The Effects of Ketogenic Diet on Brain Gene Expressions in Type 2 Diabetes Background.

Type 2 diabetes mellitus (T2DM) is a major risk factor of a number of neurodegenerative diseases (NDDs). Ketogenic diet (KD) has significant beneficial effects on glycemic control and may act effectively against NDDs, but the mechanism remains unclear. In this study, we aimed to investigate the potential effects of KD on gene expressions in the brains of T2DM model mice. Male db/db mice at the age of 9 weeks were fed with KD or normal diet to the age of 6 months, and the whole brains were subjected to mRNA-seq analysis for differentially expressed genes. KD significantly lowered fasting glucose and body weights in db/db mice (P < 0.05), and the expression of 189 genes in the brain were significantly changed (P < 0.05, |log2| > 1). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that the differentially expressed genes upon KD are involved in inflammatory responses and the functions of biosynthesis. In inflammatory responses, NF-κB signaling pathway, viral protein interaction with cytokine and cytokine receptor, and cytokine-cytokine receptor interaction pathways were enriched, and in biosynthesis pathways, genes functioning in lipid and amino acid metabolism, protein synthesis, and energy metabolism were enriched. Moreover, consistent with the gene set enrichment analysis results, proteasomal activity measured biochemically were enhanced in KD-fed T2DM mice. These data may facilitate the understanding of how KD can be protective to the brain in T2DM background. KD could be a new strategy for the prevention of NDDs in T2DM patients.

Quantitative profiling and diagnostic potential of one-carbon and central metabolism pools in MODY2 and T1DM.

BACKGROUND: Maturity-onset diabetes of the young type 2 (MODY2) is a rare genetic disorder characterized as mild fasting hyperglycemia with low risk of vascular complications caused by glucokinase gene mutation. This study aims to investigate metabolites alteration associated with MODY2, exploring possible mechanism underlying characteristic clinical manifestations and low cardiovascular risks of MODY2 and providing serum metabolite biomarkers to facilitating MODY2 diagnosis. METHODS: Fasting serum samples from MODY2, type 1 diabetes (T1DM) and healthy individuals were collected. By using targeted metabolomics via liquid chromatography-tandem mass spectrometry platform, we quantified the metabolites involved in tricarboxylic acid (TCA) cycle and one-carbon metabolism. RESULTS: Metabolomic profiling revealed significant difference of intermediates from central metabolism cycle, methionine cycle and several amino acids between MODY2 and T1DM groups. Among these, serum citrate, α-ketoglutaric acid, serine, glycine, glutamine and homocysteine were significantly elevated in MODY2 patients compared with T1DM patients; and compared with healthy subjects, malate and methionine levels were significantly increased in the two groups of diabetic patients. The correlation analysis with clinical indexes showed that α- ketoglutarate, serine, glycine, and glutamine were negatively correlated with blood glucose indicators including fasting blood glucose, HbA1c, and GA, while citrate was positively correlated with C-peptide. And homocysteine displayed positive correlation with HDL and negative with C-reactive protein, which shed light on the mechanism of mild symptoms and low risk of cardiovascular complications in MODY2 patients. A panel of 4 metabolites differentiated MODY2 from T1DM with AUC of 0.924, and a combination of clinical indices and metabolite also gained good diagnostic value with AUC 0.948. CONCLUSION: In this research, we characterized the metabolite profiles of TCA cycle and one-carbon metabolism in MODY2 and T1DM and identified promising diagnostic biomarkers for MODY2. This study may provide novel insights into the pathogenesis and clinical manifestations of MODY2.

Association between body fat and sarcopenia in older adults with type 2 diabetes mellitus: A cross-sectional study.

