Intermittent gait disturbance in idiopathic normal pressure hydrocephalus.

OBJECTIVES: We identified intermittent gait disturbance (IGD) observed in the mild stage of idiopathic normal pressure hydrocephalus (iNPH). The first purpose of this study was to clarify the temporal gait profile of IGD during long-distance gait. The second purpose was to confirm the difference in treatment effect after cerebrospinal fluid (CSF) shunting in patients with and without IGD. MATERIALS AND METHODS: Fourteen consecutive iNPH patients with mild gait disturbance with a timed up-and-go (TUG) of <20 seconds were prospectively enrolled in the study. All patients were asked "Do you experience gait difficulty after over five minutes of walking?" Seven "yes" patients formed the IGD group, and seven "no" patients formed the persistent gait disturbance (PGD) group. One day before and 7 days after CSF shunting, gait function was evaluated by the 6-minute walk test (6MWT) and TUG. RESULTS: Preoperatively, all patients in the IGD group demonstrated features of IGD during the 6MWT, characterized by a progressive pattern of decreased gait speed and step length with increased cadence and absence of leg pain. Post-operatively, these features of IGD improved in all patients. In the PGD group, preoperative walking did not significantly worsen during the 6MWT and did not significantly change 7 days after treatment. Improvement of gait symptoms 1 week after CSF shunting could be detected with 6MWT instead of TUG. CONCLUSIONS: Intermittent gait disturbance is not a rare symptom in mild stage of iNPH and may serve as an important clinical diagnostic marker for identifying mild iNPH patients.

Intraoperative 5-aminolevulinic acid-induced photodynamic diagnosis of metastatic brain tumors with histopathological analysis.

BACKGROUND: Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is a promising real-time navigation method in the surgical resection of malignant gliomas. In order to determine whether this method is applicable to metastatic brain tumors, we evaluated the usefulness of intraoperative fluorescence patterns and histopathological features in patients with metastatic brain tumors. METHODS: We retrospectively reviewed the cases of 16 patients with metastatic brain tumors who underwent intraoperative 5-ALA fluorescence-guided resection. Patients were given 20 mg/kg of 5-ALA orally 2 h prior to the surgery. High-powered excitation illumination and a low-pass filter (420, 450, or 500 nm) were used to visualize the fluorescence of protoporphyrin IX (PpIX), the 5-ALA metabolite. We evaluated the relationships between the fluorescence and histopathological findings in both tumoral and peritumoral brain tissue. RESULTS: Tumoral PpIX fluorescence was seen in only 5 patients (31%); in the remaining 11 patients (69%), there was no fluorescence in the tumor bulk itself. In 14 patients (86%), vague fluorescence was seen in peritumoral brain tissue, at a thickness of 2-6 mm. The histopathological examination found cancer cell invasion of adjacent brain tissue in 75% of patients (12/16), at a mean ± SD depth of 1.4 ± 1.0 mm (range 0.2-3.4 mm) from the microscopic border of the tumor. There was a moderate correlation between vague fluorescence in adjacent brain tissue and the depth of cancer cell invasion (P = 0.004). CONCLUSION: Peritumoral fluorescence may be a good intraoperative indicator of tumor extent, preceding more complete microscopic gross total resection. TRIAL REGISTRATION: Institutional Review Board of Osaka Medical College No. 42, registered February 17, 1998, and No. 300, registered April 1, 2008. They were retrospectively registered.

Combination of transcranial sonography, olfactory testing, and MIBG myocardial scintigraphy as a diagnostic indicator for Parkinson's disease.

