Impact of diabetes and Krebs von den Lungen-6 on coronavirus disease 2019 severity: A single-center study from Japan.

AIMS/INTRODUCTION: Diabetes mellitus is reported as a risk factor for increased coronavirus disease 2019 (COVID-19) severity and mortality, but there have been few reports from Japan. Associations between diabetes mellitus and COVID-19 severity and mortality were investigated in a single Japanese hospital. MATERIALS AND METHODS: Patients aged ≥20 years admitted to Osaka City General Hospital for COVID-19 treatment between April 2020 and March 2021 were included in this retrospective, observational study. Multivariable logistic regression analysis was carried out to examine whether diabetes mellitus contributes to COVID-19-related death and severity. RESULTS: Of the 262 patients included, 108 (41.2%) required invasive ventilation, and 34 (13.0%) died in hospital. The diabetes group (n = 92) was significantly older, more obese, had longer hospital stays, more severe illness and higher mortality than the non-diabetes group (n = 170). On multivariable logistic regression analysis, age (odds ratio [OR] 1.054, 95% confidence interval [CI] 1.023-1.086), body mass index (OR 1.111, 95% CI 1.028-1.201), history of diabetes mellitus (OR 2.429, 95% CI 1.152-5.123), neutrophil count (OR 1.222, 95% CI 1.077-1.385), C-reactive protein (OR 1.096, 95% CI 1.030-1.166) and Krebs von den Lungen-6 (OR 1.002, 95% CI 1.000-1.003) were predictors for COVID-19 severity (R2 = 0.468). Meanwhile, age (OR 1.104, 95% CI 1.037-1.175) and Krebs von den Lungen-6 (OR 1.003, 95% CI 1.001-1.005) were predictors for COVID-19-related death (R2 = 0.475). CONCLUSIONS: Diabetes mellitus was a definite risk factor for COVID-19 severity in a single Japanese hospital treating moderately-to-severely ill patients.

A case of hypopituitarism due to inflammatory myofibroblastic tumor of the sella turnica.

An 18-year-old man with 4-year history of central diabetes insipidus and partial pituitary dysfunction was admitted to our hospital because of headache and nasal discharge. Magnetic resonance imaging (MRI) revealed abnormal mass in the sella turnica invading into the cavernous sinus and sinus maxillaries along with thickened tentorium cerebelli. Histopathology of the mass in the sinus maxillaries revealed spindle-shaped cells arranged in a fascicular pattern with varied myxoid and collagenized regions with various inflammatory cells. Immunostaining revealed the spindle-shaped cells were positive for smooth muscle actin. These features were identical to those of inflammatory myofibroblastic tumor (IMT). He was diagnosed with IMT in the sella turnica and other regions. Corticosteroid therapy improved clinical symptoms and follow-up MRI revealed amelioration of the thickened tentorium cerebelli. However, the other lesions were unchanged and pituitary dysfunction did not improve. Although rare, IMT should be considered in the differential diagnosis of a sellar mass. Early treatment with corticosteroid therapy may reduce the risk of disease progression.

A case of IgG4-related multifocal fibrosclerosis complicated by central diabetes insipidus.

A 55-years-old man was admitted to our hospital with a 6-month history of general fatigue, purulent nasal discharge, polyuria, and polydipsia. Endocrinological findings revealed central diabetes insipidus (CDI) with mild anterior pituitary dysfunction. Imaging studies revealed thickening of the proximal end of the pituitary stalk just below the third ventricle, a mass in the paranasal sinus, and a mass encompassing the abdominal aorta. Histopathology of the mass in the paranasal sinus revealed abundant IgG4-positive plasma cells, and the IgG4 serum level was markedly elevated. Thus, he was diagnosed with IgG4-related multifocal fibrosclerosis. Therapy with prednisolone resulted in complete resolution of clinical symptoms and reduction in size of the masses in the affected organs. However, CDI remained unchanged. This is the first case in which the cause of CDI was IgG4-related multifocal fibrosclerosis. IgG4-related sclerosing disease should be included in the differential diagnosis of thickening of the pituitary stalk with CDI, and a search for extra-pituitary involvement is essential.

Effectiveness of sitagliptin in a patient with late dumping syndrome after total gastrectomy.

