A new mechanism of thyroid hormone receptor ß agonists ameliorating nonalcoholic steatohepatitis by inhibiting intestinal lipid absorption via remodeling bile acid profiles.

Excessive dietary calories lead to systemic metabolic disorders, disturb hepatic lipid metabolism, and aggravate nonalcoholic steatohepatitis (NASH). Bile acids (BAs) play key roles in regulating nutrition absorption and systemic energy homeostasis. Resmetirom is a selective thyroid hormone receptor ß (THRß) agonist and the first approved drug for NASH treatment. It is well known that the THRß activation could promote intrahepatic lipid catabolism and improve mitochondrial function, however, its effects on intestinal lipid absorption and BA compositions remain unknown. In the present study, the choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) and high-fat diet plus CCl4 (HFD+CCl4)-induced NASH mice were used to evaluate the effects of resmetirom on lipid and BA composition. We showed that resmetirom administration (10 mg·kg-1·d-1, i.g.) significantly altered hepatic lipid composition, especially reduced the C18:2 fatty acyl chain-containing triglyceride (TG) and phosphatidylcholine (PC) in the two NASH mouse models, suggesting that THRß activation inhibited intestinal lipid absorption since C18:2 fatty acid could be obtained only from diet. Targeted analysis of BAs showed that resmetirom treatment markedly reduced the hepatic and intestinal 12-OH to non-12-OH BAs ratio by suppressing cytochrome P450 8B1 (CYP8B1) expression in both NASH mouse models. The direct inhibition by resmetirom on intestinal lipid absorption was further verified by the BODIPY gavage and the oral fat tolerance test. In addition, disturbance of the altered BA profiles by exogenous cholic acid (CA) supplementation abolished the inhibitory effects of resmetirom on intestinal lipid absorption in both normal and CDAHFD-fed mice, suggesting that resmetirom inhibited intestinal lipid absorption by reducing 12-OH BAs content. In conclusion, we discovered a novel mechanism of THRß agonists on NASH treatment by inhibiting intestinal lipid absorption through remodeling BAs composition, which highlights the multiple regulation of THRß activation on lipid metabolism and extends the current knowledge on the action mechanisms of THRß agonists in NASH treatment.

Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice.

Promotion of hepatic glycogen synthesis and inhibition of hepatic glucose production are effective strategies for controlling hyperglycemia in type 2 diabetes mellitus (T2DM), but agents with both properties were limited. Herein we report coronarin A, a natural compound isolated from rhizomes of Hedychium gardnerianum, which simultaneously stimulates glycogen synthesis and suppresses gluconeogenesis in rat primary hepatocytes. We showed that coronarin A (3, 10 µM) dose-dependently stimulated glycogen synthesis accompanied by increased Akt and GSK3ß phosphorylation in rat primary hepatocytes. Pretreatment with Akt inhibitor MK-2206 (2 µM) or PI3K inhibitor LY294002 (10 µM) blocked coronarin A-induced glycogen synthesis. Meanwhile, coronarin A (10 µM) significantly suppressed gluconeogenesis accompanied by increased phosphorylation of MEK, ERK1/2, ß-catenin and increased the gene expression of TCF7L2 in rat primary hepatocytes. Pretreatment with ß-catenin inhibitor IWR-1-endo (10 µM) or ERK inhibitor SCH772984 (1 µM) abolished the coronarin A-suppressed gluconeogenesis. More importantly, we revealed that coronarin A activated PI3K/Akt/GSK3ß and ERK/Wnt/ß-catenin signaling via regulation of a key upstream molecule IRS1. Coronarin A (10, 30 µM) decreased the phosphorylation of mTOR and S6K1, the downstream target of mTORC1, which further inhibited the serine phosphorylation of IRS1, and subsequently increased the tyrosine phosphorylation of IRS1. In type 2 diabetic ob/ob mice, chronic administration of coronarin A significantly reduced the non-fasting and fasting blood glucose levels and improved glucose tolerance, accompanied by the inhibited hepatic mTOR/S6K1 signaling and activated IRS1 along with enhanced PI3K/Akt/GSK3ß and ERK/Wnt/ß-catenin pathways. These results demonstrate the anti-hyperglycemic effect of coronarin A with a novel mechanism by inhibiting mTORC1/S6K1 to increase IRS1 activity, and highlighted coronarin A as a valuable lead compound for the treatment of T2DM.

