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Bone is now regarded as an endocrine organ modulating energy metabolism. Osteocalcin, which was a traditional bone remodeling marker, especially in its undercarboxylated form, was believed to be a metabolic active molecule involving in glucose homeostasis. Bone can uptake glucose through glucose transporter 1 expressed on osteoblasts, and this process is crucial for osteoblasts differentiation and bone formation. In addition, the osteoblasts specific insulin resistance may also lead to the dysregulation of whole body glucose metabolism. Clinical investigations generally echo the findings from mice studies. More work, especially prospective clinical studies are needed to prove the clinical utility of osteocalcin and/or other bone turnover parameters as solid predictors of pancreaticβcell function and incident diabetes, as well as the potential use of osteocalcin and/or its undercarboxylated form as an anti-diabetic agent. In the 11th issue of Diabetes in 2016, a review paper entitled asRegulation of glucose handling by the skeleton:Insights from mouse and human studies was published [Diabetes, 2016,65(11):3225-3232]. With the permission of Diabetes and American Diabetes Association, we translated the most important part of this review into Chinese with a new title:The regulatory role of skeleton in maintaining glucose homeostasis.
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More and more extrapancreatic actions of incretin-based therapies have been demonstrated and recently case reports have linked glucagon-like peptide-1 (GLP-1) receptor agouist therapy with the improvements in psoriasis.Psoriasis is a common skin disorder characterized by chronic inflammation.Epideminological studies have showed that patients with psoriasis exhibit increased rates of cardiovascular disease,obesity,and type 2 diabetes,owing probably to the enhanced local and (or) systemic inflammation.The observations of anti-inflammatory actions of GLP-1,which exerts direct and indirect actions on immune function,together with the improved psoriasis,offer new insights into the investigation of non-classical anti-inflammatory actions of incretin-based therapeutics and provide a new direction for the research of the novel clinical application of GLP-1.
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Objective To investigate the association of single nucleotide polymorphisms (SNPs) in the SCGB3A2(secretoglobin family 3A member 2) gene promoter with susceptibility of Graves' disease.Methods One-hundred and seventy-nine SNPs within a 3.0 Mb region surrounding marker D5s2090 were scanned in a case-control study.The size of the region(s) associated with GD was then narrowed.Results Total 179 SNPs within a 3.0 Mb region surrounding marker D5s2090 were analyzed.The most significant association signal was found at SNP rs1368408 (P =3.69 × 10-5).Subsequent association analysis was then performed and the results suggested that the SNP76 (P =4.11 × 10-8) and SNP75 (P =1.37 × 10-8) in the promoter of SCGB3A2 gene may be the causal variants of GD.Logistic regression analysis suggested these 2 SNPs in this region may contribute to GD susceptibility.Conclusion A significant association seems to exist between GD with the SCGB3A2 gene.
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Objective To analyze CYP17A1 gene mutation in a patient with 46,XY disordered sex development and to explore the possible influence on the phenotype of the patient.Methods Eight exons of CYP17AI gene in the patient and her parents were amplified and directly sequenced.In order to construct Mini-gene system,PCR fragments containing wildtype and mutant splicing sites were inserted in expression vector,and then transfected into cells.RT-PCR was used to observe the influence of splicing site mutation.Wildtype and aberrant splicing CYP17A1 cDNA expression plasmids were constructed and transfected into cells respectively,and CYP17A1 enzyme activity was tested in vitro.Results Mutation analysis revealed compound heterozygous CYP17A1 mutations,with Y329fs in one allele and a synonymous substitution( c.1263G＞A:GCG＞GCA) in another allele.In vitro analysis showed that the synonymous substitution induced a novel splicing site,which resulted in aberrant splicing of CYP17A1 mRNA and lacked six or seven amino acids after 415 in splicing product.In vitro transfection and enzyme activity experiment showed that the aberrant splicing product abolished the enzyme activity completely.However,this mutation did not completely influence splicing.The patient also had a part of normal splicing product,which was a coincidence to the phenotype of the patient.Conclusion This is the first description of an exonic splicing mutation in CYP17A1 relevant to the 17ot-hydroxylase deficiency phenotype.The functional study of the aberrant splicing variant has been initiated.