Objectives: To investigate the association between body fat (BF%) and sarcopenia in older adults with type 2 diabetes mellitus (T2DM) and potential link with increased levels of inflammatory indicators and insulin resistance. Methods: A total of 543 older adults with T2DM were included in this cross-sectional study. Appendicular skeletal muscle (ASM), handgrip strength and gait speed were measured to diagnose sarcopenia according to the updated Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Body composition data were tested using dual-energy X-ray absorptiometry (DEXA). Levels of serum high-sensitive C-reactive protein (hs-CRP), interleukin-6, fasting blood insulin (FINS), hemoglobin A1c (HbA1c), 25-hydroxyvitamin D3 [25(OH) D3] were also determined. Results: The prevalence of sarcopenia in all participants was 8.84%, of which 11.90% were male and 5.84% females. The Pearson's correlation analysis revealed that BF% was negatively correlated with gait speed in men and women (R =-0.195, P=0.001; R = -0.136, P =0.025, respectively). After adjusting for all potential confounders, sarcopenia was positive associated with BF% (male, OR: 1.38, 95% CI: 1.15-1.65, P< 0.001; female, OR: 1.30, 95% CI: 1.07-1.56, P=0.007), and negatively associated with body mass index (BMI) (male, OR: 0.57, 95% CI: 0.44-0.73, P<0.001; female, OR: 0.48, 95% CI: 0.33-0.70, P<0.001). No significant differences were found in hs-CRP, interleukin-6, and insulin resistance between older T2DM adults with and without sarcopenia. Conclusion: Higher BF% was linked to an increased risk of sarcopenia in older adults with T2DM, suggesting the importance of assessing BF% rather than BMI alone to manage sarcopenia.

Serum metabolomics identified metabolite biomarkers and distinguished maturity-onset diabetes of the young from type 1 diabetes in the Chinese population.

BACKGROUND: Maturity-onset diabetes of the young (MODY) patients have unique clinical manifestations and need individualized treatments. We identified novel serum metabolic biomarkers to distinguish MODY and explore the possible mechanism of the clinical manifestation and complications of MODY. METHODS: Fasting serum samples were collected from MODY3 (n = 17), MODY2 (n = 33), type 1 diabetes (T1DM) (n = 34) and healthy individuals (n = 30), and were analyzed using the ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) metabolomic platform. RESULTS: 4 metabolites were found significantly fluctuated between groups, including glycerophosphocholine, LysoPC(18:2(9Z,12Z)), sphinganine and l-Phenylalanine. Glycerophosphocholine was selected as a diagnostic biomarker. The the area under the ROC curve (AUC) for distinguishing MODYs from healthy controls and differentiating MODY3 from T1DM reached 1.0. The combination of metabolites also gained good diagnostic value. The AUC of the combination of LysoPC(18:2(9Z,12Z)), sphinganine and l-Phenylalanine for discriminating MODY3 from T1DM was 0.983. Besides, the combination of clinical indices and metabolites helped to better differentiate the 2 MODY subtypes. CONCLUSIONS: We identified the metabolic profiles of MODY2 and MODY3 and found promising biomarkers for distinguishing MODY from T1DM, which provides evidence for the pathogenesis and characteristic clinical manifestations of patients with MODY2 and MODY3.

Distinguishing the lipid profile of GCK-MODY patients and its correlation with hsCRP levels.

Aims: Glucokinase-maturity-onset diabetes of the young (GCK-MODY) is the most common monogenic diabetes in China. We have previously reported on the low levels of high-sensitivity C-reactive protein (hsCRP) in patients with GCK-MODY. In this study, we further explored the correlation between the serum lipid profiles and hsCRP levels of patients with different types of diabetes. We also proposed to determine the possible mechanism of macrovascular protection in GCK genetic variants. Methods: The serum lipid profiles of the GCK-MODY group (n = 50) were compared with those of the hepatocyte nuclear factor-1 alpha (HNF1A)-MODY group (n = 19), the type 1 diabetes (T1D) group (n = 50), and the type 2 diabetes (T2D) group (n = 54). The associations between the lipid compositions and the hsCRP levels in each group were also explored. Results: Elevated levels of high-density lipoprotein cholesterol (HDL-C) were found in the GCK-MODY group (1.5 ± 0.27) compared with the T1D (1.2 ± 0.47, p < 0.01) and T2D (1.3 ± 0.3, p < 0.01) groups. On the other hand, a significantly lower LDL-C level (2.4 ± 0.69) in the GCK-MODY group compared with the T1D (2.7 ± 0.72, p < 0.01) and T2D (2.9 ± 0.68, p < 0.01) groups was also noted. A lower ratio of triglyceride to HDL-C (TG/HDL) and a lower hsCRP level were also found in the GCK-MODY group [TG/HDL = 0.38 (0.25-0.52), hsCRP = 0.2 mg/L (0.16-0.37)] compared with the T1D group [(TG/HDL = 0.56 (0.39-1.29), hsCRP = 0.56 mg/L (0.39-1.29), p < 0.01] and the T2D group [(TG/HDL = 1.6 (1.1-2.68), hsCRP = 1.11 mg/L (0.66-2.34), p < 0.01]. Although patients with HNF1A-MODY showed similar hsCRP levels [0.17 (0.08-0.52), p > 0.05] compared with the patients in the GCK-MODY group, they had higher TG levels [1.01 (0.66-1.76), p < 0.05] and TG/HDL ratios [0.84 (0.56-1.31), p < 0.05]. Analysis of the correlations between the hsCRP levels and lipid profiles of each group confirmed that the LnhsCRP (natural logarithm-transformed hsCRP level) was positively correlated with the LnTG (natural logarithm-transformed TG) (r = 0.352, p = 0.011) and the Ln(TG/HDL) ratio (r = 0.283, p = 0.047) only in individuals with GCK-MODY. Conclusions: Individuals harboring GCK variants have the characteristics of protective lipid profiles manifested as a higher level of HDL-C and a lower level of LDL-C compared with type 1 and 2 diabetes milletus (T1DM and T2DM, respectively) patients. In addition, lower ratios of TG/HDL were found to be associated with the inhibition of secretion of hsCRP, even when adjusted for the HbA1c levels in patients with GCK-MODY. It is suggested that the protective effect of macrovascular complications in GCK-MODY patients might partly be due to their unique lipid profiles associated with the suppression of inflammation.

