Metabolism: Clinical and Experimental

Published by WB Saunders
Online ISSN: 0026-0495
Publications
Article
Postprandial hyperglycemia and hyperinsulinemia are often present in obese subjects with glucose intolerance in whom insufficient early phase insulin secretion and subsequent delayed hyperinsulin response are observed. To address this problem, a novel palatinose-based enteral formula designated as MHN-01 was developed for the prevention of postprandial hyperglycemia and hyperinsulinemia. The effects of MHN-01 on carbohydrate and lipid metabolism in Sprague-Dawley (SD) rats were compared with those of the standard balanced formula (SBF). After a bolus intragastric injection of each formula equivalent to 0.9 g/kg carbohydrate, the peak levels of plasma glucose (PG) and insulin (IRI) in peripheral and portal veins of the MHN-01 group were significantly lower than those of the SBF group. The areas under the curve of PG and IRI in the MHN-01 group were 58.0% and 43.1% of those in the SBF group in the femoral vein and 65.0% and 69.3% in the portal vein, respectively. In the 2-month study, serum levels of IRI and triglyceride in peripheral blood in the MHN-01 group decreased and those in the SBF group increased compared with initial levels. Consequently, both levels in the MHN-01 group were significantly lower than those in the SBF group. In addition, the amount of accumulated fat in abdominal adipose tissue and liver tissue of the MHN-01 group was markedly reduced in comparison to that of the SBF group. Insulin sensitivity, evaluated as glucose infusion rate using the hyperinsulinemic euglycemic clamp technique, in the MHN-01 group was higher than that in the SBF group. Thus, in comparison to SBF, MHN-01 suppressed postprandial hyperglycemia and hyperinsulinemia, reduced visceral fat accumulation, and improved insulin sensitivity. Therefore, human study on the effects of MHN-01 on carbohydrate and lipid metabolism will be recommended to confirm whether MHN-01 may be a useful functional food for the treatment and prevention of insulin resistance.
 
Article
The association of hypertension with obesity has been well recognized, but the etiology remains poorly understood. Obesity is characterized by hyperinsulinemia, which reflects peripheral insulin resistance. Insulin resistance may participate in the development of hypertension with obesity. CS-045 [(I)-5-[4-(5-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)be nzy l]-2,4- thiazolidiendion] is a new orally effective antidiabetic agent that potentiates insulin action and reduces insulin resistance in obese Zucker rats and other obese diabetic animals. In this study, we examined the antihypertensive effect of CS-045 in obese male and female Zucker rats as a model of hypertension associated with obesity. CS-045 was administered as a food admixture (approximately 16 and approximately 70 mg/kg/d) for 4 weeks (female) and (approximately 15 and approximately 67 mg/kg/d) 8 weeks (male) in obese Zucker rats at 5 to 7 months of age. CS-045 slightly but significantly decreased plasma glucose levels. Plasma insulin levels were significantly decreased in obese male rats, but were not significantly decreased in obese female rats. Drug administration led to significant decreases in plasma triglyceride and cholesterol levels and systolic blood pressure (SBP) in a dose-dependent manner from 1 week after administration in obese Zucker rats. CS-045 increased urinary sodium excretion, sodium/potassium ratio, and creatine clearance in a dose-dependent manner, and also led to a remarkable decrease in urinary protein excretion. However, CS-045 did not reduce urinary catecholamine excretion. These data indicate that CS-045 may promote renal sodium excretion and improve decreased glomerular filtration rates, which may reflect the amelioration of insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Article
Rats fed a sucrose-rich diet ([SRD] 63% wt/wt) up to 270 days develop stable hypertriglyceridemia, impaired glucose tolerance, and insulin insensitivity. The aim of the present study is to investigate whether the hypoglycemic agent troglitazone introduced as a pharmacologic intervention could improve and/or reverse the whole-body insulin insensitivity and related abnormalities present after feeding normal rats with a SRD long-term. For this purpose, male Wistar rats were fed a SRD for 210 days. While half of the animals continued with this diet for up to 270 days, troglitazone (0.2 g/dL wt/wt) was added to the SRD of the other half for up to 270 days. Troglitazone markedly reduced in vivo the hepatic triglyceride secretion rate (TGSR) and enhanced its removal from the circulation, leading to a normalization of plasma triglyceride levels. It also normalized the whole-body peripheral insulin resistance, the glucose homeostasis, and the elevated free fatty acids (FFAs) without detectable changes in plasma insulin levels. The clear alteration of the biphasic pattern of glucose-stimulated insulin secretion in the in vitro perfused beta-cell islets of rats fed the SRD long-term (270 days) was also completely normalized when the SRD was supplemented with troglitazone for 2 months. The normalization of the altered patterns of glucose-stimulated insulin secretion, as well as the enhancement of peripheral insulin sensitivity without detectable changes in plasma insulin, might be largely a result of the significant action of troglitazone in the decrease of circulating lipids and enhancement of whole-body glucose metabolism.
 
Article
Antidiabetic effects of CS-045 were evaluated in 5-month-old C57BL/KsJ-db/db mice (db/db). CS-045 administered for 3 weeks to diabetic db/db mice as a 0.2% food admixture improved hyperglycemia (855 +/- 25 v 298 +/- 62 mg/dL, P less than .01) and glucose intolerance, and lowered plasma triglyceride (299.6 +/- 28.7 v 76.3 +/- 20.7 mg/dL, P less than .01) and free fatty acid (FFA) levels (1.16 +/- 0.14 v 0.57 +/- 0.07 mEq/L, P less than .01). Food intake was not changed, while a small but significant increase in body weight was observed in CS-045-treated mice. Plasma insulin levels gradually increased after 5 days of CS-045 treatment, and a nonsignificant increase was observed in plasma insulin levels after 3 weeks (1.85 +/- 0.50 v 4.54 +/- 1.47 mg/mL). In contrast, the plasma glucagon levels decreased after 3 weeks of CS-045 treatment. Histological examination by aldehyde-fucshin staining demonstrated that pancreatic beta cells in CS-045-treated db/db mice were heavily regranulated, whereas most of the beta cells were extensively degranulated in nontreated db/db mice. The heavily regranulated state of beta cells was also compatible with an increase in pancreatic insulin content in CS-045-treated db/db mice. Electron microscopic analysis showed a well-developed endoplasmic reticulum and the accumulation of much amorphous structural material in the intracisternal space of beta cells from CS-045-treated db/db mice, which were suggestive of an increase in insulin synthesis. Moreover, CS-045 treatment decreased exocrine-containing islets, which was associated with the islets' degeneration process. Immunohistochemical staining of islets showed that CS-045 treatment normalized the distribution pattern of endocrine cells in the islets of db/db mice, reflected by a predominantly peripheral location of alpha and delta cells.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Article
To clarify the relationship between lipid and glucose metabolism abnormalities in fructose-fed rats, we examined whether an improvement of insulin sensitivity by troglitazone (CS-045) or a decrease in plasma lipids by bezafibrate affects the relationship between serum levels of lipid and glucose. In addition, we also examined changes in liver glycogen metabolism and beta-oxidation in fructose-fed rats. Troglitazone ameliorated fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia. In addition, it augmented glycogen synthase activity by 53%, and decreased the mitochondrial palmitic acid beta-oxidation rate and ketone body production rate by 27% and 55%, respectively. However, hyperglycemia and liver glycogen synthase activity were not improved by bezafibrate treatment despite a marked reduction of serum triglyceride (TG) levels resulting from a 1.76-fold increase in mitochondrial oxidation and a 2.04-fold increase in hepatic ketone body production. These results suggest that abnormalities in glucose and lipid metabolism in fructose-fed rats, which are ameliorated by troglitazone, may be closely linked to reduced glycogen synthase activity in the liver.
 
