A number of whole-genome association studies show the cdk5 regulatory associated protein 1-like 1 (cdkal1) gene to be one of the most reproducible risk genes in type 2 diabetes (T2D). Variations in the gene are associated with impaired insulin secretion but not insulin resistance or obesity. Although the physiological functions of Cdkal1 had been unclear, recent studies show that it is a tRNA modification enzyme, a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) at position 37 of tRNALys(UUU). The ms2t6A modification in tRNALys(UUU) is important for preventing the misreading of its cognate codons, especially when the rate of translation is relatively high. In both general and pancreatic β-cell-specific cdkal1-deficient mice, impaired mitochondrial ATP generation and first-phase insulin secretion are observed. Moreover, the β-cell-specific knockout mice show pancreatic islet hypertrophy and impaired blood glucose control. The mice are also hypersensitive to high-fat diet-induced ER stress. In this review, we provide an overview of the physiological functions of Cdkal1 and the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.
Tertiary hyperparathyroidism (tHPT) most commonly refers to a persistent secondary hyperparathyroidism even after successful renal transplantation. Parathyroidectomy (PTX) is an efficient method for treatment of tHPT. In this study, we examined our 31-year experience with patients who underwent PTX for tHPT after KTX and assessed the effects of PTX on graft function according to the type of surgery. Among 2,981 recipients who underwent renal allograft between April 1979 and Dec. 2010, 15 patients (0.5%) were identified as having tHPT and underwent PTX. Levels of intact parathyroid hormone (iPTH) and serum calcium were measured before and after PTX for evaluation of the therapeutic effect, and glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) equation for investigation of any effect on graft function. One patient showed persistent hyperparathyroidism and hypercalcemia after limited PTX. We experienced 14 successful PTXs, including 3 total PTX with autotransplantations, 8 subtotal PTXs, and 3 limited PTXs. Level of iPTH and serum calcium were at normal range after PTX. Estimated GFR decreased after PTX. Total PTX with autotransplantation showed a tendency of more decrease in the values of iPTH, and GFR after PTX than Subtotal PTX. PTX can cure tHPT-specific symptoms and signs by recovery of hypercalcemia, but may carry the risk of deterioration of kidney graft function. We suspect that subtotal PTX, rather than total PTX with AT, prevent any risk of kidney graft deterioration in surgical treatment of tHPT, and, in selective tHPT patients, limited PTX might be recommended.
The aim of this study is to evaluate the effectiveness of blood sugar control by a short-course reinforcement program, consisting of using continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) for young adult type 1 diabetic patients. Twenty-six pump-naïve type 1 diabetic patients were successively enrolled in two years. The mean disease duration was 13 years and the mean HbA1c was 8.8 %. Initially, a 3-day course of CGM was used to evaluate the baseline glycemic status of the subjects, followed by 6-day intensive insulin adjustment by CSII therapy. Thereafter, a second course of CGM was performed to evaluate the effectiveness of our outcomes in comparison to the initial measurements. All participants received necessary education and instruction as required throughout the course of the program. The glucose variability as measured by standard deviation of plasma glucose and mean amplitude of glucose excursion decreased significantly (67.8 ± 2.7 to 52.0 ± 1.8 mg/dL and 140.4 ± 6.5 to 105.5 ± 5.3 mg/dL, p < 0.001). The hypoglycemic events noted per patient were reduced by 46.4% (p = 0.003) and occurred significantly less often during nocturnal periods (-63.2%, p = 0.002). Following the adjustment, the mean daily insulin requirement was reduced by 28.05% (from 0.82 to 0.59 IU/kg) and the new proportion of 40% as basal insulin was found. The short-term CSII program provided significant improvement in blood sugar control for type 1 diabetic patients, by reducing hypoglycemic events, glucose excursion, and insulin dosage in our examined subjects.
To examine the association of serum retinol-binding protein 4 (RBP4) concentrations with carotid intima-media thickness (CIMT) in type 2 diabetic subjects with chronic kidney disease (CKD). A total of 239 type 2 diabetic patients (64 ± 13 years, 154 males) were divided into two groups: one with CKD, defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73m2 (n = 86), and one without (n = 153). We recorded clinical and biochemical data as well as CIMT. The patients with CKD were older, had had diabetes mellitus longer, and had higher incidence of hypertension, dyslipidemia and microalbuminuria than those without. They also had higher serum concentrations of RBP4 (44.8 ± 6.4 vs 39.5 ± 4.9 μg/mL, p < 0.001), higher mean CIMT (0.75 ± 0.16 vs 0.69 ± 0.14 mm, p = 0.0070), and higher incidence of carotid plaques (27.9 vs 11.8 %, p = 0.002). The RBP4 were negatively correlated with eGFR (r = -0.514, p < 0.001). However, the RBP4 were not correlated with mean CIMT (r = 0.065, p = 0.318). Moreover, when dividing the patients into two groups by the mean CIMT, those with mean CIMT above 0.71 mm did not have different RBP4 concentrations compared with those below (41.5 ± 5.7 vs 41.3 ± 6.3 μg/mL, p = 0.856). In conclusion, we observed an elevation of serum RBP4 concentrations and CIMT levels in type 2 diabetic subjects with CKD. However, the elevated RBP4 were not associated with the higher CIMT among these patients.
