bluuebunny/crossref_metadata_2025 huggingface dataset:
Osteocyte-Specific TGFβ Signaling Mitigates Obesity-Induced Deregulated Energy Metabolism and Compromised Bone Quality
Authors: Dole Neha S , Yee Cristal , Alliston Tamara
Published: May 2021

Bone fragility associated with obesity is well recognized and is attributed to a cumulative decline in bone quality despite high BMD. Moreover, novel insights into skeletal physiology have revealed that bone-derived factors are key regulators of systemic energy balance. Despite the revelation that bone is both a target and a driver of energy metabolism, it is not entirely clear how obesity compromises the metabolic function of bone and whether deregulated energetics in bone play a causal role in declining bone quality.

Transforming growth factor-beta (TGFβ), a key mediator of bone homeostasis, was recently shown by us to play a positive role in osteocytes, where its ablation (TβRIIocy-/-) compromised bone quality. TGFβ signaling has been previously implicated in etiologies of obesity and type 2 diabetes. Also, our unpublished unbiased transcriptomic analysis in TβRIIocy-/- mouse bones (osteocyte-enriched RNA) has shown that osteocytic ablation of TGFβ signaling causes profound changes in the expression of genes implicated in glucose and fatty metabolism. Together these observations led us to hypothesize that osteocytic TGFβ plays an integral role in regulating obesity impacted bone architecture and function in metabolism.

Using hyperglycemia to model the metabolic milieu of obesity in vitro, we found that hyperglycemia upregulated TGFβ signaling in osteocytes. We also found that TGFβ acts similarly to hyperglycemia in reprogramming osteocyte cellular metabolism to promote glycolysis at the expense of oxidative phosphorylation. Thus, TGFβ may be a crucial mediator of hyperglycemia-induced metabolic reprogramming in osteocytes.

In TβRIIocy-/- mice, inhibition of osteocyte-intrinsic TGFβ signaling reduced age-dependent weight gain and improved glycemic control relative to littermate controls. When subjected to a high-fat diet (HFD, 18 weeks), TβRIIocy-/- mice continued to be leaner, with lower food intake, and higher levels of activity and fatty acid metabolism in the liver compared to HFD fed littermate controls. This implicates osteocyte-intrinsic TGFβ signaling as a crucial regulator of systemic energy metabolism. TβRIIocy-/- mice on HFD also showed increased trabecular and cortical bone mass, increased bone mineral density, and protection against reduced bone strength compared to littermate controls on a similar diet.

Overall, our study identifies a novel role for osteocytic TGFβ signaling in regulating energy metabolism and bone health in obesity.
The Role of TGFβ Ligands and Signalling on Insulin Resistance in Skeletal Muscle in Women With PCOS
Authors: Moreno-Asso Alba , McIlvenna Luke C , Patten Rhiannon K , McAinch Andrew J , Rodgers Raymond J , Stepto Nigel K
Published: May 2021

Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy affecting metabolic and reproductive health of 8–13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 38–95% of women with PCOS. This underlying IR has been identified as unique from, but synergistic with, obesity-induced IR (1). Skeletal muscle accounts for up to 85% of whole-body insulin-stimulated glucose uptake; however, in PCOS this is reduced by about 27% when assessed by a euglycaemic-hyperinsulinaemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that in vivo environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). A potential environmental mechanism contributing to the development of peripheral IR may be the extracellular matrix remodelling and aberrant transforming growth factor beta (TGFβ) signalling. Previous work demonstrated that TGFβ superfamily ligands are involved in the increased collagen deposition and fibrotic tissue in the ovaries, and suggested that these ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5 ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30 ng/ml), a TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=5) and healthy controls (n=5). TGFβ1 did not have a significant effect on insulin signalling but induced expression of some ECM related genes and proteins, and increased glucose uptake via Smad2/3 signalling in myotubes from both groups. Conversely, AMH did not appear to activate the TGFβ/Smad signalling pathway and had no significant impact on insulin signalling or glucose uptake in any of the groups. In conclusion, these findings suggest that TGFβ1, but not AMH, may play a role in skeletal muscle ECM remodelling/fibrosis and glucose metabolism in PCOS but does not have a direct effect on insulin signalling pathway. Further research is required to elucidate its contribution to the development of in vivo skeletal muscle IR and broader impact in this syndrome. References: (1) Stepto et al., Hum Reprod 2013 Mar;28(3):777–784. (2) Cassar et al., Hum Reprod 2016 Nov;31(11):2619–2631. (3) Corbould et al., Am J Physiol-Endoc 2005 May;88(5):E1047-54. (4) Stepto et al., J Clin Endocrinol Metab, 2019 Nov 1;104(11):5372–5381. (5) Raja-Khan et al., Reprod Sci 2014 Jan;21(1):20–31.
Use of Intranasal Insulin as Neuroprotection From Hyperglycemia in Rat Model of Extremely Preterm Infants
Authors: Yauch Lauren McClure , Ennis Kathleen , Tkac Ivan , Rao Raghavendra
Published: May 2021