Article
We studied the effect of troglitazone, a new oral antidiabetic agent that potentiates insulin action and reduces insulin resistance, on albuminuria in streptozotocin (STZ)-treated diabetic rats. Without affecting blood glucose level, blood pressure, and creatinine clearance, troglitazone treatment of diabetic rats significantly decreased the diabetes-associated albuminuria at all time points studied 14 to 12 weeks of treatment: diabetic 510 +/- 161 micrograms/24 h v diabetic treated 112 +/- 34 micrograms/24 h at 12 weeks, P < .05). These data suggest that troglitazone has potential in the treatment of diabetic nephropathy.
 
Article
We recently discovered that glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide can both prevent the development of atherosclerosis in apolipoprotein E-null (Apoe(-/-)) mice. In the present study, we attempted to extend these findings to orally administered dipeptidyl peptidase (DPP)-4 inhibitor. Seventeen-week-old Apoe(-/-) mice fed an atherogenic diet were administered a DPP-4 inhibitor, vildagliptin analogue (PKF275-055 [PKF], 100 µm/[kg d]), in drinking water over a period of 4 weeks. Aortic atherosclerosis and oxidized low-density lipoprotein-induced foam cell formation were determined. Orally administered PKF increased plasma levels of active glucagon-like peptide-1 by 3.5-fold, increased total glucose-dependent insulinotropic polypeptide levels by 2-fold, reduced body weight by 13%, and reduced plasma cholesterol levels by 30%. Compared with drinking water controls, PKF significantly suppressed total aortic atherosclerotic lesions, atheromatous plaque in the aortic root, and macrophage accumulation in the aortic wall by 30% to 40% (P < .001). None of these changes were associated with the PKF-induced reductions in body weight and plasma cholesterol levels. Foam cell formation was suppressed by 40% in the exudate peritoneal macrophages obtained from the PKF-treated mice. The DPP-4 inhibitor prevents the development of atherosclerotic lesions by suppressing macrophage foam cell formation.
 
Article
The increment for the prevalence of diabetes mellitus and impaired glucose tolerance warrants lowering the cutoffs of normoglycemia to help predict the future development of diabetes. The aim of this study was to find out whether insulin resistance and high-sensitivity C-reactive protein (hsCRP), a nontraditional cardiovascular risk factor, were related to the fasting glucose level, even in normoglycemic range that was categorized by the newly recommended criteria by the American Diabetes Association. Among the participants undergoing medical checkup program at Kangbuk Samsung Hospital, 10059 subjects (5535 men and 4524 women; mean age, 45 years) with normal fasting glucose levels, as defined by the newly recommended criteria (<5.6 mmol/L), were enrolled in this study. The blood pressures, body mass index (BMI), fasting blood glucose, fasting insulin, lipid batteries, and hsCRP levels were checked. The homeostatic model assessment-insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check indexes (QUICKI) were calculated. All subjects were subdivided into 4 groups according to the fasting glucose level. The HOMA-IR, QUICKI, and log-transformed (log) hsCRP, or log(hsCRP), level significantly increased according to the increment in fasting glucose, and these associations were consistent after adjustment for age and BMI, except for the log(hsCRP) (P = .124 after adjustment). Log(hsCRP) increased as the HOMA-IR increased and as the QUICKI decreased, and when multiple regression analysis was done with log(hsCRP) as the dependent variable, age, high BMI, male sex, high HOMA-IR, hypertriglyceridemia, and low high-density lipoprotein cholesterol were the significant predictor for log(hsCRP). In conclusion, the insulin resistance indexes and hsCRP increased gradually even in the normal fasting glucose range, as categorized by the newly recommended criteria for abnormal fasting glucose levels, supporting the rationale for expanding the range of fasting hyperglycemia.
 
Article
The objective was to investigate circulating concentrations of bone formation markers (undercarboxylated osteocalcin [Glu-OC], an established marker of bone formation during fetal and early postnatal life], and Dickkopf-1 [DKK-1], a natural inhibitor of osteoblastogenesis during fetal development]) in intrauterine-growth-restricted (IUGR; associated with impaired fetal skeletal development) and appropriate-for-gestational-age (AGA) pregnancies. Circulating concentrations of Glu-OC and DKK-1 were determined by enzyme immunoassay in 40 mothers and their 20 asymmetric IUGR and 20 AGA singleton full-term fetuses and neonates on postnatal day 1 (N1) and 4 (N4). Parametric tests were applied in the statistical analysis. No significant differences in Glu-OC concentrations were observed between IUGR and AGA groups, whereas fetal DKK-1 concentrations were lower in the IUGR group (P = .028). In both groups, maternal Glu-OC and DKK-1 concentrations were lower than fetal, N1, and N4 concentrations (P ≤ .012 in all cases), whereas fetal Glu-OC concentrations were higher than N1 and N4 ones (P ≤ .037 in all cases). In addition, N1 Glu-OC concentrations were higher than N4 concentrations (P = .047). Finally, maternal Glu-OC and DKK-1 concentrations positively correlated with fetal, N1, and N4 ones (r ≥ 0.404, P ≤ .01 in all cases). Fetal/neonatal bone formation may not be impaired in full-term asymmetric IUGR infants, as indicated by the similar Glu-OC concentrations in both groups. Fetal DDK-1 concentrations are lower in the IUGR group, representing probably a compensatory mechanism, favoring the formation of mineralized bone. Fetal/neonatal bone turnover is markedly enhanced compared with maternal one and seems to be associated with the latter in both late pregnancy and early postpartum.
 
Chemical structure of CLX-0921.  
Effect of CLX-0921 on in vitro glycogen synthesis in HepG2 cells. (A) Dose-dependent stimulation of glycogen synthesis from glucose by CLX- 0921 in the absence of insulin at 48 h. Stimulation of glycogen synthesis is expressed as a percentage of basal (vehicle), which is defined as 100%. (B) Time-dependent increase in CLX-0921– stimulated glycogen synthesis. The maximal effect occurs at 48 to 72 h of treatment. (C) Cycloheximide blocks glycogen synthesis induced by CLX-0921 (30 mol/L, 48 h). Vehicle (white bars), CLX-0921 (black bars), rosiglitazone (hatched bars), CHX (cycloheximide, checked bars); rosi, rosiglitazone.  
In vivo antihyperglycemic activity of CLX-0921 in diabetic animals. Diabetic ob/ob and db/db mice and diabetic ZDF rats were treated with single daily doses of CLX-0921 (50 mg/kg 96.2 mol/kg) or vehicle (0.5% carboxymethyl cellulose ) by oral gavage for 8 or 9 days. Blood glucose measurements were made in the fed state. *P < .05, # P < .01, † P < .001. Vehicle (F), CLX-0921 (OE).  
In vivo antihyperglycemic activity of CLX-0921 v rosiglitazone in ob/ob mice. Diabetic ob/ob mice were treated with single daily doses of CLX-0921 and rosiglitazone at 10 mg/kg (19.2 and 28.0 mol/kg, respectively) or vehicle (0.5% carboxymethyl cellulose) by oral gavage. Blood glucose (A) and body weight (B) were measured during the 8-day treatment period. Vehicle (F), CLX-0921 (s), rosiglitazone (OE).  
In vivo dose-dependent antihyperglycemic activity of CLX- 0921 in ob/ob mice. Diabetic ob/ob mice were treated once daily, by oral gavage, with either vehicle (0.5 % carboxymethyl cellulose) or different doses of CLX-0921 (3.1, 6.3, and 12.5 mg/kg body weight) for 19 days and blood glucose was monitored in alternate days. Vehicle (s), CLX-0921 3.1 mg/kg (OE), 6.3 mg/kg (), and 12.5 mg/kg (F).  
Article
Agonists of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) are pharmacologically active antihyperglycemic agents that act by increasing peripheral tissue sensitivity to insulin. Many of these agonists have antihyperglycemic activity that is directly proportional to their ability to bind and activate PPAR gamma; however, recent data bring this relationship into question. In this report we describe a new PPAR gamma agonist, CLX-0921, that is derived from a natural product. This thiazolidinedione (TZD) has a spectrum of activity that differs from commercially available TZDs. It is a weak activator of PPAR gamma (EC(50) of 0.284 micromol/L) compared to rosiglitazone (EC(50) 0.009 micromol/L). Despite this difference, the drug maintains potent glucose uptake activity in vitro and glucose-lowering activity in vivo that is equipotent to that of rosiglitazone. Moreover, CLX-0921 showed a 10-fold reduction in in vitro adipogenic potential compared to rosiglitazone. CLX-0921 also increases glycogen synthesis, an activity not typically associated with rosiglitazone or pioglitazone. Thus CLX-0921 appears to have a distinct spectrum of activity relative to other TZDs.
 
