Type 2 Diabetes Subjects Research Articles

853-P: Effect of Ketogenic Diet with Weight Maintenance in Type 2 Diabetes (T2D)

Aim: To examine the effect of ketogenic diet in T2D patients on glucose tolerance, beta cell function, insulin sensitivity and body fat content. Methods: 29 T2D subjects were randomized to receive for 10 days a weight maintaining diet containing: GROUP I - 30% protein, 50% CHO, 20% fat (n=8); GROUP II - isocaloric ketogenic diet with 15% protein, 5% CHO, 80% fat (n=10); GROUP III - isocaloric ketogenic diet plus ketone ester of β-OH-B, 8 grams every 8h (n=11). Subjects ate breakfast daily in the TDI Metabolic Kitchen and picked up food for lunch and dinner. Results: After 10 days, body weight remained constant: Group I (89.0 vs 89.0 kg), II (93.0 vs 92.5) and III (96.0 vs 97.0), as did body fat content. HbA1c and fructosamine did not change in any of the 3 groups. During OGTT, FPG, 2-h PG, mean PG, fasting PI, mean PI, [Delta]I/[Delta]G, and Matsuda index of insulin sensitivity did not change in Groups I, II, III. Subjects received a 2-step euglycemic insulin clamp (20 and 60 mU/m2.min) with 3-3H-glucose and indirect calorimetry. Before and after 10 days basal HGP and suppression of HGP (step I) were similar in all 3 groups. Insulin-stimulated glucose disposal (step 2) did not change in group I (4.23 vs 4.38 mg/kg.min), II (3.62 vs 3.55), or III (3.26 vs 3.35). After 10 days, basal lipid oxidation increased, while CHO oxidation decreased (both P<0.01) in groups II and III and was unchanged in group I. Disclosure A.Merovci: None. B.Finley: None. A.Chavez: None. A.A.Hansis-diarte: None. S.Neppala: None. D.Tripathy: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk, Research Support; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc., Speaker's Bureau; AstraZeneca.

224-LB: Shared Genetic Architecture of Complication of Diabetes

Introduction: Approximately 1 in 10 Americans have diabetes (~37 million), 90-95% of which is type 2 diabetes (T2D). T2D is the leading cause of kidney disease (DKD), retinopathy, neuropathy, peripheral vascular disease (PVD), stroke, and coronary heart disease (CHD). Inherited variation is known to contribute to the risk of T2D complications, however, the relationship between and role of genetic variants on risk across complications is not fully understood. Method: We used data from our recently completed genomic investigations of a broad set of 18 diabetic complications, which included ~64K T2D subjects across five race-ethnic groups (Admixed Americas-, African-, East Asian-, European- and South Asian-ancestry samples) from 24 studies retrieved from dbGaP and UKBB biomedical repositories. Using these GWAS summary statistics, we calculated the genetic correlation between complication pairs with Z-scores (beta/SE) to investigate their relationship and guide post hoc pleiotropy analysis. Results: Genetic correlation analysis revealed four clusters of complications that shared strong correlation. Pleiotropy analysis identified three novel pleiotropic loci for T2D complications at SNX17 (Albuminuria, CHD & PVD), UBE2E2 (Albuminuria & end-stage kidney disease) and GCKR (Albuminuria, DKD, retinopathy, fatty liver disease, CHD & PVD). Conclusion: These findings support the hypothesis of shared heritability between diabetic complications. Additional work is needed to increase genetic discovery of pleiotropic variants across diabetic complications. Disclosure R. M. Salem: Other Relationship; Travere Inc. S. Cao: None. E. L. Richard: None. Funding Foundation for the National Institutes of Health; National Institutes of Health (R00HL122515)

Discrepancies in type of first major osteoporotic fracture and anti-osteoporotic therapy in elderly people with type 2 diabetes mellitus: A retrospective Danish cohort study.