A Study of the Relationship between Blood Glucose and Serum Insulin in Acute Cerebrovascular Disease.

Objective: The objective of this study was to examine the correlation between blood glucose and serum insulin with acute cerebrovascular disease. Methods: A total of 1548 patients with acute cerebrovascular illness and 364 patients with a normal physical examination who were admitted to our hospital (endocrinology department) between January 2017 and July 2020 were recruited. Patients with acute cerebrovascular illness were included in the experimental group, while healthy individuals after physical examinations were included in the control group. All patients' blood glucose and serum insulin levels were measured, and the association of blood glucose and serum insulin with acute cerebrovascular illness was investigated. Results: Acute cerebrovascular disease is associated with significantly higher blood glucose and serum insulin levels versus healthy status (P < 0.05). Blood glucose and serum insulin levels were observed to be significantly higher in the hemorrhagic stroke group than in the ischemic stroke or mild hemorrhagic group (P < 0.05). Severe ischemic strokes were associated with significantly higher blood glucose levels versus mild ischemic strokes (P < 0.05). There were no significant differences in serum insulin levels between the severe ischemic stroke group and the mild ischemic stroke group (P > 0.05). Conclusion: A rise in blood glucose and serum insulin levels is associated with the incidence and prognosis of acute cerebrovascular disease, and it is positively correlated with the severity of the acute cerebrovascular disease.

Free fatty acids are associated with muscle dysfunction in Chinese adults with type 2 diabetes.

PURPOSE: Muscle dysfunction is considered a sign of poor prognosis in patients with type 2 diabetes (T2D). Thus, early detection of muscle disorders is particularly important in the T2D population. Free fatty acids (FFAs) are clinical indicators of metabolic diseases and muscle function; hence, we aimed to investigate the association between FFAs and muscle function. METHODS: A total of 160 adult subjects with T2D were characterized and analyzed in this study. Muscle mass and function were measured by walking speed, grip strength and height-adjusted appendicular skeletal muscle mass (ASMM). Partial correlation was applied to explore the correlations between FFAs and muscle indicators. Receiver operating characteristic (ROC) curves were utilized to determine the diagnostic value of FFAs in muscle mass and function. RESULTS: The FFAs levels were negatively correlated with ASMM (r = -0.347, P = 1.0E-05), grip strength (r = -0.313, P = 7.1E-05) and walking speed (r = -0.167, P = 0.039). Notably, the relationships between FFAs levels and ASMM and walking speed remained significant even after adjusting for age, sex, body mass index (BMI), diabetes duration, and hemoglobin A1C (HbA1c). The combination of conventional indicators, including age, BMI, and HbA1c levels, provided a discrimination of low grip strength with an AUC of 0.648, and low walking speed with an AUC of 0.714. Importantly, when FFAs levels were added to the model, the value of the ROC curve was further improved, with an AUC of 0.785 for low grip strength and 0.755 for low walking speed. CONCLUSIONS: The current study demonstrated a negative correlation between FFAs and muscle indicators in adult patients with T2D after adjusting for HbA1c levels. FFAs may play an important role in the pathological processes of muscle dysfunction in adults with T2D.

Hemoglobin level and osteoporosis in Chinese elders with type 2 diabetes mellitus.