An 83-year-old man developed hypoglycemia after undergoing total gastrectomy for gastric cancer in 200X-4. The patient was admitted to our hospital in May 200X and placed on continuous glucose monitoring (CGM). Glycemic excursions were examined while on 3-meal/day (1700kcal) and 6-meal/day (1800kcal) diets. Oxyhyperglycemia followed about 2h later by a sudden drop in glucose levels was seen with both regimens. These findings were consistent with late dumping syndrome. CGM was continued, oral miglitol at 150mg/day or sitagliptin at 50mg/day was started, and glycemic excursions were compared. Results were similar for both drugs, with reductions in postprandial glucose elevations. Meal tolerance testing 3 months after oral sitagliptin, compared to before starting treatment, showed reductions in both early postprandial hyperglycemia and insulin hypersecretion. These findings suggest that DPP-4 inhibitors such as sitagliptin may be effective for treating post-gastrectomy late dumping syndrome.

Endometrial thickness in Japanese women with hypertension or/and type 2 diabetes mellitus.

OBJECTIVES: The purpose of this study was: (a) to examine whether the endometrium of postmenopausal women with hypertension (HT) and/or type 2 diabetes mellitus (DM) was thicker than that of healthy controls (HC) and (b) whether endometrial thickness (ET) was associated with endometrial cancer risk factors. STUDY DESIGN: A total of 242 postmenopausal women were included in this study. Thirty women with type 2 DM, 49 women with HT, 23 women with DM and HT and 140 HCs were studied. Clinical evaluation of all women was done using TVS and endometrial cytology. RESULTS: In the 140 HCs, the mean ET of nulliparous women was larger than multiparous women (3.0 mm versus 1.6 mm, p = 0.017). However, there was no significant relationship between ET and other clinical parameters such as a history of sterility or BMI. There was no significant difference in ET amongst the four groups. The relationship between ET, age, pregnancy history, menopause age, BMI and presence of DM or HT were analyzed using stepwise multivariate analysis. There was no significant relationship between these risk factors and ET (p = 0.063). CONCLUSIONS: The risk factors such as age, pregnancy history, menopause age, BMI and presence of DM or HT were not related to ET in Japanese women.

Supplementary management of functional, temporary alcoholic hepatic damage with Robuvit® (French oak wood extract).

BACKGROUND: The aim of this registry study was to evaluate Robuvit® (French oak wood extract) supplementation in the evolution of moderate functional hepatic failure (MTHF) due to alcohol. Recent studies have indicated the protective effect of oak wood (QR) extracts on liver injury. This registry included patients with MTHF characterized by: decreased albumin levels; increased total bilirubin, altered hepatic functions enzymes, increased oxidative stress, negative viral hepatitis markers. METHODS: The two groups resulted divided into a best management (BM) group and a comparative group (BM + Robuvit®): 23 Robuvit® patients and 21 comparable controls completed the 12-week registry. At inclusion, blood parameters in the two groups were comparable. RESULTS: During the observation period, the increase in albumin levels was significantly (P<0.05 at 6 weeks) faster and higher in the Robuvit® group in comparison with controls. The decrease in ALT-SGPT and AST-ASAT were significantly more important in the supplement group (P<0.05 at 6 and 12 weeks). Alkaline phosphatase was significantly lower at 6 and 12 weeks in Robuvit® patients; (Robuvit® group's values were significantly better; P<0.05). Total bilirubin improved more in Robuvit® subjects at 6 weeks. Results were statistically significant in comparison with controls (P<0.05). Also, direct bilirubin values were higher in the Robuvit® group at 6 and 12 weeks (P<0.05). Gamma GT values were normalized at 6 and 12 weeks in the Robuvit® group. There was a less important decrease in controls (P<0.05) without normalization at 12 weeks. Plasma free radicals, high at inclusion, showed a more significant decrease in Robuvit® subjects (at 6 and 12 weeks), with normalization at 12 weeks. Persisting high values in controls were observed even at 12 weeks (P<0.05). Erythrocytes sedimentation rate (ESR) decreased in both groups with a more important decrease in the Robuvit® group (P<0.05). Hepatitis markers were negative when repeated at 6 and 12 weeks. CONCLUSIONS: In conclusion, observations from this pilot, supplement registry study indicate a significant protective activity of the supplementation with Robuvit®, associated with a very good safety profile, in patients with temporary alcoholic hepatic failure. The activity of Robuvit® seems to be mediated by its anti-inflammatory activity associated to its important action on oxidative stress.

