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Guido Kramer, Christof Kloos, Ulrich A. Müller, Gunter Wolf,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-7; doi:10.1186/s13098-021-00700-0

Abstract:
Aims The aim of this study was to compare individuals with type 1 diabetes with continuous subcutaneous insulin infusion (CSII) and intensified insulin therapy (ICT) in routine care regarding metabolic control and treatment satisfaction. Methods Individuals with type 1 diabetes (CSII n = 74; ICT n = 163) were analysed regarding metabolic control, frequency of hypoglycaemia and treatment satisfaction (DTSQs range 0–36). Results Individuals with CSII (duration of CSII: 14.1 ± 7.2 years) were younger (51.1 ± 15.8 vs. 56.2 ± 16.2 years, p = 0.023), had longer diabetes duration (28.7 ± 12.4 vs. 24.6 ± 14.3 years, p = 0.033), lower insulin dosage (0.6 ± 0.2 vs. 0.7 ± 0.4 IU/kg, p = 0.004), used more frequently short-acting analogue insulin (90.5% vs. 48.5%, p < 0.001) and flash/continuous glucose monitoring (50.0% vs. 31.9%, p = 0.009) than people with ICT. HbA1c was similar between CSII and ICT (7.1 ± 0.8%/54.4 ± 9.1 mmol/mol vs. 7.2 ± 1.0%/55.7 ± 10.9 mmol/mol, p = 0.353). Individuals with CSII had higher frequency of non-severe hypoglycaemia per week (in people with blood glucose monitoring: 1.9 ± 1.7 vs. 1.2 ± 1.6, p = 0.014; in people with flash/continuous glucose monitoring: 3.3 ± 2.2 vs. 2.1 ± 2.0, p = 0.006). Prevalence of polyneuropathy (18.9% vs. 38.0%, p = 0.004) and systolic blood pressure (138.0 ± 16.4 vs. 143.9 ± 17.1 mmHg, p = 0.014) was lower in CSII. Satisfaction with diabetes treatment (26.7 ± 7.3 vs. 26.0 ± 6.8, p = 0.600) did not differ between CSII and ICT. Conclusions CSII and ICT yielded comparable metabolic control and treatment satisfaction but CSII was associated with higher incidence of non-severe hypoglycaemia and lower insulin dosage.
, Patric J. D. Delhanty, Martin Huisman, Jenny A. Visser, Sebastian J. Neggers, Aart Jan van der Lely
Diabetology & Metabolic Syndrome, Volume 13; doi:10.1186/s13098-021-00699-4

Abstract:
Several studies have demonstrated suppressed levels of acylated (AG) and unacylated ghrelin (UAG) in patients with type 2 diabetes. However, the role of these hormones in type 1 diabetes has not been extensively studied. This study assessed the relationship between AG and UAG levels and body composition in patients with type 1 diabetes. We selected eighteen patients with type 1 diabetes and divided them into two groups: non-obese (BMI < 25 kg/m2) and overweight (BMI ≥ 25 kg/m2). Demographics, parameters of body composition and serum parameters including AG and UAG, were assessed. The patients with a BMI ≥ 25 kg/m2 were older and had a longer duration of diabetes. AG and UAG levels were not significantly different between non-obese and overweight groups (mean AG non-obese ± SD: 44.5 ± 29.4 pg/ml and mean UAG non-obese 42.4 ± 20.7 pg/ml vs mean AG overweight ± SD: 46.1 ± 29.6 pg/ml and mean UAG overweight 47.2 ± 18.2 pg/ml). AG/UAG ratios did not discriminate between these groups. There was a positive association of insuline dose/kg bodyweight with BMI (r2 = 0.45, p = 0.002). Surprisingly, unlike non-diabetics and in T2D, we did not observe a difference in plasma levels of AG and UAG between normal weight and overweight adult type 1 diabetics. However, we did observe a positive correlation between BMI and insuline dose/kg bodyweight, suggesting that exogenous insulin is more important than the ghrelin system in the development of obesity in type 1 diabetes.
Rodrigo Esaki Tamura, Said Muhammad Said, Leticia Mussin de Freitas,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-13; doi:10.1186/s13098-021-00695-8

Abstract:
Background COVID-19 has stroke Brazil harshly, deaths by COVID-19 in Brazil represent almost 13% of the total deaths by COVID-19 in the world, even though Brazilian population represents only 2.6% of the world population. Our aim in this study was to evaluate death and intubation outcomes and risk factors associated with COVID-19, and treatment options focusing on diabetes patients and the use of metformin pre-admission and during hospitalization. Methods In this Brazilian single-center study we evaluated 1170 patients hospitalized due to COVID-19. Diabetes patients (n = 188) were divided based on their use of pre-hospital and in-hospital metformin (non-met-group and met-group). Results In the total cohort most comorbidities were risk factors for orotracheal intubation and death. The use of chloroquine/hydroxychloroquine was significantly associated with increased death and intubation risk in uni- and multivariate analysis. Diabetes patients showed worst clinical feature compared with non-diabetes patients. In-hospital non-met-group had increased mortality (20.5%) compared to met-group (3.5%) (p = 0.0002) and univariable cox proportion hazard regression indicated in-hospital metformin reduced mortality (HR = 0.325, p = 0.035). Patients that used pre-hospital metformin showed lower severity parameters at hospital admission. (met-group: 2.45 ± 2.5; non-met-group: 4.25 ± 3.4). In all the groups older patients showed more severe clinical conditions and high risk of death and intubation. Conclusion Even though this is a single-center study, results from other reports have shown a similar trend, indicating that patients that used metformin during hospitalization have a better prognosis and reduced risk of death.
Jianguo Liu, , Hezhongrong Nie, Yong Pan, Yan Liu, Zhentian Zhang, Xiuping Lin, Yuan Zhang, Jinchuang Cai, Muxiu Yang, et al.
Diabetology & Metabolic Syndrome, Volume 13, pp 1-9; doi:10.1186/s13098-021-00697-6

Abstract:
Objective To investigate the impact of microecological preparation combined with modified low-carbon diet on the glucolipid metabolism and cardiovascular complication in obese patients. Methods From August 2017 to July 2020, 66 obese patients were recruited, and administrated with an modified low-carbon diet with (group A) or without (Group B) microecology preparation and a balanced diet in control group (group C) for 6 months. Meanwhile, 20 volunteers administrated with a balanced diet were recruited as the healthy control group (group D). Results After 6-month intervention, obese subjects in group A and B showed significant improvement of body and liver fat mass, reduction of serum lipid levels, intestinal barrier function markers, insulin resistance index (IRI), high blood pressure (HBP) and carotid intima thickness, as compared with subjects in group C. More importantly, subjects in group A had better improvement of vascular endothelial elasticity and intimal thickness than subjects in group B. However, these intervention had no effect on carotid atherosclerotic plaque. Conclusion Administration of microecological preparation combined with modified low-carbon diet had better improvement of intestinal barrier function, glucose and lipid metabolism, and cardiovascular complications than low-carbon diet in obese patients, but the effect of a simple low-carb diet on carotid atherosclerotic plaque need to be further addressed.
Hong-Liang Jiang, , Ying-Jun Deng, Xue Liang
Diabetology & Metabolic Syndrome, Volume 13, pp 1-15; doi:10.1186/s13098-021-00683-y

Abstract:
Objectives Previous studies have analyzed the potential effect of KCNQ1 rs2237892 polymorphism on the predisposition to type 2 diabetes mellitus, but the findings are inconclusive and the subject of debate. The purpose of our study was to provide further insight into the potential association between KCNQ1 rs2237892 polymorphism and the risk of type 2 diabetes mellitus. Methods In total, 50 articles (60 studies) with 77,276 cases and 76,054 controls were utilized in our analysis. The pooled odds ratio (OR), 95% confidence interval (95% CI), and p value were used to evaluate the significance of our findings. Funnel plots and Beggar’s regression tests were utilized to determine the presence of publication bias. Results Our meta-analysis results indicated that KCNQ1 rs2237892 polymorphism could be correlated with the risk of type 2 diabetes mellitus under the C allelic, recessive, and dominant genetic models (OR = 1.25, 95% 1.19–1.32, p < 0.001; OR = 1.50, 95% CI 1.34–1.68, p < 0.001; OR = 1.26, 95% CI 1.14–1.40, p < 0.001, respectively). Additionally, ethnicity analysis revealed that the source of control, case size, and Hardy–Weinberg Equilibrium status were correlated to the polymorphism in the three genetic models. Conclusions Our meta-analysis demonstrated significant evidence to support the association between KCNQ1 rs2237892 polymorphism and predisposition to type 2 diabetes mellitus.
Xin Liang, Wei Zheng, Cheng Liu, Lirui Zhang, Li Zhang, Zhihong Tian,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-8; doi:10.1186/s13098-021-00694-9

Abstract:
Background Pregnant women with a history of gestational diabetes mellitus (GDM) are at high risk of GDM. It is unclear whether this population has pregnancy characteristics different from the general population. Whether these features affect the perinatal outcome has not yet been elucidated. Methods A retrospective study was conducted, including baseline characteristics, laboratory data, gestational weight gain (GWG), and pregnancy outcomes of 441 pregnant women with prior GDM. Besides, 1637 women without a history of GDM treated in the same period were randomly selected as the control group. The above indicators of the two groups were compared. Multivariable logistic regression analysis was performed to investigate how GWG was associated with perinatal outcomes for previous GDM women. Results Among women with GDM history, triglycerides (TG) and fasting plasma glucose (FPG) in the 1st trimester were higher than those without GDM history. GWG was lower in women with prior GDM relative to the control group at various pregnancy stages. However, women with GDM history had a higher risk of developing GDM (OR 3.25, 95% CI 2.26–4.68) and pregnancy-induced hypertension (OR 1.50, 95% CI 1.05–2.45). In women with previous GDM, excessive GWG before OGTT exhibited a positive correlation with pregnancy-induced hypertension (OR 1.47, 95% CI 1.05–3.32), while inadequate GWG was not a protective factor for GDM and pregnancy-induced hypertension. Conclusion Women with prior GDM have glucose and lipid metabolism disorders in the 1st trimester. Limited reduction of GWG before oral glucose tolerance test (OGTT) was insufficient to offset the adverse effects of glucose and lipid metabolism disorders in women with previous GDM. Relevant interventions may be required at early stage or even before pregnancy.
Bruno Vecchiatto, Rafael C. da Silva, Talita S. Higa, Cynthia R. Muller, Anna Laura V. Américo, Vanessa C. Fortunato-Lima, Marília M. Ferreira, Luiz Felipe Martucci, Miriam H. Fonseca-Alaniz,
Diabetology & Metabolic Syndrome, Volume 13; doi:10.1186/s13098-021-00693-w

Abstract:
Background We investigate the effect of aerobic physical training (APT) on muscle morphofunctional markers and Angiotensin Converting Enzyme 2/Angiotensin 1-7/Mas receptor (ACE2/Ang 1-7/Mas) axis in an obesity-linked insulin resistance (IR) animal model induced by cafeteria diet (CAF). Methods Male C57BL/6J mice were assigned into groups CHOW-SED (chow diet, sedentary; n = 10), CHOW-TR (chow diet, trained; n = 10), CAF-SED (n = 10) and CAF-TR (n = 10). APT consisted in running sessions of 60 min at 60% of maximal speed, 5 days per week for 8 weeks. Results Trained groups had lower body weight and adiposity compared with sedentary groups. CAF-TR improved the glucose and insulin tolerance tests compared with CAF-SED group (AUC = 28.896 ± 1589 vs. 35.200 ± 1076 mg dL−1 120 min−1; kITT = 4.1 ± 0.27 vs. 2.5 ± 0.28% min−1, respectively). CHOW-TR and CAF-TR groups increased exercise tolerance, running intensity at which VO2 max was reached, the expression of p-AMPK, p-ACC and PGC1-α proteins compared with CHOW-SED and CAF-SED. Mithocondrial protein expression of Mfn1, Mfn2 and Drp1 did not change. Lipid deposition reduced in CAF-TR compared with CAF-SED group (3.71 vs. 5.53%/area), but fiber typing, glycogen content, ACE2 activity, Ang 1-7 concentration and Mas receptor expression did not change. Conclusions The APT prevents obesity-linked IR by modifying the skeletal muscle phenotype to one more oxidative independent of changes in the muscle ACE2/Ang 1-7/Mas axis.
Diabetology & Metabolic Syndrome, Volume 13, pp 1-10; doi:10.1186/s13098-021-00690-z

