To validate magnetic resonance spectroscopy (MRS) as a tool for non-invasive quantification of pancreatic triglyceride (TG) content and to measure the pancreatic TG content in a diverse human population with a wide range of body mass index (BMI) and glucose control.
To validate the MRS method, we measured TG content in the pancreatic tissue of 12 lean and 12 fatty ZDF rats (ages 5-14 weeks) both by MRS and the gold standard biochemical assay. We used MRS to measure pancreatic TG content in vivo in 79 human volunteers. Additionally, to assess the reproducibility of the method, in 33 volunteers we obtained duplicate MRS measurements 1-2 weeks apart.
MRS quantifies pancreatic TG content with high reproducibility and concordance to the biochemical measurement (Spearman's rank correlation coefficient = 0.91). In humans, median pancreatic TG content was as follows: (1) normal weight and normoglycemic group 0.46 f/w%, (2) overweight or obese but normoglycemic group 3.16 f/w%, (3) impaired fasting glucose or impaired glucose tolerance group (BMI matched with group 2) 5.64 f/w%, and (4) untreated type 2 diabetes group (BMI matched with group 2) 5.54 f/w% (Jonckheere-Terpstra trend test across groups p < 0.001).
Human pancreatic steatosis, as measured by MRS, increases with BMI and with impaired glycemia. MRS is a quantitative and reproducible non-invasive clinical research tool which will enable systematic studies of the relationship between ectopic fat accumulation in the pancreas and development of type 2 diabetes.
"To study the role of steatosis in the clinical setting, we and others have developed non-invasive, in vivo technique that permits the precise and reproducible quantification of intracellular triglyceride in various human organs, including skeletal muscle [12-15], liver [16,17], myocardium [16,18-21], and pancreas . This method offers a technological advantage as it distinguishes the large compartments of triglyceride in adipose tissue cells from the triglyceride droplets that are stored within the cytosol of parenchymal cells. "
[Show abstract][Hide abstract] ABSTRACT: The 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.
This 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.
Hepatic TG levels increased by 57% post HCTZ treatment: DeltahTG HCTZ = 4.12% and remained unchanged post Valsartan treatment: DeltahTG V = 0.06%. The elevation of hepatic TG levels after HCTZ treatment was additionally accompanied by a reduction in insulin sensitivity: DeltaSI HCTZ = -1.14. Treatment with Valsartan resulted in improved insulin sensitivity: DeltaSI 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: DeltaDI HCTZ = -141 but it was increased by a factor of 2 after treatment with Valsartan: DeltaDI 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.
Our 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.
"For example, an association with obesity as manifested by increased BMI and AG was observed. This finding is compatible with those of an autopsy report  and with those of several human fatty pancreas studies involving the use of ultrasonography , EUS [10,11,17], CT , and MRI [12,14,15]. In animal study, Mathur et al. also documented that obese mice have heavier pancreas and more pancreatic fat, especially triglycerides, and concluded that obesity leads to fat infiltration of the pancreas . "
[Show abstract][Hide abstract] ABSTRACT: Background
Fatty liver is associated with insulin resistance, dyslipidemia, and obesity and is therefore considered a phenotype of metabolic syndrome. However, less is known regarding the metabolic abnormalities associated with non-alcoholic fatty pancreatic disease (NAFPD; fatty pancreas). The present study was performed to ascertain whether fatty pancreas is associated with specific metabolic risk factors and with metabolic syndrome as defined by the Adult Treatment Panel III.
Five-hundred-fifty-seven healthy and consecutive subjects without known hypertension or diabetes and who received a health investigation at the National Taiwan University Hospital Health Management Center were enrolled in this retrospective study. Fatty pancreas was diagnosed via trans-abdominal ultrasonographic findings.
Seventy-two (12.9%) subjects diagnosed with fatty pancreas comprised the fatty pancreas group, and remaining subjects comprised the normal pancreas group. The presence of various demographic and metabolic risk factors was recorded for all subjects, and the two groups were examined for statistically significant differences in these factors. As compared to the absence of fatty pancreas, the presence of the disease was associated with older age and with higher values for each of the following: BMI, abdominal girth/height, abdominal girth (both genders), fasting and postprandial blood glucose, HbA1c, total cholesterol, triglycerides, LDL-cholesterol, systolic blood pressure, and platelet count. In contrast to previously reported findings, serum amylase values were lower in the fatty pancreas as compared to the control group.
The presence of fatty pancreas represents a meaningful manifestation of metabolic syndrome together with obesity.
"Intracellular lipid accumulation causing lipotoxicity in humans with the metabolic syndrome or type-2 diabetes mellitus, as assessed with 1H-MRS, has been associated with organ dysfunction, such as non-alcoholic fatty liver disease , cardiac diastolic dysfunction ,  and pancreatic beta cell dysfunction , . Moreover, respiratory motion compensation techniques to assess these lipid pools have been used in 1H-MRS previously, including the heart and pancreas , , . The mean percentage of renal TG content in the present study content is in line with previous, Dixon-based techniques . "
[Show abstract][Hide abstract] ABSTRACT: To assess the feasibility of renal proton magnetic resonance spectroscopy for quantification of triglyceride content and to compare spectral quality and reproducibility without and with respiratory motion compensation in vivo.
The Institutional Review Board of our institution approved the study protocol, and written informed consent was obtained. After technical optimization, a total of 20 healthy volunteers underwent renal proton magnetic resonance spectroscopy of the renal cortex both without and with respiratory motion compensation and volume tracking. After the first session the subjects were repositioned and the protocol was repeated to assess reproducibility. Spectral quality (linewidth of the water signal) and triglyceride content were quantified. Bland-Altman analyses and a test by Pitman were performed.
Linewidth changed from 11.5±0.4 Hz to 10.7±0.4 Hz (all data pooled, p<0.05), without and with respiratory motion compensation respectively. Mean % triglyceride content in the first and second session without respiratory motion compensation were respectively 0.58±0.12% and 0.51±0.14% (P = NS). Mean % triglyceride content in the first and second session with respiratory motion compensation were respectively 0.44±0.10% and 0.43±0.10% (P = NS between sessions and P = NS compared to measurements with respiratory motion compensation). Bland-Altman analyses showed narrower limits of agreement and a significant difference in the correlated variances (correlation of -0.59, P<0.05).
Metabolic imaging of the human kidney using renal proton magnetic resonance spectroscopy is a feasible tool to assess cortical triglyceride content in humans in vivo and the use of respiratory motion compensation significantly improves spectral quality and reproducibility. Therefore, respiratory motion compensation seems a necessity for metabolic imaging of renal triglyceride content in vivo.
PLoS ONE 04/2013; 8(4):e62209. DOI:10.1371/journal.pone.0062209 · 3.23 Impact Factor
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