Supplementary management of functional, temporary alcoholic hepatic damage with Robuvit® (French oak wood extract).

The aim of this registry study was to evaluate Robuvit® (quercus robur wood extract) supplementation in the evolution of moderate functional hepatic failure (MTHF) due to alcohol. Recent studies have indicated the protective effect of oak wood (QR) extracts on liver injury. This registry included patients with MTHF characterized by: decreased albumin levels; increased total bilirubin, altered hepatic functions enzymes, increased oxidative stress, negative viral hepatitis markers. RESULTS: The two groups resulted divided into a best management (BM) group and a comparative group (BM+ Robuvit ® were comparable): 23 Robuvit® patients and 21 comparable controls completed the 12-week registry. At inclusion, blood parameters in the two groups were comparable. At the end of the observation period, the increase in albumin levels was significantly (P<0.05 at 12 weeks) faster and higher in the Robuvit® group. The decreasee in ALT-SGPT and AST-ASAT were significantly larger in the supplement group (P<0.05 at 6 and 12 weeks). Alkaline phosphatase was reduced more, at 6 and 12 weeks in Robuvit® patients; (Robuvit® group's values were significantly better; P<0.05). Total bilirubin improved better in Robuvit® subjects at 6 and 12 weeks. Results were significantly better in comparison with controls (P<0.05). Also, direct bilirubin values increased more in the Robuvit® group at 6 and 12 weeks (P<0.05). Gamma GT values were normalized at 6 and 12 weeks in the Robuvit® group. There was a less important decrease in controls (P<0.05) without normalization at 12 weeks. Plasma free radicals, increased at inclusion, showed a more significant decrease in Robuvit® subject (at 6 and 12 weeks), with normalization at 12 weeks. Persisting, elevated values in controls were observed even at 12 weeks (P<0.05). ESR decreased in both groups with a more important decrease in the Robuvit® group (P<0.05). Hepatitis markers were negative when repeated at 6 and 12 weeks. In conclusion, observations from this pilot, supplement registry study indicate a significant protective activity of the supplementation with Robuvit®, associated with a very good safety profile, in patients with temporary hepatic failure. The activity of Robuvit ® seems to be mediated by its anti-inflammatory activity associated to its important action on oxidative stress.

Fibrillar collagen regulation of plasminogen activator inhibitor-1 is involved in altered smooth muscle cell migration.

OBJECTIVE: Vascular smooth muscle cells (SMCs) cultured on polymerized type I collagen fibrils are arrested in the G1 phase of the cell cycle, and their phenotypic markers and pattern of expressed genes are markedly altered. In this study, we examined polymerized collagen regulation of plasminogen activator inhibitor (PAI)-1 and its involvement in SMC migration. METHODS AND RESULTS: We demonstrate that secretion and cell surface accumulation of PAI-1 are suppressed in SMCs cultured on polymerized collagen compared with SMCs cultured on monomer collagen. SMCs replated on vitronectin after culture on monomer collagen result in PAI-1 accumulation at focal adhesions and colocalization with alpha(v)beta3 integrins. In contrast, polymerized collagen inhibits PAI-1 accumulation at focal adhesions when the SMCs are replated on vitronectin. Furthermore, for SMCs cultured on polymerized collagen, platelet-derived growth factor-stimulated migration on vitronectin is enhanced by PAI-1, with its function counteracted by urinary plasminogen activator. Finally, exogenous addition of PAI-1 appears to partly restore platelet-derived growth factor-stimulated alpha(v)beta3-dependent SMC migration that is specifically suppressed by polymerized collagen. CONCLUSIONS: Polymerized type I collagen fibrils dynamically regulate PAI-1, which may be involved in altered alpha(v)beta3 integrin-dependent SMC migration.

Intrarenal hemodynamic changes after captopril test in patients with type 2 diabetes: a duplex Doppler sonography study.