Development and structure-activity relationships of tanshinones as selective 11ß-hydroxysteroid dehydrogenase 1 inhibitors.

11ß-Hydroxysteroid dehydrogenase 1 (11ß-HSD1) represents a promising drug target for metabolic syndrome, including obesity and type 2 diabetes. Our initial screen of a collection of natural products from Danshen led to the identification of tanshinones as the potent and selective 11ß-HSD1 inhibitors. To improve the druggability and explore the structure-activity relationships (SARs), more than 40 derivatives have been designed and synthesized using tanshinone IIA and cryptotanshinone as the starting materials. More than 10 derivatives exhibited potent in vitro 11ß-HSD1 inhibitory activity and good selectivity over 11ß-HSD2 across human and mouse species. Based on the biological results, SARs were further discussed, which was also partially rationalized by a molecular docking model of 1 bound to the 11ß-HSD1. Remarkably, compounds 1, 17 and 30 significantly inhibited 11ß-HSD1 in 3T3-L1 adipocyte and in livers of ob/ob mice, which merits further investigations as anti-diabetic agents. This study not only provides a series of novel selective 11ß-HSD1 inhibitors with promising therapeutic potentials in metabolic syndromes, but also expands the boundaries of the chemical and biological spaces of tanshinones.

Spicatulides A-G, Phenolic-Monoterpenoid Hybrids from Chloranthus spicatus.

Spicatulides A-G (1-7), seven new phenolic-monoterpenoid hybrid molecules, along with two known compounds, 8 and 9, were isolated and identified from Chloranthus spicatus. Compound 1 represents an unprecedented skeleton featuring an aryl-fused 2-oxabicyclo[4.3.1]decane moiety, and compound 2 is the first example of a denudaquinol-normonoterpenoid adduct. Their structures with absolute configurations were elucidated on the basis of spectroscopic data analyses and TDDFT-ECD calculations. Compounds 3, 5, 6, and 9 exhibited the activity of reducing lipogenesis in HepG2 cells in a dose-dependent manner.

SL010110, a lead compound, inhibits gluconeogenesis via SIRT2-p300-mediated PEPCK1 degradation and improves glucose homeostasis in diabetic mice.

Suppression of excessive hepatic gluconeogenesis is an effective strategy for controlling hyperglycemia in type 2 diabetes (T2D). In the present study, we screened our compounds library to discover the active molecules inhibiting gluconeogenesis in primary mouse hepatocytes. We found that SL010110 (5-((4-allyl-2-methoxyphenoxy) methyl) furan-2-carboxylic acid) potently inhibited gluconeogenesis with 3 µM and 10 µM leading to a reduction of 45.5% and 67.5%, respectively. Moreover, SL010110 caused suppression of gluconeogenesis resulted from downregulating the protein level of phosphoenolpyruvate carboxykinase 1 (PEPCK1), but not from affecting the gene expressions of PEPCK, glucose-6-phosphatase, and fructose-1,6-bisphosphatase. Furthermore, SL010110 increased PEPCK1 acetylation, and promoted PEPCK1 ubiquitination and degradation. SL010110 activated p300 acetyltransferase activity in primary mouse hepatocytes. The enhanced PEPCK1 acetylation and suppressed gluconeogenesis caused by SL010110 were blocked by C646, a histone acetyltransferase p300 inhibitor, suggested that SL010110 inhibited gluconeogenesis by activating p300. SL010110 decreased NAD+/NADH ratio, inhibited SIRT2 activity, and further promoted p300 acetyltransferase activation and PEPCK1 acetylation. These effects were blocked by NMN, an NAD+ precursor, suggested that SL010110 inhibited gluconeogenesis by inhibiting SIRT2, activating p300, and subsequently promoting PEPCK1 acetylation. In type 2 diabetic ob/ob mice, single oral dose of SL010110 (100 mg/kg) suppressed gluconeogenesis accompanied by the suppressed hepatic SIRT2 activity, increased p300 activity, enhanced PEPCK1 acetylation and degradation. Chronic oral administration of SL010110 (15 or 50 mg/kg) significantly reduced the blood glucose levels in ob/ob and db/db mice. This study reveals that SL010110 is a lead compound with a distinct mechanism of suppressing gluconeogenesis via SIRT2-p300-mediated PEPCK1 degradation and potent anti-hyperglycemic activity for the treatment of T2D.