Article
Acute osteoporosis is known to occur after immobilization in spinal cord injured patients and is related to an early increase in osteoclastic bone resorption. Whether osteoporosis develops in healthy immobilized human patients is still a matter of controversy. Furthermore, acute osteoporosis was thought to be a good model to study the effects of weightlessness on the human skeleton and to adapt preventive procedures. A bed rest experiment was developed in the USSR on 15 healthy human volunteers to determine the precise effects on bone structure and cell activities. A preventive protocol, including an anti-osteoclastic drug (1-hydroxyethylidene-1,1 bisphosphonic acid; K salt) was investigated. Two transiliac bone biopsies were performed on the 15 individuals before and at the end of the 120-day bed rest period. Undecalcified bone biopsies were studied with automatic and semi-automatic image analyzers specially devoted to bone histomorphometry. Trabecular bone volume, osteoid amount, and eroded surfaces were measured. Osteoclast number was measured after histochemical identification of tartrate-resistant acid phosphatase. After the bed rest period, an insignificant bone loss was observed in healthy humans while osteoclast number was highly increased. In bisphosphonate-treated subjects, osteoclast number was markedly reduced and so was osteoid amount. Bisphosphonates were shown to present a highly cytotoxic activity on osteoclasts, a finding that has never been demonstrated in normal subjects.
 
Article
Experiments in humans and rodents using oral doses of glycine and phenylalanine have suggested that the metabolism of these amino acids contributes to urinary oxalate excretion. To better define this contribution, we have examined the primed, constant infusion of [1-(13)C(1)] phenylalanine and [1,2-(13)C(2)] glycine in the postabsorptive state in healthy adults. Subjects were infused for 5 hours, hourly urines were collected, and blood was drawn every 30 minutes. Ion chromatography/mass spectrometry was used to measure [(13)C] enrichment in urinary oxalate, glycolate, and hippurate; and the enrichment of (13)C-amino acids in plasma samples was measured by gas chromatography/mass spectrometry. Following infusion with either 6 μmol/(kg h) [1-(13)C(1)] phenylalanine or 6 μmol/(kg h) [1,2-(13)C(2)] glycine, no isotopic glycolate or oxalate was detected in urine. Based on the limits of detection of our ion chromatography/mass spectroscopy method, these data indicate that less than 0.7% of the urinary oxalate could be derived from phenylalanine catabolism and less than 5% from glycine catabolism. Infusions with high levels of [1,2-(13)C(2)] glycine, 60 μmol/(kg h), increased mean plasma glycine by 29% and the whole-body flux of glycine by 72%. Under these conditions, glycine contributed 16.0% ± 1.6% and 16.6% ± 3.2% to urinary oxalate and glycolate excretion, respectively. Experiments using cultured hepatoma cells demonstrated that only at supraphysiological levels (>1 mmol/L) did glycine and phenylalanine metabolism increase oxalate synthesis. These data suggest that glycine and phenylalanine metabolism make only minor contributions to oxalate synthesis and urinary oxalate excretion.
 
Article
In order to determine the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on bone matrix appositional rate (Ma AR) and bone mineral appositional rate (Mi AR), three doses (0.06, 0.13 and 0.20 microgram/kg/d) of 1,25(OH)2D3 were continuously infused for seven days in young mice. Histologic parameters of bone formation and resorption were evaluated by morphometric and autoradiographic methods. All doses of 1,25(OH)2D3 increased serum calcium and produced a dose-related increase in the metaphyseal osteoclastic surface and in the number of acid phosphatase-stained osteoclasts. The Mi AR evaluated by double tetracycline labeling was enhanced at all dosage levels. By contrast the Ma AR evaluated by double 3H-proline labeling was decreased at the two highest doses of 1,25(OH)2D3 which also produced growth impairment. We concluded that the continuous administration of 1,25(OH)2D3 in the mouse produces contrasting effects on bone matrix synthesis and calcification, resulting in a dose-related reduction in the amount of osteoid.
 
Article
In diabetic animals, there is a decrease in serum 1,25-dihydroxyvitamin D [1,25(OH)2D] and in renal production of 1,25(OH)2D. In nondiabetic animals, renal 1,25(OH)2D production is markedly stimulated by parathyroid hormone (PTH) and calcitonin (CT). There is evidence that diabetes impairs the responsiveness of the kidney to PTH. The effect of diabetes on responsiveness to CT is unknown. The studies reported here determined the effect of streptozotocin-induced diabetes on renal responsiveness to PTH and CT. Experiments were performed in 7- to 8-week-old rats that were fed a diet sufficient in calcium and vitamin D and were thyroparathyroidectomized (TPTX) 5 days before hormone treatment. PTH (0.33 U/g body weight at 24, 12, and 2 hours before death) significantly increased renal 1,25(OH)2D production by threefold in nondiabetic rats. This effect was markedly attenuated by diabetes. On the other hand, CT (20 U/100 g body weight at 12 and 2 hours before death) produced a maximal response in both groups of animals. In diabetic rats, CT stimulated renal 1,25(OH)2D production fivefold, whereas PTH stimulated production only 1.5-fold. Diabetes did not affect the capacity of PTH to increase serum calcium or decrease renal tubular reabsorption of phosphorus (TRP). These findings suggest that the decrease in renal 1,25(OH)2D production seen in experimental diabetes may be due to decreased renal responsiveness to PTH, but not to decreased responsiveness to CT.
 
Article
Six patients with Paget disease of bone were treated with a 6-mo course of disodium-ethane-1-hydroxy-1, 1-diphosphate (EHDP) at a dosage of 5 mg/kg/day (one patient) or 20 mg/kg/day (five patients). In addition to symptomatic and biochemical improvement which persisted 3 mo after discontinuance of therapy, EHDP resulted in a significant increase in intestinal calcium absorption that was not correlated with a change in serum 1 alpha, 25-(OH)2-vitamin D concentration. EHDP appears to stimulate intestinal calcium transport by either a vitamin D independent process or by an increased intestinal mucosal cell sensitivity to vitamin D.
 
Article
We examined ten cellular or tissue sources of lymphocytes for specific binding of 1,25(OH)2D3, the hormonally active form of vitamin D3. A specific-binding protein was found in three of these sources. Scatchard analysis of cytosol from a follicular lymphoma cell line revealed binding sites with a Kd of 7.0 X 10(-11) and a receptor concentration of 6.6 fmol/mg protein. Sucrose density centrifugation of 3H-1,25(OH)2D3 labeled cytosol showed a 3.75 peak which was absent in cytosols incubated with excess nonradioactive 1,25(OH)2D3. The relative amounts of vitamin D3 metabolites required to displace 50% of the specifically bound 3H-1,25(OH)2D3 were 1,25(OH)2D3: 1,24,25(OH)3D3: 25(OH)D3: 24,25(OH)2D3 = 1: 180: 1000: 2700. Excess vitamin D3, cortisol, and estradiol failed to displace 3H-1,25(OH)2D3. Scatchard analysis of spleen cytosol from a patient with prolymphocytic transformation of chronic lymphocytic leukemia demonstrated a binding protein with a Kd of 1.2 X 10(-10) and a receptor concentration of 0.2 fmol/mg protein. DNA cellulose binding confirmed the presence of the specific-binding protein in this cytosol. Specific binding of 3H-1,25(OH)2D3 was also quantitated in a cell line from a patient with Burkitt's lymphoma with a Kd of 0.3 X 10(-10) and a receptor concentration of 29.6 fmol/mg protein. No specific binding of 3H-1,25(OH)2D3 was observed in lymphocytes from seven other malignant and nonmalignant sources. These results are the first to demonstrate a specific-binding protein for 1,25(OH)2D3 in lymphocytes from tissue and from these specific cell lines. The presence of this protein in some lymphocytes but not others may reflect the state of activation of the lymphocytes.
 