OBJECTIVE: ACE inhibitors are known to be effective in preventing the progression of diabetic nephropathy. Activation of the renin-angiotensin system (RAS) is reported to contribute to intrarenal hemodynamic abnormality in diabetic patients. We examined whether RAS blockade by captopril induces intrarenal hemodynamic changes in normotensive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The patients ranged in age from 40 to 65 years (20 men and 20 women). A total of 15 age- and sex-matched healthy individuals served as control subjects. Resistive index (RI) of interlobar arteries was examined by duplex Doppler sonography before and after the oral captopril (25 mg) test. RESULTS: At baseline, no significant differences in RI values or plasma renin activity (PRA) were seen between the patients and healthy subjects. In healthy subjects, the RI values after the captopril test were significantly higher than baseline values (P < 0.01). However, in patients with type 2 diabetes, both with normoalbuminuria and microalbuminuria, RI values after the test were significantly lower than baseline values (P < 0.001). There were significant negative correlations between DeltaRI value and HbA1c (r = -0.458, P < 0.005) and between DeltaRI value and baseline PRA in diabetic patients (r = -0.339, P < 0.05). Multiple regression analysis showed that HbA1c and baseline PRA significantly and independently affected the magnitude of decrease in RI values after captopril administration in diabetic patients (R2 = 0.391, P < 0.0001). CONCLUSIONS: These results indicate that the intrarenal RAS may be activated in diabetic patients, that such activation may be affected by poor glycemic control, and that blockade of RAS activation by ACE inhibitor reduces intrarenal vascular resistance in diabetic patients. The results emphasize the beneficial effects of ACE inhibition in improving intrarenal hemodynamics in diabetic patients.

Impact of diabetes on coronary stenosis and coronary artery calcification detected by electron-beam computed tomography in symptomatic patients.

OBJECTIVE: Ischemic heart disease is a pivotal complication for diabetic patients. Electron-beam computed tomography (EBCT) represents the only noninvasive method that allows for accurate quantification of coronary artery calcification that reflects underlying atherosclerotic disease. Although coronary calcium score (CCS) cut points that predict the presence of angiographic stenosis have been established in nondiabetic individuals, it is not known whether coronary calcifications in diabetic patients are associated with the presence of significant coronary stenoses. In this study, we evaluated the relationship between coronary calcifications and angiographic stenosis in symptomatic patients with or without type 2 diabetes. RESEARCH DESIGN AND METHODS: In this study, 282 patients (204 men and 78 women) with chest pain, including 101 diabetic patients and 181 nondiabetic patients (mean age 63 +/- 9.6 years), underwent coronary angiography and EBCT with determination of CCS using Agatston's method. Luminal stenosis >or= 50% was defined as significant coronary stenosis. RESULTS: Angiography identified 205 patients with significant stenoses (89 of 101 diabetic patients, 114 of 181 nondiabetic patients). The sensitivity and specificity of EBCT to detect significant coronary stenosis were not significantly different between diabetic and nondiabetic patients. In diabetic patients, a CCS >or=90 was associated with 75% sensitivity and 75% specificity, whereas a CCS >or=200 was associated with 64% sensitivity and 83% specificity. CONCLUSIONS: We demonstrated that calcification of the coronary arteries in symptomatic diabetic patients is well associated with severity of coronary stenosis, as in nondiabetic patients.

Sitagliptin reduces the urine albumin-to-creatinine ratio in type 2 diabetes through decreasing both blood pressure and estimated glomerular filtration rate.

BACKGROUND: We investigated the change in the urine albumin-to-creatinine ratio (ACR) to examine the effect of sitagliptin on diabetic nephropathy. METHODS: Sitagliptin at a dose of 50 mg was administered to 247 outpatients with type 2 diabetes. Data were collected on the patients' laboratory results (including the ACR), blood pressure, and body weight. Clinical data were compared before and after 3 months' administration of sitagliptin. RESULTS: The ACR changed from 150.0 ± 538.6 mg/gCre to 148.3 ± 764.6 mg/gCre over 3 months. In the patients with micro- and macro-albuminuria, the ACR after 3 months significantly decreased compared with the baseline (P = 0.04 and P = 0.02, respectively). The subjects whose ACR decreased experienced significantly larger decreases over the 3-month period in blood pressure and estimated glomerular filtration rate (eGFR) than the other subjects. There was no significant correlation between change in ACR (ΔACR) and change in hemoglobin A1c (ΔHbA1c) during 3 months (r = 0.04, P = 0.59), but there was a significant correlation between change in ΔACR and change in systolic blood pressure (r = 0.16, P = 0.03). Multiple regression analysis revealed that the significant predictors for ΔACR were change in systolic blood pressure (ß = 0.21, P = 0.016) and change in eGFR (ß = 0.20, P = 0.024) over 3 months (r = 0.35, P = 0.04). CONCLUSIONS: Sitagliptin reduces the ACR through decreasing both blood pressure and eGFR, with no correlation with a decrease in HbA1c over a 3-month period. These results may reflect the direct action of sitagliptin on the kidneys.