Abstract:
Background Serum fatty acid-binding protein 4 (FABP4), as an intracellular lipid chaperone and adipokine, was reported to be related to the incidence of type 2 diabetes (T2D) and diabetic complications, but its association with pancreatic islet β-cell and α-cell functions has not been fully elucidated. So the present study was to investigate the serum FABP4 levels and responses of islet β-cells and α-cells in patients with T2D. Methods 115 patients with T2D and 89 healthy controls (HC), who received serum FABP4 levels test, were recruited to participate in this study. Moreover, 75-g oral glucose tolerance test (OGTT) was performed in T2D patients to evaluate islet β-cell and α-cell functions. Systemic insulin sensitivity and overall insulin secretion of islet β-cell function were assessed by Matsuda index using C peptide (ISIM-cp) and ratio of the area under the C peptide curve to the glucose curve (AUCcp/glu) during OGTT, respectively. Fasting glucagon (Gluca0min) and postchallenge glucagon assessed by the area under the glucagon curve (AUCgluca) were determined during OGTT to evaluate islet α-cell function. And other various clinical variables were also measured in all participants. Skewed variables were natural log-transformed (ln), such as lnFABP4. Results The serum FABP4 levels in T2D patients were significantly higher than those in HC (p < 0.05). And after partially adjusting for fasting plasma glucose, serum lnFABP4 levels were negatively correlated with lnISIM-cp (r = − 0.332, p < 0.001) and positively correlated with lnAUCcp/glu (r = 0.324, p < 0.001), lnGluca0min (r = 0.200, p = 0.040) and lnAUCgluca (r = 0.311, p < 0.001), respectively, in patients with T2D. Furthermore, when multiple linear regression analyses were applied to adjust for other various clinical variables, serum lnFABP4 levels were found to remain associated with lnISIM-cp (β = − 0.296, t = − 2.900, p = 0.005), lnAUCcp/glu (β = 0.223, t = 2.038, p = 0.046), lnGluca0min (β = 0.272, t = 2.330, p = 0.024) and lnAUCgluca (β = 0.341, t = 3.065, p = 0.004), respectively. Conclusion Increased serum FABP4 levels were closely associated with blunted insulin sensitivity, increased insulin secretion, and elevated fasting and postchallenge glucagon levels in patients with T2D.
Jie Yun, Jinyu Ren, Yufei Liu, Lijuan Dai, Liqun Song, Xiaopeng Ma, Shan Luo,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-12; doi:10.1186/s13098-021-00692-x

Abstract:
Background Circular RNAs (circRNAs) have been considered as pivotal biomarkers in Diabetic nephropathy (DN). CircRNA ARP2 actin-related protein 2 homolog (circ-ACTR2) could promote the HG-induced cell injury in DN. However, how circ-ACTR2 acts in DN is still unclear. This study aimed to explore the molecular mechanism of circ-ACTR2 in DN progression, intending to provide support for the diagnostic and therapeutic potentials of circ-ACTR2 in DN. Methods RNA expression analysis was conducted by the quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Cell growth was measured via Cell Counting Kit-8 and EdU assays. Inflammatory response was assessed by Enzyme-linked immunosorbent assay. The protein detection was performed via western blot. Oxidative stress was evaluated by the commercial kits. The molecular interaction was affirmed through dual-luciferase reporter and RNA immunoprecipitation assays. Results Circ-ACTR2 level was upregulated in DN samples and high glucose (HG)-treated human renal mesangial cells (HRMCs). Silencing the circ-ACTR2 expression partly abolished the HG-induced cell proliferation, inflammation and extracellular matrix accumulation and oxidative stress in HRMCs. Circ-ACTR2 was confirmed as a sponge for miR-205-5p. Circ-ACTR2 regulated the effects of HG on HRMCs by targeting miR-205-5p. MiR-205-5p directly targeted high-mobility group AT-hook 2 (HMGA2), and HMGA2 downregulation also protected against cell injury in HG-treated HRMCs. HG-mediated cell dysfunction was repressed by miR-205-5p/HMGA2 axis. Moreover, circ-ACTR2 increased the expression of HMGA2 through the sponge effect on miR-205-5p in HG-treated HRMCs. Conclusion All data have manifested that circ-ACTR2 contributed to the HG-induced DN progression in HRMCs by the mediation of miR-205-5p/HMGA2 axis.
, Esben Laugesen, Pernille Høyem, Brian Stausbøl-Grøn, Won Y. Kim, Leif Østergaard, Dora Grauballe, Troels K. Hansen, Christian S. Buhl, Per L. Poulsen
Diabetology & Metabolic Syndrome, Volume 13, pp 1-9; doi:10.1186/s13098-021-00691-y

Abstract:
Background Stroke is a serious complication in patients with type 2 diabetes (T2DM). Arterial stiffness may improve stroke prediction. We investigated the association between carotid-femoral pulse wave velocity [PWV] and the progression of cerebral white matter hyperintensities (WMH), a marker of stroke risk, in patients with T2DM and controls. Methods In a 5-year cohort study, data from 45 patients and 59 non-diabetic controls were available for analysis. At baseline, participants had a mean (± SD) age of 59 ± 10 years and patients had a median (range) diabetes duration of 1.8 (0.8–3.2) years. PWV was obtained by tonometry and WMH volume by an automated segmentation algorithm based on cerebral T2-FLAIR and T1 MRI (corrected by intracranial volume, cWMH). High PWV was defined above 8.94 m/s (corresponding to the reference of high PWV above 10 m/s using the standardized path length method). Results Patients with T2DM had a higher PWV than controls (8.8 ± 2.2 vs. 7.9 ± 1.4 m/s, p < 0.01). WMH progression were similar in the two groups (p = 0.5). One m/s increase in baseline PWV was associated with a 16% [95% CI 1–32%], p < 0.05) increase in cWMH volume at 5 years follow-up after adjustment for age, sex, diabetes, pulse pressure and smoking. High PWV was associated with cWMH progression in the combined cohort (p < 0.05). We found no interaction between diabetes and PWV on cWMH progression. Conclusions PWV is associated with cWMH progression in patients with type 2 diabetes and non-diabetic controls. Our results indicate that arterial stiffness may be involved early in the pathophysiology leading to cerebrovascular diseases.
, Cassiane Dezoti da Fonseca, Mirian Watanabe, Maria De Fátima Fernandes Vattimo
Diabetology & Metabolic Syndrome, Volume 13, pp 1-10; doi:10.1186/s13098-021-00689-6

Abstract:
Background Diabetes mellitus (DM) is a major risk factor for contrast-induced acute kidney injury (CI-AKI). DM and CI-AKI result in oxidative damage and inflammation that can be reduced when treated with the coenzyme Q-10 (CoQ10). The aim of this study was to investigate the therapeutic potential of CoQ10 in renal function, renal hemodynamics, oxidative profile and renal histology in diabetic rats subjected to CI-AKI. Methods Wistar rats, male, randomized into five groups: citrate: control animals received citrate buffer (streptozotocin vehicle, 0.4 mL); Tween: control animals of CoQ10 treatment received 1% Tween 80 (CoQ10 vehicle, 0.5 mL); DM: animals that received streptozotocin (60 mg/kg); DM + IC: DM animals treated with iodinated contrast (IC, 6 mL/kg); DM + IC + CoQ10: DM animals treated with CoQ10 (10 mg/kg) and that received IC (6 mL/kg). The protocols lasted 4 weeks. An evaluation was made to measure renal function, inulin clearance and serum creatinine, renal hemodynamics by renal blood flow (RBF) and renal vascular resistance (RVR), markers of oxidative stress such as urinary peroxides and nitrate, lipid peroxidation, thiols in renal tissue and renal histological analysis. Results DM animals showed reduced renal function, which was followed by an increase inserum creatinine and significant reduction of inulin clearance and RBF. It was noticed an increase in RVR and redox imbalance with higher urinary peroxides and nitrate lipid peroxidation levels with depletion of thiols in renal tissue. IC treatment exacerbated these changes in DM + IC. CoQ10 administration ameliorated renal function, prevented hemodynamic changes and neutralized oxidative damage and progression of the histologic damage in the DM + IC + CoQ10 group. Conclusion This study demonstrated the renoprotection properties of CoQ10 in an experimental model of risk factor of DM for CI-AKI. CoQ10 presented an antioxidant effect on the CI-AKI in male diabetic rats by improving renal function and renal hemodynamics, preserving morphology and reducing oxidative stress.
, Juan P. Manosalva, Chantal Mathieu, Pieter Proot, Hernan Yupanqui Lozno, Päivi M. Paldánius
Diabetology & Metabolic Syndrome, Volume 13, pp 1-13; doi:10.1186/s13098-021-00686-9

Abstract:
Background Patients with type 2 diabetes mellitus (T2DM) from Latin American countries face challenges in access to healthcare, leading to under-diagnosis, under-achievement of glycemic target, and long-term complications. Early diagnosis and treatment initiation are of paramount importance in this population due to the high prevalence of risk factors such as obesity and metabolic syndrome. The VERIFY study in patients with newly diagnosed T2DM (across 34 countries), assessed the normoglycemic durability (5 years), with early combination (EC) therapy approach versus the traditional stepwise approach of initiating treatment with metformin monotherapy (MET). Here we present the results from the VERIFY study for participants from eight countries in Latin America. Methods Newly diagnosed adult patients with T2DM, HbA1c 6.5–7.5% and body-mass index (BMI) of 22–40 kg/m2 were enrolled. The primary endpoint was time to initial treatment failure (TF; HbA1c ≥ 7.0% at two consecutive scheduled visits 13 weeks apart). Time to second TF was evaluated when patients in both groups were receiving and failing on the vildagliptin combination. Safety and tolerability were also assessed for both treatment approaches during the study. Results A total of 537 eligible patients (female, 58.8%) were randomly assigned to receive either EC (n = 266) or MET (n = 271). EC significantly reduced the relative risk of time to initial TF by 47% versus MET [HR (95% CI) 0.53 (0.4, 0.7) p < 0.0001]. Overall, 46.4% versus 66.3% of patients achieved the primary endpoint in the EC and MET groups, with a median [interquartile range (IQR)] time to TF of 59.8 (27.5, not evaluable) and 33.4 (12.2, 60.1) months, respectively. The risk for time to second TF was 31% lower with EC (p < 0.0092). A higher proportion of patients receiving EC maintained durable HbA1c < 7.0%, < 6.5%, and < 6.0%. Both treatment approaches were well tolerated, and only 3.2% of participants discontinued the study due to adverse events. All hypoglycemic events (EC: n = 7 and MET: n = 3) were single, mild episodes and did not lead to study discontinuation. Conclusion Similar to the global population, long-term clinical benefits were achieved more frequently and without tolerability issues with EC versus standard-of-care MET in this Latin American sub-population. This study is registered with ClinicalTrials.gov, NCT01528254.
Yuan Jiang, Yalan Dou, Hongyan Chen, Yi Zhang, Xiaotian Chen, Yin Wang, Myanca Rodrigues,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-13; doi:10.1186/s13098-021-00688-7