Structural Elucidation and Bioinspired Total Syntheses of Ascorbylated Diterpenoid Hongkonoids A-D.

Hongkonoids A-D (1-4), the first example of ascorbylated terpenoids featuring a unique 5,5,5-fused tricyclic spiroketal butyrolactone moiety and diterpenoid-derived long chain, were isolated from Dysoxylum hongkongense. Their structures were unambiguously assigned by a combination of spectroscopic data, chemical degradation, X-ray crystallography, CD analysis, and total synthesis. The total syntheses of compounds 1-4 were effectively accomplished by a convergent strategy with the longest linear sequences of 12-14 steps and overall yields of 5.4-9.6%. Notably, we exploited a bioinspired one-pot method to construct the key intermediate 14 from an easily made compound 12 by involving the cascade reactions of an elaborate Claisen rearrangement, deprotections, and a 5-exo-trig cyclization. The desired major epimer 14a was then transformed to the main building block 21. Assembly of 21 and the long chain vinyl iodide 7 was made by an NHK coupling reaction to furnish the framework of 1-4. Some of the hongkonoids and/or synthetic analogs showed significant to moderate inhibitory activities against NF-κB, 11ß-HSD1, and sterol synthesis. The most active NF-κB inhibitor 34 exhibited distinct inhibition on the LPS-induced inflammatory responses in RAW 246.7 and primary BMDM cells.

AICAR and Metformin Exert AMPK-dependent Effects on INS-1E Pancreatic ß-cell Apoptosis via Differential Downstream Mechanisms.

The role of AMP-activated protein kinase (AMPK) in pancreatic ß-cell apoptosis is still controversial, and the reasons for the discrepancies have not been clarified. In the current study, we observed the effects of two well-known AMPK activators 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and metformin, on apoptosis in rat insulinoma INS-1E cells, and further explored their possible mechanisms. Both AICAR and metformin protected INS-1E cells from palmitate-induced apoptosis, as reflected by decreases in both cleaved caspase 3 protein expression and caspase 3/7 activity, and these protective effects were abrogated by AMPK inhibitor compound C. The protective action of AICAR was probably mediated by the suppression of triacylglycerol accumulation, increase in Akt phosphorylation and decrease in p38 MAPK phosphorylation, while metformin might exert its protective effect on INS-1E cells by decreases in both JNK and p38 MAPK phosphorylation. All these regulations were dependent on AMPK activation. However, under standard culture condition, AICAR increased JNK phosphorylation and promoted INS-1E cell apoptosis in an AMPK-dependent manner, whereas metformin showed no effect on apoptosis. Our study revealed that AMPK activators AICAR and metformin exhibited different effects on INS-1E cell apoptosis under different culture conditions, which might be largely attributed to different downstream mediators. Our results provided new and informative clues for better understanding of the role of AMPK in ß-cell apoptosis.

HC toxin (a HDAC inhibitor) enhances IRS1-Akt signalling and metabolism in mouse myotubes.

Exercise enhances numerous signalling pathways and activates substrate metabolism in skeletal muscle. Small molecule compounds that activate these cellular responses have been shown to recapitulate the metabolic benefits of exercise. In this study, a histone deacetylase (HDAC) inhibitor, HC toxin, was investigated as a small molecule compound that activates exercise-induced adaptations. In C2C12 myotubes, HC toxin treatment activated two exercise-stimulated pathways: AMP-activated protein kinase (AMPK) and Akt pathways. HC toxin increased the protein content and phosphorylation of insulin receptor substrate 1 as well as the activation of downstream Akt signalling. The effects of HC toxin on IRS1-Akt signalling were PI3K-dependent as wortmannin abolishes its effects on IRS1 protein accumulation and Akt phosphorylation. HC toxin-induced Akt activation was sufficient to enhance downstream mTOR complex 1 (mTORC1) signalling including p70S6K and S6, which were consistently abolished by PI3K inhibition. Insulin-stimulated glucose uptake, glycolysis, mitochondrial respiration and fatty acid oxidation were also enhanced in HC toxin-treated myotubes. When myotubes were challenged with serum starvation for the induction of atrophy, HC toxin treatment prevented the induction of genes that are involved in autophagy and proteasomal proteolysis. Conversely, IRS1-Akt signalling was not induced by HC toxin in several hepatoma cell lines, providing evidence for a favourable safety profile of this small molecule. These data highlight the potential of HDAC inhibitors as a novel class of small molecules for the induction of exercise-like signalling pathways and metabolism.