Subjects with diabetes mellitus have an increased risk of fractures. We aimed to identify discrepancies in the first type of major osteoporotic fracture (MOF) and anti-osteoporotic therapy between subjects with type 2 diabetes (T2D) and subjects without diabetes. Methods and research design. We conducted a retrospective national cohort study by access to all discharge diagnoses (ICD-10 system) and redeemed drug prescriptions (ATC classification system). We included all subjects alive and Danish citizens in 2010 and identified subjects with T2D diagnosed after the age of 50 between 1998 and 2018. Only subjects with a MOF after the index date were included in the main analysis. The type of MOF was identified by diagnosis codes and categorized into Humerus, Forearm, Spine, and Hip. Multinomial logistic regression modeling was used to assess the predicted probability changes in MOF type between T2D and control subjects. Data on first anti-osteoporotic therapy after the MOF was assessed by redeemed drug prescriptions. Mortality and time to therapy after the MOF were evaluated by cox proportional hazards. We included 26,588 subjects with T2D and 97,982 subjects without diabetes. The mean age was age 69.33 (±10.34) for T2D and 69.85 (±10.19) for control subjects. The cohort was primarily females (67%). Subjects with T2D had a higher probability of hip (3.98% [95% CI 3.29; 4.67]) and humerus (2.82% [95% CI 2.17; 3.46]) fractures as the first MOF compared to control subjects. However, the probability of forearm fractures as the first MOF was 6.77% (95% CI 6.08; 7.46) lower among subjects with T2D. The multiple adjusted hazard ratio for anti-osteoporotic treatment after the first MOF was 0.80 (95% CI 0.77; 0.88) for T2D compared to controls among treatment-naïve subjects. Forearm fractures were the most frequent type of MOF and were more prevalent in control subjects. Subjects with T2D had a significantly higher probability of hip and humerus fractures as the first MOF but had a 20% lower chance of anti-osteoporotic treatment afterwards.

Blood DNA methylation biomarkers for cognitive decline in older adults with type 2 diabetes

AbstractBackgroundIndividuals with type 2 diabetes (T2D) are at particularly high risk for cognitive decline and dementia. Finding early, pre‐clinical biomarkers for detecting and tracking cognitive impairment and dementia in this population is important for personalized medicine approach. Our study aims to find blood DNA methylation biomarkers for cognitive decline among elderly T2D patients.MethodTwo groups of 30 T2D subjects each, from the Israel Diabetes and Cognitive Decline (IDCD) cohort, were included. One group (converters) was cognitively normal at baseline, yet at 36‐54 months follow‐up deteriorated from a Clinical Dementia Rating scale CDR = 0 (no dementia) to CDR≥0.5 (questionable dementia or frank dementia). The control group (non‐converters) was cognitively normal at baseline and maintained normal cognition during the follow‐up period (CDR = 0). We performed an epigenome‐wide association study, using the Illumina Infinium MethylationEPIC microarray, and searched for differentially methylated positions (DMPs) with significant methylation alterations (≥ 2 fold and FDR corrected p value <0.05) between the baseline and the follow‐up time points for each of the two groups.ResultParticipants were 65‐83 years of age (mean‐73.6 ± 4.1), 72% were men. The mean hemoglobin A1C value was 6.9 ± 0.8%, and T2D duration was 9.4 ± 4.7 years. Converters and non‐converters did not differ in any of these characteristics. Results show significant changes in multiple DMPs among the converters, but only in a few DMPs in the non‐converters. Gene ontology analyses indicates primarily involvement of central nervous system‐related pathways, mainly neurodevelopmental disorders.ConclusionThese preliminary results, employing a high‐throughput approach for methylation profile in blood, suggest methylomic alterations as a potential biomarker for cognitive decline in T2D elderly. A priori identification of patients at risk for cognitive decline may lead to early intervention in modifiable risk factors in this population, which is highly susceptible to dementia.

The Burden of Obesity in Type 1 Diabetic Subjects: A Sex-specific Analysis From the AMD Annals Initiative.

