Thyroid dysfunction has been implicated as a potential pathophysiological factor in glucose homeostasis and insulin resistance (IR). This study aimed to identify the correlation between thyroid ...dysfunction and IR. We used data from the sixth Korean National Health and Nutrition Examination Survey to evaluate a total of 5727 participants. The triglyceride glucose (TyG) index and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated to represent IR. Correlation analysis was performed between thyroid dysfunction and IR. The log-transformed TSH (LnTSH) and free T4 were significantly correlated with the TyG index (TSH, beta coefficient 0.025, 95% confidence interval CI 0.014-0.036, p < 0.001; free T4, - 0.110 (- 0.166 to - 0.054), p < 0.001) but not HOMA-IR. Overt hypothyroidism is correlated with increased TyG index in pre-menopausal females (0.215 (0.122-0.309) p < 0.001). On the other hand, overt hyperthyroidism is correlated with increased HOMA-IR in males (0.304 (0.193-0.416), p < 0.001) and post-menopausal females (1.812 (1.717-1.907), p < 0.001). In euthyroid subjects, LnTSH and TyG index were significantly correlated in females. In conclusion, both hyperthyroidism and hypothyroidism might be associated with IR but by different mechanisms. It might be helpful to assess IR with appropriate indexes in patients with thyroid dysfunction.
Background
We examined the incidence and predictors of clinical outcomes in metabolic dysfunction‐associated fatty liver disease (MAFLD), focusing on anthropometric parameters.
Methods
Adult patients ...with MAFLD were identified in nationwide databases and a hospital cohort. Primary endpoints were atherosclerotic cardiovascular disease (ASCVD) and advanced fibrosis. Logistic and Cox regression analyses were used to analyse the association between anthropometric parameters and endpoints.
Results
In total, 4407 of 15 256 (28.9%) and 6274 of 25 784 subjects (24.3%) had MAFLD in the nationwide database; of these, 403 (9.2%) and 437 (7.0%) subjects were of lean/normal weight, respectively. Compared to the overweight/obese group, the lean/normal weight group had a significantly lower muscle mass (15.0 vs. 18.9 kg) and handgrip strength (31.9 vs. 35.1 kg) and had a higher ASCVD risk (9.0% vs. 6.3% and 15.9% vs. 8.5%; Ps < 0.001). Sarcopenia (odds ratio OR, 6.66; 95% confidence interval CI, 1.79–24.80) and handgrip strength (OR, 0.92; 95% CI, 0.86–0.97; Ps = 0.005) were associated with the ASCVD risk in the lean/normal weight group. In a hospital cohort (n = 1363), the ASCVD risk was significantly higher in the lean/normal weight group than in the overweight/obese group (median follow‐up, 39.1 months). Muscle mass was inversely correlated with the ASCVD risk (hazard ratio HR, 0.72; 95% CI, 0.56–0.94), while visceral adiposity was associated with advanced fibrosis (HR, 1.36; 95% CI, 1.10–1.69; Ps < 0.05).
Conclusions
Muscle mass/strength was significantly associated with the ASCVD risk in patients with MAFLD. Visceral adiposity was an independent predictor of advanced fibrosis.
Aims
The study aimed to evaluate and compare the efficacy and safety of enavogliflozin, a newly developed sodium‐glucose cotransporter 2 inhibitor, with placebo in Korean patients with type 2 ...diabetes mellitus.
Materials and Methods
Patients with glycated haemoglobin (HbA1c) of 7.0‐10.0%, entered a 2‐week placebo run‐in period, and were randomized to receive once‐daily enavogliflozin (0.1, 0.3 or 0.5 mg) or placebo for 12 weeks. The primary efficacy endpoint was the change in HbA1c from baseline at week 12.
Results
Overall, 194 patients were included in the full analysis set placebo, n = 46; enavogliflozin (0.1 mg, n = 49; 0.3 mg, n = 50; 0.5 mg, n = 49). Patients receiving 0.1, 0.3 and 0.5 mg enavogliflozin showed significantly reduced HbA1c compared with those receiving placebo at week 12 (−0.79%, −0.89%, −0.92% and −0.08%, respectively; p < .001 vs. placebo). Mean changes in fasting plasma glucose from baseline at week 12 were −30.5, −31.1, −35.0 and 4.9 mg/dl in patients receiving enavogliflozin doses and placebo, respectively. The proportion of patients achieving HbA1c <7.0% at week 12 was significantly higher in the three enavogliflozin groups than in the placebo group (42.9%, 44.0%, 61.2% and 17.4%, respectively). A higher proportion of patients showed HbA1c reduction by >0.5% after receiving enavogliflozin doses than those receiving placebo (61.2%, 72.0%, 65.3% and 26.1%, respectively). There were no significant differences in incidences of adverse events of hypoglycaemia and genital infection between the groups.
Conclusions
Once‐daily enavogliflozin monotherapy for 12 weeks is an effective, safe, and well‐tolerated treatment for Korean patients with type 2 diabetes mellitus.
To evaluate the long-term safety and efficacy of enavogliflozin 0.3 mg/day added to metformin in patients with type 2 diabetes mellitus.