OBJECTIVES: Several studies demonstrated a positive relationship between hemoglobin level and bone mineral density (BMD). Thus, the association between hemoglobin concentration and osteoporosis in elders with type 2 diabetes mellitus (T2DM) was explored in this study. METHODS: Totally, 573 elders with T2DM were included in the study. BMD was measured by dual-energy X-ray absorptiometry. Hemoglobin levels were tested. The association between the hemoglobin level and osteoporosis was subjected to logistic regression analysis. RESULTS: For men, the hemoglobin levels were significantly lower in osteoporosis group than that in non-osteoporosis group (135.98 ± 16.20 vs. 142.84 ± 13.78 g/L, P = 0.002). Hemoglobin levels were positively related with BMD of total hip and femoral neck in men (r = 0.170, P = 0.004; r = 0.148, P = 0.012, respectively). After adjusting for age, body mass index (BMI), hemoglobin A1c (HbA1c), estimated glomerular filtration rate (eGFR) and 25-hydroxyvitamin D3 [25(OH) D3], the hemoglobin level was related with a 0.97-fold lower risk of osteoporosis (odds ratio (OR): 0.97; 95% confidence interval (CI): 0.95-0.99; P = 0.004) in men, but no such association was found in women. CONCLUSION: Higher levels of hemoglobin play a protective role against osteoporosis in older men with T2DM.

Associations between homocysteine, inflammatory cytokines and sarcopenia in Chinese older adults with type 2 diabetes.

BACKGROUND: Sarcopenia, an age-related disease, has been implicated as both a cause and consequence of type 2 diabetes mellitus (T2DM) and a symbol of poor prognosis in older adults with T2DM. Therefore, early detection and effective treatment of sarcopenia are particularly important in older adults with T2DM. We aimed to investigate the prevalence of sarcopenia in Chinese older T2DM patients and explore whether homocysteine and inflammatory indexes could serve as biomarkers and participate in the development process of sarcopenia. METHODS: T2DM patients aged over 60 years were consecutively recruited from the ward of department of Endocrinology, Xuanwu Hospital between April 2017 and April 2019. Sarcopenia was defined based on the standard of the Asian Working Group of Sarcopenia, including muscle mass, grip strength and gait speed. Logistic regression was used to explore the association between biochemical indicators and sarcopenia. Receiver operating characteristic (ROC) curves were applied to determine the diagnostic effect of these clinical indicators. RESULTS: Totally 582 older adults with T2DM were characterized and analyzed in the study. Approximately 8.9% of the older T2DM patients had sarcopenia. After adjusting for age, sex, body mass index (BMI) and hemoglobin A1c (HbA1c), increased concentrations of homocysteine [odds ratio (OR): 2.829; 95% confidence interval (CI), 1.064-7.525] and high-sensitive C-reactive protein (hs-CRP) (OR: 1.021; 95% CI, 1.001-1.042) were independent predictors of sarcopenia; but not interleukin-6. The combination of age, sex, BMI and HbA1c provided a discriminatory effect of sarcopenia with an area under the curve (AUC) of 0.856, when homocysteine was added to the model, the value of the ROC curve was further improved, with an AUC of 0.861. CONCLUSION: In the current study, we demonstrated a positive correlation of homocysteine, hs-CRP with sarcopenia in older adults with T2DM and the relationship remained significant even after adjustment for HbA1c. These biomarkers (homocysteine and hs-CRP) may play important roles in the pathological process of sarcopenia.

Low prealbumin levels are associated with sarcopenia in older men with type 2 diabetes mellitus: A cross-sectional study.

OBJECTIVES: The aim of this study was to evaluate the association between the serum levels of prealbumin and sarcopenia in older adults with type 2 diabetes mellitus. METHODS: This cross-sectional study included 582 older adults with type 2 diabetes mellitus. Sarcopenia was defined based on the recently updated Asian Working Group for Sarcopenia 2019 criteria. Appendicular skeletal muscle was measured by dual energy x-ray absorptiometry. Serum levels of prealbumin, hemoglobin, hemoglobin A1c, and 25-hydroxyvitamin D3 were also tested. Multivariate analyses were used to assess the association between prealbumin levels and sarcopenia, adjusted for potential confounders. RESULTS: The overall prevalence of sarcopenia was 9%, of which 12% for men and 6% for women. Male participants with sarcopenia had lower prealbumin levels than those without sarcopenia (213 ± 72 versus 260 ± 56 mg/L, P < 0.001). The proportion of men with low prealbumin level (<170 mg/L) was significantly higher in individuals with sarcopenia than in those without (31% versus 6%, respectively). In a logistic regression model, after adjusting for all potential covariates, low prealbumin (odds ratio, 4.15; 95% confidence interval, 1.13-15.25; P = 0.03) was significantly associated with sarcopenia in men, but the relationship between prealbumin and sarcopenia was not found in women. CONCLUSION: Low prealbumin levels were associated with an increased risk for sarcopenia in older men with T2DM.

