ABSTRACT
PURPOSE: To compare vertebral bone marrow fat content quantified with proton MR spectroscopy ((1)H-MRS) with the volume of abdominal adipose tissue, lumbar spine volumetric bone mineral density (vBMD), and blood biomarkers in postmenopausal women with and without type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Thirteen postmenopausal women with T2DM and 13 age- and body mass index-matched healthy controls were included in this study. All subjects underwent (1)H-MRS of L1-L3 to quantify vertebral bone marrow fat content (FC) and unsaturated lipid fraction (ULF). Quantitative computed tomography (QCT) was performed to assess vBMD of L1-L3. The volumes of abdominal subcutaneous/visceral/total adipose tissue were determined from the QCT images and adjusted for abdominal body volume (SAT(adj)/VAT(adj)/TAT(adj)). Fasting blood tests included plasma glucose and HbA1c. RESULTS: Mean FC showed an inverse correlation with vBMD (r = -0.452; P < 0.05) in the whole study population. While mean FC was similar in the diabetic women and healthy controls (69.3 ± 7.5% versus 67.5 ± 6.1%; P > 0.05), mean ULF was significantly lower in the diabetic group (6.7 ± 1.0% versus 7.9 ± 1.6%; P < 0.05). SAT(adj) and TAT(adj) correlated significantly with mean FC in the whole study population (r = 0.538 and r = 0.466; P < 0.05). In contrast to the control group, significant correlations of mean FC with VAT(adj) and HbA1c were observed in the diabetic group (r = 0.642 and r = 0.825; P < 0.05). CONCLUSION: This study demonstrated that vertebral bone marrow fat content correlates significantly with SAT(adj), TAT(adj), and lumbar spine vBMD in postmenopausal women with and without T2DM, but with VAT(adj) and HbA1c only in women with T2DM.
Subject(s)
Abdominal Fat/pathology , Adipose Tissue/pathology , Biomarkers/metabolism , Bone Marrow/pathology , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/therapy , Lumbar Vertebrae/metabolism , Aged , Biomarkers/blood , Bone Density , Case-Control Studies , Female , Humans , Image Processing, Computer-Assisted , Lumbar Vertebrae/pathology , Magnetic Resonance Spectroscopy/methods , Middle Aged , Postmenopause , Reproducibility of Results , Tomography, X-Ray Computed/methodsABSTRACT
BACKGROUND: The pathogenesis of insulin resistance in the absence of obesity is unknown. In obesity, multiple stress kinases have been identified that impair the insulin signaling pathway via serine phosphorylation of key second messenger proteins. These stress kinases are activated through various mechanisms related to lipid oversupply locally in insulin target tissues and in various adipose depots. METHODOLOGY/PRINCIPAL FINDINGS: To explore whether specific stress kinases that have been implicated in the insulin resistance of obesity are potentially contributing to insulin resistance in non-obese individuals, twenty healthy, non-obese, normoglycemic subjects identified as insulin sensitive or resistant were studied. Vastus lateralis muscle biopsies obtained during euglycemic, hyperinsulinemic clamp were evaluated for insulin signaling and for activation of stress kinase pathways. Total and regional adipose stores and intramyocellular lipids (IMCL) were assessed by DXA, MRI and (1)H-MRS. In muscle of resistant subjects, phosphorylation of JNK was increased (1.36±0.23 vs. 0.78±0.10 OD units, P<0.05), while there was no evidence for activation of p38 MAPK or IKKß. IRS-1 serine phosphorylation was increased (1.30±0.09 vs. 0.22±0.03 OD units, P<0.005) while insulin-stimulated tyrosine phosphorylation decreased (10.97±0.95 vs. 0.89±0.50 OD units, P<0.005). IMCL levels were twice as high in insulin resistant subjects (3.26±0.48 vs. 1.58±0.35% H(2)O peak, P<0.05), who also displayed increased total fat and abdominal fat when compared to insulin sensitive controls. CONCLUSIONS: This is the first report demonstrating that insulin resistance in non-obese, normoglycemic subjects is associated with activation of the JNK pathway related to increased IMCL and higher total body and abdominal adipose stores. While JNK activation is consistent with a primary impact of muscle lipid accumulation on metabolic stress, further work is necessary to determine the relative contributions of the various mediators of impaired insulin signaling in this population.