BACKGROUND: Appropriate diagnostic biomarkers are useful for improving speed and accuracy of a diagnosis. Substantia nigra (SN) hyperechogenicity visualized by transcranial sonography (TCS), olfactory dysfunction, and the reduced uptake of (123) I-metaiodobenzylguanidine (MIBG) in myocardial scintigraphy have been suggested as potential biomarkers for the identification of Parkinson's disease (PD). OBJECTIVES: To evaluate the diagnostic potential of these tests and to determine whether combining them increases their diagnostic power. METHODS: Subjects were 44 patients with clinically diagnosed PD and 36 healthy controls. TCS of the SN, the odor stick identification test for Japanese (OSIT-J), and MIBG myocardial scintigraphy were conducted. RESULTS: Eleven patients with PD (25%) and four controls (11%) were excluded because of an insufficient acoustic temporal bone window in the TCS. Thus, 33 patients with PD and 32 healthy controls were finally included. The diagnostic sensitivity of TCS, OSIT-J, and MIBG myocardial scintigraphy was 78.8%, 84.8%, and 60.6%, respectively. The specificity of TCS and OSIT-J was 93.8% and 78.1%, respectively. The combination of TCS of the SN and OSIT-J substantially increased the sensitivity to a sufficient level for discriminating patients with PD from controls. CONCLUSION: TCS of the SN and olfactory testing play complementary roles in increasing diagnostic power in PD. As both tests are easy to perform, noninvasive, and inexpensive, the combination of TCS of the SN and olfactory testing may contribute to early and accurate diagnosis of PD.

GCIG-Consensus guideline for Long-term survivorship in gynecologic Cancer: A position paper from the gynecologic cancer Intergroup (GCIG) symptom benefit committee.

INTRODUCTION: Long-term survivors of gynecological cancers may be cured but still have ongoing health concerns and long-term side effects following cancer treatment. The aim of this brainstorming meeting was to develop recommendations for long-term follow-up for survivors from gynecologic cancer. METHODS: International experts, representing each member group within the Gynecologic Cancer InterGroup (GCIG), met to define long-term survival, propose guidelines for long term follow-up and propose ways to implement long term survivorship follow-up in clinical trials involving gynecological cancers. RESULTS: Long-term survival with/from gynecological cancers was defined as survival of at least five years from diagnosis, irrespective of disease recurrences. Review of the literature showed that more than 50% of cancer survivors with gynecological cancer still experienced health concerns/long-term side effects. Main side effects included neurologic symptoms, sleep disturbance, fatigue, sexual dysfunction, bowel and urinary problems and lymphedema. In this article, long-term side effects are discussed in detail and treatment options are proposed. Screening for second primary cancers and lifestyle counselling (nutrition, physical activity, mental health) may improve quality of life and overall health status, as well as prevent cardiovascular events. Clinical trials should address cancer survivorship and report patient reported outcome measures (PROMs) for cancer survivors. CONCLUSION: Long-term survivors after gynecological cancer have unique longer term challenges that need to be addressed systematically by care givers. Follow-up after completing treatment for primary gynecological cancer should be offered lifelong. Survivorship care plans may help to summarize cancer history, long-term side effects and to give information on health promotion and prevention.

Suppression of transcription factor PDX-1/IPF1/STF-1/IDX-1 causes no decrease in insulin mRNA in MIN6 cells.

The insulin gene transcription factor PDX-1/IPF1/STF-1/ IDX-1 plays a key role in directing beta cell-specific gene expressions. Recently, impairment of PDX-1 expression or activity has been observed in beta cell-derived HIT cells cultured under high glucose concentrations, and this has been suggested as a possible cause of the decrease in insulin gene transcription. To investigate the pathophysiological significance of PDX-1 as a determinant of the rate of insulin gene transcription, we suppressed its expression in beta cell-derived MIN6 cells using an antisense oligodeoxynucleotide (ODN) and searched for possible changes in the beta cell-specific gene expression. Treatment of MIN6 cells with an 18-mer phosphorothioate ODN complementary to a sequence starting at the translation initiation codon of PDX-1 caused a potent, concentration-dependent reduction in PDX-1 expression; addition of 2 microM antisense ODN could reduce PDX-1 expression to 14+/-4% of the control. There was also a decrease in its DNA binding to the insulin gene A element. Despite such suppression of PDX-1, Northern blot analysis revealed no decrease in the amount of insulin mRNA in the MIN6 cells. Similarly, no changes were detected in the transcription of the glucokinase or islet amyloid polypeptide gene, for which PDX-1 was shown to function as a transcription factor. Thus, our findings dispute the physiological significance of PDX-1 in determining the rate of insulin gene transcription. This means that other components constituting the transcription-controlling machinery need to be evaluated in order to understand the molecular basis of impaired insulin biosynthesis such as that observed due to glucose toxicity.

Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells.

Prolonged poor glycemic control in non-insulin-dependent diabetes mellitus patients often leads to a decline in insulin secretion from pancreatic beta cells, accompanied by a decrease in the insulin content of the cells. As a step toward elucidating the pathophysiological background of the so-called glucose toxicity to pancreatic beta cells, we induced glycation in HIT-T15 cells using a sugar with strong deoxidizing activity, D-ribose, and examined the effects on insulin gene transcription. The results of reporter gene analyses revealed that the insulin gene promoter is more sensitive to glycation than the control beta-actin gene promoter; approximately 50 and 80% of the insulin gene promoter activity was lost when the cells were kept for 3 d in the presence of 40 and 60 mM D-ribose, respectively. In agreement with this, decrease in the insulin mRNA and insulin content was observed in the glycation-induced cells. Also, gel mobility shift analyses using specific antiserum revealed decrease in the DNA-binding activity of an insulin gene transcription factor, PDX-1/IPF1/STF-1. These effects of D-ribose seemed almost irreversible but could be prevented by addition of 1 mM aminoguanidine or 10 mM N-acetylcysteine, thus suggesting that glycation and reactive oxygen species, generated through the glycation reaction, serve as mediators of the phenomena. These observations suggest that protein glycation in pancreatic beta cells, which occurs in vivo under chronic hyperglycemia, suppresses insulin gene transcription and thus can explain part of the beta cell glucose toxicity.

Identification of a portable repression domain and an E1A-responsive activation domain in Pax4: a possible role of Pax4 as a transcriptional repressor in the pancreas.

Pax4 is a paired-domain (PD)-containing transcription factor which plays a crucial role in pancreatic beta/delta-cell development. In this study, we characterized the DNA-binding and transactivation properties of mouse Pax4. Repetitive rounds of PCR-based selection led to identification of the optimal DNA-binding sequences for the PD of Pax4. In agreement with the conservation of the optimal binding sequences among the Pax family transcription factors, Pax4 could bind to the potential binding sites for Pax6, another member of the Pax family also involved in endocrine pancreas development. The overexpression of Pax4 in HIT-T15 cells dose dependently inhibited the basal transcriptional activity as well as Pax6-induced activity. Detailed domain mapping analyses using GAL4-Pax4 chimeras revealed that the C-terminal region of Pax4 contains both activation and repression domains. The activation domain was active in the embryonic kidney-derived 293/293T cells and embryonal carcinoma-derived F9 cells, containing adenoviral E1A protein or E1A-like activity, respectively but was inactive or very weakly active in other cells including those of pancreatic beta- and alpha-cell origin. Indeed, the exogenous overexpression of type 13S E1A in heterologous cell types could convert the activation domain to an active one. On the other hand, the repression domain was active regardless of the cell type. When the repression domain was linked to the transactivation domain of a heterologous transcription factor, PDX-1, it could completely abolish the transactivation potential of PDX-1. These observations suggest a primary role of Pax4 as a transcriptional repressor whose function may involve the competitive inhibition of Pax6 function. The identification of the E1A-responsive transactivation domain, however, indicates that the function of Pax4 is subject to posttranslational regulation, providing further support for the complexity of mechanisms that regulate pancreas development.

Effect of corosolic acid on postchallenge plasma glucose levels.

Corosolic acid (CRA) is a substance extracted from Lagerstroemia speciosa L. and has been reported to have biological activities in in vitro and experimental animal studies. In this study, 31 subjects were orally administered 10mg CRA or a placebo, on different occasions, in a capsule 5min before the 75-g oral glucose tolerance test (OGTT) in a double-blind and cross-over design. Nineteen subjects had diabetes, seven had impaired glucose tolerance, one had impaired fasting glucose, and four had normal glucose tolerance according to the 1998 WHO criteria. There were no significant differences in plasma glucose levels before and 30min after the administration. CRA treatment subjects showed lower glucose levels from 60min until 120min and reached statistical significance at 90min. In this study, we have shown for the first time that CRA has a lowering effect on postchallenge plasma glucose levels in vivo in humans.