Obesity is a growing emergency in type 1 diabetes (T1D). Sex differences in obesity prevalence and its clinical consequences in adult T1D subjects have been poorly investigated. The aim of this study was to investigate the prevalence of obesity and severe obesity, clinical correlates, and potential sex differences in a large cohort of T1D subjects participating to the AMD (Associazione Medici Diabetologi) Annals Initiative in Italy. The prevalence of obesity [body mass index(BMI) ≥30 kg/m2] and severe obesity (BMI ≥ 35 kg/m2) according to sex and age, as well as obesity-associated clinical variables, long-term diabetes complications, pharmacological treatment, process indicators and outcomes, and overall quality of care (Q-score) were evaluated in 37 436 T1D subjects (45.3% women) attending 282 Italian diabetes clinics during 2019. Overall, the prevalence of obesity was similar in the 2 sexes (13.0% in men and 13.9% in women; mean age 50 years), and it increased with age, affecting 1 out of 6 subjects ages >65 years. Only severe obesity (BMI >35 kg/m2) was more prevalent among women, who showed a 45% higher risk of severe obesity, compared with men at multivariate analysis. Cardiovascular disease risk factors (lipid profile, glucose, and blood pressure control), and the overall quality of diabetes care were worse in obese subjects, with no major sex-related differences. Also, micro- and macrovascular complications were more frequent among obese than nonobese T1D men and women. Obesity is a frequent finding in T1D adult subjects, and it is associated with a higher burden of cardiovascular disease risk factors, micro- and macrovascular complications, and a lower quality of care, with no major sex differences. T1D women are at higher risk of severe obesity.

Human complement component C3 N-glycome changes in type 1 diabetes complications.

Changes in N-glycosylation have been described in numerous diseases and are being considered as biomarkers of ongoing pathological condition. Previous studies demonstrated the interrelation of N-glycosylation and type 1 diabetes (T1D), particularly linking serum N-glycan changes with complications accompanying the disease. Moreover, the role of complement component C3 in diabetic nephropathy and retinopathy has been implicated, and C3 N-glycome was found to be altered in young T1D patients. Therefore, we investigated associations between C3 N-glycan profiles and albuminuria and retinopathy accompanying T1D, as well as glycosylation connection with other known T1D complication risk factors. Complement component C3 N-glycosylation profiles have been analyzed from 189 serum samples of T1D patients (median age 46) recruited at a Croatian hospital centre. Using our recently developed high-throughput method, relative abundances of all six of the C3 glycopeptides have been determined. Assessment of C3 N-glycome interconnection with T1D complications, hypertension, smoking status, estimated glomerular filtration rate (eGFR), glycaemic control and duration of the disease was done using linear modelling. Significant changes of C3 N-glycome in severe albuminuria accompanying type 1 diabetes were observed, as well as in T1D subjects with hypertension. All except one of the C3 glycopeptides proved to be associated with measured HbA1c levels. One of the glycoforms was shown to be changed in non-proliferative T1D retinopathy. Smoking and eGFR showed no effect on C3 N-glycome. Furthermore, C3 N-glycosylation profile was shown to be independent of disease duration. This study empowered the role of C3 N-glycosylation in T1D, showing value in distinguishing subjects with different diabetic complications. Being independent of the disease duration, these changes may be associated with the disease onset, making C3 N-glycome a potential novel marker of the disease progression and severity.

Identification of Probucol as a candidate for combination therapy with Metformin for Type 2 diabetes

Type 2 Diabetes (T2D) is often managed with metformin as the drug of choice. While it is effective overall, many patients progress to exhibit complications. Strategic drug combinations to tackle this problem would be useful. We constructed a genome-wide protein-protein interaction network capturing a global perspective of perturbations in diabetes by integrating T2D subjects’ transcriptomic data. We computed a ‘frequently perturbed subnetwork’ in T2D that captures common perturbations across tissue types and mapped the possible effects of Metformin onto it. We then identified a set of remaining T2D perturbations and potential drug targets among them, related to oxidative stress and hypercholesterolemia. We then identified Probucol as the potential co-drug for adjunct therapy with Metformin and evaluated the efficacy of the combination in a rat model of diabetes. We find Metformin-Probucol at 5:0.5 mg/kg effective in restoring near-normal serum glucose, lipid, and cholesterol levels.

NET Proteome in Established Type 1 Diabetes Is Enriched in Metabolic Proteins.