Abstract:
Objective To provide the latest evidence of performance and robustness of waist-to-height ratio (WHtR) in discriminating clusters of cardiometabolic risk factors (CMRs) and promote WHtR in routine primary health care practice in children, a meta-analysis was used. Methods Searches was performed in eight databases from inception to July 03, 2020. Inclusion criteria were: (1) observational study, (2) children and adolescents, (3) provided WHtR measurements, (4) had CMRs as outcomes, and (5) diagnostic studies. Exclusion criteria were: (1) non-original articles, (2) unable to extract 2 × 2 contingency tables, (3) not in English or Chinese language, (4) populations comprising clinical patients, or (5) duplicate articles. WHtR cutoff points, 2 × 2 contingency tables were extracted from published reports. Outcomes included: CMR clusters of at least three CMRs (CMR3), two (CMR2), one (CMR1), and CMR components. Bivariate mixed-effects models were performed to estimate the summarised area under the curves (AUSROC) with 95% CIs and related indexes. We conducted subgroup analyses by sex and East Asian ethnicity. Results Fifty-three observational studies were included. The AUSROC reached 0.91 (95% CI: 0.88–0.93), 0.85 (95% CI: 0.81, 0.88) and 0.75 (95% CI: 0.71, 0.79) for CMR3, CMR2, and CMR1, respectively. The pooled sensitivity and specificity for CMR3 reached 0.84 and exceeded 0.75 for CMR2. For CMR1, the sensitivity achieved 0.55 with 0.84 for specificity. We had similar findings for our subgroup and sensitivity analyses. Conclusions WHtR shows good and robust performance in identifying CMRs clustering across racial populations, suggesting its promising utility in public health practice globally.
Correction
Himani Thakkar, Vinnyfred Vincent, Sakshi Shukla, Manraj Sra, Uma Kanga, Sandeep Aggarwal,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-1; doi:10.1186/s13098-021-00684-x

Abstract:
An amendment to this paper has been published and can be accessed via the original article.
Diabetology & Metabolic Syndrome, Volume 13, pp 1-9; doi:10.1186/s13098-021-00680-1

Abstract:
Background A new strain of human coronavirus (HCoV) spread rapidly around the world. Diabetes and obesity are associated with a worse prognosis in these patients. Congenital Generalized Lipodystrophy (CGL) patients generally have poorly controlled diabetes and require extremely high doses of insulin. There is no documentation in the literature of cases of COVID in CGL patients. Thus, we aimed to evaluate the prevalence of SARS-CoV-2 infection in CGL patients, and the association of their clinical and metabolic characteristics and outcomes. Methods This is a cross-sectional study carried out between July and October 2020. Clinical data collected were respiratory or other flu-like symptoms, need of hospitalization in the last three months, CGL comorbidities, and medications in use. Cholesterol, triglycerides, glycohemoglobin A1c levels, anti-SARS-CoV-2 antibodies and nasopharyngeal swab for RT-qPCR were also obtained in all CGL patients. Mann-Whitney U test was used to analyze the characteristics of the participants, verifying the non-adherence of the data to the Gaussian distribution. In investigating the association between categorical variables, we used Pearson's chi-square test and Fisher's exact test. A significance level of 5% was adopted. Results Twenty-two CGL patients were assessed. Eight subjects (36.4%) had reactive anti-SARS-CoV-2 antibodies. Only one of these, also presented detectable RT-qPCR. Five individuals (62.5%) were women, median age of 13.5 years (1 to 37). Symptoms like fever, malaise, nausea, diarrhea and chest pain were present, and all asymptomatic patients were children. All subjects had inadequate metabolic control, with no difference between groups. Among positive individuals there was no difference between those with AGPAT2 (75%) and BSCL2 gene mutations (25%) (p > 0.05). No patient needed hospitalization or died. Conclusions We described a high prevalence of SARS-CoV-2 infection in CGL patients with a good outcome in all of them. These findings suggest that at least young CGL patients infected by SARS-COV-2 are not at higher risk of poor outcome, despite known severe metabolic comorbidities.
, Gustavo Fonseca Cipriani, Henrique Umpierre Pedroso, Rafaela Ramos Nunes, Thayme Luisa Souza Pires, Raquel Ferreira, Betina Vescovi, Gabriela Pereira de Moura, Ticiana Costa Rodrigues
Diabetology & Metabolic Syndrome, Volume 13, pp 1-9; doi:10.1186/s13098-021-00675-y

Abstract:
Background Diabetes mellitus (DM) is a prevalent disease among elderly population. As the disease progresses, insulin may become necessary. The use of pens application seems to be more practical. However, the influence of this method on glycemic control needs to be defined in elderly people. Methods Randomized clinical trial comparing pens and syringes for insulin application among patients with type 2 DM over 60 years old and Glycated Hemoglobin > 8.5% at baseline. The follow-up was 24 weeks, with monthly medical visits to adjust the treatment. All patients received insulin NPH and, if necessary, insulin Regular. We assessed glycemic control, adherence to treatment, hypoglycemia occurrence, need for adjustment in treatment and impact on quality of life, Results We included 121 patients with mean age of 65.75 years. Sixty-one were randomized for pen group (PG) and 60 patients for syringe group (SG). At baseline, mean HbA1c was 10.34 ± 1.66% and 9.90 ± 1.25% (p = 0.103) in PG and SG respectively. Mean HbA1c was 8.39 ± 1.28% in PG and 8.85 ± 1.74% in SG (p = 0.101) at 24 weeks. However, there was a more significant reduction in PG (− 1.94 ± 1.93% in PG and − 1.04 ± 1.46% in SG, p < 0.05) during follow-up. We found no difference in treatment adherence rates, hypoglycemia, greater need for insulin doses or oral medication, and progression to basal-bolus insulin scheme. We also found no difference in the impact of the disease on quality of life between groups. Conclusion Although we did not find any difference in the impact on quality of life, frequency of hypoglycemia or adherence, the PG showed a reduction in HbA1c higher in 24 weeks of follow-up. Clinical trial registration: NCT02517242
, Monica S. V. M. Silveira, Mehri Doosti-Irani, Paulo Fanti, Katherine Miller-Bains, Elizabeth João Pavin, Edimariz Buin Cardoso, Leila Rafiee Vardanjani, Kobra Noorian, Danielle Hessler
Published: 11 June 2021
by 10.1186
Diabetology & Metabolic Syndrome, Volume 13, pp 1-12; doi:10.1186/s13098-021-00681-0

Abstract:
Background The COVID-19 pandemic is a global public health emergency, which presents wide-ranging negative impacts on individuals with diabetes. To examine psychosocial well-being and diabetes outcomes in individuals with type 1 diabetes during the COVID-19 pandemic, and investigate how these factors vary in different countries. Methods Between April and June 2020 we employed a cross national comparative research study in the United States (US), Brazil, and Iran to collect data from 1788 adults with type 1 diabetes using web-based survey. Study participants answered questions relevant to diabetes distress, diabetes burnout, depressive symptoms, COVID-19 related changes, and socio-demographic characteristics. They also reported their last Hemoglobin A1c (HbA1c) and daily Time-in-Range (TiR) blood glucose. We analyzed data using comparative tests (Chi-square, Kruskal–Wallis and McNemar test), logistic and linear regression adjusted for fixed effects. Results There were significant changes prior and during the pandemic regarding access to diabetes care, diabetes supplies and medications, healthy food and safe places to exercise in all countries (p < 0.05). Participants in Iran experienced higher levels of diabetes distress (57.1%), diabetes burnout (50%), and depressive symptoms (60.9%), followed by Brazil and US (p < 0.0001). US participants reported better glycemic control (HbA1c = 6.97%, T1R = 69.64%) compared to Brazil (HbA1c = 7.94%, T1R = 51.95%) and Iran (HbA1c = 7.47%, T1R = 51.53%) (p < 0.0001). There were also significant relationships between psychosocial well-being, diabetes outcomes, socio-demographic data, and COVID-19 related challenges in overall sample (p < 0.05). Conclusions Regardless of differences among US, Brazil, and Iran, our findings revealed that different countries may experience similar challenges related to the COVID-19 pandemic which can impact negatively diabetes outcomes and psychosocial well-being in individuals with type 1 diabetes. Countries need to consider modifiable variables associated with poor diabetes outcomes and sub optimal psychosocial well-being and target vulnerable population using significant socio-demographic variables.
Diabetology & Metabolic Syndrome, Volume 13, pp 1-11; doi:10.1186/s13098-021-00677-w

Abstract:
Background Prediabetes is characterized by a hemoglobin A1c of 5.7–6.4% and fasting blood glucose of 100–125 mg/dl. A high percentage of prediabetes subjects develop type 2 diabetes mellitus in the next years. The effects of opioid peptides and their receptors, in addition to immunological cytokines, on prediabetes are not well understood. Therefore, molecular, physiological, and clinical studies are required to link the opioid system, immune system, and insulin resistance (IR) in prediabetes. We hypothesize that opioid peptides (endomorphin-2 (EM2), and β-endorphin (βEP)), and their receptors (µ-opioid receptors (MOR) and κ-opioid receptors (KOR)), in addition to the inflammatory cytokines (IL-6) and anti-inflammatory cytokine (IL-10), affect IR parameters in patients with prediabetes. Methods Sixty prediabetes patients with IR (prediabetes+IR) and sixty prediabetes patients without IR (prediabetes-IR), in addition to 58 controls, have participated in the study. IL-6, IL-10, EM2, βEP, MOR, and KOR were measured by the ELISA technique. Results In general, most prediabetes subjects have dyslipidemia. The IL-6, IL-10, β-endorphin, MOR, and endomorphin-2 were higher in the prediabetes subgroups than the control group. The immune system was activated in the prediabetes in an IR-dependent manner. Prediabetes+IR can be predicted by the increased levels of IL-10, βEP, and EM2 and by the combination of IL-10 and EM2/KOR with good sensitivity and specificity. Conclusion Opioid peptides and their receptors were upregulated in patients with prediabetes, depending on the significance of IR and the immune cytokines. The intercorrelation between the immune system, EOS, and insulin in prediabetes was confirmed.
Hye Yoon Jang, Youngmin Han, Hye Jin Yoo, Jong Ho Lee,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-10; doi:10.1186/s13098-021-00679-8

Abstract:
Background Research elucidating the metabolic mechanisms that differentiate subtypes of obesity has been increasing. We aimed to investigate the effects of a 12-week dietary intervention on the metabolomic profiles of obese subjects. Methods Subjects followed a 12-week dietary restriction protocol consisting of a 300 kcal/day reduction in their usual caloric intake. Twenty-nine obese subjects were included and divided into two groups: the metabolic status maintenance group (n = 17, controls) and the metabolic status improvement group (n = 12, tests). We analyzed the somatometric and biochemical parameters and performed ultra-performance liquid chromatography-mass spectrometry analysis of the plasma metabolites. Results At 12 weeks, the fat percentage, whole fat area (WFA), subcutaneous fat area (SFA) at the L1 vertebra, and the levels of triglycerides, gamma-glutamyltransferase (gamma-GT), and leptin were markedly decreased in the metabolic status improvement group, while the level of high-density lipoprotein cholesterol increased compared with that in the metabolic status maintenance group. Metabolomic profiling at 12 weeks showed substantial differences in 4-aminobutyraldehyde (p = 0.005) and 4’-apo-β-carotenal (p = 0.024) between the two groups. Furthermore, an AUC value of 0.89 was obtained for the following seven featured biomarkers: triglycerides, gamma-GT, leptin, fat percentage, WFA, and SFA at the L1 vertebra, and 4-aminobutyraldehyde. Conclusions We demonstrated that 4-aminobutyraldehyde and related regional fat distribution parameters were strongly associated with obesity according to metabolic status. Thus, these biomarkers are potentially valuable in confirming the efficacy of short-term interventions and predicting metabolic status in obese individuals. Trials registration: This study was registered at ClinicalTrials.gov under NCT03135132 (registered 1 May 2017—retrospectively registered).
, Yücel Arman, Şengül Aydın Yoldemir, Ayşe Selcen Pala, Perihan Özkan Gümüşkaya, Mustafa Özcan, Mustafa Karataş, Okan Dikker, Tufan Tükek
Diabetology & Metabolic Syndrome, Volume 13, pp 1-7; doi:10.1186/s13098-021-00682-z