Subject(s)
Insulin Resistance , Insulin/metabolism , MAP Kinase Kinase 4/metabolism , Muscle, Skeletal/metabolism , Signal Transduction , Adult , Enzyme Activation , Female , Humans , Male , PhosphorylationABSTRACT
IMPORTANCE OF THE FIELD: Type 1 diabetes mellitus (T1D) is a T-cell mediated autoimmune disease with selective destruction of beta cells. Immunological interventions are directed at arresting the loss of beta-cell function with the promise that this will make it easier for patients to control their glucose levels. AREAS COVERED IN THIS REVIEW: This review provides a summary of the preclinical and clinical research published between 1992 and 2009 using teplizumab and other anti-CD3 antibodies to arrest the loss of beta-cell function in new onset T1D. Data from animal and human studies on the probable mechanism of action of teplizumab are also reviewed. WHAT THE READER WILL GAIN: A broad perspective on the use of teplizumab in inducing disease specific tolerance. TAKE HOME MESSAGE: In Phase I/II randomized control trials, in patients with new onset T1D, teplizumab slowed the rate of loss of beta-cell function over 2 years of follow-up. Treated patients had better glycemic control and lower insulin requirements. Adverse events so far are mild and of limited duration. Phase III clinical trials are underway to confirm these results and to determine if two courses of drug have greater efficacy in arresting loss of beta-cell function.
Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Muromonab-CD3/therapeutic use , Antibodies, Monoclonal, Humanized , Clinical Trials as Topic , Diabetes Mellitus, Type 1/immunology , Humans , Immunotherapy , Islets of Langerhans/immunologyABSTRACT
OBJECTIVES: The objectives of this study were to develop protocols that measure abdominal fat and calf muscle lipids with magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS), respectively, at 3 T and to examine the correlation between these parameters and insulin sensitivity. MATERIALS AND METHODS: Ten nondiabetic subjects [five insulin-sensitive (IS) subjects and five insulin-resistant (IR) subjects] were scanned at 3 T. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were segmented semiautomatically from abdominal imaging. Intramyocellular lipids (IMCL) in calf muscles were quantified with single-voxel MRS in both soleus and tibialis anterior muscles and with magnetic resonance spectroscopic imaging (MRSI). RESULTS: The average coefficient of variation (CV) of VAT/(VAT+SAT) was 5.2%. The interoperator CV was 1.1% and 5.3% for SAT and VAT estimates, respectively. The CV of IMCL was 13.7% in soleus, 11.9% in tibialis anterior and 2.9% with MRSI. IMCL based on MRSI (3.8+/-1.2%) were significantly inversely correlated with glucose disposal rate, as measured by a hyperinsulinemic-euglycemic clamp. VAT volume correlated significantly with IMCL. IMCL based on MRSI for IR subjects was significantly greater than that for IS subjects (4.5+/-0.9% vs. 2.8+/-0.5%, P=.02). CONCLUSION: MRI and MRS techniques provide a robust noninvasive measurement of abdominal fat and muscle IMCL, which are correlated with insulin action in humans.
Subject(s)
Abdominal Fat/anatomy & histology , Lipids/analysis , Magnetic Resonance Imaging/methods , Magnetic Resonance Spectroscopy/methods , Muscle, Skeletal/metabolism , Adult , Female , Humans , Image Processing, Computer-Assisted , Insulin Resistance , Leg , Male , Middle AgedABSTRACT
OBJECTIVE: We sought to study the combined effects of multiple home indoor environmental exposures in adult asthma and rhinitis. METHODS: We studied 226 adults with asthma and rhinitis by structured interviews and home assessments. Environmental factors included dust allergen, endotoxin and glucan concentrations, and indoor air quality (IAQ) variables. Outcomes included forced expiratory volume in 1 second (FEV1) percent predicted, Severity of Asthma Score (SAS), Short-Form (SF)-12 Physical Component Scale (PCS), and asthma Quality of Life (QOL) score. RESULTS: House dust-associated exposures together with limited IAQ variables were related to FEV1 % predicted (R = 0.24; P = 0.0001) and SAS (R = 0.18; P = 0.007). IAQ and limited dust variables were associated with SF-12 PCS (R = 0.15; P = 0.02), but not QOL (R = 0.13; P = 0.16). CONCLUSIONS: The home environment is strongly linked to lung function, health status, and disease severity in adult asthma and rhinitis.