Disturbed gastric motility in patients with long-standing diabetes mellitus.

PURPOSE: Gastric dysmotility has been reported in patients with long-standing diabetes mellitus (DM). Some patients with DM are diagnosed as diabetes gastroparesis and have several upper gastrointestinal (GI) symptoms such as appetite loss and abdominal pain. This study aimed to identify the relationship between gastric motility and upper GI symptoms in patients with long-standing DM. METHOD: This study was conducted among 23 patients with DM and 15 healthy controls. All the patients with DM were receiving insulin treatment and had at least one history of incidence of diabetic nephropathy, retinopathy or neuropathy. Gastric motility was evaluated using electrogastrography (EGG) and gastric emptying using the 13C-acetic acid breath test. The most severe upper gastrointestinal symptoms were assessed in all patients. RESULTS: Compared to healthy controls, patients with long-standing DM showed a significantly lower percentage of normogastria at the postprandial state with a lower power ratio in EGG. Gastric emptying was significantly delayed in patients with DM in the overall analysis. Sixteen patients with DM (69.6%) demonstrated abnormalities in either gastric myoelectrical activity or gastric emptying. Among patients with abnormal EGG or delayed gastric emptying, 12 had some GI symptoms, compared with 3 patients with normal gastric motility. No significant correlation was observed between the gastric emptying parameters and HbA1c values. CONCLUSION: Patients with long-standing DM showed gastric dysmotility, including impaired gastric myoelectrical activity and delayed gastric emptying. Gastric dysmotility appears to be closely correlated with upper GI symptoms in patients with long-standing DM.

Maturity-onset diabetes of the young type 5, presenting as diabetic ketoacidosis with alkalemia: A report of a case.

A 34-year-old man visited our Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, because of dry mouth and weight loss. His plasma glucose level was 32.8 mmol/L and serum levels of ketone bodies were increased, but with metabolic alkalemia. He was also suffering from renal tubular hypomagnesemia and hypokalemia. Abdominal computed tomography showed bilateral renal cysts. These findings were suggestive of maturity-onset diabetes of the young type 5. Genetic testing showed heterozygous hepatocyte nuclear factor 1 beta gene deletion. In the present case, it seemed reasonable to view hepatocyte nuclear factor 1 beta gene deletion as the common cause of maturity-onset diabetes of the young type 5-associated diabetic ketoacidosis and tubular malfunction-induced hypokalemic alkalosis. This case exemplifies the importance of hepatocyte nuclear factor 1 beta gene abnormality as a potential cause of diabetic ketoacidosis with alkalemia.

Streptococcal Toxic Shock Syndrome Induced by Group A Streptococcus with the emm28 Genotype That Developed after a Uterine Cancer Test.

A 69-year-old woman without pre-existing disease visited our hospital due to general malaise, diarrhea, and arthralgia 3 days after a uterine cancer test. We diagnosed her with sepsis of unknown focus and started treatment immediately, but she died 20 hours after the first visit due to multi-organ failure and septic shock. Later, group A streptococcus was detected from the blood culture, and streptococcal toxic shock syndrome (STSS) was diagnosed. The strain had the emm28 genotype and a mutation in csrR with increased NADase activity. These virulence factors were considered to be related to STSS development in this patient.

Pemafibrate, a selective PPARα modulator, and fenofibrate suppress microglial activation through distinct PPARα and SIRT1-dependent pathways.

Pemafibrate, a selective peroxisome proliferator-activated receptor (PPAR) α modulator, is a new drug that specifically modulates PPARα conformation and co-activator recruitment, thereby lowers plasma triglycerides with less off-target effects. Classical PPARα ligands such as fenofibrate suppress inflammatory cells including microglia. However, effects of pemafibrate on microglia have never been addressed. Here we show that pemafibrate, like other PPARα ligands, potently suppressed NF-κB phosphorylation and cytokine expression in microglial cells. PPARα knockdown significantly amplified LPS-induced cytokine expression. Pemafibrate-induced suppression of IL-6 expression was reversed by PPARα knockdown. However, suppression by fenofibrate was not reversed by PPARα knockdown but by Sirtuin 1 (SIRT1) knockdown. In conclusion, pemafibrate and fenofibrate similarly suppresses microglial activation but through distinct PPARα and SIRT1-dependet pathways.