Article
The effects of 1alpha-OH D3 or 1,25-(OH)2D3 on calcium and phosphorus metabolism have been evaluated in five hypoparathyroid patients to establish the direct effects of these compounds in adult humans, uncomplicated by compensatory changes in parathyroid hormone secretion. Doses of 1-2.5 mug/day in four patients (5 mug/day in a fifth patient on diphenylhydantoin and phenobarbital) caused a marked increase in serum calcium concentration and urinary calcium excretion, without significant changes in renal calcium clearance or urinary hydroxyproline excretion. These results suggest that the correction of hypocalcemia involved primarily a stimulation of intestinal calcium absorption rather than a stimulation of skeletal calcium resorption. Simultaneously, there were increases in urinary phosphorus excretion and variable changes in serum inorganic phosphate concentration. These effects were produced by doses of 1alpha-OH D3 and 1,25-(OH)2D3 which approach the dose needed to prevent rickets, in contrast to the very large doses of vitamin D or 25-OH D3 required for comparable effects in hypoparathyroid patients. The increased relative effectiveness of these one-hydroxylated forms of vitamin D reveals a deficiency of vitamin D one-hydroxylation in hypoparathyroidism. The rapidity of action of 1alpha-OH D3 and 1,25-(OH)2D3 was also striking. Apart from its physiologic implications, the potency of the one-hydroxylated forms of vitamin D offers significant therapeutic advantages in some patients whose hypoparathyroidism is difficult to control with vitamin D itself.
 
Article
In postmenopausal osteoporotics, malabsorption of calcium is associated with reduced levels of serum 1,25-dihydroxyvitamin D. Metabolic studies have shown that calcium absorption can be normalized and calcium balance improved after administration of oral doses of synthetic 1,25-dihydroxyvitamin D3 (Rocaltrol) 0.25 micrograms twice daily. Further studies performed at two centers compared the effect of Rocaltrol 0.25 micrograms twice daily versus placebo on vertebral fracture rates in osteoporotics. A significant reduction in vertebral fracture rates was seen at the end of 1 year. Those patients who continued on Rocaltrol for a second and third year showed a progressive decrease in vertebral fractures. Rocaltrol, administered at a dose of 0.25 micrograms twice daily, seldom causes hypercalcuria or hypercalcemia in osteoporotic patients on a typical calcium intake of 700 to 800 mg/d. Careful measurements of renal function over a period of 3 years in patients treated with Rocaltrol, 0.25 micrograms twice daily, showed no deterioration in renal function. These data suggest that 1,25-dihydroxyvitamin D3 is a useful therapy in the management of patients with postmenopausal osteoporosis, particularly those who have malabsorption of calcium. We found that it improves calcium balance, reduces the vertebral fracture rate, and is safe to use provided that the dietary calcium is monitored and does not exceed 800 mg/d.
 
Article
To clarify the mechanisms of hypocalcemia with renal insufficiency and to gain more insight into the mechanisms of secondary hyperparathyroidism in these patients, an 85-day study was conducted to examine the effect of dietary phosphate restriction on divalent ion metabolism in patients with early renal insufficiency. The study was conducted on four male patients with stable mild renal insufficiency who had creatinine clearances of 55 to 60 mL/min. Our results correspond with those of other studies that indicate that phosphate restriction is adequate to reverse and correct secondary hyperparathyroidism as well as other abnormalities in divalent ion metabolism. Because dietary phosphate restriction appears to exert its effect through the increased production of 1,25(OH)2D, an alternative therapeutic approach would be supplementation of 1,25(OH)2D3 (calcitriol). To test this, another study was conducted evaluating the effect of 1-year therapy with 1,25(OH)2D3 on blood levels of parathyroid hormone (PTH) and on various parameters of bone pathology in patients with creatinine clearances of 15 to 55 mL/min. Our results showed that the use of calcitriol is safe and effective in the management of secondary hyperparathyroidism and bone disease in patients with moderate renal failure.
 
Article
To investigate the role of transforming growth factor-beta 1 (TGF beta) in bone metabolism, the effects of this agent on the differentiation characteristics of human bone cells were studied in vitro. Human bone cells were isolated from femoral head samples by collagenase digestion. Differentiation characteristics included alkaline phosphatase activity, osteocalcin production, and mRNA levels for alkaline phosphatase, type I alpha 2-procollagen, and osteocalcin. The effect of TGF beta on alkaline phosphatase was not constant, but varied with the incubation conditions. At high cell density and in the presence of serum, TGF beta decreased alkaline phosphatase activity. However, at low cell density and under serum-free conditions, TGF beta stimulated alkaline phosphatase activity. The addition of 1,25(OH)2 vitamin D3 also stimulated alkaline phosphatase. The combination of the two agents gave a greater increase in activity than the sum of the activities when the two agents were given alone. The percentage of cells that stain positively for alkaline phosphatase changed in parallel with the change in specific activity. The percentage of positive cells increased from 17% to 64%, while the specific activity increased from 22 to 169 mU/mg protein. To investigate the mechanism of this stimulation, mRNA levels were measured at 24 hours. Individually, TGF beta and 1,25(OH)2D3 increased message levels for alkaline phosphatase and type I procollagen, but the greatest effect was produced by the combination of the two factors. 1,25(OH)2D3 increased osteocalcin mRNA levels, but TGF beta markedly inhibited this stimulation. TGF beta also inhibited production of osteocalcin by the human bone cells. TGF beta appears to modulate differentiation of human bone cells in combination with 1,25(OH)2D3 and other factors.
 
Article
Human colon carcinoma (HT-29) cells were examined for their capacity to bind and respond to 1,25-dihydroxycholecalciferol [1,25-(OH)2D3]. These cells are known to differentiate and increase their population doubling time when galactose is substituted for glucose in their media. High-affinity and specific binding of 1,25-(OH)2[3H]D3 was observed in extracts of these cells grown in glucose. The binder sedimented in sucrose gradients and eluted from DEAE-cellulose columns in a manner indistinguishable from rabbit intestinal 1,25-(OH)2D3-receptor. Smaller amounts of this binder were seen in HT-29 cells grown in galactose. Both glucose-fed and galactose-fed cells exhibited a dose-dependent decrease in growth rate on exposure to 10(-12) to 10(-6) mol/L 1,25-(OH)2D3. Ultrastructural examination of galactose-fed and glucose + 1,25-(OH)2D3-treated cells showed enterocytic differentiation and features that were not distinguishable between these groups. Sucrase activity was higher in galactose-fed cells and did not change with 1,25-(OH)2D3 treatment. However, the lower sucrase activity in glucose-fed cells increased after exposure to 10(-8) mol/L 1,25-(OH)2D3. These results indicate receptor content and bioresponsivity to 1,25-(OH)2D3 in a human enterocytic cell line, suggesting that it will be a useful model for the study of the mechanisms of action of this sterol.
 
Article
To investigate the effect of dietary 1,3-diacylglycerol (DAG) on the development of insulin resistance (IR) and obesity, brown adipose tissue-deficient mice, a model of high-fat diet-induced IR and obesity, were fed Western-type diets (WTD) containing either DAG oil (n = 8) or standard triacylglycerol (TAG) oil (n = 9) for 15 weeks, beginning at 8 weeks of age. Although brown adipose tissue-deficient mice became obese on both TAG- and DAG-enriched WTD (TAG-WTD and DAG-WTD), the mice eating DAG-WTD gained less weight and had less body fat accumulation. The results of glucose tolerance tests conducted after 5 weeks of each WTD were not different. However, after 10 weeks of each WTD, impaired glucose tolerance developed in the TAG-WTD group but was prevented by DAG-WTD. Exploratory analyses of gene expression suggested that consumption of DAG-WTD was associated with reduced phosphoenolpyruvate carboxykinase gene expression in liver and increased expression of the genes for peroxisome proliferator-activated receptor alpha, lipoprotein lipase, and uncoupling proteins 2 and 3 in skeletal muscle. There were no effects of the DAG-WTD on fasting and postprandial plasma triglyceride (TG) levels, hepatic TG content, or the rate of secretion of TG from the liver. These findings suggest that diets enriched in 1,3-DAG oil may reduce WTD-induced IR and body fat accumulation by suppressing gluconeogenesis in liver and stimulating fat oxidation in skeletal muscle.
 
