Edward W. Szczepaniak

Pancreatic Steatosis and Its Relationship to β-Cell Dysfunction in Humans Racial and ethnic variations

OBJECTIVE To evaluate racial/ethnic differences in pancreatic triglyceride (TG) levels and their relationship to β-cell dysfunction in humans. RESEARCH DESIGN AND METHODS We studied black, Hispanic, and white adults who completed three research visits: screening and an oral glucose tolerance test; frequently sampled intravenous glucose tolerance tests for evaluation of β-cell function and insulin resistance; and proton magnetic resonance spectroscopy for evaluation of pancreatic and hepatic TG levels. RESULTS Pancreatic TG levels were higher in Hispanics and whites than in blacks (P = 0.006). Hepatic TG levels were highest in Hispanics (P = 0.004). Compensatory insulin secretion and disposition index were higher in blacks (P = 0.003 and P = 0.024, respectively). Insulin sensitivity was comparable between Hispanics and blacks and was lower than in whites (P = 0.005). In blacks, compensatory insulin secretion increased steeply with small increments in pancreatic TG levels (R2 = 0.45, slope = 247). In whites, the range of pancreatic TG levels was higher, and the slope was less steep than in blacks (R2 = 0.27, slope = 27). In Hispanics, pancreatic TG levels were similar to those of whites, but compensatory insulin secretion was described by a combination of pancreatic and hepatic TG levels and visceral fat mass ( R2 = 0.32). CONCLUSIONS In a multiethnic sample of adults with mild obesity and without diabetes, we found striking ethnic differences in the levels of pancreatic TGs and in the relationship between pancreatic TGs and β-cell dysfunction. Our data implicate pancreatic TG content measured by proton magnetic resonance spectroscopy as a noninvasive novel biomarker for pancreatic β-cell dysfunction, especially in the Hispanic population.

Measurement of pancreatic volume by abdominal MRI: a validation study.

Objective To develop abdominal magnetic resonance imaging (MRI) protocol to measure pancreatic volume in humans and to validate it in large animals. Materials and Methods We performed abdominal MRI in eight mini-pigs using a clinical 3T MRI system. We used consecutive parallel abdominal slices, covering the entire pancreas to calculate pancreatic volume. Following MRI, animals were sacrificed, the pancreas was removed, and the volume of the pancreas was measured by water displacement. We used the same MRI protocol to measure pancreatic volume in 21 humans. To assess reproducibility of in vivo measurement we repeated MRI pancreas volume evaluation within 24 hours in additional five humans. Results In mini-pigs the measurements of pancreatic volume by MRI and by water displacement were almost identical (R2 = 0.9867; p<0.0001). In humans the average pancreas volume was 72.7+/−4.5 ml, range from 35.0 to 105.5 ml. This result is in strong agreement with results of previous large postmortem and computed tomography (CT) studies. Repeated measurements of pancreatic volume in humans were highly reproducible. Pancreatic volume measured in vivo was negatively correlated with age, body fat mass, pancreatic TG levels, and visceral fat mass. Conclusions These initial results are highly encouraging and our protocol for pancreatic volume estimation in vivo may prove useful in obesity research to follow in vivo changes of pancreatic volume and structure during time course of obesity and type 2 diabetes development.

Myocardial steatosis as a possible mechanistic link between diastolic dysfunction and coronary microvascular dysfunction in women

