Central Role of Fatty Liver in the Pathogenesis of Insulin Resistance in Obese Adolescents

OBJECTIVE

We evaluated the role of fatty liver in the alteration of insulin sensitivity and β-cell function in two groups of obese adolescents, differing in hepatic fat content (hepatic fat fraction [HFF]) but with similar intrabdominal intramyocellular lipid content (IMCL) and overall degree of obesity.

RESEARCH DESIGN AND METHODS

We studied 23 obese adolescents with high HFF (HFF >5.5%) and 20 obese adolescents with low HFF (HFF <5.5%), matched for age, Tanner stage, BMI z score, and percentages of body fat, visceral fat, and IMCL. All subjects underwent an oral glucose tolerance test and a two-step hyperinsulinemic-euglycemic clamp, magnetic resonance imaging and ¹H nuclear magnetic resonance to assess abdominal fat distribution, HFF, and IMCL, respectively.

RESULTS

The high HFF group showed significantly lower whole-body insulin sensitivity index (P = 0.001) and estimates of insulin secretion (P = 0.03). The baseline hepatic glucose production (EGP) rate was not different between the two groups. Suppression of EGP was significantly lower (P = 0.04) in the high HFF group during low-dose insulin; no differences were observed during the second step. Baseline fatty acids, glycerol concentrations, and clamp suppression of glycerol turnover did not differ between the groups. During the second step, the glucose disposal rate was significantly lower (P = 0.01) in the high HFF group.

CONCLUSIONS

Fatty liver, independent of visceral fat and IMCL, plays a central role in the insulin-resistant state in obese adolescents.Fat accumulation in the liver is becoming a common complication in pediatric obesity and is strongly associated with alterations in glucose and lipid metabolism, possibly because of the presence of insulin resistance (1). The mechanisms responsible for the interrelationships between fatty liver disease and insulin resistance are not clearly understood; in fact, it remains unclear whether hepatic steatosis is a consequence or a cause of derangements in insulin sensitivity. As recently shown by our group, the severity of fatty liver, independent of obesity, is associated with the presence of pre-diabetes (2). Of note is the fact that in those studies, fatty liver accumulation rose in parallel with increasing visceral fat as well as intramyocellular fat (intramyocellular lipid content [IMCL]) (2,3). Therefore, from those earlier studies it was virtually impossible to assess the independent contribution of the liver to the development of insulin resistance, because both visceral fat and intramyocellular fat are also known to modulate insulin sensitivity (4,5).Thus, herein we examined the exclusive role of fatty liver in the alteration of insulin sensitivity and β-cell function in two groups of obese adolescents, differing in the amount of hepatic fat content (hepatic fat fraction [HFF]), but characterized by similar distribution of abdominal and muscle fat and overall degree of obesity. We hypothesized that, independent of visceral fat and IMCL, liver fat content would be a key determinant of global insulin resistance, involving liver, muscle, and adipose tissue.     

Sudden death presenting cardiac tamponade in a case of coronary dissection]

A case is reported of a 56-year-old man with primary coronary dissection presenting as sudden death due to aortic rupture and cardiac tamponade. He was admitted because of loss of consciousness and chest pain. ECG showed complete atrioventricular block and myocardial infarction. Coronary angiography demonstrated coronary dissection and total obstruction of right coronary artery (RCA). Intracoronary injection of urokinase was not effective for recanalization of RCA. He died suddenly two days later. At autopsy, the proximal site of the ascending aorta was dissected locally and had ruptured into a pericardial space. RCA was torn off. The perivascular area around the torn coronary artery communicated with the dissecting space of the ascending aorta. Histologically, no degeneration or infiltration of inflammatory cells was observed in the media of the aorta and the right coronary artery. Histological change was observed only at the media of the torn site of the coronary artery. The thickness of the media was about half of that at the other site of the coronary artery. This is the third case reported in world medical literature of primary coronary dissection presenting as cardiac tamponade.     

Evaluation of the radiosensitizing effects of RK28 intravenous, intraarterial, and intratumoral injections on the rabbit VX2 tumor system

To evaluate the differences in the radiosensitizing effects of itnravenous (i.v.) injection, intraarterial (i.a.) injection, and intratumoral (i.t.) injections of the hypoxic cell radiosensitizer RK28 ([1-[4′-hydroxy-2′-butenoxy)methyl-2-nitroimidazole, 1 2-nitroimidazole with an acyclic sugar analogue substituted at the N-1 position of the imidazole ring) using an animal experimental syste.

Rabbit VX2 tumors, which were implanted in the muscle of left hind legs and grown to 3 cm in diameter, were treated with RK28 (80 mg/kg·b.wt) before 15 Gy of local x-ray irradiation. The auricular vein and the left saphenous artery were used for systemic injection and regional injection, respectively. For i.t. injection, a 21-gauge needle with three lateral holes was positioned in the central area of the tumor. Tumor regression was precisely evaluated by computed tomography (CT), and survival time was also studied. Using high-performance liquid chromatography (HPLC), pharmacokinetic studies for RK28 and its seven major metabolites were performed in tumor and serum at 0, 10, 20, 30, and 60 min after drug injection was completed.