Effect of Asfotase Alfa on Muscle Weakness in a Japanese Adult Patient of Hypophosphatasia with Low ALP Levels.

A 40-year-old Japanese woman presented to our hospital with general fatigue and muscle weakness. She had a history of premature loss of deciduous teeth at 4 years old, her serum alkaline phosphatase (ALP) activity was as low as 91 U/L, and radiologic studies revealed thoracic deformity and sacroiliac calcification. Genetic sequencing revealed a heterozygous c.1559delT mutation in the tissue non-specific alkaline phosphatase gene (ALPL). Based on these findings, she was diagnosed with hypophosphatasia (HPP), and treatment with asfotase alfa, a recombinant human tissue-nonspecific alkaline phosphatase (TNSALP), was initiated. After six months of treatment with asfotase alfa, improvements were observed in the SF-36 score, six-minute walk distance, and grasping power. Although the overdiagnosis needs to be avoided, HPP should be considered in patients with undiagnosed musculoskeletal symptoms and a low serum ALP activity.

[Effect of Statins on Glycemic Status and Plasma Adiponectin Concentrations in Patients with Type 2 Diabetes Mellitus and Hypercholesterolemia].

It is reported that statins have inconsistent effects on glycemic status and adiponectin concentrations in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the effect of statins on these variables in patients with T2DM and hypercholesterolemia. A control group comprising 24 patients with T2DM but without hypercholesterolemia was observed for more than 12 weeks, while 24 patients with T2DM and hypercholesterolemia were treated with statins for the same period (statin group). The percentage changes in the glycemic status [blood glucose and glycated hemoglobin (HbA1c)], and levels of plasma adiponectin [total and high molecular weight (HMW)] were compared between the two groups. The statin group had reduced percentage changes in HbA1c, blood glucose, and total and HMW-adiponectin concentration percentage changes that were similar to those in the control group. However, when matched for sex, age (±5 years) and HbA1c (±0.5%) with the control group, the pravastatin group had reduced percentage changes in the plasma HMW-adiponectin concentrations than the matched controls (p=0.023). However, there were no differences in the percentage changes in the plasma total adiponectin (p=0.137), HbA1c (p=0.202), or blood glucose concentrations (p=0.450) between the two groups. Pravastatin treatment had no effect on the glycemic status of patients with T2DM and hypercholesterolemia, but may reduce the percentage changes in the plasma HMW-adiponectin concentrations. Hence, patients with T2DM and hypercholesterolemia receiving long-term treatment with pravastatin might experience increased insulin resistance.

A Case of Euthyroid Graves' Ophthalmopathy in a Patient Sero-Negative for TSH Receptor Autoantibody.

We report of a case of Graves' ophthalmopathy presented solely with symptoms of the eyes with normal thyroid function tests and negative immunoreactive TSH receptor autoantibody. 40-year-old male was referred to our hospital due to 2-month history of ocular focusing deficit without any signs or symptoms of hyper- or hypothyroidism. Serum thyroid function tests and 99mTc uptake were both within the normal range. Anti-thyroid autoantibodies were all negative except for the cell-based assay for serum TSH receptor stimulating activity. Since orbital CT scan and MRI gave typical results compatible with Graves' ophthalmopathy, we treated the patients with corticosteroid pulse therapy and orbital radiation therapy, leading to a partial improvement of the symptoms. This case gives insights into the potential pathophysiologic mechanism underlying Graves' ophthalmopathy and casts light upon the difficulties of establishing the diagnosis in a euthyroid case with minimal positive results for anti-thyroid autoantibodies.

An Autopsy Case of Pulmonary Tumor Thrombotic Microangiopathy Due to Rapidly Progressing Colon Cancer in a Patient with Type 2 Diabetes.