After 24 weeks of a randomized, double-blind treatment period ...with enavogliflozin 0.3 mg/day (n = 101) or dapagliflozin 10 mg/day (n = 99) added to metformin, all patients received enavogliflozin 0.3 mg/day plus metformin for an additional 28 weeks during the open-label extension period.
Eighty-two patients continued enavogliflozin (maintenance group), and 77 were switched from dapagliflozin to enavogliflozin (switch group). All adverse drug reactions (ADR) were mild in severity. In the maintenance group, ADRs (cystitis and vaginal infection) were reported in two patients (2.44%) during 52 weeks. In the switch group, ADR (hypoglycaemia) was reported in one patient (1.30%) during a 28-week open-label extension period. At week 52, glycated haemoglobin and fasting plasma glucose were significantly lower than at the baseline, by 0.85% and 29.08 mg/dl, respectively, in the maintenance group (p < .0001 for both), and by 0.81% and 32.77 mg/dl, respectively, in the switch group (p < .0001 for both). At week 52, 68.92% of patients from the maintenance group and 64.29% from the switch group achieved glycated haemoglobin <7%. A significant increase in the urine glucose-creatinine ratio was observed at week 52, by 58.81 g/g and 63.77 g/g in the maintenance and switch groups, respectively (p < .0001).
Enavogliflozin added to metformin was tolerated well for up to 52 weeks and provided continual glycaemic control in type 2 diabetes mellitus, along with a significant increase in the urine glucose-creatinine ratio.
Although macroautophagy/autophagy deficiency causes degenerative diseases, the deletion of essential autophagy genes in adipocytes paradoxically reduces body weight. Brown adipose tissue (BAT) plays ...an important role in body weight regulation and metabolic control. However, the key cellular mechanisms that maintain BAT function remain poorly understood. in this study, we showed that global or brown adipocyte-specific deletion of pink1, a Parkinson disease-related gene involved in selective mitochondrial autophagy (mitophagy), induced BAT dysfunction, and obesity-prone type in mice. Defective mitochondrial function is among the upstream signals that activate the NLRP3 inflammasome. NLRP3 was induced in brown adipocyte precursors (BAPs) from pink1 knockout (KO) mice. Unexpectedly, NLRP3 induction did not induce canonical inflammasome activity. Instead, NLRP3 induction led to the differentiation of pink1 KO BAPs into white-like adipocytes by increasing the expression of white adipocyte-specific genes and repressing the expression of brown adipocyte-specific genes. nlrp3 deletion in pink1 knockout mice reversed BAT dysfunction. Conversely, adipose tissue-specific atg7 KO mice showed significantly lower expression of Nlrp3 in their BAT. Overall, our data suggest that the role of mitophagy is different from general autophagy in regulating adipose tissue and whole-body energy metabolism. Our results uncovered a new mitochondria-NLRP3 pathway that induces BAT dysfunction. The ability of the nlrp3 knockouts to rescue BAT dysfunction suggests the transcriptional function of NLRP3 as an unexpected, but a quite specific therapeutic target for obesity-related metabolic diseases.
Abbreviations: ACTB: actin, beta; BAPs: brown adipocyte precursors; BAT: brown adipose tissue; BMDMs: bone marrow-derived macrophages; CASP1: caspase 1; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; ChIP: chromatin immunoprecipitation; EE: energy expenditure; HFD: high-fat diet; IL1B: interleukin 1 beta; ITT: insulin tolerance test; KO: knockout; LPS: lipopolysaccharide; NLRP3: NLR family, pyrin domain containing 3; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RD: regular diet; ROS: reactive oxygen species; RT: room temperature; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); WT: wild-type.
Liver-Specific Deletion of Protein-Tyrosine Phosphatase 1B (PTP1B) Improves Metabolic Syndrome and Attenuates Diet-Induced
Endoplasmic Reticulum Stress
Mirela Delibegovic 1 6 ,
Derek Zimmer 2 ,
...Caitlin Kauffman 2 ,
Kimberly Rak 2 ,
Eun-Gyoung Hong 3 4 ,
You-Ree Cho 4 ,
Jason K. Kim 3 4 ,
Barbara B. Kahn 5 ,
Benjamin G. Neel 1 7 and
Kendra K. Bence 2
1 Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
2 Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
3 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania
4 Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut
5 Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard
Medical School, Boston, Massachusetts
6 School of Biological Sciences, University of Aberdeen, Aberdeen, U.K
7 Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, Toronto, Canada
Corresponding authors: Kendra Bence, kbence{at}vet.upenn.edu , and Mirela Delibegovic, m.delibegovic{at}abdn.ac.uk
Abstract
OBJECTIVE— The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling; consequently, mice deficient in PTP1B
are hypersensitive to insulin. Because PTP1B −/− mice have diminished fat stores, the extent to which PTP1B directly regulates glucose homeostasis is unclear. Previously,
we showed that brain-specific PTP1B −/− mice are protected against high-fat diet–induced obesity and glucose intolerance, whereas muscle-specific PTP1B −/− mice have increased insulin sensitivity independent of changes in adiposity. Here we studied the role of liver PTP1B in glucose
homeostasis and lipid metabolism.
