Kristina M Utzschneider

VA Puget Sound Health Care System, Washington, Washington, D.C., United States

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Publications (63)401.96 Total impact

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    ABSTRACT: Dietary fat and oxidative stress are hypothesized to contribute to non-alcoholic fatty liver disease and progression to steatohepatitis. To determine the effects of dietary fat content on hepatic triglyceride, body fat distribution and markers of inflammation and oxidative stress, overweight/obese subjects with normal glucose tolerance consumed a control diet (CONT: 35% fat/12% saturated fat/47% carbohydrate) for ten days, followed by four weeks on a low fat (LFD (n = 10): 20% fat/8% saturated fat/62% carbohydrate) or high fat diet (HFD (n = 10): 55% fat/25% saturated fat/27% carbohydrate). Hepatic triglyceride content was quantified by MRS and abdominal fat distribution by MRI. Fasting biomarkers of inflammation (plasma hsCRP, IL-6, IL-12, TNFα, IFN-γ) and oxidative stress (urinary F2-α isoprostanes) were measured. Body weight remained stable. Compared to the CONT, hepatic triglyceride decreased on the LFD (mean (95% CI): change -2.13% (-3.74%, -0.52%)), but did not change on the HFD and there was no significant difference between the LFD and HFD. Intra-abdominal fat did not change significantly on either diet, but subcutaneous abdominal fat increased on the HFD. There were no significant changes in fasting metabolic markers, inflammatory markers and urinary F2-α isoprostanes. We conclude that in otherwise healthy overweight/obese adults under weight-neutral conditions, a diet low in fat and saturated fat has modest effects to decrease liver fat and may be beneficial. On the other hand, a diet very high in fat and saturated fat had no effect on hepatic triglyceride or markers of metabolism, inflammation and oxidative stress.
    Nutrients 11/2014; 6(11):4678-90. · 3.15 Impact Factor
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    ABSTRACT: Plasma phospholipid concentrations of trans-palmitoleic acid (trans-16:1n-7), a biomarker of dairy fat intake, are inversely associated with incident type 2 diabetes in 2 US cohorts. The objective was to investigate whether the intake of trans-16:1n-7 in particular, or dairy fat in general, is associated with glucose tolerance and key factors determining glucose tolerance. A cross-sectional investigation was undertaken in 17 men and women with nonalcoholic fatty liver disease and 15 body mass index (BMI)- and age-matched controls. The concentrations of trans-16:1n-7 and 2 other biomarkers of dairy fat intake, 15:0 and 17:0, were measured in plasma phospholipids and free fatty acids (FFAs). Liver fat was estimated by computed tomography-derived liver-spleen ratio. Intravenous-glucose-tolerance tests and oral-glucose-tolerance test (OGTT) and hyperinsulinemic-euglycemic clamps were performed to assess β-cell function and hepatic and systemic insulin sensitivity. In multivariate analyses adjusted for age, sex, and BMI, phospholipid 17:0, phospholipid trans-16:1n-7, FFA 15:0, and FFA 17:0 were inversely associated with fasting plasma glucose, the area under the curve for glucose during an OGTT, and liver fat. Phospholipid trans-16:1n-7 was also positively associated with hepatic and systemic insulin sensitivity. None of the biomarkers were associated with β-cell function. The associations between dairy fat intake and glucose tolerance were attenuated by adjusting for insulin sensitivity or liver fat, but strengthened by adjusting for β-cell function. Although we cannot rule out reverse causation, these data support the hypothesis that dairy fat improves glucose tolerance, possibly through a mechanism involving improved hepatic and systemic insulin sensitivity and reduced liver fat. This trial was registered at as NCT01289639.