We herein describe a case of pulmonary tumor thrombotic microangiopathy (PTTM) with rapidly progressing colon cancer. A 61-year-old man who had been receiving treatment for type 2 diabetes mellitus for 3 years was hospitalized due to critical hypoxemia. Computed tomography, which had not shown any abnormalities 3 months previously, revealed a tumor in the ascending colon, multiple nodules in the liver, and the absence of any lung abnormalities. On day 3 of hospitalization, a sudden onset of severe dyspnea and tachycardia occurred, followed by death. Autopsy revealed microscopic metastatic tumor emboli in multiple pulmonary vessels with fibrin thrombus and intimal proliferation, which led to a diagnosis of PTTM.

Glucagon promotes colon cancer cell growth via regulating AMPK and MAPK pathways.

Cancer is one of the major causes of death in diabetic patients, and an association between antidiabetic drugs and cancer risk has been reported. Such evidence implies a strong connection between diabetes and cancer. Recently, glucagon has been recognized as a pivotal factor implicated in the pathophysiology of diabetes. Glucagon acts through binding to its receptor, glucagon receptor (GCGR), and cross-talk between GCGR-mediated signals and signaling pathways that regulate cancer cell fate has been unveiled. In the current study, expression of GCGR in colon cancer cell lines and colon cancer tissue obtained from patients was demonstrated. Glucagon significantly promoted colon cancer cell growth, and GCGR knockdown with small interfering RNA attenuated the proliferation-promoting effect of glucagon on colon cancer cells. Molecular assays showed that glucagon acted as an activator of cancer cell growth through deactivation of AMPK and activation of MAPK in a GCGR-dependent manner. Moreover, a stable GCGR knockdown mouse colon cancer cell line, CMT93, grew significantly slower than control in a syngeneic mouse model of type 2 diabetes with glycemia and hyperglucagonemia. The present observations provide experimental evidence that hyperglucagonemia in type 2 diabetes promotes colon cancer progression via GCGR-mediated regulation of AMPK and MAPK pathways.

Nocturnal reactive hypoglycaemia well treated subjectively and objectively with voglibose.

Clinicians sometimes encounter difficulty in diagnosing hypoglycaemia. Here, we present a case report of a 53-year-old woman with recurrent nocturnal hypoglycaemia. A continuous glucose monitoring system (CGMS) revealed postprandial hyperglycaemia and subsequent hypoglycaemia, and an oral glucose tolerance test showed an impaired glycaemic and delayed hyperinsulinaemic pattern. On the basis of these clinical findings, we diagnosed her unexplained hypoglycaemia as reactive hypoglycaemia. CGMS showed a sharp contrast of diurnal variation in blood glucose levels including hypoglycaemia between before and after treatment with an alpha-glucosidase inhibitor, voglibose. Her hypoglycaemic attacks disappeared.

Epidermal growth factor receptor transactivation is necessary for glucagon-like peptide-1 to protect PC12 cells from apoptosis.

AIM: Patients with long-standing diabetes commonly develop diabetic encephalopathy, which is characterized by cognitive impairment and dementia. To identify potential treatments for diabetic encephalopathy, we focused on the protective action of glucagon-like peptide-1 (GLP-1) against neural cell apoptosis. In this study, we evaluated whether exposure of cells to GLP-1 leads to epidermal growth factor receptor (EGFR) transactivation and signaling through the PI3K/Akt/mTOR/GCLc/redox pathway, which we previously reported. METHODS: We monitored the phosphorylation of EGFR and Akt in PC12 cells exposed to MG and GLP-1 that had been first incubated in the presence or absence of various inhibitors of EGFR transactivation. RESULTS: DAPI staining revealed that pretreatment of cells with BiPS, HB-EGF and anti-TGF-α neutralization antibodies or AG1478 abrogated the ability of GLP-1 to rescue cells from MG-induced apoptosis. We show that exposure of PC12 cells to GLP-1 induces EGFR phosphorylation and that this effect was inhibited by prior exposure of the cells to BiPS, HB-EGF and anti-TGF-α neutralization antibodies or AG1478. Interestingly, these agents also diminished the capacity of GLP-1 to protect cells from MG-induced apoptosis. Moreover, these agents reduced GLP-1-induced phosphorylation of Akt. EGF itself also protected the cells from MG-induced apoptosis and induced phosphorylation of Akt, which was inhibited by LY294002. CONCLUSION: The neuroprotective effects of GLP-1 against MG-induced apoptosis are mediated by EGFR transactivation, which signals through the PI3K/Akt/mTOR/GCLc/redox pathway in PC12 cells.