A Clinical Prediction Model to Distinguish Maturity-Onset Diabetes of the Young From Type 1 and Type 2 Diabetes in the Chinese Population.

OBJECTIVE: Genetic detection for the diagnosis of maturity-onset diabetes of the young (MODY) in China has low sensitivity and specificity. Better gene detection is urgently needed to distinguish testing subjects. We proposed to use numerous and weighted clinical traits as key indicators for reasonable genetic testing to predict the probability of MODY in the Chinese population. METHODS: We created a prediction model based on data from 306 patients, including 140 patients with MODY, 84 patients with type 1 diabetes (T1D), and 82 patients with type 2 diabetes (T2D). This model was evaluated using receiver operating characteristic curves. RESULTS: Compared with patients with T1D, patients with MODY had higher C-peptide levels and negative antibodies, and most patients with MODY had a family history of diabetes. Different from T2D, MODY was characterized by lower body mass index and younger diagnostic age. A clinical prediction model was established to define the comprehensive probability of MODY by a weighted consolidation of the most distinguishing features, and the model showed excellent discrimination (areas under the curve of 0.916 in MODY vs T1D and 0.942 in MODY vs T2D). Further, high-sensitivity C-reactive protein, glycated hemoglobin A1c, 2-h postprandial glucose, and triglyceride were used as indicators for glucokinase-MODY, while triglyceride, high-sensitivity C-reactive protein, and hepatocellular adenoma were used as indicators for hepatocyte nuclear factor 1-α MODY. CONCLUSION: We developed a practical prediction model that could predict the probability of MODY and provide information to identify glucokinase-MODY and hepatocyte nuclear factor 1-α MODY. These results provide an advanced and more reasonable process to identify the most appropriate patients for genetic testing.

A Novel Type of Extreme Insulin Resistance: Nonhypoglycemic Insulin Autoimmune Syndrome.

CONTEXT: Extreme insulin resistance is caused by genetic defects intersecting with the insulin action pathway or by the insulin receptor antibodies. Insulin autoimmune syndrome (IAS) is not considered one of the causes of extreme insulin resistance. OBJECTIVE: This work aimed to expand the current knowledge of extreme insulin resistance and to propose the diagnostic criteria and management strategy of a novel type of extreme insulin resistance. METHODS: A patient with IAS never experienced hypoglycemia but had persistent hyperglycemia and extreme insulin resistance with treatment with 200 U of intravenous insulin per day. Immunoreactive insulin (IRI), free insulin, and total insulin were measured. The ratio of free insulin to total insulin (insulin-free ratio, IFR) was calculated. RESULTS: Extreme insulin resistance has not been reported to be caused by IAS. At admission, IRI and free insulin were undetectable in our patient; total insulin was more than 20 160 pmol/L; and the IFR was lower than 0.03% (control, 90.9%). After adding 500 U porcine insulin to the precipitate containing insulin antibodies, the IRI was still undetectable. Since the patient started glucocorticoid therapy, the free insulin has gradually increased to 11.16 pmol/L, his total insulin has decreased to 5040 pmol/L, and the IFR has increased to 18.26%. Intravenous insulin was stopped, with good glycemic control. CONCLUSION: High-affinity insulin autoantibodies with a large capacity can induce a novel type of extreme insulin resistance characterized by extremely high total insulin and very low free insulin levels. The IFR can be used to evaluate therapeutic effects.

Puberty Status Modifies the Effects of Genetic Variants, Lifestyle Factors and Their Interactions on Adiponectin: The BCAMS Study.