Glycemic response during exercise after administration of insulin lispro compared with that after administration of regular human insulin.

To examine the glycemic response during exercise after administration of short-acting insulin lispro, we compared changes in plasma glucose concentrations during exercise performed by patients with diabetes after the administration of either insulin lispro or regular human insulin. Seven patients with diabetes (two with type 1 and five with type 2) participated in this study. Each of the insulin-depleted subjects received the same number of units of either insulin lispro or regular human insulin, delivered subcutaneously to the abdomen. The next day, each subject received a similar injection of the solution not previously administered. After each injection, the subjects were fed a standard meal of approximately 9 kcal/kg body weight. One hour after eating the test meal, the subjects performed 30 min of cycle ergometer exercise at 50% maximal oxygen uptake. Plasma glucose, insulin, glucagon, growth hormone (GH), and catecholamine concentrations were then measured at specific intervals. Insulin concentrations were higher and peaked earlier after administration of insulin lispro than after administration of regular human insulin. The length of time, needed to reach minimum plasma glucose concentration after exercise was begun, was significantly shorter after administration of insulin lispro, and the percentage of plasma glucose decrease induced by exercise relative to the peak concentration was significantly greater. No differences were found in the concentration changes of counterregulatory hormones between the insulin lispro data and the regular human insulin data. Compared with regular human insulin, insulin lispro induces a more rapid and greater decrease in plasma glucose concentration during exercise because of its faster absorption.

Role for thromboxane A2 from glomerular thrombi in nephropathy with type 2 diabetic rats.

We used rats (the Otsuka Long-Evans Tokushima Fatty strain) as a model of type 2 diabetes to find whether thromboxane (TX) A2 is involved in diabetic nephropathy, and if so, to identify where it is synthesized. We measured urinary excretion of TXB2 and 2,3-dinor-TXB2 in rats up to 60 weeks of age as markers of renal and platelet synthesis of TXA2, respectively. Some diabetic rats were given daily oral doses of OKY-046 (100 mg/kg), a TXA2 synthase inhibitor, starting when they were 10 weeks of age. Healthy Long-Evans Tokushima Otsuka rats served as the controls. Urinary excretion of protein was greater in diabetic rats at 26 weeks than in controls, and the difference increased with age. Urinary excretion of TXB2 by diabetic rats was about 150% that of controls at 14 weeks, and remained at that level. In diabetic rats, urinary excretion of 2,3-dinor-TXB2 increased with age in parallel to increases in proteinuria, but in controls, excretion of these metabolites did not change with age. In diabetic rats, OKY-046 prevented the increase in urinary excretion of both metabolites, and decreased the proteinuria. Histologic examination at 60 weeks showed intraglomerular thrombi in diabetic rats but not in controls. OKY-046 reduced intraglomerular thrombi formation and the score for glomerulosclerosis. When platelet aggregation began, more TXA2 than before was released from the thrombi that formed, and the TXA2 contributed to the progress of nephropathy in this rat model of type 2 diabetes.

Treatment of lymphocytic hypophysitis by high-dose methylprednisolone pulse therapy.

A 26-year-old woman 3 months post-partum was admitted to our hospital suffering from gross visual disturbance. Magnetic resonance imaging (MRI) revealed a pituitary mass, extending into the suprasellar cistern, with intense gadolinium enhancement. Lymphocytic hypophysitis (LHy) was suspected, and the patient received high dose methylprednisolone pulse therapy (HDMPT). Her visual disturbance was dramatically ameliorated on the first day following initiation of HDMPT, and MRI revealed marked mass reduction. Her pituitary function recovered 6 months after therapy. This case report suggests that HDMPT proved effective for mass reduction of severe LHy and could obviate the need for a useless surgery.