Yhhu981, a novel compound, stimulates fatty acid oxidation via the activation of AMPK and ameliorates lipid metabolism disorder in ob/ob mice.

AIM: Defects in fatty acid metabolism contribute to the pathogenesis of insulin resistance and obesity. In this study, we investigated the effects of a novel compound yhhu981 on fatty acid metabolism in vitro and in vivo. METHODS: The capacity to stimulate fatty acid oxidation was assessed in C2C12 myotubes. The fatty acid synthesis was studied in HepG2 cells using isotope tracing. The phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) was examined with Western blot analysis. For in vivo experiments, ob/ob mice were orally treated with yhhu981 acutely (300 mg/kg) or chronically (150 or 300 mg·kg(-1)·d(-1) for 22 d). On the last day of treatment, serum and tissue samples were collected for analysis. RESULTS: Yhhu981 (12.5-25 µmol/L) significantly increased fatty acid oxidation and the expression of related genes (Sirt1, Pgc1α and Mcad) in C2C12 myotubes, and inhibited fatty acid synthesis in HepG2 cells. Furthermore, yhhu981 dose-dependently increased the phosphorylation of AMPK and ACC in both C2C12 myotubes and HepG2 cells. Compound C, an AMPK inhibitor, blocked fatty acid oxidation in yhhu981-treated C2C12 myotubes and fatty acid synthesis decrease in yhhu981-treated HepG2 cells. Acute administration of yhhu981 decreased the respiratory exchange ratio in ob/ob mice, whereas chronic treatment with yhhu981 ameliorated the lipid abnormalities and ectopic lipid deposition in skeletal muscle and liver of ob/ob mice. CONCLUSION: Yhhu981 is a potent compound that stimulates fatty acid oxidation, and exerts pleiotropic effects on lipid metabolism by activating AMPK.

Emodin, an 11ß-hydroxysteroid dehydrogenase type 1 inhibitor, regulates adipocyte function in vitro and exerts anti-diabetic effect in ob/ob mice.

AIM: Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a potent and selective inhibitor of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) with the ability to ameliorate metabolic disorders in diet-induced obese mice. In the present study, we investigated the effects of emodin on adipocyte function and the underlying mechanisms in vitro, and its anti-diabetic effects in ob/ob mice. METHODS: 3T3-L1 adipocytes were used for in vitro studies. 11ß-HSD1A activity was evaluated with a scintillation proximity assay. The adipogenesis, glucose uptake, lipolysis and adiponectin secretion were investigated in 3T3-L1 adipocytes treated with emodin in the presence of active (corticosterone) or inactive glucocorticoid (11-dehydrocorticosterone). For in vivo studies, ob/ob mice were administered emodin (25 and 50 mg·kg⁻¹·d⁻¹, ip) for 26 d. On the last day of administration, the serum was collected and the mesenteric and perirenal fat were dissected for analyses. RESULTS: Emodin inhibited the 11ß-HSD1 activity in 3T3-L1 adipocytes in concentration- and time-dependent manners (the IC50 values were 7.237 and 4.204 µmol/L, respectively, after 1 and 24 h treatment. In 3T3-L1 adipocytes, emodin (30 µmol/L) suppressed 11-dehydrocorticosterone-induced adipogenesis without affecting corticosterone-induced adipogenesis; emodin (3 µmol/L) reduced 11-dehydrocorticosterone-stimulated lipolysis, but had no effect on corticosterone-induced lipolysis. Moreover, emodin (3 µmol/L) partly reversed the impaired insulin-stimulated glucose uptake and adiponectin secretion induced by 11-dehydrocorticosterone but not those induced by corticosterone. In ob/ob mice, long-term emodin administration decreased 11ß-HSD1 activity in mesenteric adipose tissues, lowered non-fasting and fasting blood glucose levels, and improved glucose tolerance. CONCLUSION: Emodin improves the inactive glucocorticoid-induced adipose tissue dysfunction by selective inhibition on 11ß-HSD1 in adipocyte in vitro and improves glycemic control in ob/ob mice.