    American Journal of Clinical Nutrition 04/2014; 99(6). · 6.50 Impact Factor
  • Shauna S Runchey, Edward J Boyko, George N Ioannou, Kristina M Utzschneider
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD), circulating insulin-like growth factor-1 (IGF-1), and IGF-1/IGF-binding protein-3 (IGFBP-3) concentrations are associated with adiposity and insulin resistance. We aimed to determine whether serum IGF-1, IGFBP-3, and IGF-1/IGFBP-3 are associated with presence or severity of NAFLD independent of potential confounding. We performed a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey, 1988–1994, a representative sample of the United States adult population. Among participants who had a fasting blood draw and ultrasound examination, we excluded those with missing data, viral hepatitis, iron overload, excessive alcohol intake, pregnancy, or taking glucose-lowering therapy, yielding 4172 adults for this analysis. In logistic regression analyses adjusted for age, gender, and race/ethnicity, higher IGF-1 and IGF-1/IGFBP-3 quartiles were associated with lower likelihood of NAFLD and lower grade steatosis. These associations became non-significant when further adjusted for adiposity (body mass index, waist circumference) with the exception of the association between IGF-1/IGFBP-3 and severity of NAFLD which remained significant after adjustment for homeostasis model assessment for insulin resistance (HOMA-IR) (odds ratio [95% CI]: Q3: 0.71 [0.53–0.96], Q4: 0.62 [0.43–0.89]) and adiposity (Q4: 0.67 [0.47–0.96]). Full adjustment (age, gender, race/ethnicity, adiposity, HOMA-IR, A1C%) further attenuated associations between IGF-1 or IGF-1/IGFBP-3 and liver fat such that they were no longer significant. Adiposity explains much of the observed association between IGF-1 or IGF-1/IGFBP-3 and liver fat. These findings do not support a direct role for the growth hormone-IGF-1/IGFBP-3 axis in the pathophysiology of NAFLD.
    Journal of Gastroenterology and Hepatology 03/2014; 29(3):589-96. · 3.33 Impact Factor
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    ABSTRACT: PURPOSE: Confirmatory factor analysis (CFA) was used to test the hypothesis whether adipocytokines are associated with the risk factor cluster that characterizes the metabolic syndrome (MetS). METHODS: Data from 134 nondiabetic subjects were analyzed using CFA. Insulin sensitivity (SI) was quantified using intravenous glucose tolerance tests, visceral fat area by computed tomography and fasting high-density lipoprotein, triglycerides, monocyte chemoattractant protein-1 (MCP-1), serum amyloid A (SAA), tumor necrosis factor (TNF)-α, adiponectin, resistin, leptin, interleukin (IL)-6, C-reactive protein (CRP), and plasminogen activator inhibitor (PAI)-1 were measured. RESULTS: The basic model representing the MetS included six indicators comprising obesity, SI, lipids, and hypertension, and demonstrated excellent goodness of fit. Using multivariate analysis, MCP-1, SAA, and TNF-α were not independently associated with any of the MetS variables. Adiponectin, resistin, leptin, CRP, and IL-6 were associated with at least one of the risk factors, but when added to the basic model decreased all goodness-of-fit parameters. PAI-1 was associated with all cardiometabolic factors and improved goodness-of-fit compared with the basic model. CONCLUSIONS: Addition of PAI-1 increased the CFA model goodness of fit compared with the basic model, suggesting that this protein may represent an added feature of the MetS.
    Annals of epidemiology 03/2013; · 2.95 Impact Factor
  • Mark M Smits, George N Ioannou, Edward J Boyko, Kristina M Utzschneider
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    ABSTRACT: BACKGROUND AND AIM: The metabolic syndrome (MetS) and each of its components are strongly associated with non-alcoholic fatty liver disease (NAFLD) This has led many investigators to suggest that NAFLD is an independent component of the metabolic syndrome (MetS). We formally tested this hypothesis using Confirmatory Factor Analysis (CFA), which allows comparison of different models, with or without including NAFLD as a component of the MetS. METHODS: We analyzed data from 3846 subjects of NHANES III (1988-1994). NAFLD was defined by increased liver fat measured by ultrasonography. RESULTS: MetS by ATP-III criteria was present in 20.5% and 30.2% had NAFLD, defined as mild, moderate or severe ultrasonographic steatosis. Using CFA, a basic model representing the MetS using its currently accepted components (glucose, waist, TG/HDL ratio and mean arterial pressure) showed excellent goodness-of-fit statistics. Addition of NAFLD to the model as a fifth independent variable decreased model fit, suggesting that NAFLD is not an additional independent component of the MetS. Analysis by ethnicity showed that addition of NAFLD decreased model fit in Caucasians, but resulted in minor improvements in Non-Hispanic Blacks and Mexican-Americans. CONCLUSIONS: The MetS is strongly associated with NAFLD. However, we found no evidence that NAFLD is an independent component or manifestation of the Mets. Interestingly, ethnic differences might be important in this relationship and require further study.