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by a T-cell-mediated destruction of the pancreatic insulin-producing beta cells. A growing body of evidence suggests that abnormalities in neutrophils and neutrophil extracellular trap (NET) formation (NETosis) are associated with T1D pathophysiology. However, little information is available on whether these changes are primary neutrophil defects or related to the environmental signals encountered during active disease. In the present work, the NET proteome (NETome) of phorbol 12-myristate 13-acetate (PMA)- and ionomycin-stimulated neutrophils from people with established T1D compared to healthy controls (HC) was studied by proteomic analysis. Levels of NETosis, in addition to plasma levels of pro-inflammatory cytokines and NET markers, were comparable between T1D and HC subjects. However, the T1D NETome was distinct from that of HC in response to both stimuli. Quantitative analysis revealed that the T1D NETome was enriched in proteins belonging to metabolic pathways (i.e., phosphoglycerate kinase, glyceraldehyde-3-phosphate dehydrogenase, and UTP-glucose-1-phosphate uridylyltransferase). Complementary metabolic profiling revealed that the rate of extracellular acidification, an approximate measure for glycolysis, and mitochondrial respiration were similar between T1D and HC neutrophils in response to both stimuli. The NETome of people with established T1D was enriched in metabolic proteins without an apparent alteration in the bio-energetic profile or dysregulated NETosis. This may reflect an adaptation mechanism employed by activated T1D neutrophils to avoid impaired glycolysis and consequently excessive or suboptimal NETosis, pivotal in innate immune defence and the resolution of inflammation.

Effects of Lunar Phases on Foot Temperature, Oxidative Stress, and Inflammation in Type 2 Diabetic Subjects.

It has been observed that the lunar phases alter the fasting plasma glucose (FPG) level in type-2 diabetic (T2DM) subjects. Diabetic peripheral neuropathy (DPN) was also reported to be associated with elevated foot temperature (FT), oxidative stress, and inflammation in T2DM subjects. The purpose of the present study was to evaluate the changes in FT, oxidative stress, and inflammation levels and assess the relationship of FT with oxidative stress, antioxidant enzyme activity, and inflammatory markers in T2DM subjects at different lunar phases. The plasma glucose, glycated hemoglobin, and dorsal and plantar surface temperatures of the feet by infrared dermal thermometer were measured in 88 randomly selected T2DM subjects at different lunar phases. The levels of oxidative stress and inflammation were assessed by measuring malondialdehyde (MDA), glucose 6-phosphate dehydrogenase (G6PDH), and tumor necrosis factoralpha (TNF-α). The FTs, MDA, and TNF-α were significantly increased, and G6PDH activity was significantly decreased in the new moon (NM) and full moon (FM) than in the third quarter (TQ) and first quarter (FQ) for both sexes. The FTs, MDA, and TNF-α levels were significantly positively correlated, whereas G6PDH activity was significantly negatively correlated with FPG at NM and FM in both sexes. The MFT was significantly positively correlated with MDA and TNF-α and significantly negatively correlated with G6PDH at NM and FM in T2DM subjects. The lunar phases showed a prominent influence on the FT, oxidative stress, and inflammatory status in T2DM subjects, which might be due to the existence of biological rhythm interaction with lunar electromagnetic radiations.

Abstract 105: Lipid Regulation of Senescent Effector CD8 T Cells in Type 2 Diabetes