Women with coronary microvascular dysfunction (CMD) and no obstructive coronary artery disease (CAD) have increased rates of heart failure with preserved ejection fraction (HFpEF). The mechanisms of HFpEF are not well understood. Ectopic fat deposition in the myocardium, termed myocardial steatosis, is frequently associated with diastolic dysfunction in other metabolic diseases. We investigated the prevalence of myocardial steatosis and diastolic dysfunction in women with CMD and subclinical HFpEF. In 13 women, including eight reference controls and five women with CMD and evidence of subclinical HFpEF (left ventricular end-diastolic pressure >12 mmHg), we measured myocardial triglyceride content (TG) and diastolic function, by proton magnetic resonance spectroscopy and magnetic resonance tissue tagging, respectively. When compared with reference controls, women with CMD had higher myocardial TG content (0.83 ± 0.12% vs. 0.43 ± 0.06%; P = 0.025) and lower diastolic circumferential strain rate (168 ± 12 vs. 217 ± 15%/s; P = 0.012), with myocardial TG content correlating inversely with diastolic circumferential strain rate (r = -0.779; P = 0.002). This study provides proof-of-concept that myocardial steatosis may play an important mechanistic role in the development of diastolic dysfunction in women with CMD and no obstructive CAD. Detailed longitudinal studies are warranted to explore specific treatment strategies targeting myocardial steatosis and its effect on diastolic function.

Effects of Age and Aerobic Fitness on Myocardial Lipid Content

Background—Aging and sedentary lifestyles lead to cardiac atrophy, ventricular stiffening, and impaired diastolic function. Both conditions are marked by increased adiposity, which can lead to ectopic fat deposition in nonadipocyte tissues including the myocardium. The effect of excess intramyocardial fat on cardiac function in nonobese individuals is unknown. Methods and Results—Cardiac lipid content was measured by magnetic resonance spectroscopy in 153 healthy nonobese subjects with varying fitness levels quantified by peak oxygen uptake during treadmill exercise. Cardiac function (echo) and left ventricular (LV) filling pressures (right heart catheterization) were measured under varying preloads. LV stiffness was calculated from a curve fit of the diastolic portion of the pressure–volume curve. The strongest clinical predictors of lipid content were body mass index (&bgr;=+0.03; 95% confidence interval, 0.001–0.06) and peak oxygen uptake (&bgr;=−0.02; 95% confidence interval, −0.03 to −0.009; R2=0.14; P<0.001). Subjects in the highest quintile had smaller LV end-diastolic volumes (68±13 versus 58±12 mL/m2; P<0.01) and decreased peak early mitral annular and increased peak late mitral inflow velocities. There were no differences in LV stiffness, but a leftward shift in the pressure–volume curve suggested a less distensible ventricle with increasing myocardial lipid levels. After adjusting for age, fitness, and body mass index, echocardiographic and morphometric differences among groups were attenuated and no longer significant. Conclusions—Body mass index and fitness levels are the strongest predictors of myocardial lipid content in nonobese humans. Cardiac lipid content is associated with decreased ventricular distensibility, and it may provide a causal mechanism linking changes in LV function related to age and fitness.

Insulin access to skeletal muscle is impaired during the early stages of diet-induced obesity

Insulin must move from the blood to the interstitium to initiate signaling, yet access to the interstitium may be impaired in cases of insulin resistance, such as obesity. This study investigated whether consuming a short‐ and long‐term high‐fat diet (HFD) impairs insulin access to skeletal muscle, the major site of insulin‐mediated glucose uptake.

Rapid development of cardiac dysfunction in a canine model of insulin resistance and moderate obesity

Aims/hypothesisThe worldwide incidence of obesity and diabetes continues to rise at an alarming rate. A major cause of the morbidity and mortality associated with obesity and diabetes is heart disease, yet the mechanisms that lead to cardiovascular complications remain unclear.MethodsWe performed cardiac MRI to assess left ventricular morphology and function during the development of moderate obesity and insulin resistance in a well-established canine model (n = 26). To assess the influence of dietary fat composition, we randomised animals to a traditional lard diet (rich in saturated and monounsaturated fat; n = 12), a salmon oil diet (rich in polyunsaturated fat; n = 8) or a control diet (n = 6).ResultsHigh-fat feeding with lard increased body weight and fasting insulin and markedly reduced insulin sensitivity. Lard feeding also significantly reduced left ventricular function, evidenced by a worsening of circumferential strain and impairment in left ventricular torsion. High-fat feeding with salmon oil increased body weight; however, salmon oil feeding did not impair insulin sensitivity or cardiac function.Conclusions/interpretationThese data emphasise the importance of dietary fat composition on both metabolic and cardiac function, and have important implications for the relationship between diet and health.