Background: Hypoadiponectinemia has been associated with various cardiometabolic disease states. Previous studies in adults have shown that adiponectin levels were regulated by specific genetic and behavioral or lifestyle factors. However, little is known about the influence of these factors on adiponectin levels in children, particularly as mitigated by pubertal development. Methods: We performed a cross-sectional analysis of data from 3,402 children aged 6-18 years from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study. Pubertal progress was classified as prepubertal, midpuberty, and postpuberty. Six relevant single nucleotide polymorphisms (SNPs) were selected from previous genome-wide association studies of adiponectin in East Asians. Individual SNPs and two weighted genetic predisposition scores, as well as their interactions with 14 lifestyle factors, were analyzed to investigate their influence on adiponectin levels across puberty. The effect of these factors on adiponectin was analyzed using general linear models adjusted for age, sex, and BMI. Results: After adjustment for age, sex, and BMI, the associations between adiponectin levels and diet items, and diet score were significant at prepuberty or postpuberty, while the effect of exercise on adiponectin levels was more prominent at mid- and postpuberty. Walking to school was found to be associated with increased adiponectin levels throughout puberty. Meanwhile, the effect of WDR11-FGFR2-rs3943077 was stronger at midpuberty (P = 0.002), and ADIPOQ-rs6773957 was more effective at postpuberty (P = 0.005), while CDH13-rs4783244 showed the strongest association with adiponectin levels at all pubertal stages (all P < 3.24 × 10-15). We further found that effects of diet score (Pinteraction = 0.022) and exercise (Pinteraction = 0.049) were stronger in children with higher genetic risk of hypoadiponectinemia, while higher diet score and exercise frequency attenuated the differences in adiponectin levels among children with different genetic risks. Conclusions: Our study confirmed puberty modulates the associations between adiponectin, and genetic variants, lifestyle factors, and gene-by-lifestyle interactions. These findings provide new insight into puberty-specific lifestyle suggestions, especially in genetically susceptible individuals.

Angiopoietin-Like Protein 8/Leptin Crosstalk Influences Cardiac Mass in Youths With Cardiometabolic Risk: The BCAMS Study.

Objectives: The link between excess adiposity and left ventricular hypertrophy is multifaceted with sparse data among youths. Given that adipokines/hepatokines may influence lipid metabolism in myocardium, we aimed to investigate the relation of the novel hepatokine angiopoietin-like protein 8 (ANGPTL8) and other adipokines with cardiac structure in a cohort of youths and explore to what extent these adipokines/hepatokines affect cardiac structure through lipids. Methods: A total of 551 participants (aged 15-28 years) from the Beijing Child and Adolescent Metabolic Syndrome Study (BCAMS) cohort underwent echocardiographic measurements plus a blood draw assayed for five adipokines/hepatokines including adiponectin, leptin, retinol binding protein 4, fibroblast growth protein 21 and ANGPTL8. Results: Both ANGPTL8 (ß = -0.68 g/m2.7 per z-score, P= 0.015) and leptin (ß = -1.04 g/m2.7 per z-score, P= 0.036) were significantly inversely associated with left ventricular mass index (LVMI) independent of classical risk factors. Total cholesterol and low-density lipoprotein cholesterol significantly mediated the ANGPTL8-LVMI association (proportion: 19.0% and 17.1%, respectively), while the mediation effect of triglyceride on the ANGPTL8-LVMI relationship was strongly moderated by leptin levels, significantly accounting for 20% of the total effect among participants with higher leptin levels. Other adipokines/hepatokines showed no significant association with LVMI after adjustment for body mass index. Conclusions: Our findings suggest ANGPTL8, particularly interacting with leptin, might have a protective role in cardiac remodeling among youths with risk for metabolic syndrome. Our results offer insights into the pathogenesis of the cardiomyopathy and the potential importance of tissue-tissue crosstalk in these effects.

Two cases of immunoglobulin G4 (IgG4)-related hypophysitis diagnosed without pituitary biopsy.