Abstract:
Background Laminin, one of the largest glycoproteins of the basement membrane, is an important component of the extracellular matrix. Functions of the basement membrane include regulation of cell signaling behaviors and structural support. Laminin plays a critical role in the regulation of insulin action in muscle, liver, and adipose tissue. The study mainly investigates an association between the change in serum laminin levels and insulin resistance and non-alcoholic hepatosteatosis. Methods This prospective study included a total of 90 participants; 60 patients diagnosed with Grade 2–3 non-alcoholic hepatosteatosis and 30 age- and sex-matched healthy controls between December 2019 and December 2020. Routine laboratory tests including glucose, insulin, homeostatic model of assessment-insulin resistance (HOMA-IR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and C-reactive protein and laminin levels were measured in the serum of the patient and control groups. Enzyme-linked immunosorbent assay was used for the measurement of laminin levels. Results The median serum laminin levels were lower in patients with hepatic steatosis, compared to the control group (72 ng/L vs. 82 ng/L, respectively; p = 0.003). In the patients with insulin resistance, median laminin levels were lower, regardless of the presence of non-alcoholic hepatosteatosis (67 ng/L vs. 85 ng/L, respectively; p = 0.007). There was a weak, negative correlation between the laminin levels and HOMA-IR. Conclusions Our study results suggest that, although there is no exact link between laminin and non-alcoholic hepatosteatosis, serum laminin levels are lower in patients with insulin resistance by regulating the insulin effect through integrins.
Li Zhang, Ming Zeng, Fei Tang, Jun Chen, Dongmei Cao, Ze-Nan Tang
Diabetology & Metabolic Syndrome, Volume 13, pp 1-14; doi:10.1186/s13098-021-00678-9

Abstract:
Background Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy. CircRNA polyribonucleotide nucleotidyltransferase 1 (circ-PNPT1) has been found to be abnormally expressed in GDM patients. However, function and mechanism of circ-PNPT1 in GDM remain largely undefined. Methods Levels of circ-PNPT1, microRNA (miR)-889-3p and PAK1 (p21 (RAC1) activated kinase 1) were detected using quantitative real-time polymerase chain reaction and Western blot assays. Cell viability, apoptosis, migration and invasion were determined using cell counting kit-8 assay, flow cytometry, transwell and wound healing assays, respectively. The binding interaction between miR-889-3p and circ-PNPT1 or PAK1 was verified using dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays. Exosomes were obtained from culture media by the use of commercial kits and qualified by transmission electron microscopy (TEM). Results Circ-PNPT1 was highly expressed in the placental tissues of GDM and high glucose (HG)-induced trophoblast cells. Knockdown of circ-PNPT1 reversed HG-induced arrest of trophoblast cell viability, migration, invasion and the promotion of cell apoptosis. Mechanistically, we confirmed circ-PNPT1 could promote the expression of PAK1, the target of miR-889-3p, by directly sponging miR-889-3p, and circ-PNPT1 regulated HG-induced trophoblast cell dysfunction by miR-889-3p/PAK1 axis. Further studies showed circ-PNPT1 was packaged into exosomes and could be internalized by surrounding trophoblast cells. Conclusion Circ-PNPT1 promoted HG-induced trophoblast cell biological dysfunction through miR-889-3p/PAK1 axis. Meanwhile, it could be transferred from HG-induced trophoblast cells to surrounding untreated cells via exosomes.
Jia Y. Wan, Deborah L. Goodman, Emileigh L. Willems, Alexis R. Freedland, Trina M. Norden-Krichmar, Stephanie A. Santorico, Karen L. Edwards, Eric Boerwinkle, John Buse, Ralph DeFronzo, et al.
Diabetology & Metabolic Syndrome, Volume 13, pp 1-15; doi:10.1186/s13098-021-00670-3

Abstract:
Background To identify genetic associations of quantitative metabolic syndrome (MetS) traits and characterize heterogeneity across ethnic groups. Methods Data was collected from GENetics of Noninsulin dependent Diabetes Mellitus (GENNID), a multiethnic resource of Type 2 diabetic families and included 1520 subjects in 259 African-American, European-American, Japanese-Americans, and Mexican-American families. We focused on eight MetS traits: weight, waist circumference, systolic and diastolic blood pressure, high-density lipoprotein, triglycerides, fasting glucose, and insulin. Using genotyped and imputed data from Illumina’s Multiethnic array, we conducted genome-wide association analyses with linear mixed models for all ethnicities, except for the smaller Japanese-American group, where we used additive genetic models with gene-dropping. Results Findings included ethnic-specific genetic associations and heterogeneity across ethnicities. Most significant associations were outside our candidate linkage regions and were coincident within a gene or intergenic region, with two exceptions in European-American families: (a) within previously identified linkage region on chromosome 2, two significant GLI2-TFCP2L1 associations with weight, and (b) one chromosome 11 variant near CADM1-LINC00900 with pleiotropic blood pressure effects. Conclusions This multiethnic family study found genetic heterogeneity and coincident associations (with one case of pleiotropy), highlighting the importance of including diverse populations in genetic research and illustrating the complex genetic architecture underlying MetS.
Hamideh Dinari Ghozhdi, , Maryam Keshvari, Hassan Tavassoli
Diabetology & Metabolic Syndrome, Volume 13, pp 1-10; doi:10.1186/s13098-021-00676-x

Abstract:
Background Adipocytokines, which are secreted by the adipose tissue, contribute to the pathogenesis of obesity-related complications. To evaluate this assumption, we investigated the effects of aerobic exercise training (AET), resistance exercise training (RET), and 4 weeks of de-training on serum leptin and TNF-α levels in diabetic rats. Method 36 Wistar rats were divided into normal diet (ND) (control, RET, AET) and high-fat diet (HFD) + STZ (control, RET, AET) groups. Serum insulin, leptin, and TNF-α levels were assessed by commercial ELISA kits. Also fasting blood glucose (FBG), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) levels were measured by the colorimetric kits. Results Diabetes induction increased body weight (BW) and FBG, and decreased insulin compared to the ND rats’ groups (p < 0.001). 12-weeks of AET and RET programs in the trained diabetic rats led to a decrease in TG, LDL-C, leptin, TNF-α, and FBG, and an increase in insulin compared to the HFD + STZ-C group (p < 0.001). Besides, there was no difference between AET and RET in improving the variables studied (p > 0.05). Also, de-training led to increased BW, TG, leptin, and TNF-α compared to the end of the exercise training (p < 0.05). The correlation between the variables studied was established at different stages of the study (p < 0.05), and only BW was not correlated with insulin during exercise training and de-training (p > 0.05). Conclusion These findings indicate that both AET and RET are useful in reducing levels of serum adipocytokines (TNF-α, leptin) in diabetic and non-diabetic rats. At the same time, 4 weeks of de-training was sufficient to lose the metabolic adaptations.
Diabetology & Metabolic Syndrome, Volume 13, pp 1-15; doi:10.1186/s13098-021-00672-1

Abstract:
Background Roux-en-Y gastric bypass (RYGB) surgery is one of the most efficient procedures for the treatment of obesity, also improving metabolic and inflammatory status, in patients with mild obesity. The underlying mechanisms have not been fully understood, but gut microbiota is hypothesized to play a key role. Our aim was to evaluate the association between gut microbiota changes and anthropometric, metabolic and inflammatory profiles after metabolic surgery compared with medical therapy, in type 2 diabetic (T2DM) adults with mild obesity (BMI 30–35 kg/m2). Methods DM2 was an open-label, randomised controlled clinical trial (RCT: ISRCTN53984585) with 2 arms: (i) surgical, and (ii) medical. The main outcome was gut microbiota changes after: metabolic surgery (Roux-en-Y gastric bypass—RYGB) versus standard medical therapy. Secondary outcomes included anthropometric, metabolic and inflammatory profiles. Clinical visits, blood workup, and stool samples were collected at baseline and months (M)1, 3, 6, 12. Gut microbiota was profiled using 16S rRNA targeted sequencing. Results Twenty patients were included: 10 in surgical and 10 in medical arm. Anthropometric and metabolic comparative analysis favoured RYGB over medical arm. At M12, the percentage of weight loss was 25.5 vs. 4.9% (p < 0.001) and HbA1c was 6.2 vs. 7.7% (p < 0.001) respectively. We observed a continuous increase of genus richness after RYGB up until M12. In the medical arm, genus richness ended-up being significantly lower at M12. Composition analysis indicated significant changes of the overall microbial ecosystem (permanova p = 0.004, [R 2 = 0.17]) during the follow-up period after RYGB. There was a strong association between improvement of anthropometric/metabolic/inflammatory biomarkers and increase in microbial richness and Proteobacterial lineages. Conclusions This was the first RCT studying composite clinical, analytic, and microbiome changes in T2DM patients with class 1 obesity after RYGB versus standard medical therapy. The remarkable phenotypic improvement after surgery occurred concomitantly with changes in the gut microbiome, but at a lower level. Trial registration: ISRCTN53984585
, Silvia Selinski, Christina Bächle, Joachim Rosenbauer
Diabetology & Metabolic Syndrome, Volume 13, pp 1-7; doi:10.1186/s13098-021-00673-0

Abstract:
Background This study aims to analyze the patient-reported outcome (PRO) of treatment satisfaction in a sample of children, adolescents and young adults with long-duration type 1 diabetes and to determine potential risk factors for poor treatment satisfaction and the intraindividual changes over a 3-year period. Methods This study used data from two population-based questionnaire surveys conducted in 2015–2016 and 2018–2019. The participants were 11 to 27 years old and had a type 1 diabetes duration of 10 years or longer in 2015–2016 (n = 575). Factors that were potentially associated with poor treatment satisfaction (moderate, poor or very poor) compared to the reference group (very good or good treatment satisfaction) were analyzed by log binomial regression adjusted for sex and age group. Results In 2015–2016 (2018–2019), 26% (33%) of the respondents rated their diabetes treatment/consultation as "very good", 53% (46%) as "good", and 20% (21%) as "poor". Based on the 2018–2019 data, girls/women had an increased risk of poor treatment satisfaction (RRgirls/women: 1.64 (1.10; 2.44), p = 0.016). In addition, people with hemoglobin A1c (HbA1c) values ≥ 7.5% had a more than twice the risk of poor treatment satisfaction than people with HbA1c values < 7.5% (RRHbA1c ≥7.5%: 2.43 (1.63; 3.63), p < 0.001). A total of 42% of people with poor treatment satisfaction in 2015–2016 also reported poor treatment satisfaction at follow-up. Conclusions Most study participants were satisfied with their diabetes treatment. However, we identified risk groups that would benefit from targeted interventions to improve this important PRO.
Jie Cao, Hong Wang, , Xue-Qin Wang, Dong-Mei Zhang, Xiao-Hua Wang, Wang-Shu Liu, Xiao-Qin Ge
Diabetology & Metabolic Syndrome, Volume 13, pp 1-8; doi:10.1186/s13098-021-00671-2