Increase in visceral fat per se does not induce insulin resistance in the canine model

To determine whether a selective increase of visceral adipose tissue content will result in insulin resistance.

Cardiac steatosis and left ventricular dysfunction in HIV-infected patients treated with highly active antiretroviral therapy.

Heart disease is a major contributor to morbidity and mortality in persons infected with human immunodeficiency virus (HIV), and both HIV and highly active antiretroviral therapy (HAART) may be associated with abnormalities in cardiac function and metabolism [(1)][1]. Ectopic fat deposition in

The metabolic cost of lowering blood pressure with hydrochlorothiazide

BackgroundThe landmark Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) placed a new spotlight on thiazide diuretics as the first-line therapy for hypertension. This is concerning as thiazide-diuretics may contribute to comorbidities associated with the current epidemic of obesity. Previous randomized clinical trials have linked thiazide diuretic treatment to insulin resistance, metabolic syndrome, and increased incidence of type 2 diabetes.MethodsThis proof of concept, longitudinal, randomized, double–blind study evaluated the effects of the angiotensin II receptor blocker Valsartan and the specific thiazide diuretic Hydrochlorothiazide (HCTZ) on hepatic triglyceride level (primary outcome), as well as triglyceride levels within other organs including the heart, skeletal muscle, and pancreas. Additionally, we evaluated whether myocardial function, insulin sensitivity, and insulin secretion were affected by these treatments.ResultsHepatic TG levels increased by 57% post HCTZ treatment: ∆hTG HCTZ = 4.12% and remained unchanged post Valsartan treatment: ∆hTG V = 0.06%. The elevation of hepatic TG levels after HCTZ treatment was additionally accompanied by a reduction in insulin sensitivity: ∆SI HCTZ = -1.14. Treatment with Valsartan resulted in improved insulin sensitivity: ∆SI V = 1.24. Treatment-induced changes in hepatic TG levels and insulin sensitivity were statistically significant between groups (phTG = 0.0098 and pSI = 0.0345 respectively). Disposition index, DI, remained unchanged after HCTZ treatment: ∆DI HCTZ = -141 but it was increased by a factor of 2 after treatment with Valsartan: ∆DI V =1018). However, the change between groups was not statistically significant. Both therapies did not modify abdominal visceral and subcutaneous fat mass as well as myocardial structure and function. Additionally, myocardial, pancreatic, and skeletal muscle triglyceride deposits remained unchanged in both therapeutic arms.ConclusionsOur findings are two-fold and relate to hepatic steatosis and insulin sensitivity. HCTZ treatment worsened hepatic steatosis measured as hepatic triglyceride content and reduced insulin sensitivity. Valsartan treatment did not affect hepatic triglyceride levels and improved insulin sensitivity. The results of this study reinforce the message that in patients at risk for type 2 diabetes it is particularly important to choose an antihypertensive regimen that lowers blood pressure without exacerbating patient’s metabolic profile.

CARDIAC STEATOSIS AND LEFT VENTRICULAR DYSFUNCTION IS ASSOCIATED WITH EXPOSURE TO HUMAN IMMUNODEFICIENCY VIRUS HIGHLY ACTIVE ANTIRETROVIRAL THERAPY: A 3-TESLA CARDIAC MAGNETIC RESONANCE IMAGING STUDY

Highly-active anti-retroviral therapy (HAART) for Human Immunodeficiency Virus (HIV) infection is associated with metabolic abnormalities including dyslipidemia, hyperglycemia, and increased risk of cardiovascular disease. We hypothesized that HIV patients on HAART would have increased intra-