A short bout of stair climbing-descending exercise attenuates postprandial hyperglycemia in middle-aged males with impaired glucose tolerance.

Exercise is a useful modality to ameliorate postprandial hyperglycemia. Here we show that a short bout (∼6 min) of stair climbing-descending exercise (STAIR) starting at 90 min after meal accelerates the decrease in blood glucose concentrations in middle-aged sedentary men with impaired glucose tolerance, although STAIR is easy to perform and keeps the exercise intensity at a moderate level.

The effect of omeprazole on gastric myoelectrical activity and emptying.

Omeprazole, a proton pump inhibitor, is widely used for the treatment of patients with peptic ulcer, gastroesophageal reflux disease and functional dyspepsia (FD), although some studies have demonstrated that omeprazole delays gastric emptying. The purpose of this study was to investigate the efficacy of omeprazole on gastric motility including gastric myoelectrical activity and gastric emptying. This study was performed on 12 healthy volunteers. Gastric motility was evaluated with cutaneously recorded electrogastrography (EGG) and gastric emptying of semi-solid meals using the (13)C-acetic acid breath test. EGG and gastric emptying were measured before and after treatment with 20 mg omeprazole orally for 7 days. In the fasting state, the percentage of EGG normogastria increased significantly compared to the baseline. No significant changes were observed in other EGG parameters including the percentage of tachygastria and bradygastria in both fasting and postprandial states, and the power ratios between both before and after ingestion of omeprazole. In addition, administrated omeprazole did not show any significant differences in the gastric emptying parameters such as the half emptying time. We conclude that administration of omeprazole did not affect gastric motility but improved gastric myoelectrical activity. These effects of omeprazole may be one of the mechanisms involved in its efficacy in relieving dyspeptic symptoms in FD patients.

[Hepato-biliary and pancreatic disease and osteodystrophy].

It is well known that insulin resistance affects osteodystrophy, and there is an important relationship between insulin resistance and hepato-biliary disease. It is also well known that hepato-biliary and pancreatic disease is associated with osteodystrophy. In the present review, we describe the mechanism of diabetes and osteodystrophy due to hepato-biliary and pancreatic disease. Hepatic osteodystrophy is associated with malabsorption, abnormalities of vitamin D metabolism, inflammatory cytokines, receptor activator of NF-kappaB ligand, and insulin-like growth factor-1. In particular, tumor necrosis factor-alpha and malabsorption are important factors for viral and alcoholic hepatitis, respectively. Malabsorption due to steatorrhea is important for cholestatic disease and chronic pancreatitis. A greater focus on non-alcoholic steatohepatitis (NASH) and further investigations to clarify the relationship between osteodystrophy and NASH are needed.

Modulation of the activity of two pacemakers by transmural nerve stimulation in circular smooth muscle preparations isolated from the rat proximal colon.