    Journal of Gastroenterology and Hepatology 01/2013; · 3.33 Impact Factor
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    ABSTRACT: Aims We sought to determine whether NAFLD is associated with poorer β-cell function and if any β-cell dysfunction is associated with abnormal markers of iron or inflammation. Methods This was a cross-sectional study of 15 non-diabetic adults with NAFLD and 15 non-diabetic age and BMI-matched controls. Insulin sensitivity was measured by isotope-labeled hyperinsulinemic-euglycemic clamps and β-cell function by both oral (OGTT) and intravenous glucose tolerance tests. Liver and abdominal fat composition was evaluated by CT scan. Fasting serum levels of ferritin, transferrin-iron saturation, IL-6, TNFα and hsCRP were measured. Results Compared to controls, subjects with NAFLD had lower hepatic and systemic insulin sensitivity and β-cell function was decreased as measured by the oral disposition index. Fasting serum ferritin and transferrin-iron saturation were higher in NAFLD and were positively associated with liver fat. Serum ferritin was negatively associated with β-cell function measured by both oral and intravenous tests, but was not associated with insulin sensitivity. IL-6, TNFα and hsCRP did not differ between groups and did not correlate with serum ferritin, liver fat or measures of β-cell function. Conclusions These findings support a potential pathophysiological link between iron metabolism, liver fat and diabetes risk.
    Journal of diabetes and its complications 01/2013; · 2.11 Impact Factor
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    ABSTRACT: OBJECTIVE: To determine the prevalence of a negative insulinogenic index (change in plasma insulin/change in plasma glucose from 0 to 30min) from an oral glucose tolerance test according to glucose tolerance category. MATERIALS AND METHODS: Data from the San Antonio Heart Study (n=2494), Japanese American Community Diabetes Study (JACDS; n=594) and Genetics of NIDDM Study (n=1519) were examined. Glucose tolerance was defined by ADA criteria. RESULTS: In the combined cohort, the prevalence of a negative insulinogenic index was significantly higher in diabetes 20/616 (3.2%) compared to normal glucose tolerance 43/2667 (1.6%) (p<0.05). Longitudinally, in the JACDS cohort, the prevalence did not change from baseline (3/594; 0.5%) to 5 (4/505; 0.7%) and 10years (8/426; 1.9%) (p=0.9) and no subject had a repeat negative insulinogenic index. CONCLUSIONS: A negative insulinogenic index occurs at a low prevalence across glucose tolerance categories although more often in diabetes, but without recurrence over time.
    Journal of diabetes and its complications 11/2012; · 2.11 Impact Factor
  • S E Kahn, S Suvag, L A Wright, K M Utzschneider
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    ABSTRACT: An interaction between genes and the environment is a critical component underlying the pathogenesis of the hyperglycaemia of type 2 diabetes. The development of more sophisticated techniques for studying gene variants and for analysing genetic data has led to the discovery of some 40 genes associated with type 2 diabetes. Most of these genes are related to changes in β-cell function, with a few associated with decreased insulin sensitivity and obesity. Interestingly, using quantitative traits based on continuous measures rather than dichotomous ones, it has become evident that not all genes associated with changes in fasting or post-prandial glucose are also associated with a diagnosis of type 2 diabetes. Identification of these gene variants has provided novel insights into the physiology and pathophysiology of the β-cell, including the identification of molecules involved in β-cell function that were not previously recognized as playing a role in this critical cell.