Atherosclerosis in carotid artery of young IDDM patients monitored by ultrasound high-resolution B-mode imaging.

Ultrasound high-resolution B-mode imaging was used to assess the carotid arteries in 105 patients with insulin-dependent diabetes mellitus (IDDM), 4-25 years of age, with duration of diabetes ranging from 0.5-17 years, 529 patients with non-insulin-dependent diabetes (NIDDM), 31-86 years of age, with duration of diabetes ranging from 0.5-49 years, and 104 nondiabetic healthy subjects, 7-76 years of age, to determine the intimal plus medial thickness (IMT) of the arterial wall. The IMT values for IDDM patients 10-19 years of age (0.525 +/- 0.123 mm, n = 68) or 20-25 years of age (0.696 +/- 0.124 mm, n = 14) were significantly greater than those in age-matched nondiabetic subjects (0.444 +/- 0.057 mm, n = 12, P = 0.01169; 0.538 +/- 0.098 mm, n = 34, P < 0.00006). NIDDM patients showed IMT values equivalent to those in normal adults > or = 20 years of age. Multiple regression analysis showed that IMT in IDDM patients was positively related to the duration of diabetes (P = 0.00061) as well as to age (P = 0.00046). No other possible risk factors, such as serum total cholesterol level, serum high-density lipoprotein (HDL)-cholesterol level, serum low-density lipoprotein-cholesterol level, serum triglycerides, serum lipoprotein(a) level, or systolic or diastolic blood pressure, have shown significant correlations with IMT in IDDM patients. However, non-HDL-cholesterol, smoking, and systolic hypertension were independently responsible for increases in IMT values of NIDDM patients as well as age and duration of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity.

Oxidative stress is produced under diabetic conditions and possibly causes various forms of tissue damage in patients with diabetes. The aim of this study was to examine the involvement of oxidative stress in the progression of pancreatic beta-cell dysfunction in type 2 diabetes and to evaluate the potential usefulness of antioxidants in the treatment of type 2 diabetes. We used diabetic C57BL/KsJ-db/db mice, in whom antioxidant treatment (N-acetyl-L-cysteine [NAC], vitamins C plus E, or both) was started at 6 weeks of age; its effects were evaluated at 10 and 16 weeks of age. According to an intraperitoneal glucose tolerance test, the treatment with NAC retained glucose-stimulated insulin secretion and moderately decreased blood glucose levels. Vitamins C and E were not effective when used alone but slightly effective when used in combination with NAC. No effect on insulin secretion was observed when the same set of antioxidants was given to nondiabetic control mice. Histologic analyses of the pancreases revealed that the beta-cell mass was significantly larger in the diabetic mice treated with the antioxidants than in the untreated mice. As a possible cause, the antioxidant treatment suppressed apoptosis in beta-cells without changing the rate of beta-cell proliferation, supporting the hypothesis that in chronic hyperglycemia, apoptosis induced by oxidative stress causes reduction of beta-cell mass. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA, making the extent of insulin degranulation less evident. Furthermore, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), a beta-cell-specific transcription factor, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. In conclusion, our observations indicate that antioxidant treatment can exert beneficial effects in diabetes, with preservation of in vivo beta-cell function. This finding suggests a potential usefulness of antioxidants for treating diabetes and provides further support for the implication of oxidative stress in beta-cell dysfunction in diabetes.

The human glucokinase gene beta-cell-type promoter: an essential role of insulin promoter factor 1/PDX-1 in its activation in HIT-T15 cells.

The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription. An anti-IPF1 antiserum used in gel-mobility shift analysis supershifted the DNA protein complex formed with the hUPE3 probe and nuclear extracts from HIT-T15 cells, thus supporting the involvement of IPF1 in GK gene activation in HIT-T15 cells. In contrast to the insulin gene, however, neither the synergistic effect of the Pan1 expression on the IPF1-induced promoter activation nor the glucose responsiveness of the activity was observed for the GK gene promoter. These results revealed some conservative but unique features for the transcriptional regulation of the beta-cell-specific genes in humans. Being implicated in insulin and GK gene regulations as a common transcription factor, IPF1/STF-1/PDX-1 is likely to play an essential role in maintaining normal beta-cell functions.