Introduction: Atherosclerotic plaques from patients with Type 2 Diabetes (T2D) present a more severe pathology than non-T2D (ND) plaques and response to cholesterol-lowering is compromised. An increased level of circulating senescent CD8 T cells in T2D patients is associated with increased risk for myocardial infarction. However, whether senescent T cells infiltrate human atherosclerotic plaques and how they are regulated by lipid lowering is unknown. Hypothesis: Senescent CD8+ T cells are increased in atherosclerotic plaques and circulation of T2D, and are normalized by aggressive lipid lowering in T2D. Methods: We performed unbiased scRNA-seq analysis (75,049 total cells) of immune cells in plaques from T2D (n=12) and ND patients (n=10) to identify senescent T cells in human atherosclerotic plaques. Using CyTOF we tested the effect of aggressive lipid lowering on circulating CD8 T cells in T2D (n=16) and ND (n=6) patients. Results: We identified senescent T cells within atherosclerotic plaques and found that senescent CD8 T cells largely accumulate in plaques from T2D patients (p<0.001). Plaque CD8 T cells showed a terminally differentiated effector memory phenotype with high expression of CX3CR1 and low expression of SELL and CCR7 genes. CD8 T cell clusters express senescence markers ( B3GAT1,KLRG1,KLRD1,KLRF1 ) and presented senescence associated secretory phenotype with high expression of cytotoxic ( GZMB,PRF1,GNLY ) and proatherogenic ( IFNG,TNFA,CCL5 ) genes. CyTOF analysis showed higher levels of circulating senescent CD57+CD28-CD8 T cells in patients with T2D vs ND controls (p<0.001). Potent lipid lowering with PCSK9 inhibitor + statin/ezetimibe, which reduced LDL-C levels by >70% in all patients at 4 weeks, normalized the frequency of circulating senescent CD8 T cells (p<0.001) in T2D patients to the levels found in ND. Conclusion: Our results show that senescent CD8 T cells accumulated in blood and plaques of T2D patients and that potent lipid lowering diminished circulating aged CD8 T cells, suggesting that CD8 T cell senescence can be improved by aggressive lipid control in high-risk T2D subjects. Further analyses are needed to understand the role of lipid metabolism in the T cell senescence and the impact on atherosclerosis progression.

Alterations of the intestinal mucus layer correlate with dysbiosis and immune dysregulation in human Type 1 Diabetes

In preclinical models of Type 1 Diabetes (T1D) the integrity of the gut barrier (GB) is instrumental to avoid dysregulated crosstalk between the commensal microbiota and immune cells and to prevent autoimmunity. The GB is composed of the intestinal epithelial barrier (IEB) and of the mucus layer containing mucins and antimicrobial peptides (AMPs) that are crucial to maintain immune tolerance. In preclinical models of T1D the alterations of the GB primarily affect the mucus layer. In human T1D increased gut permeability and IEB damage have been demonstrated but the integrity of the mucus layer was never assessed. We evaluated GB integrity by measuring serological markers of IEB damage (serological levels of zonulin) and bacterial translocation such as lipopolysaccharide binding protein (LBP) and myeloid differentiation protein 2 (MD2), and mRNA expression of tight junction proteins, mucins and AMPs in intestinal tissue of T1D patients and healthy controls (HC). Simultaneously, we performed immunological profiling on intestinal tissue and 16S rRNA analysis on the mucus-associated gut microbiota (MAGM). Our data show a GB damage with mucus layer alterations and reduced mRNA expression of several mucins (MUC2, MUC12, MUC13, MUC15, MUC20, MUC21) and AMPs (HD4 and HD5) in T1D patients. Mucus layer alterations correlated with reduced relative abundance of short chain fatty acids (SCFA)-producing bacteria such as Bifidobacterium dentium, Clostridium butyricum and Roseburia intestinalis that regulate mucin expression and intestinal immune homeostasis. In T1D patients we also found intestinal immune dysregulation with higher percentages of effector T cells such as T helper (Th) 1, Th17 and TNF-α+ T cells. Our data show that mucus layer alterations are present in T1D subjects and associated with dysbiosis and immune dysregulation. Research Grants from the Juvenile Diabetes Foundation (Grant 1-INO-2018-640-A-N to MF and 2-SRA-2019-680-S-B to JD) and from the Italian Ministry of Health (Grant RF19-12370721 to MF).

Adequacy of knowledge of new medical graduates about diagnosis and management of children and adolescents with type 1 diabetes in a developing country