    Diabetes Obesity and Metabolism 10/2012; 14 Suppl 3:46-56. · 5.18 Impact Factor
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    ABSTRACT: Patients with chronic kidney disease are often insulin resistant and glucose intolerant-abnormalities that promote cardiovascular disease. Administration of 1,25-dihydroxyvitamin D (calcitriol) has improved glucose metabolism in patients with end-stage renal disease. We conducted a randomized, placebo-controlled clinical trial to test whether paricalcitol, a 1,25-dihydroxyvitamin D analog, changes glucose tolerance in earlier stages of chronic kidney disease. In a crossover design, 22 nondiabetic patients with estimated glomerular filtration rates of stage 3-4 chronic kidney disease and fasting plasma glucose of 100-125 mg/dl were given daily oral paricalcitol for 8 weeks and matching placebo for 8 weeks, separated by an 8-week washout period. The order of interventions was random and blinded to both participants and investigators. Paricalcitol significantly reduced serum concentrations of parathyroid hormone, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D while significantly increasing serum concentrations of fibroblast growth factor-23 and 24,25-dihydroxyvitamin D. Paricalcitol, however, had no significant effect on glucose tolerance (the primary outcome measure), insulin sensitivity, beta-cell insulin response, plasma free fatty acid suppression, or urinary F2-isoprostane excretion. Thus, despite substantial effects on vitamin D metabolism, paricalcitol did not improve glucose metabolism in nondiabetic patients with stage 3-4 chronic kidney disease.Kidney International advance online publication, 22 August 2012; doi:10.1038/ki.2012.311.
    Kidney International 08/2012; · 8.52 Impact Factor
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    ABSTRACT: Non-alcoholic fatty liver disease is associated with insulin resistance and dyslipidaemia and can progress to steatohepatitis and cirrhosis. We sought to determine whether dietary fat and saturated fat content alter liver fat in the absence of weight change in an older population. Liver fat was quantified by magnetic resonance spectroscopy before and after 4 weeks on an isoenergetic low-fat/low-saturated fat/low-glycaemic index (LGI) (LSAT: 23 % fat/7 % saturated fat/GI < 55) or a high-fat/high-saturated fat/high-GI (HSAT: 43 % fat/24 % saturated fat/GI>70) diet in older subjects. In the present study, twenty subjects (seven males/thirteen females; age 69·3 (sem 1·6) years, BMI 26·9 (sem 0·8) kg/m2) were randomised to the LSAT diet and fifteen subjects (six males/nine females; age 68·6 (sem 1·8) years, BMI 28·1 (sem 0·9) kg/m2) to the HSAT diet. Weight remained stable. Liver fat decreased significantly on the LSAT diet (median 2·2 (interquartile range (IQR) 3·1) to 1·7 (IQR 1·8) %, P = 0·002) but did not change on the HSAT diet (median 1·2 (IQR 4·1) to 1·6 (IQR 3·9) %). The LSAT diet lowered fasting glucose and total cholesterol, HDL-cholesterol and LDL-cholesterol and raised TAG (P < 0·05), while the HSAT diet had no effect on glucose or HDL-cholesterol but increased total cholesterol and LDL-cholesterol (P < 0·05). Fasting insulin and homeostasis model of insulin resistance did not change significantly on either diet, but the Matsuda index of insulin sensitivity improved on the LSAT diet (P < 0·05). Assignment to the LSAT v. HSAT diet was a predictor of changes in lipid parameters but not liver fat. We conclude that diet composition may be an important factor in the accumulation of liver fat, with a low-fat/low-saturated fat/LGI diet being beneficial.
    The British journal of nutrition 07/2012; · 3.45 Impact Factor
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    ABSTRACT: To determine the mechanism by which the bile acid sequestrant colesevelam improves glycemic control. We performed a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis and a meal tolerance test (MTT) in 20 subjects with impaired fasting glucose (11 men, 9 women; mean age 60.7 ± 1.9 years, BMI 29.4 ± 0.9 kg/m(2)) in a single-blind study after 2 weeks of placebo treatment and 8 weeks of colesevelam 3.75 g daily. From these tests, insulin sensitivity, β-cell function, and glucose tolerance were determined, along with gastrointestinal peptide levels during the MTT. Fasting plasma glucose and HbA(1c) decreased with colesevelam (from 5.9 ± 0.1 to 5.7 ± 0.1 mmol/L, P < 0.05, and from 5.86 ± 0.06 to 5.76 ± 0.06%, P = 0.01, respectively), but fasting insulin did not change. Colesevelam had no effect on any FSIGT measures. In contrast, the MTT incremental area under the curve (iAUC) for both glucose (from 249.3 ± 28.5 to 198.8 ± 23.6 mmol/L · min, P < 0.01) and insulin (from 20,130 [13,542-35,292] to 13,086 [9,804-21,138] pmol/L · min, P < 0.05) decreased with colesevelam. However, the ratio of iAUC insulin to iAUC glucose was not changed. iAUC for cholecystokinin (CCK) increased (from 43.2 [0-130.1] to 127.1 [47.2-295.2] pmol/L · min, P < 0.01), while iAUC for fibroblast growth factor 19 decreased (from 11,185 [1,346-17,661] to 2,093 [673-6,707] pg/mL · min, P < 0.01) with colesevelam. However, iAUC for glucagon, glucose-dependent insulinotropic peptide, and glucagon-like peptide 1 did not change. Colesevelam improves oral but not intravenous glucose tolerance without changing insulin sensitivity, β-cell function, or incretins. This effect may be at least partially explained by the colesevelam-induced increase in CCK.