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In 2011 ADA/Lancet Forum, a randomized control trial in England was reported. Participants were with intensive diet intervention, or plus a physical activity program. The primary endpoints were improved in both groups, compared to control group, without any difference between two intervention groups. In another multinational trial, although significant improvement of cardiovascular risk factors in the intensive treatment group compared to routine group treated by general practitioners (GP), no significant differences on first cardiovascular event and all-cause mortality were found. This result is attributed to the good practice following guidelines by GP. While in China, a survey on current status of patients with type 2 diabetes who failed to reach the glycemic control target, and an another survey by a questionnaire about Chinese guidelines of diabetes treatment, answered by medical staff at different levels in Shanghai,gave us worrisome concerns. The training of medical staff from community hospitals seems to be particular emergent.
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Objective To investigate the current status of type 2 diabetic patients who failed to achieve the glycemic control target, and provide theoretic evidences for making corresponding strategies. Methods The 2 diabetic patients who failed to reach the glycemic target were recruited from 181 hospitals in 26 cities and received a standard questionnaire, the conditions of their blood glucose level, lifestyle intervention, blood sugar monitoring, and drug therapy were recorded. Totally 3 861 questionnaires with complete information were collected. And the causes which account for glycemic control status were analyzed. Results Among these patients, the mean HbA1c was 7.9%, the mean fasting plasma glucose was 8.2 mmol/L, and the mean postprandial plasma glucose was 11.5 mmol/L. Only 25.6% of patients take their diet control strictly as prescribed and 44. 5% of patients have little exercise. 35. 8% and 47.8% of patients did not monitor their fasting and postprandial plasma glucose,respectively. Glycemic control in the patients aged ＞ 60 years was similar to the younger patients, but the hypoglycemia incidence in the elder group reached 35.5%, which was higher than those in the other 2 groups (20.8% and 21.4%, both P＜0. 05 ). The proportion of patients with mono-therapy and combination therapy was 46. 1% and 51.7%, while the proportion with combination therapy rose in the patients aged ＞60 years (58.7%;Compared with the other age-groups, all P＜0.05 ). 75 % of patients have adjusted their drug administration regimen since initial treatment. Conclusions Inadequate or inappropriate drug therapy regimen is a major cause responsible for this poor glycemic control status. In addition, the unhealthy life styles, insufficient blood sugar monitoring, and poor compliance were also important causes. Thus, for these patients, it is necessary to further enhance patients' education, to improve life style intervention, as well as to select more effective, safer, and compliant drug therapy regimens. Finally, the glycemic control target for the elder patients should be more flexible.
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Increasing clinical evidence shows that modern lifestyle interrupting circadian rhythm contributes to the prevalence of obesity and diabetes.Recent genetic animal models further support the interaction of circadian rhythms and metabolic state.Circadian clock is not limited to be in central nervous system,and is also present in nearly all cells of the body,which constitute hierarchically circadian systems.The molecular circadian clock is evolved to allow organisms to anticipate and prepared for predictable,daily changes in the environment and regulates cellular and tissue function by driving patterns of gene expression and enzymatic activity.At present,basic science in this field has progressed at an extraordinary pace and is expected to continue unraveling the mechanisms linking circadian clocks to metabolism,which is important for understanding the pathophysiology of metabolic diseases such as obesity and diabetes,and provides a conceptual basis for the prevention and therapeutics of these diseases.
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To investigate the clinical features, genetic diagnosis, and treatment of a patient with Prader-Willi syndrome(PWS). For a case with clinically suspected PWS, methylation specific PCR(MSPCR)amplification was applied to CpG islands of SNRPN(exon α)gene locus in the 15q11-q13. Furthermore, the diagnosis was comfirmed by the method of bisulfite sequencing PCR(BSPCR). Metabolic status before and after the operation of sleeve gastrectomy were compared. Absence of amplification of paternal allele on chromosome 15q11-q13 was detected in the case by MSPCR, different from the normal control. Results of BSPCR further proved a full methylation of CpG islands in the SNRPN gene locus. Four months after sleeve gastrectomy, systemic metabolic status and ventricular function were improved. MSPCR and BSPCR were both consistent with genetic diagnosis of PWS. Weight loss surgery is expected to be a major therapy of this disease.