Radiosensitizing effects of RK28 were considered present after i.a. injection (p < 0.05) and i.t. injection (p < 0.05) after analyzing tumor volumes on day 21 after treatment. Increased survival was not observed in any group with RK28 injection compared with survival in the group treated by x-ray irradiation alone. Pharmacokinetic studies showed the average concentration of RK28 in the tumor during x-ray irradiation was 1.3 times higher after i.a. injection and 3.5 times higher after i.t. injection than that after i.v. injection. The time modifying factor₅₀ (TMF₅₀:ratio of time for tumor to decrease by 50%, radiation alone vs. radiation plus drug) was calculated to be 1.5 after i.v. injection, 1.7 after i.a. injection, and 2.3 after i.t. injection. The values of TMF₅₀ correlated to the average concentrations of RK28 in the tumor. As to metabolites of RK28, β-glucoronated compound and cysteine conjugate were highly detected. The concentrations of cysteine conjugate were higher in the tumor than in serum via i.v. injection.

Radiosensitizing effects of RK28 were observed on the rabbit VX-2 tumor system after i.a. or i.t. injection. Pharmacokinetic studies proved that radiosensitizing effects depended on the concentration in the tumor, though the administration routes were different. Combined forms with nonprotein thiols were detected. However, survival benefits were not obtained by RK28. For clinical applications of RK28, i.a. or i.t. injection could facilitate better local of cancer.     

Ontogeny, distribution and amine/peptide colocalization of chromogranin A- and B-immunoreactive cells in the chicken gizzard and antrum

The ontogeny and the distribution of chromogranin A (CgA)- and chromogranin B (CgB)-immunoreactive endocrine cells was studied in the chicken gizzard and gizzard-duodenal junction (also called pylorus or antrum) during embryonic and postnatal life. The same tissue sections were then double-immunostained to identify the CgA- and CgB-immunoreactive cells, with a panel of polyclonal antibodies raised against main gut amine/peptides. In the gizzard, positive cells were observed only in its two diverticula (proximal and distal caeca), where the first CgA- and CgB-immunoreactive cells were found on day 12 of incubation. They always remained moderate in number and co-stored mainly serotonin, gastrin/CCK and neurotensin. A few also co-stored somatostatin, but only during the embryonic period. Others co-stored PYY, but only after hatching. Co-localization with motilin was rare and never occurred with bombesin. In the chicken antrum, the first CgA- and CgB-immunoreactive cells were observed on day 12 of incubation and soon reached very high numbers. Antral positive cells showed almost the same co-localization pattern as the gizzard diverticula. Despite their high chromogranin content, the antral cells had weak argyrophilia, whereas in the gizzard diverticula the two staining patterns corresponded.     

Early experiences of endocardial catheter mapping of the left ventricle in patients with sustained ventricular tachycardia--efficacy, safety and complications

In 23 patients with recurrent sustained ventricular tachycardia (VT) which originated from the left ventricle, endocardial catheter mapping has performed. In an additional 14 patients we also stimulated their left ventricle for non-sustained VT. Multiple sites could be mapped for the recording of local electrical activity, for pacing and for the induction of VT. These procedures could be done without complication. A careful, reasonable, and safe method of endocardial mapping will facilitate clinical electrophysiologic study.     

Studies of anti-cytomegalovirus IgG antibody positive rate and cytomegalovirus mononucleosis in adults

We analyzed anti-Cytomegalovirus (CMV) IgG and IgM antibody (EIA) and anti-Epstein-Barr virus (EBV) viral capsid antigen (VCA) IgG and IgM antibody (FA) in adults during 1994-1999. We examined these IgM sero-positive patient's medical records, and diagnosed CMV mononucleosis and EBV mononucleosis. Anti-CMV antibody positive rates decreased from 87.6% in 1994 to 77.8% in 1999. Especially in twenties, anti-CMV antibody positive rates decreased from 65.2% in 1994 to 53.3% in 1999. On the other hand, anti-EBV VCA antibody positive rates were not changed (91-94%). Number of cases of CMV mononucleosis increased from 2 cases in 1994 to 16 cases in 1999, but EBV mononucleosis was not changed. These results suggested that increasing cases of CMV mononucleosis was influenced by decreasing anti-CMV antibody positive rate.     

Analysis of cases of central nervous system fungal infections reported in Japan between January 1979 and June 1989.

Data from 129 cases of central nervous systemic fungal infections reported in Japan between January 1979 and June 1989 were analyzed. Of 129 cases, 116 were cryptococcal meningitis, 6 candidal meningitis (including meningitis due to Trichosporon cutaneum) and 7 Aspergillus meningoencephalitis. Fifty-six of the patients with cryptococcal meningitis had an underlying systemic disease or condition. The overall survival rate was 72.4%, which was a markedly improved rate compared to earlier reports. Cryptococcal meningitis was treated most often with the combination of intravenous amphotericin B and 5-fluorocytosine and was associated with a survival rate of 81.8%. All 7 patients treated with fluconazole alone survived. Candidal meningitis occurred secondary to a shunt infection; some patients with candidemia did well when adequate therapy was instituted. Aspergillus meningoencephalitis is most often diagnosed at autopsy or in surgical specimens and the prognosis of Aspergillus meningoencephalitis is generally poor.