BackgroundKnowledge of diabetes by the graduate physicians had been reported to be deficient in many aspects of diagnosis and management of type 1 diabetes (T1D). This will reflect on patient care and quality of health services especially in limited-resources countries. Our aim was to assess knowledge of basic management of T1D in new medical graduates in Jordan.MethodsA questionnaire was developed to collect information concerning demographics and knowledge and was distributed in paper form and online using google forms. The knowledge was assessed using 28 questions on different aspects of the disease.ResultsA total of 358 new medicine graduates responded to the survey and female respondents were significantly higher than male respondents. Average number of lectures concerning diabetes during the medical school years was 3.92 ± 1.37. High knowledge scores were on pathophysiology of T1D, hypoglycemia, and certain aspects of diabetic ketoacidosis. Female gender, higher number of persons with T1D the participant had encountered during medical school, and good or excellent expected degree of self-knowledge of diabetes were associated with high knowledge score, p values = 0.01, 0.009, and < 0.001, respectively. Female gender and good or excellent expected degree of knowledge of diabetes predicted high knowledge score, p value = 0.008, and < 0.001, respectively.ConclusionGaps in knowledge of new medical graduates in certain T1D subjects exist. This can be corrected by many strategies including changes in curricula, elective courses, more clinical exposure, and interprofessional education. These measures must be evaluated for their short and long-term benefits.

Impact of Insulin Degludec/Liraglutide Fixed Combination on the Gut Microbiomes of Elderly Patients With Type 2 Diabetes: Results From A Subanalysis of A Small Non-Randomised Single Arm Study.

In elderly Type 2 Diabetes (T2D) patients the relationship between the destabilization of gut microbiome and reversal of dysbiosis via glucose lowering drugs has not been explored. We investigated the effect of 6 months therapy with a fixed combination of Liraglutide and Degludec on the composition of the gut microbiome and its relationship with Quality of Life, glucose metabolism, depression, cognitive function, and markers of inflammation in a group of very old T2D subjects (n=24, 5 women, 19 men, mean age=82 years). While we observed no significant differences in microbiome biodiversity or community among study participants (N = 24, 19 men, mean age 82 years) who responded with decreased HbA1c (n=13) versus those who did not (n=11), our results revealed a significant increase in Gram-negative Alistipes among the former group (p=0.013). Among the responders, changes in the Alistipes content were associated directly with cognitive improvement (r=0.545, p=0.062) and inversely with TNFα levels (r=-0.608, p=0.036). Our results suggest that this combination drug may have a significant impact on both gastrointestinal microbes and cognitive function in elderly T2D individuals.

Prevalence of cardiovascular disease and its associated factors among middle-aged type-2 diabetic subjects: a cross-sectional study in selected hospitals in Bangladesh

Prevalence of cardiovascular disease and its associated factors among middle-aged type-2 diabetic subjects: a cross-sectional study in selected hospitals in Bangladesh

The Impact of Different Types of Rice and Cooking on Postprandial Glycemic Trends in Children with Type 1 Diabetes with or without Celiac Disease

The aims of this study were to evaluate: (i) the chemical and nutritional composition of rice before and after cooking and (ii) postprandial glycemic impacts in children and adolescents with type 1 diabetes (T1D) after eating two different types of rice ("Gigante Vercelli" white rice and "Artemide" black rice) or white rice cooked "risotto" style or boiled using an advanced hybrid closed loop (AHCL) system (Tandem Control-IQTM). General composition and spectrophotometric analyses of raw and cooked rice were performed. Eight T1D subjects (four males and four females, aged 11 ± 1.4 years), two with celiac disease (CD), using an AHCL system were enrolled. "Gigante Vercelli" white rice cooked as risotto or boiled and boiled "Artemide" rice were prepared by the same cook on two evenings. Continuous glucose monitoring metrics were evaluated for 12 h after meal consumption. Total dietary fiber was higher for both rice types after cooking compared with raw rice. Cooking as risotto increased polyphenols and antioxidants (p < 0.05) in both rice varieties, and total starch decreased after boiling (p < 0.05) in white rice. There was a significant peak in glycemia after consuming risotto and boiled white rice (p < 0.05), while the mean glycemic peak remained <180 mg/dL in individuals eating boiled Artemide rice. There were no significant differences in automatic basal or auto-bolus insulin deliveries by the AHCL according to different types of rice or cooking method. Our findings suggest that glycemic trends are impacted by the different chemical and nutritional profiles of rice but are nevertheless well controlled by AHCL systems.