PDX-1 induces insulin and glucokinase gene expressions in alphaTC1 clone 6 cells in the presence of betacellulin.

The pancreatic beta- and alpha-cells are developmentally related to each other but reveal diverse gene expression patterns. Among the two important transcription factors for insulin gene expression, IEF1 is present both in alpha- and beta-cells, but PDX-1/IPF1/STF-1/IDX-1, a homeodomain-containing transcription factor, is present in beta-cells but not in alpha-cells. To elucidate the function of PDX-1 in the expression of beta-cell-specific genes, we established stable alphaTC1 clone 6 (alphaTC1.6)-derived transfectants expressing PDX-1 and examined the changes in the gene expression patterns in them. The exogenous expression of PDX-1 in alphaTC1.6 cells alone could induce islet amyloid polypeptide (IAPP) mRNA expression in the cells but not the expression of insulin, glucokinase, or GLUT2 gene. However, when betacellulin was added to the medium, the PDX-1-expressing alphaTC1.6 cells, but not the control alphaTC1.6 cells, came to express insulin and glucokinase mRNAs. This did not occur with other growth factors such as epidermal growth factor, transforming growth factor alpha, and insulin-like growth factor I. GLUT2 mRNA remained undetectable in the PDX-1--expressing alphaTC1.6 cells. These observations demonstrate the potency of PDX-1 for the expression of the insulin, glucokinase, and IAPP genes and suggest that certain regulatory factors, which can partially be modified by betacellulin, also contribute to the beta-cell specificity of gene expression.

A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese.

Pax4 is one of the transcription factors that play an important role in the differentiation of islet beta-cells. We scanned the Pax4 gene in 200 unrelated Japanese type 2 diabetic patients and found a missense mutation (R121W) in 6 heterozygous patients and 1 homozygous patient (mutant allele frequency 2.0%). The mutation was not found in 161 nondiabetic subjects. The R121W mutation was located in the paired domain and was thought to affect its transcription activity through lack of DNA binding. Six of seven patients had family history of diabetes or impaired glucose tolerance, and four of seven had transient insulin therapy at the onset. One of them, a homozygous carrier, had relatively early onset diabetes and slowly fell into an insulin-dependent state without an autoimmune-mediated process. This is the first report of a Pax4 gene mutation that exhibits loss of function and seems to be associated with type 2 diabetes. This work provides significant implications for the Pax4 gene as one of the predisposing genes for type 2 diabetes in the Japanese.

Demonstration of two different processes of beta-cell regeneration in a new diabetic mouse model induced by selective perfusion of alloxan.

To clarify the regeneration process of pancreatic beta-cells, we established a new mouse model of diabetes induced by selective perfusion of alloxan after clamping the superior mesenteric artery. In this model, diabetes could be induced by the destruction of beta-cells in alloxan-perfused segments, while beta-cells in nonperfused segments were spared. Intraperitoneal glucose tolerance tests showed glucose intolerance, which gradually ameliorated and was completely normalized in 1 year with a concomitant increase of insulin content in the pancreas. Histological examination showed neo-islet formation in the alloxan-perfused segment and the proliferation of spared beta-cells in the nonperfused segment. In the alloxan-perfused segment, despite a marked reduction of islets in size and number at an early stage, both the number of islets, including islet-like cell clusters (ICCs), and the relative islet area significantly increased at a later stage. Increased single beta-cells and ICCs were located in close contact with duct cell lining, suggesting that they differentiated from duct cells and that such extra-islet precursor cells may be important for beta-cell regeneration in beta-cell-depleted segment. In addition to beta-cells, some nonhormone cells in ICCs were positive for nuclear insulin promoter factor 1, which indicated that most, if not all, nonhormone cells positive for this factor were beta-cell precursors. In the nonperfused segment, the islet area increased significantly, and the highest 5-bromo-2-deoxyuridine-labeling index in beta-cells was observed at day 5, while the number of islets did not increase significantly. This indicated that the regeneration of islet endocrine cells occurs mostly through the proliferation of preexisting intra-islet beta-cells in the nonperfused segment. In conclusion, the regeneration process of beta-cells varied by circumstance. Our mouse model is useful for studying the mechanism of regeneration, since differentiation and proliferation could be analyzed separately in one pancreas.

