Antecedent glycemic control reduces severe hypoglycemia-induced neuronal damage in diabetic rats.

Brain damage due to severe hypoglycemia occurs in insulin-treated people with diabetes. This study tests the hypothesis that chronic insulin therapy that normalizes elevated blood glucose in diabetic rats would be neuroprotective against brain damage induced by an acute episode of severe hypoglycemia. Male Sprague-Dawley rats were split into three groups: 1) control, non-diabetic; 2) STZ-diabetic; and 3) insulin-treated STZ-diabetic. After 3 wk of chronic treatment, unrestrained awake rats underwent acute hyperinsulinemic severe hypoglycemic (10-15 mg/dl) clamps for 1 h. Rats were subsequently analyzed for brain damage and cognitive function. Severe hypoglycemia induced 15-fold more neuronal damage in STZ-diabetic rats compared with nondiabetic rats. Chronic insulin treatment of diabetic rats, which nearly normalized glucose levels, markedly reduced neuronal damage induced by severe hypoglycemia. Fortunately, no cognitive defects associated with the hypoglycemia-induced brain damage were observed in any group. In conclusion, antecedent blood glucose control represents a major modifiable therapeutic intervention that can afford diabetic subjects neuroprotection against severe hypoglycemia-induced brain damage.

First Reported Case of Dulaglutide-Induced Acute Pancreatitis With Normal Serum Lipase Level.

Dulaglutide is being extensively used for non-insulin-dependent diabetes mellitus and congestive heart failure and is also being used as an off-label weight loss aid. Due to its wide use, we had to shed some light on this rare finding of normal lipase level in a patient with signs and symptoms suggestive of acute pancreatitis. A high index of clinical suspicion for acute pancreatitis despite normal lipase should warrant a low threshold for radiological imaging to rule it out.

Hyperpolarized 3He MR imaging: physiologic monitoring observations and safety considerations in 100 consecutive subjects.

PURPOSE: To evaluate the safety of hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging. MATERIALS AND METHODS: Local institutional review board approval and informed consent were obtained. Physiologic monitoring data were obtained before, during, and after hyperpolarized (3)He MR imaging in 100 consecutive subjects (57 men, 43 women; mean age, 52 years +/- 14 [standard deviation]). The subjects inhaled 1-3 L of a gas mixture containing 300-500 mL (3)He and 0-2700 mL N(2) and held their breath for up to 15 seconds during MR imaging. Heart rate and rhythm and oxygen saturation of hemoglobin as measured by pulse oximetry (Spo(2)) were monitored continuously throughout each study. The effects of (3)He MR imaging on vital signs and Spo(2) and the relationship between pulmonary function, number of doses, and clinical classification (healthy volunteers, patients with asthma, heavy smokers, patients undergoing lung volume reduction surgery for severe emphysema, and patients with lung cancer) and the lowest observed Spo(2) were assessed. Any subjective symptoms were noted. RESULTS: Except for a small postimaging decrease in mean heart rate (from 78 beats per minute +/- 13 to 73 beats per minute +/- 11, P < .001), there was no effect on vital signs. A mean transient decrease in Spo(2) of 4% +/- 3 was observed during the first minute after gas inhalation (P < .001) in 77 subjects who inhaled a dose of 1 L for 10 seconds or less, reaching a nadir of less than 90% at least once in 20 subjects and of less than 85% in four subjects. There was no correlation between the lowest Spo(2) and pulmonary function parameters other than baseline Spo(2) (r = 0.36, P = .001). The lowest mean Spo(2) varied by 1% between the first and second and second and third doses (P < .001) and was unrelated to clinical classification (P = .40). Minor subjective symptoms were noted by 10 subjects. No serious adverse events occurred. CONCLUSION: Hyperpolarized (3)He MR imaging can be safely performed in healthy subjects, heavy smokers, and those with severe obstructive airflow limitation, although unpredictable transient desaturation suggests that potential subjects should be carefully screened for comorbidities.