    Diabetes care 03/2012; 35(5):1119-25. · 7.74 Impact Factor
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    ABSTRACT: The aim of the study was to examine the association of type 2 diabetes mellitus with arm length as a marker for early life environment and development. This was a cross-sectional analysis of 658 second- and third-generation Japanese-Americans (349 men and 309 women). Different arm length (total, upper and forearm length) and leg length (total and lower leg length) measurements were performed. Type 2 diabetes was defined by the use of hypoglycaemic medication, fasting plasma glucose (FPG) ≥ 7 mmol/l or glucose at 2 h ≥ 11.1 mmol/l during an OGTT. Persons meeting the criteria for impaired glucose tolerance were excluded from these analyses (FPG <7 mmol/l and 2 h glucose during an OGGT <11.1 but ≥ 7.8 mmol/l). Multivariable logistic regression was used to estimate associations between prevalence of diabetes and limb length while adjusting for possible confounders. A total of 145 individuals had diabetes. On univariate analysis, arm and leg length were not associated with diabetes. After adjustment for age, sex, computed tomography-measured intra-abdominal fat area, height, weight, smoking status and family history of diabetes, total arm length and upper arm length were inversely related to diabetes (OR for a 1 SD increase 0.49, 95% CI 0.29, 0.84 for total arm length, and OR 0.56, 95% CI 0.36, 0.87 for upper arm length). Forearm length, height and leg length were not associated with diabetes after adjustment for confounding variables. Our findings of associations between arm lengths and prevalence of type 2 diabetes supports a role for factors that determine bone growth or their correlates in the development of this condition.
    Diabetologia 02/2012; 55(6):1679-84. · 6.88 Impact Factor
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    Hien Pham, Kristina M Utzschneider, Ian H de Boer
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    ABSTRACT: Insulin resistance is a known complication of end-stage renal disease that also appears to be present in earlier stages of chronic kidney disease (CKD). It is a risk factor for cardiovascular disease and an important potential therapeutic target in this population. Measurement of insulin resistance is reviewed in the context of known pathophysiologic abnormalities in CKD. Insulin resistance in CKD is due to a high prevalence of known risk factors (e.g. obesity) and to unique metabolic abnormalities. The site of insulin resistance in CKD is localized to skeletal muscle. Estimates based on fasting insulin concentration may not adequately capture insulin resistance in CKD because they largely reflect hepatic defects and because CKD impairs insulin catabolism. A variety of dynamic tests are available to directly measure insulin-mediated glucose uptake. Insulin resistance may be an important therapeutic target in CKD. Complementary methods are available to assess insulin resistance, and each method has unique advantages, disadvantages, and levels of complexity. These characteristics, and the likelihood that CKD alters the performance of some insulin resistance measurements, must be considered when designing and interpreting clinical studies.
    Current opinion in nephrology and hypertension 08/2011; 20(6):640-6. · 3.96 Impact Factor
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    Steven E Kahn, Kristina M Utzschneider
    Diabetes care 07/2011; 34(7):1678-80. · 7.74 Impact Factor
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    ABSTRACT: We evaluated the association of 1-h oral glucose challenge test (OGCT) and 3-h oral glucose tolerance test (OGTT) results with preeclampsia. A retrospective cohort study was performed among 26,105 women. Preeclampsia was associated with the upper OGCT quartiles [114-132 mg/dL: odds ratio (OR) = 1.25, 95% confidence interval (CI) 1.09-1.44; >132 mg/dL: OR = 1.40, 95% CI 1.21-1.61] compared with <98 mg/dL adjusting for age, primigravidity, and gestational diabetes, and also to one abnormal OGTT value (adjusted OR 1.38, 95% CI 1.09-1.75) or gestational diabetes (adjusted OR 1.45, 95% CI 1.15-1.83). Higher glucose levels are associated with preeclampsia suggesting a pathophysiological role for glucose metabolism.