Article
Diets containing 1,3 butanediol (BD) as a replacement of carbohydrate were fed to normal, diabetic, and diabetic insulintreated rats for two weeks. The diabetic animals fed BD survived longer than the diabetic animals on essentially the same diet without BD. The activities of malic enzyme in 105,000 × g. (1 hour) supernatant fractions of liver were determined. The PEPcK activity in liver was increased by 320 per cent in diabetic and by 240 per cent in diabetic rats fed the BD diet. Insulin decreased the PEPcK activity toward normal. In liver and adipose tissues malic enzyme activity was greatly decreased in diabetic and increased in diabetic insulin treated rats. The incorporation of radioactive bicarbonate into organic acids by liver mitochondrial pyruvate carboxylase and the formation of intermediates for gluconeogenesis were examined. The concentration of metabolites in liver was also examined and all changes were found to be minimal. Oral administration of BD greatly increased blood ketone levels and the ratio of β-hydroxybutyrate to acetoacetate. Normal animals fed BD had significantly lower blood glucose levels. Liver perfused with BD also showed decreased glucose production from lactate. Analysis of metabolites from livers perfused with BD showed a large increase in the lactate to pyruvate ratios (from 13.1 to 81.0). Malate and aspartate were increased, whereas pyruvate, PEP, 2 PGA, and 3 PGA were decreased. It is concluded that BD exerts its hypoglycemic effect at the conversion of malate to oxalacetate and hence to PEP.
 
Article
The effects of 2-ethylamino-1,3,4-thiadiazole have been assessed in two patients with a disorder of uric acid metabolism and cerebral function. Patients with this inborn error of metabolism have marked overproduction of purine, and absent activity of hypoxanthine, guanine phosphoribosyl transferase. It was found that this uricogenic thiadiazole increased further, the elevated concentrations of uric acid in blood and urine. Clinical reactions were dramatic, required vigorous therapy, and suggested that the investigation of this compound should not be undertaken lightly in patients with this disease. There was an increase in the cumulative conversion of 14C-labeled glycine into urinary uric acid. These observations indicate that the increased de novo purine synthesis of this condition is capable of further increase. They suggest the possibility that the overproduction of purine found in the disease and that which follows thiadiazoles, are both related to the role of guanine nucleotide in the feedback regulation of purine synthesis.
 
Article
The metabolism of ornithine and putrescine was studied in vivo in chronically uremic and control rats. Rats were injected intraperitoneally with 1,4-14C-ornithine or 1,4-14C-putrescine and expired 14CO2 was collected for 4 hr. After injection of 1-14C-ornithine. 14CO2 expiration was decreased in uremic rats as compared to controls. Conversely, after 1,4-14C-putrescine injection, expiration of 14CO2 was increased in uremic rats as compared to controls. Four hours after the injection of 1-14C-ornithine, there was more radioactivity in liver and muscle and less radioactivity in kidney of uremic rats as compared to the respective sources in control rats. In uremic rats, 4 hr after 1,4-14C-putrescine injection, the radioactivity retained in the muscle and plasma was greater than in corresponding sources in control rats; whereas the radioactivity retained in uremic liver and kidney was similar to that of control rats. The greater putrescine-derived radioactivity retained in uremic tissues reflects either the retention of injection racer compounds, or retention or decreased catabolism of putrescine metabolites. From 14CO2 expiration data obtained, it appears that ornithine catabolism is reduced while putrescine catabolism is increased in uremia.
 
Article
Experimental cystathioninuria was induced in rats by administration of the cystathionine gamma-lyase inhibitor, D,L-propargylglycine. The cystathionine metabolites, cystathionine ketimine (CK) and perhydro-1,4-thiazepine-3,5-dicarboxylic acid (PHTZDC), were identified in whole brain and various regions of the brain in D,L-propargylglycine-treated rats. The concentration of CK and PHTZDC in whole brain and various regions of the brain increased gradually after administration of D,L-propargylglycine, and reached the highest value at about 20 hours. CK and PHTZDC accumulated in whole brain and various regions of the brain in proportion to the amount of accumulated cystathionine after D,L-propargylglycine administration. The concentration of these compounds in the cerebellum was higher versus the other regions of the rat brain.
 
Article
Experimental cystathioninuria was induced by injection of D,L-propargylglycine in rats. The novel cystathionine metabolites, N-monoacetylcystathionine (NAc-cysta), perhydro-1,4-thiazepine-3,5-dicarboxylic acid (PHTZDC), and cystathionine ketimine (CK), were identified previously in the urine of patients with cystathioninuria and D,L-propargylglycine-treated rats. In this study, we identified these compounds in the liver and kidney of D,L-propargylglycine-treated rats using liquid chromatography-mass spectrometry with an atmospheric pressure chemical ionization interface system (LC/APCI-MS) and an amino acid analyzer. The metabolism of these compounds in the liver and kidney of D,L-propargylglycine-treated rats was also studied. PHTZDC, NAc-cysta, and CK were accumulated in the rat tissues in proportion to the content of cystathionine after D,L-propargylglycine administration. The concentrations of these compounds in the liver were higher than those in the kidney, and these compounds reached maxima earlier in the liver than in the kidney.
 
Article
Our specific aim in a 10-year prospective study of 772 Cincinnati firemen (predominantly aged 26 to 46 years) was to determine the prevalence, attributes, and etiology of persistent hypobetalipoproteinemia, defined by entry low-density lipoprotein cholesterol (LDLC) less than 75 mg/dL. A second specific aim was to cross-sectionally assess hypocholesterolemia (defined by total serum cholesterol [TC] < 130 mg/dL) in 1,314 white and 165 black men aged 26 to 46 years in the National Health and Nutrition Examination Survey (NHANES I). The 141 black and 631 white firemen had 4,973 person-years of follow-up time (median, 7.1 yr/man). Of 772 men, 44 (5.7%) had entry LDL levels less than 75 mg/dL; they had a mean follow-up time of 7.3 yr/man. Of these 44 men, there were 12 (1.8% of the cohort) with entry LDLC less than 75 mg/dL, and at least 67% of their follow-up LDLC levels were less than 75. Their mean entry TC and LDLC levels were low (130 and 58 mg/dL), mean triglyceride (TG) was low (63 mg/dL), and mean high-density lipoprotein cholesterol (HDLC) was high (60 mg/dL), LDLC remained at less than 75 mg/dL in 81% of their follow-up samples. Their mean entry and follow-up cholesterol and LDLC did not differ (P > .1, 130 v 133 mg/dL and 58 v 63 mg/dL). Compared with 32 men with entry LDLC less than 75 mg/dL but with less than 87% of follow-up LDLC less than 75 mg/dL, the 12 men with persistently low LDLC had lower mean Quetelet indices and diastolic blood pressure at entry (2.36 v 2.58, P = .056; 73 v 80 mm Hg, P = .03) and on follow-up study (2.45 v 2.69, P = .04; 72 v 79 mm Hg, P = .05). Of 12 men with persistently low LDLC, two had truncated apolipoprotein (apo) B (familial hypobetalipoproteinemia, two had the apo E genotype 2/3, and two had acquired hypobetalipoproteinemia that antedated mortality from melanoma by 9 years and from alcoholism by 2 years. Comparable to white and black firemen aged 26 to 46 years, 2.9% and 3.6% of whom had entry serum TC less than 130 mg/dL, of 1,314 white and 165 black men in the NHANES I study (aged 26 to 46), 1.8% and 3.6% had hypocholesterolemia (entry TC < 130 mg/dL). Daily mean calorie, fat, and protein intake (grams per day) did not differ (P > .05) in men with entry TC less than 130 mg/dL compared with those with TC 130 to 230 or greater than 230 mg/dL. Hypocholesterolemia in white and black men in NHANES I could not be attributed to hypocaloric intake or to protein, fat, or carbohydrate undernutrition. There appear to be racial differences in the prevalence of hypocholesterolemia. Blacks comprised 18% of the firemen's cohort but 42% of those with persistent hypobetalipoproteinemia; among NHANES I subjects, 3.6% of blacks were hypocholesterolemic versus 1.8% of whites. Unless persistent hypobetalipoproteinemia reflects an underlying disease, alcoholism, etc., it is often heritable, and may be associated with a reduced likelihood of coronary heart disease (CHD) and with increased longevity.
 