Circular smooth muscle preparations isolated from the rat proximal colon periodically generated two different amplitudes and frequencies of phasic contractions: large phasic contractions (LPC) with a frequency of about 1.5 times/min and small phasic contractions (SPC) with a frequency of about 9 times/min. Preparations with no attached longitudinal smooth muscle layer (and also myenteric layer) generated SPC alone, while those with no attached submucosal layer generated only LPC, indicating that the pacemakers of the LPC and SPC are distributed in the myenteric and submucosal layers, respectively. In intact preparations, transmural nerve stimulation (TNS) applied for 1-2 min with different frequencies (0.2-2 Hz) inhibited the phasic contractions. The amplitude of LPC was reduced at >0.25 Hz and abolished at >0.3 Hz, while the amplitude but not the frequency of SPC was reduced at >0.5 Hz (in a frequency-dependent way). The TNS-induced inhibitory responses were augmented by atropine and attenuated by N(omega)-nitro-L-arginine (L-NA). In the presence of L-NA and atropine, TNS elicited biphasic (inhibitory and following excitatory) responses. The former were not antagonized by apamin, guanethidine or suramin, while the latter were antagonized by capsaicin, suggesting an innervation by non-adrenergic non-cholinergic non-nitrergic (NANCNN) inhibitory and peptidergic excitatory nerves, respectively. In preparations with the longitudinal muscle layer removed, TNS inhibited only the amplitude of SPC, which was augmented by atropine and antagonized by L-NA. In intact preparations, muscarinic stimulation with acetylcholine increased the frequency of LPC, while nitrergic stimulation with sodium nitroprusside reduced the amplitude and frequency of LPC, and also the amplitude but not the frequency of SPC. These results indicate that the rat proximal colon has two types of pacemaker cells. Myenteric pacemaker cells which receive predominantly nitrergic, but also cholinergic, peptidergic and NANCNN innervation, and submucosal pacemaker cells that are not markedly influenced by intramural nerves.

Alteration of the responses of gastric smooth muscle to endothelin in streptozotocin-induced diabetic rats.

Diabetic gastropathy is suggested to be the result of not only an autonomic neuropathy but also to disorder of the spontaneous rhythmic motility of the gastric smooth muscle. Attempts were made to investigate the alteration of the effects of endothelin-1 (ET-1), which is known to enhance the spontaneous activity of gastrointestinal smooth muscle, on gastric activity in streptozotocin (STZ)-induced diabetic rats. STZ-induced diabetic rats were prepared by the injection of Sprague-Dawley (SD) rats with STZ (i.p.). Isometric mechanical responses were recorded in isolated circular smooth muscle strips of the stomach antrum, to measure changes in the rhythmicity of the smooth muscle. ET-1 (10 nM) significantly elevated the resting tension and the frequency of spontaneous contraction, but did not alter the amplitude of the spontaneous oscillatory contractions in normal rats. In diabetic rats, ET-1 elevated the resting tension, and spontaneous contractions were increased in frequency, however they were decreased in amplitude. In normal rats, sarafotoxin S6c (S6c, 10 nM), a selective ET(B) receptor agonist, elevated the resting tension slightly and increased both the frequency and amplitude of the spontaneous contractions. However, S6c significantly elevated the resting tension alone in STZ-induced diabetic rats. Selective stimulation of endothelin type A (ET(A)) receptors with ET-1, in the presence of a selective antagonist of ET(B) receptors, produced similar responses in the gastric muscle of both normal and diabetic rats. These results indicate that ET-1 elevates the resting tension and increases the frequency of the spontaneous oscillatory contractions in both normal and STZ-induced diabetic rats, to a similar extent. However, the specific actions on ET(B) receptors were quite different between the two: the elevating actions on the resting tension were much greater in STZ-diabetic rats than in normal rats. The results suggested the facilitation of ET(B) receptor signaling in the antrum during the pathogenesis of diabetic gastropathy.

Severe ascites with hypothyroidism and elevated CA125 concentration: a case report.

Ascites caused by hypothyroidism is rare and the pathogenesis is unclear. Several reports have presented cases of progressive ascites with hypothyroidism and elevated tumor markers. We report a 31-year-old female case with massive ascites and elevated serum CA 125 concentrations. The patient had no typical feature of hypothyroidism except an accumulation of ascitic fluid which showed elevated total protein concentration and a high serum-ascites albumin gradient (SAAG). There was no finding of malignancy. Following thyroid hormone replacement, the ascites was completely resolved accompanied by reduced concentrations of serum CA125. In general, primary hypothyroidism with ascites presents with coexisting massive pericardial or pleural effusion. The massive ascites and increased serum CA125 concentrations may have led us to make the incorrect diagnosis of ovarian malignancy. The evaluation of thyroid function is useful to determine the pathology of high-protein ascites or elevated tumor markers, and ascites may be treatable by thyroid replacement therapy.