Structure and expression of a chicken insulin-like growth factor I precursor.

Insulin-like growth factor I (IGF-I) is a 70 amino acid growth-promoting polypeptide whose sequence and functions have been highly conserved among mammals. As an initial step in defining the role of IGF-I in other vertebrate species, we have isolated and characterized an IGF-I cDNA from the chicken. This cDNA encodes a 153 amino acid primary translation product which resembles in structure and sequence the IGF-IA protein of mammals. There is strong amino acid conservation between chicken and mammalian IGF-I throughout the entire protein. Sixty of 70 amino acids are identical in mature IGF-I among the chicken, rat, and human peptides, with five differences being localized to the C domain, and two to the D region. A comparable degree of amino acid identity is found in the COOH-terminal extension peptide (28/35 residues). At the NH2-terminus, where there is more amino acid divergence (32/48 identities), the most 5'-AUG codon is the only methionine residue conserved among all three species, suggesting that it functions as the authentic translation initiation site, an observation supported by cell-free studies of biosynthesis and cotranslational proteolytic processing. The pattern of IGF-I gene expression appears to be simpler in chickens than in mammals, since a single predominant mRNA of 2.6 kilobases can be detected in liver polyadenylated RNA on Northern blots. In the chicken, as in rats and humans, IGF-I mRNA is synthesized in multiple tissues, including liver, brain, skeletal muscle, and heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Evolution of insulin-like growth factor I (IGF-I): structure and expression of an IGF-I precursor from Xenopus laevis.

By means of a cloning strategy employing the polymerase chain reaction, we have isolated and characterized cDNAs for Xenopus laevis insulin-like growth factor I (IGF-I). These cDNAs encode a primary IGF-I translation product of 153 residues that demonstrates considerable amino acid sequence similarity with IGF-IA peptides from other species. Fifty-seven of 70 residues of the mature protein are identical among human, rat, chicken, and Xenopus IGF-I, while less amino acid conservation is found at the COOH-terminus (25/35 identities) or at the NH2-terminus (24/48 identities) of the precursor protein. Despite the lower degree of structural similarity at the NH2-terminus, in vitro studies of IGF-I biosynthesis and proteolytic processing support a conserved function for the atypically long 48 residue NH2-terminal signal sequence in directing the nascent IGF-I peptide through the secretory pathway. The 5'-untranslated region of Xenopus IGF-I mRNA matches the human, rat, and chicken sequences in greater than 90% of 279 nucleotides. IGF-I mRNAs from all four species encode a conserved upstream open reading frame of 14 amino acids starting 240-250 nucleotides 5' to the translation start site, suggesting a possible role for this region in modulating IGF-I gene expression. The X. laevis IGF-I gene is transcribed and processed into three mRNAs of 1.6, 2.1, and 3.0 kilobases in liver, and IGF-I mRNAs can be detected in liver, lung, heart, kidney, and peritoneal fat of adult animals. These studies demonstrate that both the IGF-I protein precursor and potential regulatory regions of IGF-I mRNA have been conserved during vertebrate evolution, and indicate that like several other polypeptide growth factors, IGF-I may be of fundamental importance in regulating specific aspects of growth and development in all vertebrates.

Effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy.