Abstract:
Objective Type 2 diabetes (T2D) is a chronic low-grade inflammatory disease, which characterized by islet beta cell dysfunction. Serum adenosine deaminase (ADA) is an important enzyme that regulates the biological activity of insulin, and its levels are greatly increased in inflammatory diseases with insulin resistance. The present study was designed to explore the relationship between serum ADA levels and islet beta cell function in patients with T2D. Methods This cross-sectional study recruited 1573 patients with T2D from the Endocrinology Department of the Affiliated Hospital 2 of Nantong University between 2015 and 2018. All participants were received serum ADA test and oral glucose tolerance test (OGTT). Insulin sensitivity index (assessed by Matsuda index using C-peptide, ISIM-cp), insulin secretion index (assessed by ratio of area under the C-peptide curve to glucose curve, AUCcp/glu) and islet beta cell function (assessed by insulin secretion-sensitivity index 2 using C-peptide, ISSI2cp) were derived from OGTT. And other clinical parameters, such as HbA1c, were also collected. Results It was showed that HbA1c was significantly increased, while ISIM-cp, AUCcp/glu and ISSI2cp significantly decreased, across ascending quartiles of serum ADA levels. Moreover, serum ADA levels were negatively correlated with ISSI2cp (r = − 0.267, p < 0.001). Furthermore, after adjusting for other clinical parameters by multiple linear regression analysis, serum ADA levels were still independently associated with ISSI2cp (β = − 0.125, t = − 5.397, p < 0.001, adjusted R 2 = 0.459). Conclusions Serum ADA levels are independently associated with islet beta cell function in patients with T2D.
Ebrahim Mokhtari, Hossein Farhadnejad, , , Fereidoun Azizi
Diabetology & Metabolic Syndrome, Volume 13, pp 1-11; doi:10.1186/s13098-021-00674-z

Abstract:
Background We aim to assess the association of empirical dietary (EDIH) and lifestyle (ELIH) index for hyperinsulinemia with the risk of insulin resistance, hyperinsulinemia, insulin sensitivity, and β-cell dysfunction in Iranian adults. Methods In this prospective study, a total of 1244 men and women aged ≥ 20 years were selected among participants of the Tehran lipid and glucose study and followed for 3.2 years. Dietary intakes were assessed using a valid semi-quantitative food frequency questionnaire. Dietary and lifestyle insulinemic potential indices were calculated using dietary intake, body mass index, and physical activity information. Multivariable logistic regression was used to estimate the associated risk of a 3-year incidence of insulin-related disorders. Results The mean ± SD age and BMI of all eligible participants (42.7% males) were 43.0 ± 13.0 and 27.4 ± 4.9 in the study's baseline. After adjusting for all potential confounders, participants in the highest tertile of ELIH score had a greater risk of developing hyperinsulinemia (OR:2.42, 95%CI:1.52–3.86, P for trend = < 0.001), insulin resistance (OR:2.71, 95%CI:1.75–4.18, P for trend = < 0.001) and insulin insensitivity (OR:2.65, 95%CI: 1.72–4.10, P for trend = < 0.001) compared with those in the lowest tertile. However, the risk of incident β-cell dysfunction was lower in individuals with a higher score of ELIH in comparison to those with the lowest score (OR:0.30, 95%CI:0.19–0.45, P for trend = < 0.001). Conclusions Empirical lifestyle index for hyperinsulinemia was directly associated with insulin resistance, insulin insensitivity, and hyperinsulinemia and was inversely associated with β-cells dysfunction.
Fatemeh Abbaszadeh, Samaneh Azizi, Majid Mobasseri,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-9; doi:10.1186/s13098-021-00669-w

Abstract:
Background This study aimed to examine the effects of l-citrulline ( l-CIT ) on low-grade inflammation (meta-inflammation) and insulin sensitivity in type 2 diabetes (T2D) patients since it has exhibited hypoglycemic and anti-inflammatory effects in most animal studies. Methods In this double-blind, placebo-controlled randomized clinical trial, 54 patients with T2D referred to specialized clinics of Tabriz University of Medical Sciences were assigned to l-CIT group (receiving orally one 3 g sachet of l-CIT daily before breakfast) or placebo group (receiving orally one 3 g sachet of microcrystalline cellulose daily before breakfast) for eight weeks. Serum levels of fasting blood glucose, hemoglobin A1c (HbA1c), CIT, monocyte chemoattractant protein 1 (MCP-1), interleukin-6 (IL-6), and toll-like receptor 4 (TLR-4) were determined. The quantitative insulin sensitivity check index (QUICKI) and homeostatic model assessment of β-cell function (HOMA-B) index were estimated at the baseline and post-intervention. Results No significant difference was observed between the studied parameters at the baseline. l-CIT supplementation significantly reduced not only serum concentrations of fasting blood glucose but also HbA1c, serum IL-6 and TLR-4 levels in the l-CIT group (p < 0.05). Additionally, at the end of the study serum levels of CIT increased significantly in l-CIT group compared to the baseline and placebo group. Fasting blood glucose concentrations and HbA1c significantly decreased after the intervention compared to the placebo. There was no significant difference in serum IL-6, TLR-4, MCP-1 levels, as well as QUICKI and HOMA-B index between the two groups, even after adjusting for baseline variables and confounders. Conclusions Our findings revealed that, although l-CIT supplementation significantly reduced fasting blood glucose concentrations, HbA1c and increased serum levels of CIT. It seems it could not significantly improve insulin sensitivity and meta-inflammation biomarkers. Additional studies with longer duration and different doses of l-CIT are required. Trial registration The protocol of this clinical trial is registered at the Iranian Registry of Clinical Trials (registration no: IRCT20100209003320N16 at www.irct.ir)
Rui Wang, Peng Lin, Huibo Sun, Wenchao Hu
Diabetology & Metabolic Syndrome, Volume 13, pp 1-6; doi:10.1186/s13098-021-00668-x

Abstract:
Objective The adipokine asprosin, which was recently discovered, facilitates hepatic glucose production. The aim of this study is to see whether serum asprosin concentrations are linked to diabetic nephropathy (DN). Methods We performed this investigation in a group of 212 type 2 diabetes (T2DM) patients. These patients were classified into three subgroups: DN0 group (normal to mildly increased), DN1 group (moderately increased), and DN2 group (severely increased) on the basis of urine albumin-to-creatinine ratio (ACR). Results When compared to the controls, T2DM patients had higher serum asprosin levels. The DN2 group had significantly higher serum asprosin than the DN0 and DN1 groups. Furthermore, the DN1 group had higher serum asprosin than the DN0 group. Serum asprosin was linked to a higher risk of T2DM and DN in a logistic regression analysis. Serum asprosin was found to be positively related with disease duration, systolic blood pressure, blood urea nitrogen, creatinine, uric acid, ACR, calcium channel blockers, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy, but negatively related with glomerular filtration rate, metformin, and acarbose therapy. Conclusion Serum asprosin increase with the progression of DN. Serum asprosin is correlated with renal function and ACR.
Miao Tian, , Cheng-Cheng Zhao, Li Liu, Fu-Li Zhang
Diabetology & Metabolic Syndrome, Volume 13, pp 1-11; doi:10.1186/s13098-021-00664-1

Abstract:
Background Hesperidin, a natural flavanone, has been proven to have multiple protective effects in diabetic rats, such as antioxidant, anti-inflammatory and anti-apoptotic effects. However, the molecular mechanisms underlying the effects of hesperidin are not well elucidated. Methods LO2 cells were stimulated with high glucose (HG, 33 mM) for 24 h to establish a model of oxidative stress. Then, cell viability was determined using the MTT assay. The antioxidant activities, including the reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels, mitochondrial membrane potential (MMP) and adenosine-triphosphate (ATP) production, were measured with the corresponding kits. The levels of gene expression, protein expression and methylation were detected using qRT-PCR, western blotting and methylation-specific PCR (MSP) assays, respectively. Results Compared to the NG treatment, hesperidin treatment increased the viability and improved the oxidative stress, mitochondrial dysfunction and insulin resistance of HG-treated LO2 cells, and these effects were correlated with heightened SOD and GPx activities, increased MMP level and ATP generation, reduced MDA, ROS and glucose levels, and activated GSK3β/AKT and inactivated IRS1 signals. Mechanistically, hesperidin treatment enhanced the miR-149 expression level by reducing its promoter methylation by inhibiting DNMT1. Importantly, knockdown of miR-149 obviously abolished the biological roles of hesperidin. Conclusions Our findings demonstrated that hesperidin treatment ameliorated HG-induced insulin resistance by reducing oxidative stress and mitochondrial dysfunction partly by suppressing DNMT1-mediated miR-149 silencing.
Diabetology & Metabolic Syndrome, Volume 13, pp 1-7; doi:10.1186/s13098-021-00667-y

Abstract:
Background As a subcomponent of low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C) has been suggested to be a better predictor of cardiovascular diseases (CVD). The aim of this research was to evaluate the predictive value of the sdLDL-C in cardiovascular events (CVs) in Chinese elderly patients with type 2 diabetes mellitus (DM). Methods A total of 386 consecutive type 2 DM patients were included into this study during December 2014 to December 2016. The serum sdLDL-C level of each subject was measured by homogeneous method. During a period of 48-month’s follow-up, the occurrence of CVs and associated clinical information were recorded. Receiver operating characteristic (ROC) curves were used to assess the predictive value of serum sdLDL-C to occurrence of major CVs. Results A total of 92 CVs occurred during the study period. The ROC curve analysis manifested that sdLDL-C in the study population had a matchable discriminatory power (AUC for sdLDL-C was 0.7366, P = 0.003). In addition, Kaplan-Meier event-free survival curves displayed an obvious increase of CVs risk for sdLDL‐C ≧ 26 mg/dL (log-rank = 9.10, P = 0.003). This phenomenon had analogous results in patients who received statins at baseline (log rank = 7.336, P = 0.007). Cox regression analysis revealed that the increase in HbA1c, glucose, LDL-C, sdLDL-C, non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB) and the decrease in apolipoprotein AI (ApoAI) were obviously interrelated with heightened CVs risk. Multiple Cox regression demonstrated that the increase of sdLDL-C and hemoglobin A1c (HbA1c) was significantly correlated with CVs. The results of the study indicated that high sdLDL-C level (> 10 mg/dL) was a risk factor for CVs in the multivariate model (HR 1.281, 95% CI 1.225–16.032; P < 0.01). Conclusion sdLDL-C level could be an effective predictor in predicting the future CVs for Chinese elderly patients with type 2 DM and dyslipidemia.
Lu Gao, Wei Zhao, Jin-Kui Yang,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-9; doi:10.1186/s13098-021-00666-z

Abstract:
Background Atherosclerosis cardiovascular disease (ASCVD) is the main cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). As most diabetic patients with ASCVD are asymptomatic, it is most neglected in clinical practice. For this reason, identifying high-risk ASCVD population with intensified treatment is very important. In recent years, the relationship between diabetic retinopathy (DR) and ASCVD has caused much academic concern, but the results are inconsistent. Moreover, whether all grades of DR increase the risk of ASCVD remains controversial. Most importantly, very few data can be found in China. Objective Our aim is to discuss whether all grades of DR increase the risk of ASCVD after adjustment for the traditional cardiovascular risk factors and to assess the independent contribution of DR to cardiovascular events in patients with T2DM, hoping to provide more evidence for early identification of ASCVD. Research design and methods A total of 425 T2DM patients with complete physical and biochemical data were included in the study. The grade of DR was assessed with two 45 color digital retinal images. Based on the presence of history of ASCVD, 425 T2DM patients were divided into 2 groups: ASCVD group and non-ASCVD group. Results ASCVD patients were older and had a significantly higher fasting plasma glucose (FPG) and glycated haemoglobin (HbA1c) and proportion of history of ASCVD. At the same time, they were more likely to be females, and had lower level of alcohol and calculated glomerular filtration rate (eGFR) than non-ASCVD patients. Their trend to develop DR with ASCVD was significantly higher than patients with non-ASCVD (χ2 = 5.805, P = 0.016). DR was an independent statistical indicator of the presence of ASCVD [odds ratio (OR) (95% CI): 2.321 (1.152–4.678), P = 0.018]. Furthermore, when DR was divided into non-proliferative retinopathy (NPDR) and proliferative retinopathy (PDR) according to its severity, only PDR was significantly associated with incident ASCVD [OR (95% CI): 8.333 (1.813–38.304), P = 0.006]. After adjusting for traditional ASCVD risk factors, such an association still existed [OR (95% CI): 7.466 (1.355–41.137), P = 0.021]. Conclusion DR associates strongly with ASCVD in the Chinese population with T2DM. With the increasing severity of DR, the risk of ASCVD also increases. After adjustment for traditional risk factors, PDR is still an independent risk marker for ASCVD.
Lauren Parlett, , Qian Shi, Geoffrey Crawford, Laura Herrera Scott, Vincent Willey, Abiy Agiro
Diabetology & Metabolic Syndrome, Volume 13, pp 1-3; doi:10.1186/s13098-021-00665-0