In vivo lung morphometry with hyperpolarized 3He diffusion MRI in canines with induced emphysema: disease progression and comparison with computed tomography.

Despite a long history of development, diagnostic tools for in vivo regional assessment of lungs in patients with pulmonary emphysema are not yet readily available. Recently, a new imaging technique, in vivo lung morphometry, was introduced by our group. This technique is based on MRI measurements of diffusion of hyperpolarized (3)He gas in lung air spaces and provides quantitative in vivo tomographic information on lung microstructure at the level of the acinar airways. Compared with standard diffusivity measurements that strongly depend on pulse sequence parameters (mainly diffusion time), our approach evaluates a "hard number," the average acinar airway radius. For healthy dogs, we find here a mean acinar airway radius of approximately 0.3 mm compared with 0.36 mm in healthy humans. The purpose of the present study is the application of this technique for quantification of emphysema progression in dogs with experimentally induced disease. The diffusivity measurements and resulting acinar airway geometrical characteristics were correlated with the local lung density and local lung-specific air volume calculated from quantitative computed tomography data obtained on the same dogs. The results establish an important association between the two modalities. The observed sensitivity of our method to emphysema progression suggests that this technique has potential for the diagnosis of emphysema and tracking of disease progression or improvement via a pharmaceutical intervention.

Absence of fatty liver in familial hypobetalipoproteinemia linked to chromosome 3p21.

Our aim was to ascertain whether fatty liver may be present in the genetic form of familial hypobetalipoproteinemia (FHBL) linked to a susceptibility locus on chromosome 3p21. Three genetic forms of FHBL exist: (a) FHBL caused by truncation-specifying mutations of apolipoprotein B (apoB), (b) FHBL linked to chr3p21, and (c) FHBL not linked either to APOB or to chr3p21. Fatty liver is common in apoB-defective FHBL. Hepatic fat contents were quantified by magnetic resonance spectroscopy in 16 subjects with 3p21-linked FHBL, 32 subjects with apoB-defective FHBL, and 39 sex- and age-matched controls. Mean liver fat of 3p21 subjects was similar to controls and approximately 60% lower than apoB-defective FHBL subjects ( P = .0012). Indices of adiposity (body mass index, waist/hip ratio) and masses of abdominal subcutaneous, retroperitoneal, and intraperitoneal adipose tissue (IPAT) were quantified by MR imaging. Mean measures of adiposity were similar in the 3 groups, suggesting that adiposity per se was not responsible for differences in liver fat. Liver fat content was positively correlated with IPAT. The intercepts of regression lines of IPAT on liver fat content were similar in controls and 3p21, but higher in apoB-defective FHBL subjects. The slopes of the lines were steepest in apoB-defective, intermediate in 3p21, and flattest in controls. Lipoprotein profiles and very low density lipoprotein-apoB100 kinetics of 3p21 and apoB-defective groups also differed. Thus, 2 genetic subtypes of FHBL also differ in several phenotypic features.

3He diffusion MRI of the lung.

RATIONALE AND OBJECTIVES: MR imaging of the restricted diffusion of laser-polarized 3He gas provides unique insights into the changes in lung microstructure in emphysema. RESULTS: We discuss measurements of ventilation (spin density), mean diffusivity, and the anisotropy of diffusion, which yields the mean acinar airway radius. In addition, the use of spatially modulated longitudinal magnetization allows diffusion to be measured over longer distances and times, with sensitivity to collateral ventilation paths. Early results are also presented for spin density and diffusivity maps made with a perfluorinated inert gas, C3F8. METHODS: Techniques for purging and imaging excised lungs are discussed.

Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity.