Emodin, a natural product, selectively inhibits 11beta-hydroxysteroid dehydrogenase type 1 and ameliorates metabolic disorder in diet-induced obese mice.

BACKGROUND AND PURPOSE: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an attractive therapeutic target of type 2 diabetes and metabolic syndrome. Emodin, a natural product and active ingredient of various Chinese herbs, has been demonstrated to possess multiple biological activities. Here, we investigated the effects of emodin on 11beta-HSD1 and its ability to ameliorate metabolic disorders in diet-induced obese (DIO) mice. EXPERIMENTAL APPROACH: Scintillation proximity assay was performed to evaluate inhibition of emodin against recombinant human and mouse 11beta-HSDs. The ability of emodin to inhibit prednisone- or dexamethasone-induced insulin resistance was investigated in C57BL/6J mice and its effect on metabolic abnormalities was observed in DIO mice. KEY RESULTS: Emodin is a potent and selective 11beta-HSD1 inhibitor with the IC(50) of 186 and 86 nM for human and mouse 11beta-HSD1, respectively. Single oral administration of emodin inhibited 11beta-HSD1 activity of liver and fat significantly in mice. Emodin reversed prednisone-induced insulin resistance in mice, whereas it did not affect dexamethasone-induced insulin resistance, which confirmed its inhibitory effect on 11beta-HSD1 in vivo. In DIO mice, oral administration of emodin improved insulin sensitivity and lipid metabolism, and lowered blood glucose and hepatic PEPCK, and glucose-6-phosphatase mRNA. CONCLUSIONS AND IMPLICATIONS: This study demonstrated a new role for emodin as a potent and selective inhibitor of 11beta-HSD1 and its beneficial effects on metabolic disorders in DIO mice. This highlights the potential value of analogues of emodin as a new class of compounds for the treatment of metabolic syndrome or type 2 diabetes.

Increased risks of congenital, neurologic, and endocrine disorders associated with autism in preschool children: cognitive ability differences.

OBJECTIVE: To investigate the increased risk of congenital, neurologic, and endocrine disorders in autistic preschool children and to probe possible cognitive impairment-associated variation in such risks. STUDY DESIGN: Using a population-based longitudinal study, a total of 3440 autistic children born in 1997-1999 and 33,391 age- and residential urbanicity-matched control subjects were identified from the National Health Insurance Research Database in Taiwan. Conditional logistic analyses were performed to estimate the strength of association stratified by the presence of cognitive impairment. RESULTS: Autistic children were found to have greatly elevated risks of congenital anomalies (eg, tuberous sclerosis: adjusted odds ratio [aOR] = 34 approximately 61) and neurologic disorders (eg, epilepsy: aOR = 5 approximately 13) compared with their matched nonautistic peers. The increased risk of medical diseases for mentally retarded autism were approximately 1.6 to 9 times greater than those for isolated autism. CONCLUSIONS: The observed cognitive impairment-related variation in the increased risk of congenital, neurological, and endocrine disorders with autism may provide some clinical and etiologic implications that warrant investigation in the future.

Transition from alcohol to other drugs among adolescents in Taiwan: the first drinking context matters.

OBJECTIVE: This study examined the extent to which youthful alcohol consumption and the initiation of tobacco, betel nut, and other illegal drugs may differ by their first drinking context in Taiwan-a society with social norms that are more tolerant of underage drinking. METHOD: In 2004, in a nationally representative sample of 11,943 school-attending youth ages 15-18, information pertaining to sociodemographic characteristics, problem behaviors, lifetime experiences of alcohol, tobacco, betel nut, and illegal drugs, as well as psychoactive, drug-specific age of initiation, context at first use, average frequency, and recency of use, was assessed by anonymous questionnaires. RESULTS: Youth who had their first alcoholic beverages in entertainment settings or at friends' houses were more likely to become frequent drinkers. After adjustment for socioeconomic background and problem behaviors, having had the first drink in entertainment settings was associated with a faster progression into the initiation of illegal drugs (hazard ratio [HR]=2.5, 95% confidence interval [CI]: 1.5-4.0) and betel nut (HR=1.5, 95% CI: 1.1-2.1). CONCLUSIONS: Youthful drinking pattern and transition from alcohol to betel nut and illegal drugs may vary modestly by the first drinking context. This context may be recognized as a proxy variable to identify youth at a higher risk for alcohol and other drug problems and to devise context-based educational or prevention programs.