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Impaired eady phase insulin secretion is an important reason for leading to postprandial hyperglycemia.Nateglinide is a rapid-acting insulin secretagogue,which reduces postprandial blood glucose of type 2diabetic patient by restoring early phase insulin secretion.The efficacy and safety have been fully verified by clinical administration and it is more widely used to treat type 2 diabetic patients.Both sulfonylureas and glinides were named insulin secretagogue agents and regarded as alternative first-line drugs in the 2010 Chinese Guideline for treatment of type 2 diabetes.AACE/ACE Consensus statement claimed that glinides would be one of the important choices after metformin.In order to further guide the clinical application of nateglinide,16 national specialists in the field of endocrinology and metabolism of China discussed,drafted,and edited this consensus.The current consensus combined clinical evidences at home and abroad.systematically reviewed and summarized tlle results of these studies about nateglinide.It will provide guiding recommendations and reference concerning how to reasonably and effectively use nateglinide in the clinical practice.
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Objective To investigate a Chinese pedigree suffering from Leydig cell hypoplasia ( LCH) based on clinical data and genetic diagnosis. Methods The patient was diagnosed by means of clinical data, hormone profiles, and human chorionic gonadotropin ( hCC) test. The luteinizing hormone/chorionic gonadotropin receptor(LHCGR) gene of the patient and family members was amplified and sequenced. Results The patient presented with male pseudohermaphroditism, low level of testosterone, which did not respond to hCG. Genetic analysis of the LHCGR revealed two novel mutations: a missense mutation located in exon 5, resulting in Ile replaced by Thr in the extracellular domain; and a splice site mutation in the 3' terminal of intron 6( IVS6-3 C→A). Proband's sister (46, XX) who lacked clinical manifestations showed the identical genotype with the patient. Conclusions A mutation in the consensus sequence of 3' splice site, in addition to a missense mutation (Ile 152Thr)in the extracellular ligand-binding domain is the cause of inactivation of the LHCGR gene in patient with Leydig cell hypoplasia.
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Objective To explore the expression of chemerin and chemerin receptor ( chemokine-like receptor 1, CMKLR1) during different periods of non-alcoholic fatty liver disease ( NAFLD) rat model induced by methionine- and choline-deficient ( MCD) diet. Methods Thirty-six Wistar rats were divided into control group and MCD group in random. After one week quarantine and acclimation period, these two groups were fed either normal chow or MCD diet. The animals were respectively sacrificed at the first week, the forth week, and the tenth week. The levels of alanine transaminase (ALT), blood lipid profile, liver function, and the content of triglyceride in liver were detected. HE staining was done to observe the morphologic change of liver. The mRNA expression changes of chemerin and CMKLR1 in liver were measured using real-time PCR, and the change in chemerin mRNA level was further confirmed in liver by Northern blot. Finally, the concentration of chemerin in serum was measured by Western blot. Results The mRNA level of chemerin decreased significantly after four and ten weeks MCD feeding, although no obvious changes were found at first week, similar changes were found in serum chemerin (1.00±0.11 vs 0.96±0.39; 1.00±0.12 vs 0.21 ±0.77; 1.00±0.42 vs 0.21 ±0. 11). Contrasting with the change of chemerin(1.00±0.08 vs 0.72±0.10;1.00±0.24 vs 0.63±0. 31 ;1.00±0.05 vs 0.50±0.13), the mRNA level of CMKLR1 increased after MCD feeding( 1.00±0. 14 vs 0. 84±0. 26; 1.00±0. 38 vs 1. 51 ±0. 33; 1. 01 ±0. 13 vs 1. 84 ± 0. 39 ). Conclusion The change of chemerin and its receptor may participate in the process of the nonalcoholic fatty liver disease.
