Maki Yamashita

Metformin restores impaired HDL-mediated cholesterol efflux due to glycation

High-density lipoprotein (HDL) mediates cholesterol efflux, which is the initial and rate-limiting step of reverse cholesterol transport. The present study was undertaken to evaluate the effect, on macrophage cholesterol efflux, of functional modification of HDL by its glycation. We also investigated the effects of the glycation-inhibitors metformin (MF) and aminoguanidine (AG) on glycated HDL-mediated cholesterol efflux. Human plasma HDL (5mg protein/mL) was glycated by incubation with 3-deoxyglucosone (3-DG). Glycation was monitored by measuring carboxymethyl-lysine (CML). HDL-mediated cholesterol efflux was determined using human THP-1-derived macrophages pre-labeled with [(3)H]-cholesterol. To measure expression of potential factors related to the efflux in the macrophages, ATP-binding cassette transporter (ABC) G1 was analyzed by real-time quantitative RT-PCR and Western blot. Glycation of HDL significantly reduced the HDL-mediated cholesterol efflux from THP-1-derived macrophages (87.7+/-4.2% of control, n=9, p<0.0001). In the presence of metformin or aminoguanidine (100mM), glycated HDL-mediated cholesterol efflux was restored to 97.5+/-4.3% and 96.9+/-3.1%, respectively. Exogenous HDL reduced ABCG1 mRNA and protein expression in THP-1-derived macrophages, but glycation deprived HDL of this effect. We conclude that glycated HDL particles are ineffective as acceptors of ABCG1-mediated cholesterol efflux; and this may explain, at least in part, accelerated atherosclerosis in diabetic patients. Metformin serves as a possible candidate to restore impaired cholesterol efflux and reverse cholesterol transport.

Altered pain perception in schizophrenia

In June, 2009, a 51-year-old woman presented with a 4-day history of abdominal swelling and fever, and a 2-week history of loss of appetite. There was no history of abdominal pain or nausea. She was febrile (38·4°C) and her abdomen was swollen but soft without spontaneous pain or tenderness. She had a history of schizophrenia since the age of 40 years which was well controlled with perospirone 12 mg/day and quetiapine 150 mg/day. At the age of 45 years, she was diagnosed with diabetes mellitus and had achieved good glycaemic control (HbA1c 6·5%) with biphasic insulin aspart 30 (6 U/day). There was no sign of obvious peripheral neuropathy. Laboratory test results showed normocytic anaemia (haemoglobin 95 g/L), leucocytosis (13·3×109/L) with neutrophilia (91·5%), high concentration of C-reactive protein (129 mg/L), and normal liver and kidney function. Urinalysis showed negative protein and no leucocytosis. Chest radiography showed normal lungs with no cardiac enlargement. Abdominal CT showed a large volume of partly encapsulated ascites (fi gure). The peritoneum in her pelvic cavity was thickened, and ascites in the right inferior abdominal cavity contained calcifi cation and air (fi gure). The aspirated ascitic fl uid had an unpleasant smell and was suppurated. Culture of the fl uid was positive for pyogenic agents, including Peptostreptococcus spp and Bacillus subtilis. Blood culture was negative. We diagnosed severe bacterial pan-peritonitis. Surprisingly, her general condition was stable and she did not complain of any abdominal pain. Abdominal drainage was done and antibiotics started (imipenem/ cilastatin 1·5 g/day), but her symptoms did not improve. Therefore, laparotomy was done on the seventh day of admission. On laparotomy, a large amount of yellowish, turbid, gel-like material fi lled the abdominal cavity with retention of pus in the pouch of Douglas. The appendix was necrotic and contained faecolith. The bacterial peritonitis was suspected to be caused by perforation associated with acute appendicitis. Postoperative course was uneventful, and the patient recovered. When last seen in October, 2009, the patient was well. Even though our patient had a purulent pan-peritonitis caused by a perforated appendix, she did not present with abdominal pain, tenderness, or guarding. Diminished pain sensitivity or loss of pain sensation in people with schizophrenia has previously been reported in cases of acute myocardial infarction and perforated gastrointestinal tract. Clinically, diminished pain sensitivity in schizophrenia has been linked to key features of the disorder, such as positive symptoms, aff ective fl attening, or attention defi cits. Disturbances in dopamine, serotonin, glutamate, and opioids have been proposed to account for hypoalgesia in schizophrenia. Hypoalgesia in schizophrenia has been reported throughout the acute phase of illnesses and in medicated stable or drug-free patients; neuroleptic drugs have been suggested to have minor analgesic eff ects. Diabetes occurs in people with schizophrenia two to four times more often than in the general population. Compared with people without diabetes, appendicitis in people with diabetes is more likely to result in perforation or other complications. Decreased pain sensation may result in aggravation of the condition and in a delay of diagnosis and treatment. Our case is an important reminder that people with schizophrenia do not always present with typical clinical features of acute abdominal disease pathology.