Abstract:
This claims-based retrospective cohort study examined the prevalence and incremental impact of non-alcoholic steatohepatitis among children with type 2 diabetes mellitus in the United States. Although diagnoses of non-alcoholic steatohepatitis were not common among diabetic children, it was associated with significantly higher incremental healthcare cost and risk of hospitalization.
Himani Thakkar, Vinnyfred Vincent, Sakshi Shukla, Manraj Sra, Uma Kanga, Sandeep Aggarwal,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-11; doi:10.1186/s13098-021-00662-3

Abstract:
Background Bariatric surgery can alleviate cardiovascular risk via effects on cardiovascular disease (CVD) risk factors such as diabetes mellitus, hypertension, and dyslipidemia. Our study aimed to assess the cholesterol efflux capacity (CEC) of HDL as a negative risk factor for CVD in individuals with obesity and identify the factors associated with improvement in CEC 3 months following bariatric surgery. Methods We recruited 40 control individuals (mean BMI of 22.2 kg/m2) and 56 obese individuals (mean BMI of 45.9 kg/m2). The biochemical parameters, inflammatory status and CEC of HDL was measured for the obese individuals before bariatric surgery and at 3 months after surgery. The CEC was measured using a cell-based cholesterol efflux system of BODIPY-cholesterol-labelled THP-1 macrophages. Results A significant reduction in BMI (− 17%, p < 0.001), resolution of insulin sensitivity (HOMA2-IR = − 23.4%, p = 0.002; Adipo IR = − 16%, p = 0.009) and inflammation [log resistin = − 6%, p = 0.07] were observed 3 months post-surgery. CEC significantly improved 3 months after surgery [Pre: 0.91 ± 0.13; Post: 1.02 ± 0.16; p = 0.001] despite a decrease in HDL-C levels. The change in CEC correlated with the change in apo A-I (r = 0.39, p = 0.02) and adiponectin levels (r = 0.35, p = 0.03). Conclusion The results suggest that improvements in CEC, through improvement in adipose tissue health in terms of adipokine secretion and insulin sensitivity could be an important pathway in modulating obesity-related CVD risk.
Akemi Tokutsu, Yosuke Okada, Keiichi Torimoto, Yoshiya Tanaka
Diabetology & Metabolic Syndrome, Volume 13, pp 1-8; doi:10.1186/s13098-021-00663-2

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Background HbA1c variability is independent of mean HbA1c, and associated with mortality due to vascular complications. However, the significance of HbA1c variability is unknown at present. In this study, we used flash glucose monitoring (FGM) and evaluated glycemic intraday variations, and then examined the association with HbA1c variability. Methods We conducted a retrospective pilot study of 26 patients treated at the Outpatient department for type 2 diabetes mellitus (T2DM), and evaluated the following items associated with blood glucose levels and their changes/variations using FGM. The primary endpoint was factor(s) associated with standard deviation (SD) HbA1c over a 6-month period. To adjust for the effect of varying numbers of HbA1c measurements, we used the adjusted SD of HbA1c. Results There were significant correlations between mean HbA1c and each of glucose management indicator, maximum, percent time at glucose > 180 mg/day, mean of daily difference of blood glucose, and high blood glucose index. Adjusted SD HbA1c correlated significantly with percent time at glucose < 70 mg/dL and low blood glucose index. We estimated the regression coefficient of adjusted SD HbA1c using multivariate linear regression analysis, and noted that the presence of hypoglycemia affected Adjusted SD HbA1c (β = 0.130, SE = 0.044, P = 0.008). Hypoglycemia was noted in 17 patients, and adjusted SD HbA1c was significantly higher (p = 0.001) in the hypoglycemic group (0.22 ± 0.12%), compared with the non-hypoglycemic group (0.08 ± 0.05%). The cut-off value of adjusted SD HbA1c was 0.109% in the hypoglycemic group. Conclusions The results showed that HbA1c variability is associated with hypoglycemia. For patients with high HbA1c variability, we recommend evaluation for the presence of hypoglycemia and reconsideration of their treatment regimen including their glucose-lowering medications. Trial registration The study protocol and opt-out method of informed consent were approved by the ethics committees of the University of Occupational and Environmental Health (Trial registration: H27-186, Registered 25 Dec 2015)
Hirohide Yokokawa, Hiroshi Fukuda, Mizue Saita, Kento Goto, Tengen Kaku, Taiju Miyagami, Yuichi Takahashi, Chieko Hamada, Teruhiko Hisaoka, Toshio Naito
Diabetology & Metabolic Syndrome, Volume 13, pp 1-10; doi:10.1186/s13098-021-00646-3

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Background The impact of subcutaneous fat accumulation remains controversial. This study assessed the association between visceral or subcutaneous fat area (VFA and SFA, respectively) and diabetes mellitus (DM) among Japanese subjects. Methods This was a cross-sectional study involving 1907 eligible participants (men, 1050; women, 857) who participated in a voluntary health check-up conducted at Juntendo University Hospital from January 2017 to December 2018, in Tokyo, Japan. Associations between VFA or SFA quartiles and DM were identified using adjusted odds ratios (AORs) and 95% confidence intervals (CIs) with multivariable logistic regression analysis adjusted for confounders. Receiver operating characteristic (ROC) curve analysis was used to assess appropriate cut-off values of VFA or SFA. Results Multivariate analyses showed that Q4 (≥ 125 cm2) of VFA was significantly positively associated with DM compared to Q1 (< 65 cm2) (AOR = 1.94, 95% CI 1.02–3.71), whereas there was no association between SFA and DM in men. Among women, Q4 (≥ 85 cm2) of VFA was significantly positively associated with DM compared to Q1 (< 30 cm2) (Q4, AOR = 6.15, 95% CI 1.65–22.99). Also, Q3 and Q4 (≥ 135 cm2) of SFA were significantly positively associated with DM compared to Q1 (< 90 cm2) (Q3, AOR = 5.64, 95% CI 1.21–26.25; Q4, AOR = 7.81, 95% CI 1.71–35.65). The appropriate cut-off value of VFA in men was 101.5 cm2. Those of VFA and SFA in women were 72.5 cm2 and 165.3 cm2, respectively. Conclusions Our results suggest the importance of considering SFA as well as VFA, especially in women, for primary and secondary prevention of DM.
Nika Aleksandra Kravos, Andrej Janež, Katja Goričar, Vita Dolžan,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-9; doi:10.1186/s13098-021-00660-5

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Background Metformin plays a consolidated role in the management of polycystic ovary syndrome (PCOS). However, there is no clear answer on how long we should treat and on how long its beneficial impact sustain after we stop treatment. We compared the effects of metformin withdrawal after long-term (LT) and short term (ST) treatment in PCOS women that had previously well responded to metformin. Methods We conducted observational longitudinal study including 44 PCOS women (31 (28–36) years and BMI 32.5 (27.7–34.9) kg/m2) that were followed for 6 months after metformin withdrawal. Prior inclusion, ST group had been treated with metformin on average for 1.03 ± 0.13 year, LT group for 5.07 ± 2.52 years. We followed anthropometric, metabolic, reproductive parameters and eating behavior as assessed by TFEQ-R18. Results After metformin withdrawal, ST group gained significant amount of weight (from 92 (75.5–107.3) kg to 96 (76–116) kg; p = 0.019). Weight tended to increase also in LT users (from 87 (75–103) to 87 (73–105) kg; p = 0.058). More women in LT group maintained stable weight (27% in LT group vs 15% in ST group). Eating behavior deteriorated in both groups. Withdrawal of metformin resulted in a decrease of menstrual frequency (6 (6–6) to 6 (4–6) menstrual bleeds per 6 months; p = 0.027) and in borderline increase of androstenedione (6.4 (4.6–7.6) to 7.8 (4.8–9.6) nmol/L; p = 0.053) in LT group. Waist circumference, HOMA and glucose homeostasis remained stable in both groups. There were no differences between groups at 6-month follow up. Conclusion Collectively, present study implies some metabolic and endocrine treatment legacy in both groups as well as some group-specific deteriorations in clinical parameters 6 months after metformin withdrawal. Trial registration: The study is registered at Clinical Trials with reference No. NCT04566718
, Jose Fernando Botero, Fernando J. Lavalle-González, Adrian Proietti, Douglas Eugenio Barbieri
Diabetology & Metabolic Syndrome, Volume 13, pp 1-10; doi:10.1186/s13098-021-00654-3

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Background Continuous glucose monitoring systems are increasingly being adopted as an alternative to self-monitoring of blood glucose (SMBG) by persons with diabetes mellitus receiving insulin therapy. Main body The FreeStyle Libre flash glucose monitoring system (Abbott Diabetes Care, Witney, United Kingdom) consists of a factory-calibrated sensor worn on the back of the arm which measures glucose levels in the interstitial fluid every minute and stores the reading automatically every 15 min. Swiping the reader device over the sensor retrieves stored data and displays current interstitial glucose levels, a glucose trend arrow, and a graph of glucose readings over the preceding 8 h. In patients with type 2 diabetes (T2D) receiving insulin therapy, pivotal efficacy data were provided by the 6-month REPLACE randomized controlled trial (RCT) and 6-month extension study. Compared to SMBG, the flash system significantly reduced the time spent in hypoglycemia and frequency of hypoglycemic events, although no significant change was observed in glycosylated hemoglobin (HbA1c) levels. Subsequent RCTs and real-world chart review studies have since shown that flash glucose monitoring significantly reduces HbA1c from baseline. Real-world studies in both type 1 diabetes or T2D populations also showed that flash glucose monitoring improved glycemic control. Higher (versus lower) scanning frequency was associated with significantly greater reductions in HbA1c and significant improvements in other measures such as time spent in hypoglycemia, time spent in hyperglycemia, and time in range. Additional benefits associated with flash glucose monitoring versus SMBG include reductions in acute diabetes events, all-cause hospitalizations and hospitalized ketoacidosis episodes; improved well-being and decreased disease burden; and greater treatment satisfaction. Conclusion T2D patients who use flash glucose monitoring might expect to achieve significant improvement in HbA1c and glycemic parameters and several associated benefits.
Shu-Ying Li, Hang Guo, Yi Zhang, Pei Li, Pei Zhou, Li-Rong Sun, Jing Li, Li-Ming Chen
Diabetology & Metabolic Syndrome, Volume 13, pp 1-7; doi:10.1186/s13098-021-00657-0