BACKGROUND: Immunoglobulin G4-related hypophysitis (IgG4-RH) is a rare disease, diagnosis of which typically depends on histopathology following an invasive pituitary biopsy, possibly leading to permanent hypopituitarism. Herein, we report two cases of IgG4-RH with favorable responses to glucocorticoids. One of them was multiple organs involved and treated with glucocorticoids and methotrexate. METHODS: We retrospectively review clinical features, radiological images, and treatment of two cases with IgG4-RH. In addition, literature on IgG4-RH was comprehensively reviewed and a new therapeutic strategy for IgG4-RH was provided. RESULTS: A 45-year-old man presented with diabetes insipidus for 6 months. Pituitary magnetic resonance imaging (MRI) indicated thickening of pituitary stalk. His serum IgG4 was 13,500 mg/l and hormonal evaluation revealed isolated growth hormone deficiency. Pituitary biopsy was denied by the patient due to fears of permanent pituitary damage. Treatment with prednisone and methotrexate (MTX) for 1 week led to improvement in sellar images and reduction in IgG4 level. His IGF1 (insulin-like growth factor-1) recovered after a 4-month treatment. The second case is a 43-year-old woman presenting with diabetes insipidus and amenorrhea for 20 months. Her pituitary MRI was similar to the patient above. Her serum IgG4 level was 5980 mg/l and hormonal measurement confirmed isolated hypogonadotropic hypogonadism. After 2 weeks of prednisone, the sellar images improved. After 3 months of treatment, her pituitary MRI was normal, IgG4 level had decreased to near normal range, and menstruation resumed. Literature review found additional patients with IgG4-RH, who were treated successfully without invasive pituitary biopsy in a manner similar to our cases. Therefore, we discuss the necessity of invasive pituitary biopsy for IgG4-RH. CONCLUSION: For suspected IgG4-RH with pituitary hormone deficiency, biopsy-induced hypopituitarism may be avoided by using diagnostic glucocorticoid treatment. Impaired pituitary hormone secretion may be recovered in response to steroid therapy. Improved pituitary MRI after 1-2 weeks of glucocorticoid treatment may provide diagnostic evidence of IgG4-RH.

Insulin resistance, beta-cell function, adipokine profiles and cardiometabolic risk factors among Chinese youth with isolated impaired fasting glucose versus impaired glucose tolerance: the BCAMS study.

OBJECTIVE: Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) may convey disparate risks of metabolic consequences. Fasting plasma glucose (FPG), while an expedient screening procedure, may not adequately assess metabolic risk, particularly among youths. In order to inform a strategy for screening Chinese youth for pre-diabetes, we examined the relative value of IFG versus IGT to define metabolic risk by assessing their association with insulin resistance, beta-cell dysfunction, adverse adipokine profiles and other cardiometabolic risk factors. RESEARCH DESIGN AND METHODS: We recruited 542 subjects (age 14-28 years) from the Beijing Child and Adolescent Metabolic Syndrome study for an in-depth assessment of cardiometabolic risk factors, including a 2-hour oral glucose tolerance test, liver ultrasound and serum levels of four adipokines. RESULTS: FPG failed to identify nearly all (32/33) youths with IGT, whereas 2-hour plasma glucose (2 h PG) missed 80.8% (21/26) of subjects with IFG. Impaired beta-cell function was evident from decreased oral disposition indices in those with isolated impaired fasting glucose (iIFG) or isolated impaired glucose tolerance (iIGT) versus normal glucose tolerance (NGT) (all p<0.001), whereas reduced insulin sensitivity (Matsuda) index was most pronounced in the iIGT group (p<0.01). Moreover, alterations in adipokine levels (fibroblast growth factor 21, adiponectin and leptin/adiponectin ratio) were associated with iIGT (p<0.05) but not iIFG. Youths with iIGT had a 2-fold to 32-fold increased incidence of hypertriglyceridemia, hypertension and metabolic syndrome (MetS) compared with those with NGT. In addition, subgroup analyses of participants with normal FPG revealed that the odds of having IGT increased 3-fold to 18-fold among those with elevated TGs, hypertension, moderate-to-severe non-alcoholic fatty liver disease or MetS. CONCLUSIONS: Chinese youth with iIGT exhibit a higher cardiometabolic risk profile than those with iIFG. Thus, 2 h PG is preferred over FPG to identify the pre-diabetes phenotype at greatest risk of subsequent development of cardiovascular disease. TRIAL REGISTRATION NUMBER: NCT03421444.

Primary hepatocellular adenoma due to biallelic HNF1A mutations and its co-occurrence with MODY 3: case-report and review of the literature.

