The first group of 89 subjects had family histories of diabetes (MODY or type 2 diabetes mellitus) and had oral glucose tolerance test (OGTT) and A1C determinations. They included 36 subjects with diabetes or IGT and 53 with normal OGTT. The second group of 58 subjects was screened for diabetes in our Diabetes Clinic by fasting plasma glucose, 2-hour plasma glucose, or OGTT and A1C; and similar comparisons were made. Subjects with diabetes or IGT, including those with fasting hyperglycemia, had A1C ranging from 5.0% to 6.4% (mean, 5.8%). The subjects with normal OGTT had A1C of 4.2% to 6.3% (mean, 5.4%), or 5.5% for the 2 groups. The A1C may be in the normal range in subjects with diabetes or IGT, including those with fasting hyperglycemia. Approximately one third of subjects with early diabetes and IGT have A1C less than 5.7%, the cut point that the American Diabetes Association recommends as indicating the onset of risk of developing diabetes in the future. The results of our study are similar to those obtained by a large Dutch epidemiologic study. If our aim is to recognize early diabetic states to apply effective prophylactic procedures to prevent or delay progression to more severe diabetes, A1C is not sufficiently sensitive or reliable for diagnosis of diabetes or IGT. A combination of A1C and plasma glucose determinations, where necessary, is recommended for diagnosis or screening of diabetes or IGT.

A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.

The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue–liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes.

Alterations in Lipid Signaling Underlie Lipodystrophy Secondary to AGPAT2 Mutations

Congenital generalized lipodystrophy (CGL), secondary to AGPAT2 mutation is characterized by the absence of adipocytes and development of severe insulin resistance. In the current study, we investigated the adipogenic defect associated with AGPAT2 mutations. Adipogenesis was studied in muscle-derived multipotent cells (MDMCs) isolated from vastus lateralis biopsies obtained from controls and subjects harboring AGPAT2 mutations and in 3T3-L1 preadipocytes after knockdown or overexpression of AGPAT2. We demonstrate an adipogenic defect using MDMCs from control and CGL human subjects with mutated AGPAT2. This defect was rescued in CGL MDMCs with a retrovirus expressing AGPAT2. Both CGL-derived MDMCs and 3T3-L1 cells with knockdown of AGPAT2 demonstrated an increase in cell death after induction of adipogenesis. Lack of AGPAT2 activity reduces Akt activation, and overexpression of constitutively active Akt can partially restore lipogenesis. AGPAT2 modulated the levels of phosphatidic acid, lysophosphatidic acid, phosphatidylinositol species, as well as the peroxisome proliferator–activated receptor γ (PPARγ) inhibitor cyclic phosphatidic acid. The PPARγ agonist pioglitazone partially rescued the adipogenic defect in CGL cells. We conclude that AGPAT2 regulates adipogenesis through the modulation of the lipome, altering normal activation of phosphatidylinositol 3-kinase (PI3K)/Akt and PPARγ pathways in the early stages of adipogenesis.

The effect of acute exposure to coarse particulate matter air pollution in a rural location on circulating endothelial progenitor cells: results from a randomized controlled study

Abstract Context: Fine particulate matter (PM) air pollution has been associated with alterations in circulating endothelial progenitor cell (EPC) levels, which may be one mechanism whereby exposures promote cardiovascular diseases. However, the impact of coarse PM on EPCs is unknown. Objective: We aimed to determine the effect of acute exposure to coarse concentrated ambient particles (CAP) on circulating EPC levels. Methods: Thirty-two adults (25.9 ± 6.6 years) were exposed to coarse CAP (76.2 ± 51.5 μg m−3) in a rural location and filtered air (FA) for 2 h in a randomized double-blind crossover study. Peripheral venous blood was collected 2 and 20 h post-exposures for circulating EPC (n = 21), white blood cell (n = 24) and vascular endothelial growth factor (VEGF) (n = 16–19) levels. The changes between exposures were compared by matched Wilcoxon signed-rank tests. Results: Circulating EPC levels were elevated 2 [108.29 (6.24–249.71) EPC mL−1; median (25th–75th percentiles), p = 0.052] and 20 h [106.86 (52.91–278.35) EPC mL−1, p = 0.008] post-CAP exposure compared to the same time points following FA [38.47 (0.00–84.83) and 50.16 (0.00–104.79) EPC mL−1]. VEGF and white blood cell (WBC) levels did not differ between exposures. Conclusions: Brief inhalation of coarse PM from a rural location elicited an increase in EPCs that persisted for at least 20 h. The underlying mechanism responsible may reflect a systemic reaction to an acute “endothelial injury” and/or a circulating EPC response to sympathetic nervous system activation.

Lipoatrophic Diabetes and Other Related Syndromes

Millions of Americans are afflicted by obesity and type 2 diabetes mellitus. Obesity is characterized by increased body adiposity and leads to insulin resistance. Paradoxically, some conditions that are characterized by a paucity of fat also cause insulin resistance, namely the syndromes of lipoatrophy (Fig. 1). The resemblance between the metabolic abnormalities of these two extreme states of adiposity emphasizes the importance of fat tissue in energy homeostasis. This review focuses on the syndromes of lipodystrophy and lipoatrophy that are at the lean extreme of the spectrum and which are characterized by near-complete absence of fat.

The metabolic fitness program: lifestyle modification for the metabolic syndrome using the resources of cardiac rehabilitation.

PURPOSE: To describe and assess the effectiveness of a lifestyle intervention program (Met Fit) designed to treat the metabolic syndrome (MetSyn) in a cardiac rehabilitation setting. METHODS: Met Fit is a physician referred and patient pay (