The diagnostic and prognostic role of thyroid ultrasound (TUS) in pregnant women positive for antibodies to thyroperoxidase (TPOAb) is unclear. The aim of our study was to compare the relation of ultrasound thyroid texture to the thyroid laboratory tests in pregnant women and controls. Using a semi-quantitative assessment we compared TUS in two groups of women with positive TPOAb and/or with thyroid dysfunction (TSH out of 0.06-3.67 mIU/L): 186 women in 1st trimester of pregnancy recruited from universal screening and 67 asymptomatic age-comparable non-pregnant non-postpartum women recruited from screening of general population (controls). Women with previous history of thyroid diseases were excluded. Only 64/131 (48.9 %) of TPOAb-positive pregnant women were TUS-positive (TUS with autoimmune pattern) in comparison with 35/49 (71.4 %) TPOAb-positive controls (p <0.011). Pregnant women had more often TSH >10.0 mIU/L if they were TPOAb-positive/TUS-positive as compared to those TPOAb-positive/TUS-negative (8/64 (12.5 %) vs. 0/67 (0 %), p = 0.009). The prevalence of preterm deliveries among TPOAb-positive women was significantly lower if TPOAb-positivity was not accompanied by TUS-positivity (2/67 (3.0 %) vs. 10/64 (15.6 %) in TPOAb-positive/TUS-positive women, p = 0.028). In conclusion, nearly half of the TPOAb-positive pregnant women did not have an autoimmune pattern in TUS. Normal TUS image in TPOAb-positive pregnant women might be a protective factor for preterm delivery.
We designed this study, to investigate the predicting effect of a single resistance exercise session on serum level of RBP4 and adiponectin in trained and untrained subjects and to evaluate whether regular training may affect the response of these adipokines to exercise. Thirty four healthy young male students including 19 trained and 15 untrained participated in this study; each group was then randomly assigned to intervention and control groups. The exercise session prolonged 120 minutes intensive resistance program at 70%-80% of 1RM. The blood samples were collected just before the start of training program and 4 hours post exercise to evaluate concentration of adiponectin, RBP4 and CRP as well as other metabolic markers. The serum level of adiponectin, RBP4 and CRP was not significantly different between trained and untrained groups at baseline. More over four hours post exercise adipokines concentration and CRP didn’t differ between groups. Adjusted regression model showed, basal adiponectin (β=0.59, p=<0.001) and HDL cholesterol (β=0.28, p=0.09) were the main predictors of post exercise adiponectin concentration. In addition, the basic level of RBP4 appeared to be the only predictor of after exercise RBP4 concentration (β=0.46, p=0.02). Neither one session of high intensity resistance exercise nor long term training had predicting effect on post exercise adiponectin and RBP4 concentration in healthy young men. In the other hand, the beneficial effect of acute resistance exercise training may not be reflected by changes in adiponectin, RBP4 and CRP concentration in healthy young individual no matter they trained or untrained.
To determine whether miglitol administration improves glycemic control and reduces the frequency of hypoglycemia in type 1 diabetes mellitus (T1DM) patients treated with intensive insulin therapy, we analyzed the effect of miglitol on daily insulin doses, body weight, hypoglycemia, and incretin hormone responses during meal tolerance tests (MTT). Eleven T1DM subjects (21-77 years) undergoing intensive insulin therapy, took 25 mg (weeks 0-4) and 50 mg miglitol (weeks 4-12) thrice daily, immediately before meals. At weeks 0 and 12, 9 of 11 subjects underwent MTT. In present study, mean HbA1c, glycoalbumin, and 1,5-anhydroglucitol levels were significantly improved. The blood glucose level 1 h after dinner was significantly lower at week 12 than at week 0 (p = 0.008). From week 0 to 12, there was a significant decrease in the body mass index (BMI; p = 0.0051), frequency of preprandial hypoglycemic events (p = 0.012), and daily bolus insulin dosage (p = 0.018). The change in active glucagon-like peptide-1 (GLP-1) at 120 min significantly increased at week 12 (p = 0.015). The change in total glucose-dependent insulinotropic peptide (GIP) significantly decreased in the MTT at week 12. These results demonstrate that addition of miglitol on intensive insulin therapy in T1DM patients has beneficial effects on reducing BMI, bolus and total insulin dosage, and frequency of preprandial hypoglycemic events. MTT findings suggest that this combination therapy improves blood glucose control by delaying carbohydrate absorption and modifying the responses of incretins, GIP, and GLP-1.