    Hypertension in Pregnancy 12/2010; 30(2):153-63. · 0.93 Impact Factor
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    ABSTRACT: The objective of the study was to characterize ethnic differences in lipid levels and low-density lipoprotein (LDL) particle size and subclasses in black and white South African women and to explore the associations with insulin sensitivity (S(I)), body composition, and lifestyle factors. Fasting serum lipids and LDL size and subclasses, body composition (dual-energy x-ray absorptiometry), and S(I) (frequently sampled intravenous glucose tolerance test) were measured in normal-weight (body mass index <25 kg/m(2)) black (n = 15) and white (n = 15), and obese (body mass index >30 kg/m(2)) black (n = 13) and white (n = 13) women. Normal-weight and obese black women had lower triglycerides (0.59 +/- 0.09 and 0.77 +/- 0.10 vs 0.89 +/- 0.09 and 0.93 +/- 0.10 mmol/L, P < .05) and high-density lipoprotein cholesterol (1.2 +/- 0.1 and 1.1 +/- 0.1 vs 1.7 +/- 0.1 and 1.6 +/- 0.3 mmol/L, P < .01) than white women. The LDL particle size was not different, but obese black women had more LDL subclass IV (17.3% +/- 1.0% vs 12.5% +/- 1.0%, P < .01). In white women, triglycerides and LDL particle size correlated with S(I) (P < .01), whereas cholesterol levels correlated with body fat (P < .05). Low socioeconomic status, low dietary protein intake, and injectable contraceptive use were the major determinants of unfavorable lipid profiles in black women. Black women had lower triglyceride and high-density lipoprotein cholesterol levels and more small dense LDL particles than white women. The major determinants of serum lipids in black women were socioeconomic status and lifestyle factors, whereas in white women, S(I) and body composition most closely correlated with serum lipids.
    Metabolism: clinical and experimental 09/2010; 59(9):1341-50. · 3.61 Impact Factor
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    ABSTRACT: Although obesity is associated with insulin resistance and the metabolic syndrome (MetS), some obese individuals are metabolically healthy. Conversely, some lean individuals are insulin resistant (IR) and at increased cardiometabolic risk. To determine the relative importance of insulin sensitivity, BMI and waist circumference (WC) in predicting MetS, we studied these two extreme groups in a high-risk population. One thousand seven hundred and sixty six subjects with a first-degree relative with type 2 diabetes were stratified by BMI and homeostasis model assessment of insulin resistance (HOMA(IR)) into groups. IR groups had higher triglycerides, fasting glucose, and more diabetes than their BMI-group insulin sensitive (IS) counterparts. Within both IS and IR groups, obesity was associated with higher HOMA(IR) and diastolic blood pressure (BP), but no difference in other metabolic variables. MetS (Adult Treatment Panel III (ATPIII)) prevalence was higher in IR groups (P < 0.001) and more subjects met each MetS criterion (P < 0.001). Within each BMI category, HOMA(IR) independently predicted MetS (P < 0.001) whereas WC did not. Within IS and IR groups, age and WC, but not BMI, were independent determinants of MetS (P < 0.001). WC was a less meaningful predictor of MetS at higher values of HOMA(IR). HOMA(IR) was a better predictor of MetS than WC or BMI (receiver operating characteristic (ROC) area under the curve 0.76 vs. 0.65 vs. 0.59, P < 0.001). In conclusion, insulin sensitivity rather than obesity is the major predictor of MetS and is better than WC at identifying obese individuals with a healthier metabolic profile. Further, as many lean individuals with a first-degree relative with type 2 diabetes are IR and metabolically unhealthy, they may all benefit from metabolic testing.
