ABSTRACT
Recent studies have demonstrated that circadian clocks are impaired in liver and adipose tissue of both leptin-deficient ob/ob and leptin-resistant KK-A(y) mice. Because impairment of peripheral clocks precedes metabolic abnormalities in ob/ob mice, leptin signaling might be important for modulating peripheral clocks. To assess this hypothesis, the authors determined daily mRNA expression profiles of clock genes Clock, Arntl, Per1, Per2, Cry1, Dbp, and Nr1d1 in several tissues of leptin-receptor-deficient Zucker diabetic fatty (ZDF) rats. Transcript levels of some of these genes around the respective peak times decreased significantly in the liver, but not in the suprachiasmatic nucleus, mesenteric adipose tissue, and heart, compared to those in control rats. In contrast, mRNA levels of Per1 and Dbp around the peak time increased in the aorta of ZDF rats. However, expression rhythms of these clock genes in serum-stimulated cultured cells isolated from the aorta of ZDF rats were quite similar to those in serum-stimulated aortic cells of control rats. These results show that systemic leptin signaling defect influences peripheral clocks in a tissue-dependent manner, suggesting the possibility that leptin indirectly modulates the clocks in at least a subset of peripheral tissues.
Subject(s)
CLOCK Proteins/metabolism , Circadian Rhythm/physiology , Diabetes Mellitus/metabolism , Gene Expression Regulation/physiology , Leptin/pharmacology , Animals , CLOCK Proteins/genetics , Hyphae , Leptin/metabolism , Male , Mice , Muscle, Smooth, Vascular/cytology , Obesity , Rats , Rats, ZuckerABSTRACT
INTRODUCTION: The in-hospital sliding scale (Sc) to determine the insulin dose was changed to a carbohydrate counting sliding scale (CSc). Blood glucose levels before and after the change were compared. METHODS: The Sc was used in 32 patients in July and August 2009 (Sc group) and the CSc was used in 32 patients in September and October 2009 (CSc group). The blood glucose levels recorded before breakfast, lunch, and supper for 14 days were analyzed. The overall and daily mean of all blood glucose data were compared between the 2 groups. RESULTS: The overall blood glucose level was significantly lower in the CSc group than in the Sc group (p<0.001). The percentage of blood glucose level below 199mg/dL was 47% in the Sc group and 59% in the CSc group. The daily blood glucose level in the Sc group was 203-229mg/dL until day 14, while the daily mean blood glucose level decreased significantly to 186mg/dL on day 4 in the CSc group and remained in the 176-200mg/dL range on subsequent days (p=0.049). CONCLUSIONS: The CSc is easy to use, safe and useful in controlling the blood glucose level.
Subject(s)
Diabetes Mellitus/drug therapy , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Insulin/administration & dosage , Insulin/therapeutic use , Aged , Aged, 80 and over , Blood Glucose/drug effects , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Treatment OutcomeABSTRACT
Recent studies have demonstrated relationships between the dysfunction of circadian clocks and the development of metabolic abnormalities, but the chicken-and-egg question remains unresolved. To address this issue, we investigated the cause-effect relationship in obese, diabetic ob/ob mice. Compared with control C57BL/6J mice, the daily mRNA expression profiles of the clock and clock-controlled genes Clock, Bmal1, Cry1, Per1, Per2, and Dbp were substantially dampened in the liver and adipose tissue, but not the hypothalamic suprachiasmatic nucleus, of 10-wk-old ob/ob mice. Four-week feeding of a low-calorie diet and administration of leptin over a 7-d period attenuated, to a significant and comparable extent, the observed metabolic abnormalities (obesity, hyperglycemia, hyperinsulinemia, and hypercholesterolemia) in the ob/ob mice. However, only leptin treatment improved the impaired peripheral clocks. In addition, clock function, assessed by measuring levels of Per1, Per2, and Dbp mRNA at around peak times, was also reduced in the peripheral tissues of 3-wk-old ob/ob mice without any overt metabolic abnormalities. Collectively these results indicate that the impairment of peripheral clocks in ob/ob mice does not result from metabolic abnormalities but may instead be at least partially caused by leptin deficiency itself. Further studies are needed to clarify how leptin deficiency affects peripheral clocks.
Subject(s)
Circadian Clocks/genetics , Obesity/genetics , ARNTL Transcription Factors/genetics , ARNTL Transcription Factors/metabolism , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , CLOCK Proteins/genetics , CLOCK Proteins/metabolism , Caloric Restriction , Circadian Clocks/drug effects , Cryptochromes/genetics , Cryptochromes/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Genotype , Leptin/pharmacology , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Period Circadian Proteins/genetics , Period Circadian Proteins/metabolism , Polymerase Chain Reaction , Radioimmunoassay , Suprachiasmatic Nucleus/drug effects , Suprachiasmatic Nucleus/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
P-glycoprotein (P-gp) is one of the ATP-binding cassette transporters and acts as an efflux pump for cytotoxic substances. P-gp mRNA expression and transporting activity show the daily rhythm and contribute to the chrono-pharmacokinetic profiles of many drugs. It is reported that the daily rhythm of abcb1a mRNA is regulated by a circadian clock-controlled output pathway. Time-restricted feeding is well known to shift the peripheral circadian phase of clock gene expression without changing the central clock function. This study was undertaken to examine the influence of a time-restricted feeding procedure during the light phase on the daily rhythms of abcb1a mRNA expression and P-gp activity. The abcb1a mRNA and P-gp activity showed a daily rhythm with a peak early in the dark phase in rat intestine under ad libitum feeding. Time-restricted feeding during the light phase shifted these rhythms to 12-h advance. The mRNA expression of clock genes (DBP and HLF, the transcript activators of abcb1a) also showed daily rhythms, and their phases were shifted by the time-restricted feeding procedure. The peak time of DBP mRNA expression was similar to that of abcb1a mRNA expression under ad libitum feeding and time-restricted feeding conditions. These results indicate that a time-restricted feeding procedure changes DBP mRNA expression, which in turn influences abcb1a mRNA expression and P-gp activity.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/genetics , Circadian Rhythm/genetics , Eating/genetics , Gene Expression , Jejunum/metabolism , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B/physiology , Animals , Biological Transport , Corticosterone/blood , Digoxin/pharmacokinetics , Male , Perfusion , RNA, Messenger/genetics , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Substrate SpecificityABSTRACT
Hypertensive patients have an increasing risk of osteoporosis. A recent case-controlled study has demonstrated that anti-hypertensive therapy reduced a risk of fracture in these patients. In this study, we investigated whether amlodipine protects against the reduction in bone density in stroke-prone spontaneously hypertensive rats (SHR-sp). Oral dosing of amlodipine (0.5 and 3.0mg/kg/day) was started when SHR-sp were 3 months old, and continued for 3 months. At the end of the experiment, bone density of femur and serum concentrations of calcium, parathyroid hormone (PTH) and C-telopeptide of type I collagen (CTx), reflecting osteoclast activity, were measured. The bone density dose-dependently increased by the treatment with amlodipine. In addition, amlodipine reduced serum concentrations of calcium, PTH and CTx. This study showed that amlodipine prevents the reduction in bone density during the repeated dosing in SHR-sp. Amlodipine might exert its effect through a direct inhibition of osteoclast function and/or suppression of PTH secretion and subsequent inhibition of osteoclast activity.
