Polycystic ovarian syndrome Trikudanathan, Subbulaxmi
The Medical clinics of North America
99, Številka:
1
Journal Article
Recenzirano
Women with PCOS present with signs of chronic anovulation, hyperandrogenism, and metabolic abnormalities. The NIH recently embraced the Rotterdam criteria to broadly identify all the phenotypes of ...PCOS. Women with PCOS are often obese with insulin resistance and hence have an increased susceptibility to glucose intolerance and type 2 diabetes. Future research should focus on the genetic, epigenetic, and environmental determinants of PCOS to develop new therapies to address the prevention of this disorder and its long-term complications.
Abstract Objective South Asians have increased visceral adiposity, insulin resistance and greater prevalence of type 2 diabetes and cardiovascular disease when compared to Caucasians of European ...origin. Surrogate markers of insulin resistance such as the composite insulin sensitivity (Matsuda) index correlate with glucose clamps in other populations, but ethnicity can affect these indices. We compared the Matsuda index, homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and triglyceride/HDL ratio to insulin sensitivity derived from euglycemic clamps in healthy South Asians and Caucasians. Materials/Methods Twenty-three healthy South Asians and 18 Caucasians matched for age (mean ± SE = 33.6 ± 2.1 vs. 36.0 ± 3.0 years) and BMI (25.2 ± 1.1 vs. 24.6 ± 0.9 kg/m2 ) underwent 75 g oral glucose tolerance test (OGTT), 2-h euglycemic hyperinsulinemic clamp (240 pmol · m − 2 · min − 1 ), fasting lipid profile, and anthropometric measures. Results South Asians had higher fasting insulin (41 ± 5 vs. 21 ± 2 pmol/l; p = 0.002) and lower HDL-C (1.25 ± 0.06 vs. 1.56 ± 0.10 mmol/l; p = 0.010), but similar fasting glucose (5.0 ± 0.1 vs. 4.9 ± 0.1 mmol/l) levels vs. Caucasians. South Asians had significantly decreased measures of insulin sensitivity derived from both the euglycemic clamp (24.9 ± 1.3 vs. 41.4 ± 1.9 μmol · kg − 1 · min − 1 ; p < 0.0001) and OGTT (Matsuda Index 7.60 ± 0.99 vs. 13.60 ± 1.79; p = 0.004). The Matsuda index correlated highly with clamp insulin sensitivity in South Asians (r = 0.50; p = 0.014) and Caucasians (r = 0.47; p = 0.046). HOMA-IR, QUICKI, and triglyceride/HDL ratio correlated with clamp values in South Asians, but not in Caucasians. Conclusions In South Asians, Matsuda index, HOMA-IR, QUICKI, and triglyceride/HDL ratio offer simple and valid surrogate measures of insulin sensitivity that can be employed in larger clinical or epidemiological studies in this ethnic group.
Abstract Parasitic infections frequently lead to immune deviation or suppression. However, the application of specific parasitic molecules in regulating autoimmune responses remains to be explored. ...Here we report on the immune modulatory function of Lacto-N-fucopentaose III (LNFPIII), a schistosome glycan, in an animal model for multiple sclerosis. We found that LNFPIII treatment significantly reduced the severity of experimental autoimmune encephalomyelitis (EAE) and CNS inflammation, and skewed peripheral immune response to a Th2 dominant profile. Inflammatory monocytes (IMCs) purified from LNFPIII-treated mice had increased expression of nitric oxide synthase 2, and mediated T cell suppression. LNFPIII treatment also significantly increased mRNA expression of arginase-1, aldehyde dehydrogenase 1 subfamily A2, indoleamine 2,3-dioxygenase and heme oxygenase 1 in splenic IMCs. Furthermore, LNFPIII treatment significantly reduced trafficking of dendritic cells across brain endothelium in vitro . In summary, our study demonstrates that LNFPIII glycan treatment suppresses EAE by modulating both innate and T cell immune response.
Abstract The PD-1–PDL1 pathway plays a critical role in regulating autoimmune diabetes as blockade or deficiency of PD-1 or PDL1 results in accelerated disease in NOD mice. We explored the cellular ...mechanisms involved in the regulation of these autoimmune responses by investigations involving various gene-deficient mice on the NOD background. Administration of blocking anti-PDL1 antibody to CD4+ T cell-deficient, CD8+ T cell-deficient and B cell-deficient mice demonstrated that PDL1-mediated regulation of autoreactive CD4+ and CD8+ T cells is critical for diabetes development. This concept was confirmed by adoptive transfer studies utilizing lymphocytes from BDC2.5 and 4.1 (CD4+) TCR transgenic mice and 8.3 (CD8+) TCR transgenic mice; efforts showing increased proliferation of both CD4+ and CD8+ T cells following PDL1 blockade in vivo . Furthermore, we observed that anti-PDL1-mediated acceleration is dependent upon events occurring in the pancreatic lymph nodes during early disease stages, but becomes independent of the pancreatic lymph nodes during later disease stages. These data provide strong evidence that PDL1 regulates autoimmune diabetes by limiting the expansion of CD4+ and CD8+ autoreactive T cells, and define the timing and locale of PDL1-mediated regulation of type 1 diabetes.
Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) ...concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control.
This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952.
Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years SD 6·5, median HbA1c 7·2% IQR 6·6–8·1, 4589 46·3% women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1–5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio HR 0·88, 95% CI 0·79–0·99; p=0·026). All-cause mortality did not differ between groups (536 10·8% in the dulaglutide group vs 592 12·0% in the placebo group; HR 0·90, 95% CI 0·80–1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001).
Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.
Eli Lilly and Company.
Introduction: Prevalence of obesity in T1D is rising, contributing to the development of hepatic steatosis (HS) with the associated risk for metabolic dysfunction associated steatotic liver disease ...(MASLD). While T2 D and MASLD are reliably linked, prevalence of MASLD in T1D varies by the imaging modality employed. We therefore estimated the prevalence of HS and examined the key determinants of HS in people with T1D with BMI≥ 30 kg/m2. Methods: In a cross-sectional study, 42 individuals with T1D on a continuous glucose monitor (CGM) with duration of diabetes >10 years and BMI ≥ 30 kg/m2 were studied. MRI-Proton Density Fat Fraction (PDFF) was used to estimate HS. Visceral (VAT) and subcutaneous adiposity (SAT) measures were obtained. Linear regression models were used to evaluate the association between HS, VAT, and SAT, with outcomes of glycemic control and insulin resistance. Results: Participants had a mean (SD) age of 47.8 (13.3) y, 59.5% were men with BMI -32.9 (3.1) kg/m2 and 30.6% had a family history of T2D. Mean A1c was 7.1 (0.77), TIR of 65% (12.5), and TAR of 32.8(12.2) and GMI of 7.2(0.45). Prevalence of HS was 9.5% in the study sample. No statistically significant associations were found between any of the parameters evaluated and HS although a trend was observed for total daily dose of insulin in units (TDDI) (p=0.06) with higher insulin doses positively associated HS. Higher A1c (p =0.004), lower TIR (p=0.02), higher TAR (p =0.009) and higher TDDI (p<0.0001) were associated with higher VAT in the unadjusted models and remained significant for TDDI and VAT (p=0.01) when adjusted for age, sex, and WC. Conclusion: Our study, which incorporates CGM metrics in a distinctive subpopulation of T1D with obesity, suggests a lower prevalence rate of HS when a sensitive imaging modality such as MRI-PDFF was used. Lack of portal hyperinsulinemia may contribute to lower HS in T1D. The results suggest that markers of insulin resistance and glycemic exposure correlate with VAT but not HS in adults with T1D and obesity. Disclosure S. Trikudanathan: Research Support; Insulet Corporation. K. Amin: None. K. Bambha: None. S.J. Melhorn: None. M. Sekhon: None. S. Navarro: None. E.A. Schur: Consultant; Amgen Inc. I.B. Hirsch: Advisory Panel; Abbott. Research Support; Dexcom, Inc. Advisory Panel; Roche Diabetes Care. Research Support; MannKind Corporation, Tandem Diabetes Care, Inc. Advisory Panel; embecta. Research Support; Tandem Diabetes Care, Inc. Advisory Panel; Vertex Pharmaceuticals Incorporated. Funding UWMDI Pilot & Feasibility Award
Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor ...agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease.
REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952.
Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1–5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio HR 0·85, 95% CI 0·77–0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68–0·87; p<0·0001), with HRs of 0·89 (0·78–1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39–1·44; p=0·39) for chronic renal replacement therapy.
Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes.
Eli Lilly and Company.
Background: Insulin resistance (IR) and central obesity are common in PCOS, but pathomechanisms for IR in PCOS are not established. Circulating microRNAs (miRNAs) are non-invasive biomarkers of ...tissue gene expression that may contribute to the pathogenesis of IR and central adiposity in PCOS.
Methods: We conducted a pilot study to examine associations of circulating miRNAs with IR and central adiposity among women with PCOS (n=11) using high-throughput miRNA sequencing. We fit generalized linear models examining associations of waist circumference and HOMA-IR with plasma miRNAs. We used false discovery rate (FDR) -adjusted cutoff p<0.1 to adjust for multiple testing. We used the miRDB’s Gene Ontology (GO) tool to identify predicted pathways for top hits.
Results: Participants were 27.9 years old on average with mean BMI 32.5 kg/m2. At an FDR<0.1, lower levels of miR-1294 were associated with higher waist circumference (β = -0.10, FDR=0.095) . While no miRNAs were associated with HOMA-IR at our predetermined cut off, 11 miRNAs were associated with waist circumference and 14 miRNAs with HOMA-IR at p<0.01 (Table 1) . Pathways identified in the GO analysis of miR-1294 include “negative regulation of insulin receptor signaling” (p=0.019) .