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Objective To investigate the adrenal steroidogenic function in genotype-proven heterozygotes carrying mutations in CYP17A1 gene in vivo. Methods Eight patients and 14 family members from 5 families with 17-hydroxylase/17,20-lyase deficiency (17OHD) were recruited. The mutations of the CYP17A1 gene in these individuals were screened by direct sequencing of PCR products. The hormonal response to ACTH was evaluated in the 14 genotype-proven carriers and 45 age- and sex-matched normal subjects. Results Three mutations were found in 5 unrelated families. 14 carriers with CYP17A1 mutation were identified, including 7 heterozygotes with D487_F489del, 6 with Y329fs, and 1 for H373L. Compared to the normal subjects, the carriers exhibited lower basal and ACTH-stimulated cortisol levels, but higher ACTH-stimulated corticosterone level. The ratios of corticosterone to cortisol in the genotype-proven heterozygotes were higher than those of normal individuals at baseline and following ACTH-stimulation. Similarly, progesterone level and ratios of progesterone to 17-hydroxyprogesterone in the male heterozygotes were also higher than that of normal individuals before and after stimulation. No significant differences were observed in the hormone levels between two genotypes (D487_F489del vs Y329fs). Conclusions Genotype-proven carriers of 17OHD without apparent clinical symptoms exhibit decreased enzyme activity,analogous to mildly impaired adrenal 21-hydroxylase activity in the carriers of CYP21 A2 gene mutation.
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Aldosterone and metabolic syndrome are known cardiovascular risk factors associated with increased morbidity and mortality. This review focuses on the recent advances and clinical significance of the relationship between aldosterone and each single component of metabolic syndrome. The possible role of aldosterone receptor antagonist or aldosterone synthetase inhibitor in the treatment of metabolic syndrome is discussed.
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Glucotoxicity, lipotoxicity and glucolipotoxieity are secondary phenomena following the primary pathogenesis, including the effects of genetic and environmental factors of type 2 diabetes. However, there exist two theories: (1) Lipotoxicity, presents before blood glucose rising, may trigger off a chain reaction which results in hyperglycemia. Hence the term " diabetes mellipidus" was proposed. (2) Hyperglycemia is a prerequisite for lipotoxicity. It seems more appropriate to state that (1) the glucotoxieity and iipotoxicity may present separately or concurrently in type 2 diabetes; (2) The combined glucolipotoxicity should describe the deleterious actions by higher levels of both glucose and free fatty acids on β-cell function, which finally causes progressive deterioration of insulin secretion.
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Objective To examine the impact of adolescent obesity on circulating visfatin levels, and to analyze the relationship between visfatin and anthropometric indices, insulin sensitivity, and blood lipids in Chinese adolescents (11-18 years). Methods Serum visfatin, adiponectin and lepfin were measured by RIA in 76 nonobese and 72 obese adolescents, and their total cholesterol, triglyceride, high-density lipoprotein-cholesterol (HDL-C) and low-density hpoprotein cholesterol were analyzed with enzymatic methods. OGTT was performed according to the World Health Organization standard procedure in obese adolescents, and homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index (ISI) and early insulin secretion index (EISI) were calculated. Results The serum visfatin level was significantly higher in obese subjects than in non-obese subjects [(37.65±18.28 vs 29.35±12.10) μg/L, P<0.01]. There were no significant correlations between the serum visfatin concentration and the anthropometrie indices or the lipid parameters in the non-obese group. However, visfatin levels were negatively correlated with age, Tanner stage and EISI, and positively correlated with HDL-C in the obese adolescents. These relationships, except that for EISI and Tanner stage,remained significant (P<0.05) after adjustment for age, gender, and body mass index. Moreover, unlike adiponectin and leptin, visfatin concentration was not correlated with testosterone in non-obese and obese boys.Conclusion Visfatin levels decrease with age and may be related to the HDL-C metabohsm in Chinese obese adolescents.
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In July 2002, the Women's Heath Initiative (WHI) clinical trial, designed to clarify the risks and benefits of combination hormone replacement therapy (HRT) to the postmenopausal women declared that interim safety review after an average follow-up of 5.2 years found that a combination of estrogen and progestin frequently prescribed to postmenopausal women in USA increased the risk of invasive breast cancer, heart disease, stroke, and pulmonary embolism while reduced bone fractures and colorectal cancer. The overall risks of HRT outweigh the benefits, which provides an opportunity for traditional Chinese medicine (TCM) going abroad. A variety of clinical and experimental evidences have showed that TCM exerts quite satisfactory effect on relieving postmenopausal symptoms with little adverse effect, hence a potential role to replace or to improve HRT or to reduce the side effect induced by HRT.