Article
Fructose-1,6-bisphosphatase (FBPase) deficiency is an autosomal recessive disorder caused by a mutation of the fructose-1,6-bisphosphatase 1 (FBP1) gene and results in impaired gluconeogenesis. We describe a male patient with typical FBPase deficiency who presented with hypoglycemia and lactic acidosis. The FBPase activity in his peripheral leukocytes and liver was very low. We amplified and sequenced the entire FBP1 coding region of the patient and his family members. Direct and allele-specific sequence analysis of the FBP1 gene revealed that the proband had a compound heterozygote for the G164S and 838delT, which he inherited from his carrier parents. His father and mother had heterozygous 838delT and G164S mutations, respectively, without any symptoms of hypoglycemia. Gene tracking within the family revealed that his elder sister had a heterozygous G164S mutation without symptoms of hypoglycemia. A G164S mutation of FBP1 in a heterozygous pattern (G164S and InsG960_961) has been reported previously, but the heterozygous 838delT mutation is novel. Transient transfection studies using COS-7 cells demonstrated that FBPase proteins with G164S or 838delT mutations were enzymatically inactive. In conclusion, we report a new case of molecular diagnosis of FBPase deficiency and provide evidence that impaired FBPase activity may be caused by novel compound heterozygous mutations in the FBP1 gene.
 
Article
The purpose of this study was to determine the effect of insulin infusion on the glucose 1,6-bisphosphate (glucose 1,6-P2) content in skeletal muscle of insulin resistant man. Euglycemic (approximately 100 mg/dL) hyperinsulinemic clamps were performed on seven men with chronically elevated fasting plasma glycemia (228 +/- 13 mg/dL, mean +/- SE) who were insulin resistant (HIR) and five men with normal fasting glycemia (115 +/- 5 mg/dL) who were insulin resistant (NIR). Insulin was infused at successive rates of 40 and 400 mU/m2/min, and biopsies were obtained from the quadriceps femoris muscle before and after insulin infusion. The results were compared with those of normoglycemic insulin-sensitive (NIS) men. The insulin-resistant groups had significantly higher percent body fat values than did the NIS group. Glucose 1,6-P2 increased from 70 +/- 6, 49 +/- 9, and 67 +/- 3 mumols/kg dry weight in the basal state to 135 +/- 12 (P less than .001 v basal), 67 +/- 11 (P greater than .05) and 79 +/- 3 (P greater than .05) after 40 mU insulin in NIS, HIR, and NIR, respectively. Glucose 1,6-P2 increased to 147 +/- 12 (P less than .001 v basal), 91 +/- 15 (P less than .01) and 99 +/- 13 (P less than .05) mumols/kg dry weight after 400 mU insulin in NIS, HIR, and NIR, respectively. The increase in glucose 1,6-P2 in response to 40 mU insulin was only 28% and 18% in HIR and NIR, respectively, of that in NIS.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Article
Fructose-1,6-diphosphate (FDP) is an important naturally occurring intracellular metabolite with a direct regulatory role in many metabolic pathways. The most important and widely studied of the FDP effects has been its regulation of glycolysis, particularly the enzyme that synthesizes FDP--phosphofructokinase (PFK). Since it was observed experimentally that FDP does indeed modulate carbohydrate metabolism, we investigated whether FDP would similarly enhance carbohydrate utilization in man. The study used indirect calorimetry and was open to healthy adults (N = 45) of either sex and above legal age. After a steady metabolic state was obtained, 5 g of FDP (10%) was infused into a brachial vein. In 10 subjects, glucose (5 g) or FDP (5 g) was sequentially infused. The rapid intravenous infusion of FDP produced a slight but significant decrease in heart and respiration rates (P < .05). A significant increase in the serum concentration of inorganic phosphate (P < .0001) and the intraerythrocytic concentration of adenosine triphosphate (ATP) (P < .01) was also observed. The FDP infusion produced a decrease in plasma cholesterol and triglycerides (P < .001 and P < .01, respectively). The indirect calorimetric data indicate that the infusion produced a highly significant increase in the respiratory quotient ([RQ] P < .0001) and the energy derived from carbohydrates (P < .0001) and a significant decrease in the energy derived from lipids (P < .0001). Glucose infusion did not cause changes in any of the parameters. These data indicate that carbohydrate metabolism is stimulated by FDP.
 
Article
The in vitro transfer of free cholesterol (FC) between human serum lipoproteins in the absence of lecithin:cholesterol acyltransferase (LCAT) activity has been examined. The results show that the amount of FC that the high-density lipoprotein (HDL) and lipoprotein-deficient serum (LDS) fractions were able to capture from low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL) was proportional to the amount of FC present in d less than 1.063 lipoproteins. The presence of HDL increased this transfer markedly. These results indicate that, in the absence of LCAT activity, FC can transfer from lower-density lipoproteins to higher-density serum fractions, and this transfer might increase under hypercholesterolemic conditions. The possible importance of this phenomena in regard to the exchange of FC between serum lipoproteins and tissue cells is discussed.
 
Article
S-100b protein was detectable in the soluble fraction of thyroid tissue. The concentration of S-100b protein in thyroid carcinoma tissue was three to five times higher than in normal thyroid tissue and thyroid adenoma. It is, however, not higher in the thyroid tissue of Graves' disease. The increase of S-100b protein concentration was not remarkable in carcinomatous tissue of the stomach and other digestive organs. The calmodulin content in the thyroid carcinoma tissue increased but the increment was low compared to that of S-100b protein. These data suggest that S-100b protein may play a significant role in cell maturation or differentiation.
 
Article
Transforming growth factor beta-1 (TGFβ-1) causes apoptosis of many epithelial cells, including the prostate, but other secondary effects of TGFβ-1 may be important in carcinogenesis. In a human prostate cancer cell line (ALVA-101), we determined the effects of TGFβ-1 and TGFβ type I and II receptor antibody on cell proliferation and TGFβ-1 receptor binding. TGFβ-1 and -2 and TGFβ type II receptor mRNA expression levels were determined by polymerase chain reaction (PCR) and Northern blot analysis. A dose-responsive suppression (0.03 to 10 ng/mL) was observed for cells treated with TGFβ-1 from 3 to 7 days(P< .01). Untreated cells had 1.1 x 103(n = 3)TGFβ receptors per cell, with a K(d) of 0.20 nmol/L(n = 3) as determined by Scatchard analysis; treatment for 3 days with TGFβ-1 (1 ng/mL) reduced the receptor number (0.9 x 103) and the K(d) (0.12 nmol/L). Antibodies to TGFβ type I and II receptor stimulated proliferation with or without added TGFβ-1 (50% ± 5% above control, P < .01, n = 6). TGFβ-1 and -2 and TGFβ type II receptor mRNA expression was observed in untreated cells. In cells treated with TGFβ-1, TGFβ-1 mRNA was not affected by treatment, but expression levels of the TGFβ type II receptor and TGFβ-2 mRNA were moderately suppressed after 72 hours of treatment. Control cells actively produced TGFβ-1 as measured by radioimmunoassay. The active and inactive forms of TGFβ-1 were approximately equal, but TGFβ-2 was secreted in smaller quantities than TGFβ-1 and the inactive form of TGFβ-2 predominated, with very small amounts of the active form. Our results suggest that the human prostate cancer cell line ALVA-101 retains negative control of proliferation in response to TGFβ-1. Inhibition of endogenous TGFβ action by antibodies to its receptor enhances the growth of ALVA-101 human prostate cancer cells, suggesting that endogenous TGFβ exerts an inhibitory control on their growth and cellular function.
 