Conclusions: Plasma miRNAs may be associated with IR and central obesity among PCOS patients.
Disclosure
P. Wander: None. D. Enquobahrie: None. T. Bammler: None. J. Macdonald: None. S. Srinouanprachanh: None. T. Kaleru: None. D. Khakpour: None. S. Trikudanathan: Research Support; Bionic pancreas, Bionic pancreas, Insulet Corporation, Insulet Corporation.
Funding
NIDDK (K08103945)
Introduction: Glycemic control for dialysis patients with diabetes mellitus (DM) is challenging due to limitations of HbA1c, risk of hypoglycemia, and fewer options for glucose-lowering agents. We ...sought to comprehensively describe glycemic patterns among dialysis patients using continuous glucose monitoring (CGM).
Methods: The Blood Sugar Sensing On Maintenance Dialysis (BLOSSOM) study is a prospective community-based cohort of people treated with dialysis, with or without DM, designed to assess the prevalence, causes, and consequences of dysglycemia. Each participant wore a Dexcom G6 CGM for 10 days. This interim analysis examined the first 153 BLOSSOM dialysis participants.
Results: Dialysis participants had a mean (SD) age of 61 (14) years, 132 (86%) underwent hemodialysis, and 21 (14%) were treated with peritoneal dialysis (PD). Among 90 dialysis participants with DM, mean (SD) glucose management indicator (GMI) was 7.9% (1.2%), time in range (TIR) (70-180 mg/dL) was 50% (29%) and 27 (30%) participants achieved TIR ≥70%. Mean (SD) time high (>180 mg/dL), very high (>250 mg/dL), low (<70 mg/dL) and very low (<54 mg/dL) was 49% (29%), 21% (23%), 2% (11%) and 1% (11%), respectively. Of 63 dialysis participants without DM, mean (SD) GMI was 6.2% (0.4%), and time in normal range (70-140 mg/dL) 75% (18%). Mean (SD) time low and very low were 2% (8%) and 0% (3%), with low and very low sensor glucose values seen in 38 (60%) and 23 (37%) participants, respectively. PD patients without known DM (n=9) had a mean (SD) GMI of 6.6% (0.3%) and spent mean (SD) 54% (21%) of time in normal range.
Conclusions: In this community-based sample of maintenance dialysis patients, uncontrolled hyperglycemia was highly prevalent among patients with DM. PD patients without DM were in normal range less than half of the time. Hypoglycemia was seen in patients with and without DM. Our findings warrant additional investigation into causes and consequences of glycemic patterns in patients on dialysis.
Disclosure
L.Mayeda: None. L.Zelnick: None. S.Trikudanathan: Research Support; Insulet Corporation, Bionic pancreas. I.B.Hirsch: Consultant; Abbott Diabetes, Lifecare, Inc., Hagar, Research Support; Beta Bionics, Inc., Insulet Corporation, Dexcom, Inc. S.Watnick: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126373)
Advances in diabetes technology have transformed the treatment paradigm for type 1 diabetes, yet the burden of disease is significant. We report on a pivotal safety study of the first tubeless, ...on-body automated insulin delivery system with customizable glycemic targets.
This single-arm, multicenter, prospective study enrolled 112 children (age 6-13.9 years) and 129 adults (age 14-70 years). A 2-week standard therapy phase (usual insulin regimen) was followed by 3 months of automated insulin delivery. Primary safety outcomes were incidence of severe hypoglycemia and diabetic ketoacidosis. Primary effectiveness outcomes were change in HbA
and percent time in sensor glucose range 70-180 mg/dL ("time in range").
A total of 235 participants (98% of enrolled, including 111 children and 124 adults) completed the study. HbA
was significantly reduced in children by 0.71% (7.8 mmol/mol) (mean ± SD: 7.67 ± 0.95% to 6.99 ± 0.63% 60 ± 10.4 mmol/mol to 53 ± 6.9 mmol/mol,
< 0.0001) and in adults by 0.38% (4.2 mmol/mol) (7.16 ± 0.86% to 6.78 ± 0.68% 55 ± 9.4 mmol/mol to 51 ± 7.4 mmol/mol,
< 0.0001). Time in range was improved from standard therapy by 15.6 ± 11.5% or 3.7 h/day in children and 9.3 ± 11.8% or 2.2 h/day in adults (both
< 0.0001). This was accomplished with a reduction in time in hypoglycemia <70 mg/dL among adults (median interquartile range: 2.00% 0.63, 4.06 to 1.09% 0.46, 1.75,
< 0.0001), while this parameter remained the same in children. There were three severe hypoglycemia events not attributable to automated insulin delivery malfunction and one diabetic ketoacidosis event from an infusion site failure.
This tubeless automated insulin delivery system was safe and allowed participants to significantly improve HbA
levels and time in target glucose range with a very low occurrence of hypoglycemia.
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