A case of multiple endocrine neoplasia type II accompanied by thyroid medullary carcinoma and pheochromocytomas expressing corticotropin-releasing factor and urocortins.

A 38-year-old woman with RET gene mutation presented with tumors in her thyroid and bilateral adrenal glands. I-metaiodobenzylguanidine scintigraphy revealed accumulation of the radioisotope in both adrenal glands. Both plasma adrenaline and noradrenaline levels were elevated. The circadian rhythms for plasma adrenocorticotropic hormone (ACTH) and cortisol levels were disturbed. Plasma ACTH and cortisol levels failed to be suppressed by an overnight dexamethasone test, suggesting autonomic secretion of ACTH and cortisol, although the patient had no typical Cushingoid features, hypertension, or impaired glucose tolerance. Pathological examination showed that these tumors were pheochromocytoma and thyroid medullary carcinoma, respectively, both of which highly expressed corticotropin-releasing factor, urocortin1, and urocortin3. Together with the endocrinological and pathological observations, the patient was diagnosed as multiple endocrine neoplasia type II with corticotropin-releasing factor- and urocortin-producing tumors that stimulated ACTH and glucocorticoid secretion.

Effects of combined PPARγ and PPARα agonist therapy on reverse cholesterol transport in the Zucker diabetic fatty rat

Aim:  We investigated the effects of the combined therapy of PPARγ and PPARα agonists on HDL metabolism, especially concerning reverse cholesterol transport (RCT), using Zucker diabetic fatty rats (ZDF/Crl‐Leprfa rats) that are the rodent model for type 2 diabetes with obesity, hyperlipidaemia and insulin resistance.

Reduced cellular cholesterol efflux and low plasma high-density lipoprotein cholesterol in a patient with type B Niemann-Pick disease because of a novel SMPD-1 mutation

BACKGROUND Type A or B Niemann-Pick disease (NPD) is characterized by the accumulation of sphingomyelin in the lysosomes and cell membranes. This accumulation results because of a mutation in the sphingomyelin phosphodiesterase-1 (SMPD-1) gene that causes a deficit in the acid sphingomyelinase (ASM). OBJECTIVE Herein, we report on a new point mutation in the SMPD-1 gene that was discovered in a patient with type B NPD. METHODS AND RESULTS A culture of the patients fibroblasts demonstrated that the observed clinical symptoms and reduced plasma high-density lipoprotein cholesterol (HDL-C) were associated with a reduced efflux of cholesterol. Examination of the skin fibroblasts demonstrated that ASM activity was reduced to approximately 60% of that observed in control cells, and a newly identified point mutation was found in codon 494 [Gly (GGT) → Cys (TGT)] in the SMPD-1 gene. Furthermore, repeated measurements of the plasma HDL-C levels remained low (17.5-20.5 mg/dL), and the Apo A-I- or HDL-mediated cholesterol efflux from the patients fibroblasts was significantly reduced as compared with control fibroblasts. CONCLUSION In summary, we identified a unique point mutation in a patient with type B NPD that was associated with various clinical findings, including a low plasma HDL-C level. This reduced cellular cholesterol efflux may be implicated, at least in part, in low plasma HDL levels.

The Evaluation of Adrenal Function in Two Cases of Hypocortisolism Accompanied by Liver Cirrhosis

Adrenal insufficiency may occur in patients with liver cirrhosis. The assessment of hypothalamus-pituitary-adrenal function is important in such patients, but there is no consensus as to how it should be performed. We herein report the results of our evaluation of the adrenal function in two patients with hypocortisolism accompanied by liver cirrhosis. The patients lacked the typical features of hypocortisolism. One was diagnosed with hypocortisolism accompanied by liver cirrhosis while the other had secondary adrenal insufficiency caused by a hypothalamic disorder. Hypocortisolism accompanied by liver cirrhosis should be evaluated by endocrine tests to determine its pathogenesis. A low-dose adrenocorticotropic hormone test may be appropriate for non-critically ill cirrhotic patients.

Fulminant Type 1 Diabetes in an 81-Year-Old Male with Rhabdomyolysis-Induced Acute Kidney Injury Successfully Withdrawn from Hemodialysis: A Case Report

ABSTRACT Objective: Fulminant type 1 diabetes mellitus (FT1DM), a distinct subtype of type 1 diabetes, is characterized by a rapid onset of severe hyperglycemia and diabetic ketoacidosis (DKA). DKA sometimes induces severe rhabdomyolysis, which causes renal failure, and it requires permanent hemodialysis (HD), especially in elderly patients. Some cases of FT1DM progress to rhabdomyolysis-induced acute kidney injury (AKI). Methods: We report the case of an 81-year-old male with rhabdomyolysis-induced AKI, the oldest patient reported to date, associated with acute FT1DM onset. Results: Although the patient required HD, he was successfully withdrawn from HD within 2 months. Conclusion: Even in such advanced age patients, prompt renal replacement therapy gives the prospect for recovering kidney function and circumvents the need for permanent renal replacement therapy.