OBJECTIVE: Although some studies have suggested a direct action of troglitazone on vascular cells, its effects on diabetic vascular diseases have not been reported. We therefore investigated the effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy. RESEARCH DESIGN AND METHODS: A total of 30 patients with type 2 diabetes associated with microalbuminuria (urinary albumin-to-creatinine ratio [ACR] [milligrams per gram creatinine] ranging from 30 to 300 mg/g creatinine) were studied. They were randomly divided into two groups: patients treated with metformin (500 mg/day, n = 13) or with troglitazone (400 mg/day, n = 17) for 12 weeks. ACR, lipid profile, blood pressure, glycated hemoglobin, and plasma glucose during meal-load tests were measured every 4 weeks. RESULTS: Anthropometric indices (BMI and percent fat), lipid profile, and blood pressure did not change with either treatment. Fasting and postmeal glucose levels decreased similarly in the two groups. Decrements in glycated hemoglobin were greater in the metformin group at 4 and 8 weeks after the initiation of treatment (P < 0.05). Troglitazone reduced ACR (median [25-75th percentiles]) from 70 (49-195) to 40 (31-90) mg/g creatinine at 4 weeks (P = 0.021) and maintained these reduced levels throughout the treatment period (8 weeks: 35 [26-68], P = 0.007; 12 weeks: 43 [26-103], P = 0.047). Metformin did not change ACR throughout the 12 weeks. CONCLUSIONS: Troglitazone ameliorated microalbuminuria in diabetic nephropathy. Furthermore, our findings suggest that troglitazone has some effects on vascular cells other than lowering plasma glucose levels. Troglitazone might be useful for diabetic angiopathy, including nephropathy and coronary artery disease.

Carotid intima-media thickness in Japanese type 2 diabetic subjects: predictors of progression and relationship with incident coronary heart disease.

OBJECTIVE: To examine carotid intima-media thickness (IMT), predictors of its progression, and its relationship with incident coronary heart disease (CHD) in type 2 diabetic Japanese patients. RESEARCH DESIGN AND METHODS: Carotid IMT of 287 subjects with type 2 diabetes (mean age 61.6 years) without CHD or cerebrovascular disease was examined at baseline and after a mean follow-up of 3.1 years. RESULTS: The annual progression of IMT (means +/- SEM) was 0.04+/-0.004 mm/year. Stepwise multivariate analysis demonstrated that independent risk factors for progress of IMT were the initial IMT (P<0.001), the average HbA1c level (P<0.001), and age (P = 0.001). Both the initial IMT (odds ratio [OR] 4.9, 95% CI 1.7-14.1) and a low average HDL cholesterol (OR 0.2, 0.1-0.8) were identified as predictors of incident nonfatal CHD (angina pectoris or nonfatal myocardial infarction; 3-year incidence 10.1%) after adjusting for age, sex, average HbA1c, and other risk factors. CONCLUSIONS: The predictors of the progression of carotid IMT in Japanese type 2 diabetic subjects were its baseline thickness and the average HbA1c during the follow-up. Baseline carotid IMT and low HDL cholesterol predicted the incidence of nonfatal CHD.

Expression of insulin-like growth factor-I during chicken development.

We have investigated the expression of insulin-like growth factor-I (IGF-I) during ontogeny in the chick. IGF-I mRNA was first detectable in whole embryos on day 6, while serum IGF-I could be measured on day 9, the earliest time point examined. Serum IGF-I values rose 10-fold from about 3 ng/ml on day 10 to a prehatch peak of 30-35 ng/ml during days 15-17, and then declined to about 10 ng/ml at the time of hatching. On days 17 and 20 of incubation, IGF-I mRNA was detected in eye, skeletal muscle, and brain, but could not be found in liver or heart until after hatching. During the posthatch period, serum IGF-I rose from 10 ng/ml in the first week to 35-40 ng/ml during weeks 3-6, and liver IGF-I mRNA increased nearly 5-fold from weeks 1-7. The increases observed during weeks 1-3 correlated with a posthatch rise in serum GH from 21 to 37 ng/ml, although GH levels declined over the subsequent 4 weeks without an appreciable change in serum IGF-I values. By contrast, before embryonic day 12 no GH could be detected in the circulation, while IGF-I was 19 ng/ml on day 11. These observations suggest that there is both GH-dependent and GH-independent regulation of IGF-I gene expression in the chick, as has been found in mammals, and support the idea that IGF-I plays a role in chicken embryonic development.