PURPOSE: Maturity-onset diabetes of the young type 3 (MODY 3) is a consequence of heterozygous germline mutations in HNF1A, and a subtype of hepatocellular adenoma (HCA) is caused by biallelic somatic HNF1A mutations; rare HCA may be related to MODY 3. This study aimed to investigate the cosegregation of HNF1A mutations with diabetes and HCA in two families. METHODS: Two patients suffering from HCA and diabetes were screened for HNF1A germline and somatic mutations using direct sequence analysis and methylation-specific multiplex-ligation-dependent probe amplification (MS-MLPA) assay. Further, we screened eight relatives in the two independent families for diabetes, HCA and HNF1A variants. Additionally, we reviewed the literature concerning the phenotypes of MODY 3 and HCA at the background of HNF1A mutations. RESULTS: Here we reported two families (a total of six relatives) with two missense germline mutations of HNF1A identified initially using direct sequence analysis (c.686G>A in family A and c.526 + 1G>A in family B). Somatic deletion of the second allele of HNF1A was found in liver tumor tissues in both probands who were diagnosed with HCA. There are a total of ten cases of both MODY 3 and HCA phenotypes reported in the literature to date; incomplete penetrance for HCA was observed, and all the patients with HCA developed diabetes. The onset of diabetes and HCA was highly variable, the treatment of diabetes varied from diet to insulin, and the clinical expression of HCA ranged from silent to hemorrhage. Further, the severity of diabetes mellitus was not related to the occurrence of HCA. CONCLUSIONS: This study describes the association of HCA and MODY 3 at the background of HNF1A mutations and highlights the importance of screening for HCA in MODY 3 families to avoid the possibility of severe complications. Further, the current study indicated that there may be a special mutational spectrum of HNF1A correlated with HCA in MODY 3 families.

Identification of insulin gene variants in patients with neonatal diabetes in the Chinese population.

AIMS/INTRODUCTION: Neonatal diabetes mellitus is created by alterations in the genes responsible for beta-cell mass and/or function. The present study aimed to evaluate the genetic variants in the insulin gene (INS) in four Chinese infants aged <12 months with diabetes onset, and to explore the clinical and genetic characteristics of permanent neonatal diabetes mellitus caused by INS mutations. MATERIALS AND METHODS: The complete coding sequences of KCNJ11, ABCC8 and INS were detected using Sanger sequencing. The pathogenicity of the mutations was determined based on the American College of Medical Genetics and Genomics, and the structure of wild-type and mutant proteins was predicted using the web-based tool, Phyre2. RESULTS: One novel mutation (p.I99_C100insSI) and three previously reported variants (p.G32S, p.R89C and p.C96R) in INS were identified in four infants with early-onset diabetes. All the mutations in the four patients were de novo. Except for mutation R89C, which causes permanent neonatal diabetes mellitus through the addition of an additional cysteine residue at the cleavage site of the A chain and C-peptide, the other three mutations affected disulfide bonds. The patients had diabetes with marked hyperglycemia or diabetic ketoacidosis, and were then treated with exogenous insulin. Mutations in crucial regions of the INS might give rise to diabetes with varying severity. CONCLUSIONS: This study enriches our awareness of the mutant spectrum in INS, and suggests the important role of INS in the development of permanent neonatal diabetes mellitus.

Childhood sleep duration modifies the polygenic risk for obesity in youth through leptin pathway: the Beijing Child and Adolescent Metabolic Syndrome cohort study.

BACKGROUND/OBJECTIVES: Short sleep is an obesity risk factor, however, little is known about its interplay with genetic predisposition and pathways involved in obesity pathogenesis, especially in the longitudinal setting. We aimed to investigate a possible sleep-gene interaction for childhood obesity risk, and whether the interaction in childhood longitudinally contributes to obesity risk at a 10-year follow-up and further to test if there is any mediation through the leptin pathway. SUBJECTS/METHODS: A total of 3211 children from China (6-18 years) at baseline and 848 participants at 10-year follow-up from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) cohort study were analyzed. Baseline leptin concentrations and 12 established adult body mass index (BMI) loci were examined for the associations with habitual sleep duration. RESULTS: After adjusting for covariates, including pubertal stages and behavioral factors, short sleep duration at baseline was significantly associated with increased overweight/obesity risk at both baseline and follow-up. Genetic predisposition scores (GPS), particularly consisting of leptin-related SNPs (GPSleptin), were robustly associated with baseline overweight/obesity in children who slept ≤8 h/day (P < 0.001), whereas the association was ablated in those who slept ≥10 h/day (P > 0.05). Comparable observations were made at follow-up. Mediation analysis revealed a modest direct effect of the GPSleptin-sleep interaction on BMI at baseline, while a significant indirect effect of this interaction was found to be mediated principally through elevated leptin (proportion: 52.6%); moreover, the mediation effect via leptin remained stable over 10 years. CONCLUSIONS: This study suggests that shorter sleep duration in children from China (< 8h/day), compared to longer sleep duration (≥10 h/day), has a long-term impact on the association of polygenic risk for obesity from childhood to young adulthood and leptin pathway explains a key mechanism via a modification effect. Therefore, adequate sleep duration during childhood is important for the early prevention of obesity, especially if there is a genetic predisposition to this trait.