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Objective To investigate the effects of intermittently scanned continuous glucose monitoring (isCGM) on blood glucose control, clinical value of blood glucose monitoring and production of urinary ketone bodies in pregestational diabetes mellitus. Method A total of 124 patients with pregestational diabetes mellitus at 12–14 weeks of gestation admitted to the gestational diabetes clinic of our hospital from December 2016 to December 2018 were selected and randomly divided into two groups. Sixty patients adopted self-monitoring of blood glucose (SMBG) were taken as the control group, and the other 64 patients adopted isCGM system by wearing the device for 14 days. Blood sugar control, glycosylated albumin level, ketone production in urine, the maximum and minimum of blood sugar value measured by different monitoring methods and their occurrence time were observed in the two groups. Result (1) No statistically significant differences were found between the groups in terms of maternal age, gestational age at first visit, family history, duration of diabetes, education level, total insulin dose, chronic hypertension, abortion history, nulliparity, assisted reproductive technology, history of macrosomia childbirth, pre-pregnancy BMI, and overweight (%) at the first visit and hypoglycemia, (2) the value of Glycated Albumin was lower in the CGM group compared to the control group at 2ed weeks (14.6 ± 2.2 vs. 16.8 ± 2.7, p < 0.001). The women in the CGM group spent increased time in the recommended glucose control target range of 3.5–7.8 mmol/L (69 ± 10% vs. 62 ± 11%, p < 0.001) and reduced time above target compared with those in the control group at 2 weeks (25 ± 7% vs. 31 ± 8%, p < 0.001). In the second week of the study, the positive rate of urinary ketone body in isCGM group was lower than that in the control group (42 ± 5 vs. 54 ± 5, p < 0.001), and (3) the minimum blood glucose of 31.2% (20/64) cases in isCGM group appeared during 0:00–2:59 at night, and 26.6% (17/64) cases appeared during 3:00–5:59 at night. The minimum values of 40.0% (24/60) cases in the control group appeared within the 30 min before lunch, 23.3% (14/60) within the 30 min before breakfast, and 11.7% (7/60) within the 30 min before dinner. The cases of minimum of blood sugar before meals accounted for 75% of all the minimum values, and the cases of minimum at night only accounted for 8.3%. Conclusion Intermittently scanned continuous glucose monitoring can reduce hyperglycemia exposure and ketone body formation in pregestational diabetes mellitus. In addition, isCGM is better than SMBG in detecting nocturnal hypoglycemia.
, Guido Kramer, Ulrich A. Müller, Gunter Wolf, Christof Kloos
Diabetology & Metabolic Syndrome, Volume 13, pp 1-8; doi:10.1186/s13098-021-00659-y

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Objective The aim of the present study was to assess diabetes-related distress in inpatients and its association with metabolic control in people with diabetes type 1 (DM1) and type 2 (DM2). Research design and methods In a cross-sectional study, 107 inpatients with DM1 (age 45.9 years, diabetes duration 18.7 years, HbA1c 8.4%/67.8 mmol/mol) and 109 with DM2 (age 62.0 years, diabetes duration 16.2 years, HbA1c 8.9%/74.3 mmol/mol) from a University department for endocrinology and metabolic diseases (Germany) were included over 2 years. Diabetes-related distress was assessed with the PAID questionnaire (range 0–100, higher scores imply higher diabetes-related distress, cut-off ≥ 40). The PAID questionnaire was completed by 214 of 216 participants. Results Fifty-one of 214 individuals (23.8%) showed high distress (PAID score ≥ 40). The mean PAID score was 28.1 ± 17.5 in all participants with no difference between DM1 and DM2 (28.1 ± 17.4 vs. 26.2 ± 16.9, p = 0.532). Individuals with DM2 on insulin scored higher than patients without insulin (27.8 ± 17.6 vs. 18.7 ± 8.5, p = 0.004). Additionally, people with DM1 treated with a system for continuous glucose monitoring (n = 50, 33.1 ± 18.8) scored higher than participants without such system (n = 32, 20.6 ± 13.3, p = 0.001). HbA1c was not correlated with the PAID score in both, DM1 (r = 0.040, p = 0.684) and DM2 (r = − 0.024, p = 0.804). Participants with DM2 and severe hypoglycaemia/last 12 months scored higher than people without (PAID score 43.0 ± 20.4 vs. 25.1 ± 16.5, p = 0.026). Frequency of non-severe hypoglycaemia was not associated with the PAID score in DM1 and DM2. Conclusions Patients with diabetes treated in hospital for problems with diabetes suffer frequently from diabetes-related distress (~ 24%) regardless of diabetes type.
Amin Salehpour, , Mehdi Hedayati, Ali Asghar Farshad, Asal Neshatbini Tehrani, Saeed Mohammadi
Diabetology & Metabolic Syndrome, Volume 13, pp 1-9; doi:10.1186/s13098-021-00661-4

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Background Obesity is considered a major health concern and mounting evidence suggests that the exposure to environmental endocrine disruptors, including Bisphenol-A (BPA), may enhance the risk to develop the disease. Moreover, growing documents propose that the vitamin D may contribute to adipogenic signaling and lipid accumulation during adipocyte differentiation. We focused on the molecular mechanism of vitamin D and BPA in human adipose-derived mesenchymal stem cells (hADMSCs) which vitamin D and BPA may influence adipose tissue development and function. Methods Human adipose-derived mesenchymal stem cells were cultured for 14 days in lipogenic differentiation media containing continuous concentrations of vitamin D plus BPA (0.1 nM or 10 nM). The expression of adipogenic markers including the peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-enhancer-binding protein α (C/EBP α) CCAAT-enhancer-binding protein β (C/EBP β), fatty acid synthase (FASN), lipoprotein lipase (LPL), sterol regulatory element-binding protein-1c (SREBP1c), insulin-induced gene-2 (INSIG2), vitamin D receptor (VDR), estrogen receptor-beta (ER-β), fatty acid-binding protein-4 (FABP4), and glucose transporter-4 (GLUT4) was measured using Quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). Lipid accumulation was visualized with staining with Oil Red O. Results In the morphological assessment of mesenchymal stem cells treated with a concentration of 10 nM vitamin D plus BPA, more lipid accumulations were observed in comparison with the group with 0.1 nM concentration. Treatment of hADMSCs with vitamin D plus BPA (0.1 nM) significantly inhibited the induction of PPARγ, C/EBP β, C/EBP α, and FASN related to adipocyte differentiation and development. However, the exposure of cells to the concentration of 10 nM vitamin D plus BPA induced the expression of these genes associated to the adipogenesis. The remarkable increase in the level of SREBP1c was associated to the suppression of INSIG2 in treated preadipocytes with 10 nM vitamin D plus BPA. Our findings showed that the expression of VDR, ERβ, GLUT4, and FABP4 were upregulated through differentiation with the highest concentrations in 0.1 nM vitamin D plus BPA group for VDR, ERβ, and GLUT4. Conclusions Vitamin D plus BPA at concentration of 10 nM boosted the adipogenesis during the critical stages of adipocytes development, whereas it seems to inhibit this process at concentration of 0.1 nM.
Zuojun Li, Dan Yi, Lijuan Zheng, Shiran Li, Weijin Fang,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-8; doi:10.1186/s13098-021-00658-z

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Background The exact incidence, clinical features and uniform diagnostic criteria of exogenous insulin autoimmune syndrome (EIAS) are still unclear. The purpose of this study is to explore the clinical characteristics of EIAS and to provide a structural approach for clinical diagnosis, treatment and prevention. Methods The literature on EIAS in Chinese and English from 1970 to 2020 was collected for retrospective analysis. Results A total of 122 patients (33 males and 73 females) were included in the study with a median age of 67 years (range 14–86) and a median HbA1c of 7.7%. EIAS mainly occurred in type 2 diabetes mellitus patients using premixed insulin. Symptoms manifested were hypoglycemia in 86.54%, recurrent episodes of symptomatic hypoglycemia in 35.58%, nocturnal hypoglycemia along with daytime hyperglycemia in 21.15% and recurrent hypoglycemia after discontinued insulin in 64.43%. The onset of symptoms occurred at night, in the early morning or during fasting, ranging from a few days to 78 months after the administration of insulin. The mean blood glucose level during the hypoglycemic phase was 2.21 mmol/L (range 1–3.4), and the serum insulin levels were mainly ≥ 100 U/mL and were associated with low C-peptide levels (≤ 10 ng/ml). Insulin autoantibodies (IAAs) were positive in all EIAS patients. The 75-g extended oral glucose tolerance test (OGTT) mainly showed a diabetic curve. Pancreatic imaging was unremarkable. Withdrawal of insulin alone or combination of oral hypoglycemic agents or replacement of insulin formulations or with corticosteroid treatment eliminated hypoglycemia in a few days to 3 months. IAA turned negative in 6 months (median, range 1–12). No hypoglycemia episodes were observed at a median follow-up of 6 months (range 0.5–60). Conclusions EIAS is an autoimmune disease caused by insulin-binding antibodies in susceptible subjects. Insulin antibodies change glucose dynamics and could increase the incidence of hypoglycemic episodes. Detection of insulin antibodies is the diagnostic test. Changing therapeutic modalities reduced the incidence of hypoglycemic episodes.
Takahisa Handa, , Aika Miya, Hiroshi Nomoto, Hiraku Kameda, Kyu Yong Cho, So Nagai, Narihito Yoshioka, Hideaki Miyoshi, Tatsuya Atsumi
Diabetology & Metabolic Syndrome, Volume 13, pp 1-8; doi:10.1186/s13098-021-00656-1

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Background This study aimed to explore predictive factors of time below target glucose range (TBR) ≥ 1% among patients’ characteristics and glycemic variability (GV) indices using continuous glucose monitoring data in elderly patients with type 2 diabetes. Methods We conducted a prospective observational study on 179 (71 female) Japanese outpatients with type 2 diabetes aged ≥ 65 years. The characteristics of the participants with TBR ≥ 1% were evaluated by multivariate logistic regression analysis. Receiver-operating characteristic (ROC) curve analyses of GV indices, comprising coefficient of variation (CV), standard deviation, and mean amplitude of glycemic excursions, were performed to identify the optimal index for the identification of patients with TBR ≥ 1%. Results In the multivariate logistic regression analysis, none of the clinical characteristics, including HbA1c and C-peptide index, were independent markers for TBR ≥ 1%, while all three GV indices showed significant associations with TBR ≥ 1%. Among the three GV indices, CV showed the best performance based on the area under the curve in the ROC curve analyses. Conclusions Among elderly patients with type 2 diabetes, CV reflected TBR ≥ 1% most appropriately among the GV indices examined. Trial registration UMIN-CTR: UMIN000029993. Registered 16 November 2017
, Rune Byrkjeland, Svein Solheim, Harald Arnesen, Marius Trøseid, Ayodeji Awoyemi, Ingebjørg Seljeflot, Ragnhild Helseth
Diabetology & Metabolic Syndrome, Volume 13, pp 1-9; doi:10.1186/s13098-021-00655-2

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Aim Gut leakage has been shown to associate with low-grade inflammation and lower cardiorespiratory fitness in diabetic subjects. We aimed to investigate whether gut leakage markers related to cardiorespiratory fitness in patients with both coronary artery disease and type 2 diabetes, and whether these were affected by long-term exercise training. Methods Patients with angiographically verified coronary artery disease and type 2 diabetes mellitus (n = 137) were randomized to either 12 months exercise intervention or conventional follow-up. A cardiopulmonary exercise test and fasting blood samples were obtained before and after intervention to assess VO2peak and the biomarkers soluble CD14, lipopolysaccharide-binding protein and intestinal fatty-acid binding protein as markers of gut leakage. Results 114 patients completed the intervention satisfactory. VO2peak correlated inversely to sCD14 (r = − 0.248, p = 0.004) at baseline. Dividing sCD14 into quartiles (Q), VO2peak was significantly higher in Q1 vs. Q2–4 (p = 0.001), and patients in Q2-4 (sCD14 > 1300 ng/mL) had an OR of 2.9 (95% CI 1.2–7.0) of having VO2peak below median (< 23.8 ml/kg/min) at baseline. There were no statistically significant differences in changes in gut leakage markers between the two randomized groups (all p > 0.05) after 12 months. Conclusions Cardiorespiratory fitness related inversely to sCD14, suggesting physical capacity to be associated with gut leakage in patients with CAD and T2DM. Long-term exercise training did not affect circulating gut leakage markers in our population. Trial registration NCT01232608, Registered 02 November 2010—Retrospectively registered at https://clinicaltrials.gov/ct2/show/NCT01232608?term=NCT01232608&draw=2&rank=1
Yunhong Huang, Liping Gu, Na Li, Fang Fang, Xiaoying Ding, Yufan Wang, Yongde Peng
Diabetology & Metabolic Syndrome, Volume 13, pp 1-8; doi:10.1186/s13098-021-00653-4