Transient central diabetes insipidus in pregnancy with a peculiar change in signal intensity on T1-weighted magnetic resonance images.

A 38-year-old woman was admitted with severe thirst and polyuria at 31 weeks' gestation. The plasma concentration of vasopressin (AVP) was very low (0.73 pg/ml) under conditions of high plasma osmolality (316 mOsm/ kg). T1-weighted magnetic resonance (MR) images revealed enlargement of the pituitary posterior lobe with absence of the hyperintense signal. After delivery, restoration of the hyperintense signal was demonstrated. This depletion-repletion process, which reflects the decrease and increase in amount of neurosecretory granules, is recognized in the case of transient central diabetes insipidus during pregnancy. We consider that an increase in cystine-aminopeptidase (CAP) activity is implicated in the pathogenesis.

An insulinoma for which secretin test and selective arterial calcium injection test were useful.

A 76-year-old woman suffered from somnolence while fasting for almost 2 years. Fasting plasma glucose (FPG) (40 mg/dl) and the immunoreactive insulin (IRI) level (8.8 microU/ml) were not compatible with Fajan's ratio or Turner's ratio observed in typical insulinoma. The secretin test showed no response to insulin secretion, suggesting the presence of insulinoma. Abdominal dynamic computed tomography (CT) revealed a 12-mm hypervascular lesion in the head of the pancreas. A selective arterial calcium infusion test (SACI) was performed, during which IRI in the hepatic venous blood was measured following selective intraarterial calcium infusion. An increase in IRI levels in the gastroduodenal and superior mesenteric arteries suggested the presence of a functional insulinoma in the head of the pancreas. Enucleation of the tumor improved FPG and IRI levels to 138 mg/dl and 3.8 microU/ml, respectively. After surgery, a secretin test showed a 5-fold increase in IRI levels, suggesting normal beta cell function. This case illustrates the value of the secretin test for the diagnosis of insulinoma and for the postoperative assessment of beta cell function. It further illustrates the value of the SACI for localizing an insulinoma.

Complete adrenocorticotropin deficiency after radiation therapy for brain tumor with a normal growth hormone reserve.

A 34-year-old man with neurofibromatosis type 1, who had received radiation therapy after the excision of a brain tumor 5 years earlier, was admitted to our hospital with vomiting and weight loss. Cortisol and adrenocorticotropin (ACTH) were undetectable before and after administration of 100 microg corticotropin releasing hormone. The level of growth hormone without stimulation was 24.7 ng/ml. We diagnosed him to have complete ACTH deficiency attributable to radiation therapy. This is the first known case of a patient with complete ACTH deficiency after radiation therapy and a growth hormone reserve that remained normal.

Epithelioid inflammatory myofibroblastic sarcoma responsive to surgery and an ALK inhibitor in a patient with panhypopituitarism.

We encountered a case of epithelioid inflammatory myofibroblastic sarcoma (EIMS) originating from an abdominal organ that rapidly regrew twice. The patient underwent two surgeries. Large tumors grew within three months after the second surgery. The patient subsequently received chemotherapy with an anaplastic lymphoma kinase (ALK) inhibitor. Although EIMS has a poor prognosis, the patient continues to be alive with disease 14 months after surgical treatment and the administration of the ALK inhibitor.

Pituitary cyclic Cushing's syndrome concomitant with solitary cryptococcal pneumonia confused with ectopic ACTH-producing tumor.

A 47-year-old man with Cushingoid appearance was admitted to our hospital showing excessive secretion of cortisol at intervals of a few days. Cyclic Cushing's disease was confirmed. Two years earlier, results of hormonal assessment had been within normal limits and macroadenoma had been incidentally detected in the pituitary. Dexamethasone suppression testing revealed various responses and a small lung tumor was detected, therefore his condition was misinterpreted as ectopic ACTH-producing tumor or pituitary cyclical Cushing's disease, leading to lung resection that confirmed cryptococcal pneumonia. The pituitary tumor was finally identified as the cause of cyclic Cushing's syndrome and fully removed, allowing remission.