Pathogenesis of pseudohypoparathyroidism type 1b (PHP-1b) is related to the loss of methylation at the GNAS exon A/B region, which is combined with epigenetic defects at other differentially methylated GNAS regions in most sporadic cases. In this study, we established a method for evaluating the methylation status of a CpG island in exon A/B using a methylation-specific polymerase chain reaction (MSPCR). We designed two primer pairs specific for the methylated and unmethylated alleles and evaluated the methylation status of GNAS exon A/B in samples from PHP-1b patients and normal controls. We examined 20 Japanese patients and 20 normal controls, and one primer set was found to be appropriate for diagnosis. Furthermore, we evaluated the clinical data of patients. Weight and height of patients were not significantly different from the normal population. Short stature (adult height ≤ 2SD) was observed in one patient and short metacarpals in two. Obesity was observed in six patients, and no patient showed ectopic subcutaneous calcification. Seven patients showed subclinical hypothyroidism because of resistance to thyroid stimulating hormone, but no patient had an abnormally low free thyroxine level, and none received oral thyroid hormone replacement. For diagnosis of PHP-1b, only clinical data is not sufficient because a few PHP-1b patients show clinical features similar to PHP-1a, and hence, molecular biology techniques are required for correct diagnosis. We concluded that MSPCR is applicable for rapid molecular diagnosis of PHP-1b.
Detailed dynamics of the hypothalamic-pituitary-adrenal (HPA) axis is complex, depending on the individual metabolic load of an organism, its current status (healthy/ill, circadian phase (day/night), ultradian phase) and environmental impact. Therefore, it is difficult to compare the HPA axis activity between different individuals or draw unequivocal conclusions about the overall status of the HPA axis in an individual using single time-point measurements of cortisol levels. The aim of this study is to identify parameters that enable us to compare different dynamic states of the HPA axis and use them to investigate self-regulation mechanisms in the HPA axis under acute and chronic stress. In this regard, a four-dimensional stoichiometric model of the HPA axis was used. Acute stress was modeled by inducing an abrupt change in cortisol level during the course of numerical integration, whereas chronic stress was modeled by changing the mean stationary state concentrations of CRH. Effects of acute stress intensity, duration and time of onset with respect to the ultradian amplitude, ultradian phase and the circadian phase of the perturbed oscillation were studied in detail. Bifurcation analysis was used to predict the response of the HPA axis to chronic stress. Model predictions were compared with experimental findings reported in the literature and relevance for pharmacotherapy with glucocorticoids was discussed.
Postprandial plasma immunoreactive active glucagon-like peptide-1 (p-active GLP-1) levels in type 1 diabetic patients who did not use bolus insulin responded normally following ingestion of test meal, while a small response of p-active GLP-1 levels was seen in type 2 diabetic patients. To determine whether p-active GLP-1 levels are affected by ingestion of test meal in type 1 diabetic Japanese patients who used bolus rapid-acting insulin analogues, plasma glucose (PG), serum immunoreactive insulin (s-IRI), serum immunoreactive C-peptide (s-CPR), and p-active GLP-1 levels were measured 0, 30, and 60 min after ingestion of test meal in Japanese patients without diabetic complications (n=10, group 1) and control subjects with normal glucose tolerance (n=15, group 2). HbA1c levels were also measured in these groups. The patients in group 1 were treated with multiple daily injections or CSII using injections of bolus rapid-acting insulin analogues before ingestion of test meal. There was no significant difference in mean of sex, age, or BMI between groups. Means of HbA1c, basal and postprandial PG, and postprandial s-IRI levels with integrated areas under curves (0-60 min) (AUC) in group 1 were significantly higher than those in group 2. Means of basal and postprandial s-CPR, and postprandial p-active GLP-1 levels with AUCs were significantly lower in group 1 than in group 2. These results indicated that postprandial p-active GLP-1 levels following ingestion of test meal in type 1 diabetic Japanese patients using bolus rapid-acting insulin analogues were decreased relative to those in controls.
The major causes of central diabetes insipidus (CDI) are neoplastic or infiltrative lesions of the hypothalamus or pituitary gland, severe head injuries, or pituitary or hypothalamic surgery. Lymphocytic infundibuloneurophysitis (LINH) is associated with autoimmune inflammatory disease of the pituitary gland, but the exact etiology is unknown. CDI caused by viral infections has been rarely reported. Here, we describe the case of a 22-year-old man who was in good health until 2 months prior to admission, presented with acute development of polyuria and polydipsia, and showed increased urinary volume up to 9000 mL/day. The patient showed elevated serum osmolality and low urine osmolality, with a low level of antidiuretic hormone. Endocrinological findings revealed CDI, but his arterial pituitary function appeared normal. Magnetic resonance imaging revealed significant enlargement of the pituitary stalk. We suspected CDI due to LINH based on non-transsphenoidal biopsy findings. He was diagnosed as type A influenza,and given oral therapeutic agents. However, acute onset of polyuria and polydipsia occurred 10 days after the influenza diagnosis. The available epidemiological information regarding the outbreak of influenza around that time strongly suggested that the patient was infected with the A/H1N1 influenza virus, although this virus had not been detected on polymerase chain reaction testing. In the present case, the autoimmune mechanism of LINH may have been associated with novel influenza A/H1N1 virus infection.