Fatty liver is frequent in the apolipoprotein B (apoB)-defective genetic form of familial hypobetalipoproteinemia (FHBL), but interindividual variability in liver fat is large. To explain this, we assessed the roles of metabolic factors in 32 affected family members with apoB-defective FHBL and 33 related and unrelated normolipidemic controls matched for age, sex, and indices of adiposity. Two hour, 75 g oral glucose tests, with measurements of plasma glucose and insulin levels, body mass index, and waist-hip ratios were obtained. Abdominal subcutaneous, intraperitoneal (IPAT), and retroperitoneal adipose tissue masses were quantified by MR imaging, and hepatic fat was quantified by MR spectroscopy. Mean +/- SD liver fat percentage values of FHBL and controls were 14.8 +/- 12.0 and 5.2 +/- 5.9, respectively (P = 0.001). Means for these measures of obesity and insulin action were similar in the two groups. Important determinants of liver fat percentage were FHBL-affected status, IPAT, and area under the curve (AUC) insulin in both groups, but the strongest predictors were IPAT in FHBL (partial R(2) = 0.55, P < 0.0002) and AUC insulin in controls (partial R(2) = 0.59, P = 0.0001). Regression of liver fat percentage on IPAT fat was significantly greater for FHBL than for controls (P < 0.001). In summary, because apoB-defective FHBL imparts heightened susceptibility to liver triglyceride accumulation, increasing IPAT and insulin resistance exert greater liver fat-increasing effects in FHBL.

Magnetization tagging decay to measure long-range (3)He diffusion in healthy and emphysematous canine lungs.

Spatial modulation (tagging) of the longitudinal magnetization allows diffusive displacements to be measured over times approximately as long as T(1) and over correspondingly long distances. Magnetization tagging is used here with hyperpolarized (3)He gas in canine lungs with unilateral elastase-induced emphysema. A new scheme for analyzing images subsequent to tagging determines the spatially-resolved fractional modulation and its decay rate, using a sliding window. The diffusivity so determined over seconds and centimeter lengths, D(sec), is smaller in all cases than the diffusivity measured over milliseconds and hundreds of microns, D(msec) (in healthy lungs, this ratio is about 0.1). While D(msec) is sensitive to lung microstructure on the alveolar level, D(sec) reflects airway connectivity and provides new information on lung structure. The results show substantial increases in D(sec) in the lungs of four dogs with clear evidence of emphysema. For these dogs, the fractional increase in long-range diffusivity D(sec) in the emphysematous lungs was greater than that in short-range diffusivity D(msec).

Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis.

Familial hypobetalipoproteinemia (FHBL) subjects may develop fatty liver. Liver fat was assessed in 21 FHBL with six different apolipoprotein B (apoB) truncations (apoB-4 to apoB-89) and 14 controls by magnetic resonance spectroscopy (MRS). Liver fat percentages were 16.7 +/- 11.5 and 3.3 +/- 2.9 (mean +/- SD) (P = 0.001). Liver fat percentage was positively correlated with body mass index, waist circumference, and areas under the insulin curves of 2 h glucose tolerance tests, suggesting that obesity may affect the severity of liver fat accumulation in both groups. Despite 5-fold differences in liver fat percentage, mean values for obesity and insulin indexes were similar. Thus, for similar degrees of obesity, FHBL subjects have more hepatic fat. VLDL-triglyceride (TG)-fatty acids arise from plasma and nonplasma sources (liver and splanchnic tissues). To assess the relative contributions of each, [2H2]palmitate was infused over 12 h in 13 FHBL subjects and 11 controls. Isotopic enrichment of plasma free palmitate and VLDL-TG-palmitate was determined by mass spectrometry. Non-plasma sources contributed 51 +/- 15% in FHBL and 37 +/- 13% in controls (P = 0.02). Correlations of liver fat percentage and percent VLDL-TG-palmitate from liver were r = 0.89 (P = 0.0001) for FHBL subjects and r = 0.69 (P = 0.01) for controls. Thus, apoB truncation-producing mutations result in fatty liver and in altered assembly of VLDL-TG.