Early alcohol experiences and adolescent mental health: a population-based study in Taiwan.

In this study, we examine whether adolescent emotional and behavior problems vary by history of early alcohol experiences. A national sample of 6974 alcohol-naïve and 4337 alcohol-experienced youths aged 15-18 years were identified within the 2004 National Survey of Illegal Drug Use among Adolescents in Taiwan. Four alcohol experience groups were created based on recency and frequency of alcohol use: (1) naïve; never drank alcohol, (2) trial use; first and only consumption of alcohol occurred more than 6 months preceding the assessment, (3) past use; alcohol used on more than one occasion but had not had a drink in the 6 months prior to the assessment, and (4) current use; consumed alcohol more than once and drank within the 6 months preceding the interview. A Chinese adaptation of the Youth Self-Report (YSR) assessed eight behavior syndromes: withdrawn, anxious/depressed, somatic complaints, social problems, thought problems, attention problems, rule-breaking behavior, and aggressive behavior. Multivariate response models (GLM/GEE) were used to examine the relationship of alcohol experiences with emotional and behavior problems. Alcohol-using youth were more likely to experience several specific emotional or behavioral syndromes than their alcohol-naïve counterparts. For example, youth with a history of alcohol use had an estimated 30-60% increase in the odds of experiencing items within the aggressive behavior syndrome as compared with alcohol-naïve youth. The type of early alcohol involvement in adolescence may exert differential effects on emotions and behaviors expressed across and within syndromes; these may warrant distinctions in informing etiological research and preventive efforts.

Urbanicity-related variation in help-seeking and services utilization among preschool-age children with autism in Taiwan.

The present study examines urbanicity-related differences in help-seeking process among preschool children with autism and investigates the factors associated with utilization of autism-related services within the year of diagnosis. Using the 1997-2004 National Health Insurance Research Database (NHIRD) in Taiwan, we identified a total of 3495 autistic children born in 1997-1999 and 13964 matched controls. Results indicate that suburban and rural autism tended to receive the diagnosis at an older age and to have a longer diagnosis process as compared with urban counterparts. Male gender, a younger age of diagnosis, and being diagnosed by psychiatric specialty strongly predict subsequent greater utilization of autism-specific services (all p < 0.05). Health policy makers and other service providers should address the needs of children with early-onset neurodevelopmental disorders in rural areas, particularly those from disadvantaged families.

Factors associated with the diagnosis of neurodevelopmental disorders: a population-based longitudinal study.

OBJECTIVES: We investigated the occurrence of newly diagnosed mental retardation, attention-deficit/hyperactivity disorder, and autism and sociodemographic factors associated with their distribution in Taiwan, and we examined urbanicity- and socioeconomic status-associated differences in the age at first diagnosis. METHODS: The data for this study were derived from the 1996-2004 National Health Insurance Research Database in Taiwan. Approximately 1.8 million beneficiaries born between 1996 and 2001 were identified, with follow-up periods ranging from 3 to 8 years. RESULTS: Each of the 3 neurodevelopmental disorders had distinct incidence rates and associated factors. For example, as compared with the birth years of 1996-1999, the rate of autism increased 14% during the period 2000-2004, whereas the rate of newly diagnosed mental retardation decreased 42% to 50% over the same period. An elevated incidence rate for attention-deficit/hyperactivity disorder and autism was observed in later birth cohorts. The risk of receiving a diagnosis of mental retardation for children in rural areas and of lower socioeconomic status was reduced in early childhood and increased in school ages as compared with their urban and higher socioeconomic status counterparts. CONCLUSIONS: Variation in the rate of newly diagnosed mental retardation, attention-deficit/hyperactivity disorder, and autism among children in Taiwan depended on age, birth year, period, and socioeconomic status. The extent of the association linking age with the first diagnosis of mental retardation varies across different urbanicity level and socioeconomic status.