Impact of Sex and Gender on Clinical Management of Patients with Advanced Chronic Liver Disease and Type 2 Diabetes

Gender differences in the epidemiology, pathophysiological mechanisms and clinical features in chronic liver diseases that may be associated with type 2 diabetes (T2D) have been increasingly reported in recent years. This sexual dimorphism is due to a complex interaction between sex- and gender-related factors, including biological, hormonal, psychological and socio-cultural variables. However, the impact of sex and gender on the management of T2D subjects with liver disease is still unclear. In this regard, sex-related differences deserve careful consideration in pharmacology, aimed at improving drug safety and optimising medical therapy, both in men and women with T2D; moreover, low adherence to and persistence of long-term drug treatment is more common among women. A better understanding of sex- and gender-related differences in this field would provide an opportunity for a tailored diagnostic and therapeutic approach to the management of T2D subjects with chronic liver disease. In this narrative review, we summarized available data on sex- and gender-related differences in chronic liver disease, including metabolic, autoimmune, alcoholic and virus-related forms and their potential evolution towards cirrhosis and/or hepatocarcinoma in T2D subjects, to support their appropriate and personalized clinical management.

Relationship between serum fibroblast growth factor 19 and vascular endothelial growth factor and soluble klotho protein in type 1 diabetic children

BackgroundFibroblast growth factor 19 (FGF19) takes part in maintaining the balance of glycolipids and may be involved in complications of type 1 diabetes(T1D) in children. This study aimed at at evaluating the relationship among the levels of serum FGF19 and vascular endothelial growth factor(VEGF)and soluble klotho protein(sklotho) in type 1 diabetic children.MethodsIn a cross-section single center study samples were obtained from 96 subjects: 66 T1D and 30 healthy children.Serum FGF19 and VEGF and sklotho concentrations were measured by ELISA. And 66 type 1 diabetes participants were divided into two groups according to T1D duration or three groups according to HbA1c.Furthermore,we compared the serum levels of FGF19 and VEGF and sklotho in different groups.ResultsThe concentration of FGF19 was lower in T1D than in the controls(226.52 ± 20.86pg/mu vs.240.08 ± 23.53 pg/L, p = 0.03),while sklotho was also lower in T1D than in the controls (2448.67 ± 791.92pg/mL vs. 3083.55 ± 1113.47pg/mL, p = 0.011). In contrast, VEGF levels were higher in diabetic patients than in controls (227.95 ± 48.65pg/mL vs. 205.92 ± 28.27 pg/mL, p = 0.016). In T1D, FGF19 and VEGF and sklotho was not correlated with the duration of diabetes. FGF19 and VEGF and sklotho were correlated with HbA1c (r=-0.349, p = 0.004 and r = 0.302, p = 0.014 and r=-0.342, p = 0.005, respectively), but not with blood glucose and lipid. Among subjects in the T1D group, concentrations of FGF19,VEGF and sklotho protein were different between different groups according to the degree of HbA1c(P < 0.005).Furthermore, there was a positive correlation between the serum FGF19 concentration and sklotho levels (r = 0.247,p = 0.045), and a negative correlation between the serum FGF19 concentration and VEGF level(r=-0.335,P = 0.006). Conclusions: The serum FGF19 levels have a close relation with serum VEGF levels and sklotho levels among T1D subjects. FGF19 may be involved in the development of complications in children with type 1 diabetes through interaction with VEGF and sklotho.

Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort.

Type 2 diabetes (T2D) is a rising pandemic worldwide. Diet and lifestyle changes are typically the first intervention for T2D. When this intervention fails, the biguanide, metformin, is the most common pharmaceutical therapy. Yet, it's full mechanisms of action remain unknown. In this work, we applied an ultrahigh resolution, mass spectrometry-based platform for untargeted plasma metabolomics to human plasma samples from a case-control observational study of non-diabetic and well-controlled T2D subjects, the latter treated conservatively with metformin or diet and lifestyle changes only. No statistically significant differences existed in baseline demographic parameters, glucose control, or clinical markers of cardiovascular disease risk between the two T2D groups, which we hypothesized would allow the identification of circulating metabolites independently associated with treatment modality. Over 3000 blank-reduced metabolic features were detected, with the majority of annotated features being lipids or lipid-like molecules. Altered abundance of multiple fatty acids and phospholipids were found in T2D subjects treated with diet and lifestyle changes as compared to non-diabetic subjects: changes that were often reversed by metformin. Our findings provide direct evidence that metformin monotherapy alters the human plasma lipidome independent of T2D disease control and support a potential cardioprotective effect of metformin worthy of future study. Significance Statement This work provides important new information on the systemic effects of metformin in type 2 diabetic subjects. We observed significant changes in the plasma lipidome with metformin therapy, with metabolite classes previously associated with cardiovascular disease risk significantly reduced as compared to diet and lifestyle changes. While cardiovascular disease risk was not a primary outcome of our study, our results provide a jumping-off point for future work into the cardioprotective effects of metformin, even in well-controlled type 2 diabetes.