    Obesity 04/2010; 18(9):1781-7. · 4.39 Impact Factor
  • Kristina M Utzschneider, Kris V Kowdley
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    ABSTRACT: Hereditary hemochromatosis (HH) is a genetic condition that can lead to unregulated absorption of iron from the gut with resultant iron overload. The most common form of HH is caused by mutations in the HFE gene, with most cases of HH presenting in patients who are homozygous for the Cys282Tyr mutation. The prevalence of HFE gene mutations in persons of Northern European ancestry is fairly high (0.3-0.7% homozygous and 9-14% heterozygous for the Cys282Tyr mutation), but the penetrance of the disease is considered fairly low and is quite variable. While routine screening of the general population is not recommended, a targeted approach to screening in symptomatic patients and in those with a family member with iron overload is warranted. Untreated, iron overload can lead to considerable morbidity including liver cirrhosis, arthritis and diabetes mellitus, and increased mortality. The pathophysiology of diabetes mellitus in HH is thought to be due primarily to defects in the early insulin response to glucose. An Hfe(-/-) mouse model of HH has demonstrated defects in beta-cell function and beta-cell apoptosis that may be mediated by increased oxidative stress. Fortunately, these defects seem to be reversible if phlebotomy treatment is initiated before the development of cirrhosis or diabetes mellitus in patients. Further research into the long-term effects of treatment on prevention of diabetes mellitus in HH is needed.
    Nature Reviews Endocrinology 01/2010; 6(1):26-33. · 11.03 Impact Factor
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    ABSTRACT: Although obesity has been, in general, associated with glomerular hyperfiltration, visceral adiposity has been suggested to be associated with reduced glomerular filtration. The aim of the study was to evaluate the differential effects of obesity and body fat distribution on glomerular filtration. We conducted a cross-sectional study of the Japanese-American community in Seattle, Washington. We studied a representative sample of second-generation Japanese-American men and women with normal glucose tolerance (n = 124) and impaired glucose metabolism (impaired fasting glucose and/or impaired glucose tolerance) (n = 144) residing in King County, Washington. Glomerular filtration rate was estimated by 24-h urinary creatinine clearance, body size by body mass index (BMI), and intra-abdominal fat (IAF), sc fat (SCF), and lean thigh areas by CT scan. Creatinine clearance was positively correlated with BMI (r = 0.429; P < 0.001), fasting glucose (r = 0.198; P = 0.001), and insulin levels (r = 0.125; P = 0.042), as well as IAF (r = 0.239; P < 0.001), SCF (r = 0.281; P < 0.001), and lean thigh (r = 0.353; P < 0.001) areas. The association between creatinine clearance and BMI remained significant after adjustments for IAF, SCF areas, and fasting insulin levels (r = 0.337; P < 0.001); whereas IAF and SCF areas were not independently associated with creatinine clearance after adjusting for BMI. Creatinine clearance increased with increasing BMI after adjusting for fasting insulin, fasting glucose, IAF and SCF areas in subjects with normal glucose tolerance (r = 0.432; P < 0.001) and impaired glucose metabolism (r = 0.471; P < 0.001). BMI rather than body fat distribution is an independent determinant of creatinine clearance in nondiabetic subjects. Lean body mass, rather than adiposity, may explain this association.
    The Journal of Clinical Endocrinology and Metabolism 08/2009; 94(10):3781-8. · 6.31 Impact Factor
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    ABSTRACT: Determine whether preeclampsia is associated with developing diabetes. Subsequent diabetes was ascertained using ICD-9 codes, pharmacy and glucose data in a retrospective cohort study of 2,032 women with preeclampsia and 29,431 without preeclampsia. During a median follow-up of 8.2 years, 342 women developed diabetes. Preeclampsia was associated with a higher risk of diabetes adjusting for age, primigravidity, and gestational diabetes (hazard ratio, HR 1.82, 95%CI 1.26, 2.62) and in women without gestational diabetes (n = 30,109; HR 1.86, 95%CI 1.22, 2.84). Women with preeclampsia have greater risk of developing diabetes, even in the absence of gestational diabetes.
    Hypertension in Pregnancy 08/2009; 28(4):435-47. · 0.93 Impact Factor

Publication Stats

4k Citations
401.96 Total Impact Points


  • 2007–2013
    • VA Puget Sound Health Care System
      Washington, Washington, D.C., United States
  • 2003–2012
    • University of Washington Seattle
      • • Division of Metabolism, Endocrinology and Nutrition
      • • Department of Medicine
      • • Department of Obstetrics and Gynecology
      Seattle, Washington, United States