Article
The newly discovered intestinal hormone, glucagon-like peptide-1 (GLP-1) (proglucagon 78-107amide), stimulates insulin secretion and inhibits glucagon secretion in man and may therefore be anticipated to influence hepatic glucose production. To study this, we infused synthetic GLP-1 sequentially at rates of 25 and 75 pmol.kg-1.h-1 into eight healthy volunteers after an overnight fast and measured plasma concentrations of glucose, insulin, and glucagon and glucose turnover by a technique involving infusion of 3-3H-glucose. Plasma levels of GLP-1 increased by 21.3 +/- 3.1 and 75.4 +/- 3.2 pmol/L during the infusion, changes that were within physiologic limits. In a control experiment only saline was infused. During GLP-1 infusion, plasma glucose level decreased significantly (from 5.3 +/- 0.1 to 4.7 +/- 0.1 and 4.3 +/- 0.1 pmol/L at the end of the two infusion periods). Despite this, plasma insulin level increased significantly (from 20.5 +/- 2.9 to a peak value of 33.5 +/- 5.2 pmol/L during the second period), and plasma glucagon level decreased (from 9.3 +/- 1.7 to 7.1 +/- 1.0 pmol/L). Glucose rate of appearance (Ra) decreased significantly to 75% +/- 6% of the preinfusion values during GLP-1 infusion. Glucose disappearance rate (Rd) did not change significantly, but glucose clearance increased significantly compared with saline. All parameters of glucose turnover remained constant during saline infusion. We conclude that GLP-1 may potently control hepatic glucose production and glucose clearance through its effects on the pancreatic glucoregulatory hormones. The effect of GLP-1 on glucose production is consistent with its proposed use in the treatment of type II diabetes.
 
Article
This study investigates the influence of changes in impaired fasting glucose (IFG) criteria by the American Diabetes Association in 2003 in estimating the prevalence and cardiovascular risks in Taiwanese with fasting plasma glucose (FPG) between 100 and 109 mg/dL. Data came from a cross-sectional study on 1411 participants aged 30 years and older without known diabetes in southern Taiwan. Besides collection of anthropometric and biochemistry data, a 75-g oral glucose tolerance test was performed. The new IFG criteria additionally identified 14.2% of all participants as having IFG100, with FPG between 100 and 109 mg/dL, among which the percentage of normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus were 7.7%, 5.0%, and 1.5%, respectively. Mean body weight, body mass index, abdominal girth, systolic blood pressure, diastolic blood pressure (DBP), 2-hour glucose, and triglyceride were significantly higher in the IFG100 group than in normal fasting glucose (NFG) group (FPG, <100 mg/dL). Moreover, body weight, body mass index, systolic blood pressure, DBP, and 2-hour glucose were statistically higher in subgroups of IFG100/IGT than in NFG/NGT. In contrast, only DBP and 2-hour glucose were significantly higher in the IFG100/NGT group than in the NFG/NGT group. The 2003 criteria increased the prevalence of IFG and identified more IGT and diabetes. However, the increase of cardiovascular risks among newly identified IFG100 subjects came from those who concomitantly had IGT.
 
Article
The objective of the study was to understand the role in vivo of elevated plasma free fatty acids (FFA), insulin, and glucose levels in the development of steatosis and altered mitochondrial gene/protein expression. We studied 4 groups of Sprague-Dawley rats: (1) high-fat diet (HFD), (2) high-dose streptozotocin-induced diabetes (T1DM), (3) low-dose streptozotocin-induced diabetic rats on an HFD (T2DM), and (4) controls. Liver histology and expression of genes/proteins related to mitochondrial fatty acid oxidation and biogenesis were analyzed. Despite an attempt to compensate by increasing expression of genes of fatty acid oxidation (carnitine palmitoyl transferase-1/medium chain acyl-CoA dehydrogenase), the HFD and diabetic groups developed marked steatosis and suffered a significant reduction in mitochondrial biogenesis gene expression (nuclear respiratory factor 1/transcriptional factor A, mitochondrial). In T2DM rats, the combination of high glucose and FFA unexpectedly did not lead to greater fat accumulation than HFD alone. Greater steatosis in HFD vs T2DM (P < .001) correlated with impairment in the gene expression of PPAR-α (ie, fatty acid oxidation) and PGC1α, a major coactivator for mitochondrial biogenesis. Steatosis was not severe in insulin-deficient T1DM rats despite very elevated FFA and glucose levels. Increased carnitine palmitoyl transferase-1/medium chain acyl-CoA dehydrogenase/PPAR-α gene expression suggested inadequate adaptation to high FFA in both T1DM/T2DM rats. Hyperinsulinemia combined with elevated FFA is the key metabolic factor driving hepatic lipogenesis in vivo (HFD rats). Mitochondrial biogenesis (nuclear respiratory factor 1; transcriptional factor A, mitochondrial) is highly susceptible to FFA-induced steatosis. In contrast, hyperglycemia does not have an additive effect (T2DM) and leads to only a modest degree of steatosis in the absence of hyperinsulinemia, even when FFA are extremely elevated as in T1DM rats.
 
Article
The effect of T-1095, an inhibitor of renal glucose reabsorption, on hyperglycemia and the expression of Na+-glucose cotransporters (SGLTs) and facilitative glucose transporter 2 (GLUT2) in streptozotocin (STZ)-induced diabetic rats was examined. There was an elevation of blood glucose, hemoglobin A1c (HbA1c), kidney weight, and urinary excretion of both glucose and albumin in STZ rats. Administration of 0.03% and 0.1% (wt/wt diet) T-1095 to STZ rats for 4 weeks improved the hyperglycemia and dose-dependently decreased HbA1c. Moreover, treatment with 0.1% (wt/wt diet) T-1095 in STZ rats for 8 weeks not only reduced blood glucose and HbA1c, levels but also prevented the elevation of urinary albumin levels and kidney weight and the development of epithelial vacuolation. The expression of renal SGLT2, a major glucose transporter in the kidney, was not different in normal, STZ, and T-1095-treated STZ rats. In contrast, the elevated renal GLUT2 level in STZ rats was suppressed by T-1095. These data suggest that T-1095 improves hyperglycemia by suppressing the renal reabsorption of glucose, which results in a suppression of the development of functional and histological changes and abnormal expression of GLUT2 in the kidney.
 
Article
The objective was to examine maternal serum levels of resistin at 11 to 13 weeks' gestation in normal and pathological pregnancies. Serum resistin, pregnancy-associated plasma protein A (PAPP-A), and uterine artery pulsatility index (PI) at 11 to 13 weeks were measured in 480 singleton pregnancies, including 240 with normal outcome, 60 that subsequently developed preeclampsia (PE), 60 that developed gestational diabetes mellitus (GDM), 60 that delivered large for gestational age (LGA) neonates, and 60 that delivered small for gestational age (SGA) neonates. Each value in both the normal and pathological outcome groups was expressed as a multiple of the expected normal median (MoM), and the median MoM values in the outcome groups were compared. In the PE group, compared with the controls, there were an increase in median resistin (1.22 MoM, P = .003) and uterine artery PI (1.25 MoM, P < .0001) and a decrease in serum PAPP-A (0.72, P < .0001). There was no significant association between serum resistin with either uterine artery PI (P = .415) or serum PAPP-A (P = .290). In the SGA, LGA, and GDM groups, serum resistin MoM was not significantly different from that of the controls (P = .415, P = .702, and P = .549, respectively). In pregnancies that develop PE, maternal serum resistin concentration at 11 to 13 weeks is increased in a manner not related to altered placental perfusion or function. In pregnancies complicated by the development of GDM or delivery of SGA or LGA neonates, serum resistin is not significantly altered.
 