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Objective To investigate the effects of long-term high-fat diet and the modern lifestyle of more food and lack of exercise on insulin resistance and islet function. Methods 75 Wistar rats were feed by routine or high-fat diet for 11 months. Some of high-fat rats were induced to diabetic models by injecting 12mg/kg streptozotocin. Islet function was evaluated by intraperitoneal glucose tolerance test. Insulin sensitivity was detected by insulin tolerance test. Results Compared with control group, 2h blood glucose of high-fat group was elevated significantly. Fasting blood glucose of high-fat group was also elevated at eleventh month. Body weight of high-fat group was increased remarkably compared with control group, and the insulin sensitivity of high-fat group was decreased by 50% at forth month. Then insulin sensitivity of both groups was declined greatly. Hypoglycemic effect of 0.5 U/kg insulin at ninth month was similar to that of 0.1U/kg insulin at forth month. Furthermore, no significant difference of insulin sensitivity was observed between high-fat group and control. Conclusions Main course for insulin resistance is the modern lifestyle of more food and lack of exercise. The main effect of high-fat diet on the occurrence of diabetes is damaging islet function.
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Objective To observe the effect of berberine on glucose transport in 3T3-L1 adipocytes and to investigate its mechanism. Methods The glucose consumption of the cells was determined by the glucose oxidase method. The glucose transportation rate of the cells was assayed by the uptake of 2-deoxy-〔 3H〕-D-glucose. Protein kinase B (Akt) activity was detected by immunoprecipitation and Western blot. The gene expression of c-Cbl-associated protein (CAP) was detected by Northern blot. Results 0.1～200 ?mol/L berberine significantly increased glucose consumption in 3T3-L1 adipocytes with a dose-dependent effect, which was independent of insulin. The glucose transportation was significantly increased in adipocytes incubated with 0.1～10 ?mol/L berberine; the action began at 2 h and reached a peak value at 12 h. The results of immunoprecipitation and Western blot showed that berberine did not enhance Akt activity. The result of Northern blot indicated that berberine significantly decreased CAP mRNA expression. Conclusion Adipocytes are the important target cells of berberine. Berberine significantly increases glucose transportation and consumption in adipocytes, the action appeares to be independent of insulin signal pathway.
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Objective To prepare rabbit antibody against mouse AD-004 by AD-004 expressed in the prokaryotic expression system and to identify its distribution in the testis and adrenal. Methods The full-length cDNA of mouse AD-004 was cloned into PET28 plasmid, and the protein was induced in E. coli BL21 bacteria by adding IPTC and then purified by Ni2+ -NTA column. The purified protein was used as an immunogen to prepare polyclonal antibody ( pAb) of AD-004. The specificity of the antibody was detected by Western blotting. Immunohistochemical staining was performed in the mouse adrenal and testis via pAb of AD-004. Results Hisfused AD-004 was expressed efficiently in the prokaryotic system. Western blot analysis showed that the polyclonal antibody was duly bound to purified AD-004 with high specificity and sensitivity. AD-004 could be abundantly identified in the adrenal medulla and mainly expressed in the Leydig cells of testis. Conclusion The mouse protein of AD-004 is obtained from the prokaryotic expression system. The rabbit anti-AD-004 antibody has been prepared successfully. AD-004 protein is mainly localized in the interstitium of testis, suggesting that AD-004 may play a role in the synthesis of sex-steroid hormone.
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Journal of Clinical Endocrinology and Metabolism (JCEM), sponsored by U.S. Endocrine Society, is particularly appreciated by clinical endocrine doctors worldwide. It is intimately related to clinical practice while still catching up state of art research methods and recent discoveries and its creativity, novelty, scientific reliability, feasibility and readability are highly appraised. Compared to JCEM, our Chinese Journal of Endocrinology and Metabolism seems to be inadequate in certain aspects and needs to be improved in the future.