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Background Traditional anthropometric indices are used in diagnosing metabolic syndrome (MetS). This study aimed to propose a novel index, a product of waist and neck circumferences (PWNC), and compared its value with traditional anthropometric parameters in identifying the presence of MetS in Chinese adults with type 2 diabetes mellitus (T2DM). Methods From September 2017 to June 2019, a total of 2017 Chinese adults with T2DM from the National Metabolic Management Center were included and categorized into a MetS group (1575 cases) and a non-MetS group (442 cases). Demographic and metabolic characteristics were compared between the two groups, and logistic regression analysis was performed for MetS. Body mass index (BMI), waist-to-hip ratio (WHR), waist circumference (WC), neck circumference (NC) and PWNC were assessed by constructing receiver operating characteristic (ROC) curves, and the area under the ROC curves was compared by DeLong’s test. Results Compared with the non-MetS group, men and women with MetS had higher blood pressure; higher levels of fasting plasma glucose, fasting insulin, and triglycerides (TGs); lower levels of high-density lipoprotein cholesterol (HDL-C); elevated homeostasis model assessment of insulin resistance (HOMA-IR); and higher BMI, WHR, WC, NC and PWNC (all P < 0.01). Logistic regression showed that PWNC, HDL-C, TGs, HOMA-IR, systolic blood pressure, hypertension and hypotensors were independent risk factors for MetS (all P < 0.01). PWNC, WC, NC, WHR and BMI displayed significant values in the ROC for MetS (all P < 0.01), while the area under the curve for PWNC was larger than that for traditional anthropometric parameters (WC, WHR and BMI) in both men and women (all P < 0.01). Conclusion PWNC outperformed traditional anthropometric parameters in identifying the presence of MetS in Chinese adults with T2DM.
Diabetology & Metabolic Syndrome, Volume 13, pp 1-6; doi:10.1186/s13098-021-00652-5

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Background Asprosin, a novel adipokine that raises glucose levels and stimulates appetite, has been proved to be pathologically increased in populations predisposed to type 2 diabetes mellitus (T2DM), obesity, and cardiovascular diseases. The mechanisms of sodium-glucose co-transporter-2 (SGLT2) inhibitors for hypoglycemic effect and cardiovascular protection have not been fully clarified. Therefore, we conducted this study to assess change in the levels of serum asprosin after treatment with SGLT2 inhibitors in patients with newly diagnosed T2DM. Methods This study was a randomized, double-blind, placebo-controlled trial. A total of 29 participants with newly diagnosed T2DM with body mass index (BMI) ≥ 23.0 kg/m2 and haemoglobin A1c (HbA1c) levels of 58–85 mmol/mol (7.5–10%) were randomized to SGLT2 inhibitors dapagliflozin 10 mg/d (n = 19) or placebo (n = 10) treatment for 24 weeks. We analyzed asprosin concentrations by an enzyme-linked immunosorbent assay. Besides, body weight, BMI, HbA1c, fasting plasma glucose (FPG), and lipid levels were measured at baseline and 24 weeks. Results At 24 weeks, participants with SGLT2 inhibitors treatment exhibited lower levels of serum asprosin (22.87 vs 45.06 ng/ml in the placebo group; P < 0.001) after adjusting for baseline values. The levels of body weight, BMI, HbA1c, FPG, and triglyceride (TG) were decreased, while high density lipoprotein-cholesterol (HDL-C) was increased after SGLT2 inhibitors dapagliflozin treatment compared with placebo (P < 0.05 for all). Low density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) levels were unchanged in the SGLT2 inhibitors group and placebo group. No statistical correlation was found between the levels of serum asprosin and body weight, BMI, HbA1c, FPG, and lipid levels during the SGLT2 inhibitor dapagliflozin treatment. Conclusions These findings indicated that SGLT2 inhibitors can lower serum asprosin levels and improve glucolipid and weight in patients with newly diagnosed T2DM, which may benefit the cardiovascular system. Trial registration CTR20131268; Registered 20 March 2014 CTR20150102; Registered 03 March 2015. http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml.
, Fernanda Cruz Monteiro, Carlos Terra, Marilia Brito Gomes
Diabetology & Metabolic Syndrome, Volume 13, pp 1-11; doi:10.1186/s13098-021-00649-0

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Background Data on non-alcoholic fatty liver disease (NAFLD) in individuals with type 1 diabetes (T1D) is controversial and so far, there are no published data on the Brazilian population. We investigated the prevalence of steatosis and hepatic fibrosis in a population with T1D from a tertiary care center in Brazil and its associated factors. Methods Ninety-five participants with T1D, aged 39 ± 13 years, with disease duration of 21 ± 9 years, being 55 (57.9%) females, from a university hospital in Rio de Janeiro, were screened for NAFLD with hepatic ultrasound (US) and transient elastography (TE). Results Prevalence of steatosis was, respectively, 12.6% and 16.8% when US and TE were used for diagnosis of NAFLD. Fibrosis was present in 8.4% of participants. A total of 31.6% of participants had at least one of the hepatic exams altered, which was associated with higher body mass index, waist circumference, hip circumference and waist-to-hip ratio,, presence of metabolic syndrome and higher triglycerides levels, even within the normal range. After multivariate analysis, presence of steatosis was only associated with metabolic syndrome and its component, triglycerides. Conclusion In our study, prevalence of NAFLD in ultrasound approximates the one found with TE. Fibrosis was not frequent. Screening should be reserved for participants with T1D and metabolic syndrome, as this was the main factor associated with NAFLD. Triglycerides levels were the only component of metabolic syndrome associated with steatosis. Further studies are necessary to determine the best screening strategy for NAFLD in individuals with T1D. Also, predisposing factors for development in fibrosis in T1D should be further explored in prospective studies.
Mariana De Moura E Dias, Sandra Aparecida dos Reis, Lisiane Lopes da Conceição, Catarina Maria Nogueira de Oliveira Sediyama, Solange Silveira Pereira, Leandro Licursi de Oliveira, Maria Do Carmo Gouveia Peluzio, J. Alfredo Martinez,
Diabetology & Metabolic Syndrome, Volume 13, pp 1-14; doi:10.1186/s13098-021-00647-2

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Overweight and obesity are a worldwide public health problem. Obesity prevalence has increased considerably, which indicates the need for more studies to better understand these diseases and related complications. Diet induced-obesity (DIO) animal models can reproduce human overweight and obesity, and there are many protocols used to lead to excess fat deposition. So, the purpose of this review was to identify the key points for the induction of obesity through diet, as well as identifying which are the necessary endpoints to be achieved when inducing fat gain. For this, we reviewed the literature in the last 6 years, looking for original articles that aimed to induce obesity through the diet. All articles evaluated should have a control group, in order to verify the results found, and had worked with Sprague–Dawley and Wistar rats, or with C57BL-/-6 mice strain. Articles that induced obesity by other methods, such as genetic manipulation, surgery, or drugs were excluded, since our main objective was to identify key points for the induction of obesity through diet. Articles in humans, in cell culture, in non-rodent animals, as well as review articles, articles that did not have obesity induction and book chapters were also excluded. Body weight and fat gain, as well as determinants related to inflammation, hormonal concentration, blood glycemia, lipid profile, and liver health, must be evaluated together to better determination of the development of obesity. In addition, to select the best model in each circumstance, it should be considered that each breed and sex respond differently to diet-induced obesity. The composition of the diet and calorie overconsumption are also relevant to the development of obesity. Finally, it is important that a non-obese control group is included in the experimental design.
Diabetology & Metabolic Syndrome, Volume 13, pp 1-13; doi:10.1186/s13098-021-00650-7

Abstract:
Background Due to diverging international recommendations, the unclear role of HbA1c and the lack of longitudinal data, we investigated the accuracy of diagnostic tests in the early and late postpartum in women with gestational diabetes (GDM) especially to predict future glucose-intolerance. Methods This longitudinal cohort included 967 women with GDM from 2011 to 2020. A 75-g oGTT and HbA1c were performed at 4–12 weeks (early) postpartum. FPG and HbA1c were measured at 1 and 3-year (late) postpartum. ADA criteria were used as gold standards. At all time-points (4–12 weeks, 1-year and 3-year postpartum) women with diabetes and prediabetes were grouped together and referred to as glucose-intolerant, because at most 3% of the entire cohort population had diabetes at any time-point. Results The prevalence of glucose-intolerance in the early postpartum was higher using FPG and HbA1c (27.5%) than oGTT criteria (18.2%). Only 48–80% of women diagnosed with glucose-intolerance in the early postpartum actually remained intolerant. This was especially low when FPG or oGTT were combined with HbA1c (1-year: ≤ 62% and 3-years: ≤ 50%). Regardless of the test used, 1/3 of women with initially normal glucose-tolerance became glucose-intolerant in the late postpartum. HbA1c was unrelated to iron status/intake, remained stable throughout, but poorly predicted future glucose-intolerance. In the longitudinal analyses, all diagnostic tests in the early postpartum showed acceptable specificities (74–96%) but poor sensitivities (all < 38%) to predict glucose-intolerance after only 10-months. At 1-year postpartum however, the combination of FPG and HbA1c could best predict glucose-intolerance 2-years later. Conclusions Combining FPG with HbA1c at 1-year postpartum represents a reliable choice to predict future glucose-intolerance. Given the poor prediction of tests including oGTT in the early postpartum, focus should rather be on continuous long-term screening.
Hossein Farhadnejad, , Hosein Rostami, , Fereidoun Azizi
Diabetology & Metabolic Syndrome, Volume 13, pp 1-10; doi:10.1186/s13098-021-00648-1

Abstract:
Background In the current study, we aimed to investigate the association of dietary inflammation scores (DIS) and lifestyle inflammation scores (LIS) with the risk of metabolic syndrome (MetS) in a prospective population-based study. Methods A total of 1625 participants without MetS were recruited from among participants of the Tehran Lipid and Glucose Study(2006–2008) and followed a mean of 6.1 years. Dietary data of subjects were collected using a food frequency questionnaire at baseline to determine LIS and DIS. Multivariable logistic regression models, were used to calculate the odds ratio (ORs) and 95 % confidence interval (CI) of MetS across tertiles of DIS and LIS. Results Mean ± SD age of individuals (45.8 % men) was 37.5 ± 13.4 years. Median (25–75 interquartile range) DIS and LIS for all participants was 0.80 (− 2.94, 3.64) and 0.48 (− 0.18, − 0.89), respectively. During the study follow-up, 291 (17.9 %) new cases of MetS were identified. Based on the age and sex-adjusted model, a positive association was found between LIS (OR = 7.56; 95% CI 5.10–11.22, P for trend < 0.001) and risk of MetS, however, the association of DIS and risk of MetS development was not statistically significant (OR = 1.30;95% CI 0.93–1.80, P for trend = 0.127). In the multivariable model, after adjustment for confounding variables, including age, sex, body mass index, physical activity, smoking, and energy intake, the risk of MetS is increased across tertiles of DIS (OR = 1.59; 95% CI 1.09–2.33, P for trend = 0.015) and LIS(OR = 8.38; 95% CI 5.51–12.7, P for trend < 0.001). Conclusions The findings of the current study showed that greater adherence to LIS and DIS, determined to indicate the inflammatory potential of diet and lifestyle, are associated with increased the risk of MetS.
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