RESEARCH DESIGN AND METHODS— We analyzed body mass/adiposity, insulin sensitivity, glucose tolerance, and lipid metabolism in liver-specific PTP1B −/− and PTP1Bfl/fl control mice, fed a chow or high-fat diet.
RESULTS— Compared with normal littermates, liver-specific PTP1B −/− mice exhibit improved glucose homeostasis and lipid profiles, independent of changes in adiposity. Liver-specific PTP1B −/− mice have increased hepatic insulin signaling, decreased expression of gluconeogenic genes PEPCK and G-6-Pase, enhanced insulin-induced
suppression of hepatic glucose production, and improved glucose tolerance. Liver-specific PTP1B −/− mice exhibit decreased triglyceride and cholesterol levels and diminished expression of lipogenic genes SREBPs, FAS, and
ACC. Liver-specific PTP1B deletion also protects against high-fat diet–induced endoplasmic reticulum stress response in vivo,
as evidenced by decreased phosphorylation of p38MAPK, JNK, PERK, and eIF2α and lower expression of the transcription factors
C/EBP homologous protein and spliced X box-binding protein 1.
CONCLUSIONS— Liver PTP1B plays an important role in glucose and lipid metabolism, independent of alterations in adiposity. Inhibition of
PTP1B in peripheral tissues may be useful for the treatment of metabolic syndrome and reduction of cardiovascular risk in
addition to diabetes.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 15 December 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.
Accepted December 8, 2008.
Received July 9, 2008.
DIABETES
Aim
To evaluate the efficacy and safety of a fixed‐dose combination (FDC) of gemigliptin and rosuvastatin in patients with type 2 diabetes and dyslipidaemia.
Research Design and Methods
A total of 33 ...hospitals in Korea participated in this randomized, double‐blind trial of diabetic patients with dyslipidaemia. A total of 290 participants were randomly assigned at a 1:1:1 ratio to receive an FDC of gemigliptin (50 mg) and rosuvastatin (20 mg) (GEMI/ROSU FDC group), gemigliptin (50 mg) (GEMI group) or rosuvastatin (20 mg) (ROSU group). Rosuvastatin was up‐titrated from 5 to 20 mg/d throughout the study period. Primary efficacy measures were changes in HbA1c and LDL‐C from baseline to Week 24 between the GEMI/ROSU FDC and ROSU groups and between the GEMI/ROSU FDC and GEMI groups, respectively. Secondary efficacy measures were changes in HbA1c and LDL‐C between the GEMI/ROSU FDC and GEMI groups and between the GEMI/ROSU FDC and ROSU groups, respectively.
Results
After 24 weeks of treatment, a significant reduction in HbA1c from baseline was noted in the GEMI/ROSU FDC group (−0.81% of LS mean; P < 0.0001 vs ROSU group), in addition to a significant reduction in LDL‐C concentration (−51.9% of LS mean percentage changes, P < 0.0001 vs GEMI group). HbA1c was significantly reduced from baseline in both the GEMI/ROSU FDC and GEMI groups, but the reduction in HbA1c was significantly greater in the GEMI group than in the GEMI/ROSU FDC group, despite receiving the same dose of gemigliptin. The decrease in LDL‐C over time was similar between the GEMI/ROSU FDC and ROSU groups. There were no significant differences in adverse events among the groups.
Conclusion
The FDC of gemigliptin and rosuvastatin is safe and is effective in reducing both blood glucose and LDL‐C levels; thus, it could be a good therapeutic choice for type 2 diabetic patients with dyslipidaemia.
To investigate associations of glomerular hyperfiltration with other metabolic factors in a nationally representative dataset.
We analyzed cross-sectional data from 15,918 subjects with estimated ...glomerular filtration rate (eGFR) >60 ml/min/1.73 m2 and urine albumin creation ratio (ACR) <30 mg/g, who participated in the 5th and 6th Korea National Health and Nutrition Examination Surveys. Hyperfiltration was defined as eGFR (CKD-EPI equation) exceeding the age- and sex-specific 95th percentile for healthy control subjects.
Prevalence of hyperfiltration was 5.2% and that among normal, prediabetic, and diabetic subjects was 4.9%, 5.6%, and 7.3%, respectively, after adjusting for age, sex, and body weight (p for trend = 0.008). In a multiple logistic regression analysis, hyperfiltration was associated with a body mass index ≥30 kg/m2 odds ratio (OR) = 3.461, p<0.001, waist circumference 85 cm (men) or 80 cm (women) (OR = 1.425, p = 0.015), systolic blood pressure 120-129 mmHg (OR = 1.644, p = 0.022), fasting plasma glucose 140 mg/dL (OR = 1.695, p = 0.033) and t serum triglyceride level 500 mg/dL (OR = 2.988, p = 0.001), and was independently associated with the ACR (B = 0.053, p<0.001).
In a general Korean population, both hyperfiltration and ACR were associated with similar metabolic parameters, and hyperfiltration correlated independently with a high ACR. Longitudinal studies are needed to further explore risks of hyperfiltration and microalbuminuria.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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