Proteomics of high-density lipoprotein subfractions and subclinical atherosclerosis in type 1 diabetes mellitus: a case–control study

BackgroundSubclinical atherosclerosis is frequently observed in type 1 diabetes (T1D) although the mechanisms and markers involved in the evolution to established cardiovascular disease are not well known. High-density lipoprotein cholesterol in T1D is normal or even high, and changes in its functionality and proteomics are considered. Our aim was to evaluate the proteomics of HDL subfractions in T1D and control subjects and its association with clinical variables, subclinical atherosclerosis markers and HDL functionality.MethodsA total of 50 individuals with T1D and 30 matched controls were included. Carotid-femoral pulse wave velocity (PWV), flow-mediated vasodilation (FMD), cardiovascular autonomic neuropathy (CAN), and ten-year cardiovascular risk (ASCVDR) were determined. Proteomics (parallel reaction monitoring) was determined in isolated HDL2 and HDL3 that were also utilized to measure cholesterol efflux from macrophages.ResultsAmong 45 quantified proteins, 13 in HDL2 and 33 in HDL3 were differentially expressed in T1D and control subjects. Six proteins related to lipid metabolism, one to inflammatory acute phase, one to complement system and one to antioxidant response were more abundant in HDL2, while 14 lipid metabolism, three acute-phase, three antioxidants and one transport in HDL3 of T1D subjects. Three proteins (lipid metabolism, transport, and unknown function) were more abundant in HDL2; and ten (lipid metabolism, transport, protease inhibition), more abundant in HDL3 of controls. Individuals with T1D had higher PWV and ten-year ASCVDR, and lower FMD, Cholesterol efflux from macrophages was similar between T1D and controls. Proteins in HDL2 and HDL3, especially related to lipid metabolism, correlated with PWV, CAN, cholesterol efflux, HDLc, hypertension, glycemic control, ten-year ASCVDR, and statins use.ConclusionHDL proteomics can be predictive of subclinical atherosclerosis in type 1 diabetes. Proteins that are not involved in reverse cholesterol transport may be associated with the protective role of HDL.

Type 2 diabetes prevalence, awareness, and risk factors in rural Mali: a cross-sectional study

Diabetes is currently a crisis in sub-Saharan West Africa (SSWA) with dramatic implications for public health and national budgets prioritizing infectious diseases. There is limited recent literature about the prevalence, awareness, and risk factors for type 2 diabetes (T2D) in rural parts of SSWA. This study characterized T2D prevalence and risk factors for the rural Malian community of Nièna, which is situated in Mali’s second-largest province of Sikasso. Between December 2020 and July 2021, a cross-sectional study of 412 participants was conducted in the Nièna community using clinical questionnaires and rapid diagnostic tests. Among 412 participants, there were 143 (34.7%) and 269 (65.3%) males and females, respectively. The overall prevalence of T2D in Nièna was 7.5% (31/412), and prevalence rates were 8.6% (23/269) and 5.6% (8/143) for females and males, respectively. Age, family history of diabetes, hypertension, waist circumference, and fetal macrosomia were significantly associated with T2D (p = 0.007, p < 0.001, p = 0.003, p = 0.013, and p < 0.001, respectively). Notably, 61.3% (19/31) of T2D subjects were unaware of their diabetic status before the study. Field surveys have considerable utility in driving T2D awareness in rural African settings.