Effects of histamine 2 receptor antagonists on endothelial-neutrophil adhesion and surface expression of endothelial adhesion molecules induced by high glucose levels.

Neutrophil-endothelial adhesion is a crucial step in vascular inflammation and is recognized as a direct cause of serious atherosclerosis-mediated diseases. We previously demonstrated that high concentrations of glucose increased adhesion in a protein kinase C (PKC)-dependent manner within 48 h of administration by increasing the surface expression of endothelial adhesion molecules. In this study, we focused on the effects of histamine 2 receptor antagonists on endothelial-neutrophil adhesion and on the surface expression of endothelial adhesion molecules mediated by high glucose levels. Histamine 2 receptor antagonists have pleiotropic effects; they not only block the secretion of gastric acid, but also inhibit cell-cell adhesion, resulting in inhibition of metastasis. However, relevant mechanisms of action are not yet fully understood. Of three histamine 2 receptor antagonists (cimetidine, ranitidine, and famotidine), only cimetidine significantly attenuated adhesion mediated by 48-h incubation with 27.8 mM glucose. Cimetidine was found to decrease the surface expression of endothelial adhesion molecules intercellular adhesion molecule-1 and P-selectin, but not E-selectin. To determine the effects of cimetidine on intracellular level, we examined the effects of cimetidine on PKC-induced changes in adhesion, as well as the effects of nitric oxide (NO) synthase inhibitors on cimetidine. We found that NO synthase inhibitors reduced the inhibitory effects of cimetidine, whereas cimetidine did not affect adhesion mediated by a PKC activator. These data suggest that cimetidine acts directly on endothelial cells to inhibit high-glucose-induced expression of adhesion molecules and neutrophil adhesion mediated by increasing endothelial NO production, but not by inhibiting PKC.

Effects of insulin on the acetylcholine-induced hyperpolarization in the guinea pig mesenteric arterioles.

BACKGROUND: Insulin induces endothelium-dependent vasodilatation, which may be casually related to the insulin resistance and hypertension. Endothelium-derived nitric oxide (NO) is the most important mechanism of insulin-induced vasodilatation, and a possible contribution of endothelium-derived hyperpolarizing factor (EDHF) is also considered. Attempts were made to observe the effects of insulin on acetylcholine (ACh)-induced hyperpolarization in the submucosal arteriole of the guinea pig ileum, the objective being to investigate possible involvement of EDHF in the actions of insulin. METHODS: Conventional microelectrode techniques were applied to measure the membrane potential of smooth muscle cells in the submucosal arteriole. EDHF-induced hyperpolarization was elicited by ACh in the presence of both N(omega)-nitro-L-arginine (L-NNA) (100 microM) and diclofenac (1 microM). RESULTS: The resting membrane potential was -70.9 mV, and Ba(2+) (0.5 mM) depolarized the membrane to -33.0 mV. Insulin (10 microU/ml to 100 mU/ml) did not change the membrane potential in the absence or presence of Ba(2+). In the presence of Ba(2+), ACh (3 microM) hyperpolarized the membrane with two components, an initial large hyperpolarization followed by a slow and small one. Low concentration of insulin (100 microU/ml) did not alter the ACh-induced hyperpolarization. High concentration of insulin (100 mU/ml) shortened the time required to reach the peak amplitude and tended to increase the peak amplitude of the ACh-induced hyperpolarization. CONCLUSIONS: The data show that insulin enhances the ACh-induced hyperpolarization in the submucosal arterioles of the guinea pig ileum. The results suggested that EDHF also accounts for one of the endothelial factors involved in the insulin-induced vasodilatation.