Article
Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) K121Q gene polymorphism has been suggested to be associated with the increased risk of developing type 2 diabetes mellitus (T2D), but relevant research results are still contradictory. To explore the relationship between ENPP1 K121Q gene polymorphism and T2D in the Chinese population, a meta-analysis was performed. Fourteen independent studies involving 11 855 subjects were retrieved from electronic databases. The pooled odds ratio (ORs) for the distribution of Q allele frequency of the ENPP1 K121Q gene and its corresponding 95% confidence interval (95% CI) were assessed using a random-effects model. Under an allelic model of inheritance, the distribution of Q allele frequency was 0.107 for the T2D group and 0.093 for the control group. The pooled OR for the distribution of Q allele frequency of ENPP1 K121Q gene was 1.29 (95% CI, 1.09-1.53; P(heterogeneity) = .006; I(2) = 55.6%). There was a significant association between ENPP1 K121Q gene polymorphism and T2D in the Chinese population (P = .003). Under a dominant model of inheritance, the KQ + QQ/KK value was 0.259 for the T2D group and 0.220 for the control group. The pooled OR for the KQ + QQ/KK value was 1.51 (95% CI, 1.20-1.91; P(heterogeneity) < .0001; I(2) = 71.8%). The association between ENPP1 K121Q gene polymorphism and T2D in the Chinese population followed a dominant model of inheritance (P = .0005). In the Chinese population, the ENPP1 K121Q gene polymorphism was implied to be involved with T2D susceptibility. People with the Q allele of the ENPP1 K121Q gene might be predisposed to T2D.
 
Article
11beta-hydroxysteroid dehydrogenase (11beta-HSD), an enzyme regulating mineralocorticoid like action of glucocorticoid, oxidizes active cortisol to inactive cortisone. Impaired activity of this enzyme is associated with apparent mineralocorticoid excess (AME) syndrome and is characterized by hypertension and hypokalemia. Recent investigations suggest the presence of hypertensive subjects with low activity of 11beta-HSD. The blood concentration ratio of cortisone/cortisol reflects the overall conversion of cortisol to cortisone and may be an index to assess the systemic activity of 11beta-HSD. We evaluated the peripheral blood concentration ratio of cortisone/cortisol as a possible marker to identify subjects with hypertension thought to represent impaired 11beta-HSD activity. We compared this ratio in healthy subjects and patients with diabetes mellitus (DM) or chronic renal failure (CRF). Peripheral blood samples were collected from 69 healthy subjects, 44 DM, and 36 CRF patients in the morning (9:00 to 11:00 AM). Twenty-six DM patients (59%) and 32 CRF patients (89%) met the criteria for having hypertension. Serum cortisol and cortisone concentrations were determined by high performance liquid chromatography (HPLC). All values for serum cortisone and cortisol levels were within the normal range. Serum cortisone/cortisol ratio in the healthy subjects was distributed with a range of 0.113 to 0.494 (median, 0.243). Compared with healthy subjects, DM and CRF patients had significantly low (P <.01) serum cortisone/cortisol levels (median, 0.188 [range, 0.092 to 0.313] in DM and 0.088 [range, 0.031 to 0.140] in CRF). Bimodal distribution of cortisone/cortisol, found in DM patients with hypertension, represented high- and low-ratio groups around the border of the ratio 0.2. Kidney function, DM duration, and complications varied between the high- and low-ratio groups. The low ratio group (<0.2), whose 11beta-HSD activity was considered low, had an increase in blood urea nitrogen (BUN) levels and experienced nephropathy, neuropathy, retinopathy, and prolonged DM duration when compared with the group with a ratio greater than 0.2. The data suggest that the serum cortisone/cortisol ratio reflects the change in 11beta-HSD activity and is dependent kidney function. This is a possible marker to evaluate glucocorticoid excess hypertension observed in DM and CRF patients.
 
Article
Objective: To examine maternal serum levels of retinol-binding protein-4 (RBP4) at 11-13 weeks' gestation in normal and pathological pregnancies. Methods: Serum RBP4 at 11-13 weeks was measured in 480 singleton pregnancies, including 240 with normal outcome, 60 that subsequently developed preeclampsia (PE), 60 that developed gestational diabetes mellitus (GDM), 60 that delivered large for gestational age (LGA) neonates and 60 that delivered small (SGA) neonates. The values in each adverse pregnancy outcome group were compared to those of normal pregnancies. Results: Serum concentration of RBP4 was not significantly different in women who subsequently developed PE (p=0.925), or GDM (p=0.074), or had pregnancies that led to delivery to SGA (p=0.085), LGA (p=0.332) neonates. Conclusion: Maternal serum RBP4 in the first trimester is not significantly altered in pathological pregnancies.
 
Article
Cardiovascular denervation complicating diabetes has been implicated in sudden cardiac death potentially by altering myocardial electrical stability and impairing myocardial blood flow. Scintigraphic evaluation of cardiac sympathetic integrity has frequently demonstrated deficits in distal left ventricular (LV) sympathetic innervation in asymptomatic diabetic subjects without abnormalities on cardiovascular reflex testing. However, the clinical significance and subsequent fate of these small regional defects is unknown. This study reports the results of a prospective observational study in which positron emission tomography (PET) with (-)-[11C]-meta-hydroxyephedrine ([11C]-HED) was used to evaluate the effects of glycemic control on the progression of small regional LV [11C]-HED retention deficits in 11 insulin-dependent diabetic subjects over a period of 3 years. The subjects were divided into two groups based on attained glycemic control during this period: group A contained six subjects with good glycemic control (individual mean HbA1c <8%), and group B contained five subjects with poor glycemic control (individual mean HbAlc > or =8%). Changes in regional [11C]-HED retention were compared with reference values obtained from 10 healthy aged-matched nondiabetic subjects. At baseline, abnormalities of [11C]-HED retention affected 7.3%+/-1.4% and 9.9%+/-6.6% of the LV in group A and B subjects, respectively, with maximal deficits of LV [ C]-HED retention involving the distal myocardial segments. At the final assessment in group A, the extent of the deficits in [11C]-HED retention decreased to involve only 1.7%+/-0.7% of LV (P<.05 v. baseline scan), with significant increases in [11C]-HED retention occurring in both the distal and proximal myocardial segments. In contrast, in group B with poor glycemic control, the extent of [11C]-HED deficits increased to involve 34%+/-3.5% of the LV (P<.01 v. baseline), with retention of [11C]-HED significantly decreasing in the distal segments ([11C]-HED retention index, 0.066+/-0.003 v. 0.057+/-0.002, P<.05, at baseline and final assessment, respectively). Poor glycemic control was associated with increased heterogeneity of LV [11C]-HED retention, since three of five group B subjects developed abnormally increased [11C]-HED retention in the proximal myocardial segments. In conclusion, defects in LV sympathetic innervation can regress or progress in diabetic subjects achieving good or poor glycemic control, respectively. In diabetic subjects with early cardiovascular denervation, institution of good glycemic control may prevent the development of myocardial sympathetic dysinnervation and enhanced cardiac risk.
 
Article
The adrenal venous blood in dogs was analyzed for its corticosteroid content by a fluorescence and the Silber-Porter method. Each animal received a constant ACTH infusion during the studies. The content of 17,21,di-hydroxy-20-ketosteroids which was determined by the Silber-Porter method did not change during Methopirapone infusion in doses which ranged from 0.3–5.13 mg./Kg./hr. The adrenal venous blood content of fluorescence-inducing substance fell precipitiously after initiating Methopirapone infusions. The relative suppression of adrenal output of fluorescence-inducing substance was utilized as a measure of the inhibition of adrenal 11-betahydroxylation. This measure of the effect of Methopirapone on adrenal steroidogenesis correlated well with the log dose of Methopirapone. The recovery of adrenal output of fluorescence-inducing substance after cessation of Methopirapone infusion varied considerably from one experiment to the next. Generally, however, the most rapid recoveries were seen in those experiments in which the smallest doses of Methopirapone were administered.
 
Top-cited authors
Charles J Glueck
  • Jewish Hospital Of Cincinnati
Ralph Defronzo
  • University of Texas Health Science Center at San Antonio
Claude Bouchard
  • Pennington Biomedical Research Center
John E Morley
  • Saint Louis University
Jean-Pierre Després
  • Laval University