Background: Hyperglycemia is common in extremely preterm infants (EPI) and is a risk factor for increased mortality and morbidity, including abnormal neurodevelopment. Hippocampus-mediated cognitive deficits are common in this population. In a rat model of insulinopenic hyperglycemia, abnormal neurochemistry in the hippocampus was found, with lactate, glutamate (Glu):glutamine (Gln) ratio lower and Phosphorylated Creatinine (PCr):Creatinine (Cr) higher. Intranasal insulin has been shown to improve cognitive function in animal models of Alzheimer’s disease and type 2 diabetes mellitus, as well as in adult human studies of Alzheimer’s disease. No study has previous investigated the use of intranasal insulin on preventing the long-term effects of hyperglycemia in the EPI population. Objective: To determine whether administration of intranasal insulin during early postnatal days would negate the effects of hyperglycemia on the developing hippocampus in neonatal rat model of streptozotocin (STZ)-induced hyperglycemia. Design/Methods: STZ (80mg/kg IP) was injected on postnatal day (P) 2, and littermates in the control group were injected with an equivalent volume of citrate buffer. STZ pups were randomized to intranasal insulin, 3U twice daily from P3-P6 (STZ + INS) or left untreated (STZ). Neurochemical profile (consisting of 20 metabolites, PCr:Cr and Glu:Gln ratios) of the hippocampus was evaluated using ultra-high-field (9.4 T) magnetic resonance spectroscopy (MRS) on P7 (acute effects) and P56 (long-term effects) compared with the control group (CON)(N=6/group). Results: Mean glucose values from P3-P6 were higher in STZ groups (STZ = 279.0 +/- 132.2 mg/dL, STZ+INS = 274.4 +/- 89.5 mg/dL, CONT = 128.4 +/- 15.1 mg/dL). The neurochemical profile was different at both P7 and P56. On P7, compared with the control, the taurine (Tau) was higher in the STZ groups (p = 0.007. At P56, PCr:Cr was higher in the STZ group compared to CONT and STZ+INS groups (p = 0.04). No difference noted between the STZ+INS and CONT groups. No other metabolites were altered. Conclusion: Neonatal hyperglycemia alters the acute and long-term neurochemical profile in the hippocampus of developing rats. The increase in PCr:Cr ratio in the STZ group indicates lower demand for ATP and PCr, secondary to decreased neuronal activity, which has been demonstrated in previous studies. PCr:Cr ratio of the STZ+INS group was no different than control, indicating that intranasal insulin reverses the negative effect on neuronal activity caused by neonatal hyperglycemia.
Hyperglycemia Requiring Insulin Among Pediatric Patients Diagnosed With Hemophagocytic Lymphohistiocytosis
Authors: Schweisberger Cintya , Palaniappan Nila , Wood Nicole , Amos Lauren , Halpin Kelsee
Published: May 2021

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder marked by massive cytokine release due to macrophage and T-cell activation. Hallmarks of the diagnosis include fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogemia, and elevations in ferritin and soluble IL-2 receptor. Given HLH is associated with critical illness, elevation in inflammatory markers, and treated with glucocorticoids, the development of hyperglycemia during its course is not unexpected. However, detailed descriptions of the severity of hyperglycemia and strategies in insulin management among HLH patients are lacking. We describe 10 years’ experience at a single tertiary pediatric health center with HLH patients who developed insulin dependent hyperglycemia.

Objectives: To describe the demographics, clinical and laboratory findings, treatment regimens, and outcomes for children with HLH treated with insulin due to hyperglycemia.

Study Design: Retrospective chart review from 2010 through 2019 of youth 0 to 21 years of age who required insulin therapy during or shortly after a hospitalization where they were diagnosed with HLH using established criteria. Descriptive statistics were used to characterize the population of interest.

Results: Of 30 patients diagnosed with HLH, 33% (n=10) required insulin therapy. Half (n=5) were female and half (n=5) male. The mean age was 8.4 years (7.8 months - 17 years). The majority (80%) were non-Hispanic white. Mean BMI at admission was 53rd percentile (5th - 87th percentile). Max serum glucose ranged from 267 to 725 mg/dL (mean 421 mg/dL). Marked inflammation was present (max CRP 2.6 - 44.9 mg/dL, max ferritin 1,091 - 90,219 ng/mL). All were treated with dexamethasone, doses ranging from 5 to 11 mg/m2/day and duration from 2 to 70 days. Most (90%) received parenteral nutrition (PN) with a mean max GIR of 8 mg/kg/min (SD=2.7). Intravenous infusions of regular insulin were used in 80% of patients, though 2 patients were later transitioned to long and short acting subcutaneous insulin. Mean duration of IV insulin therapy was 9.5 days (2–24 days); however, 2 patients died while on IV insulin therapy. The majority (70%) needed insulin within 5 days of starting steroids. Two patients (20%) were treated with subcutaneous insulin only (no IV). Only 1 patient was discharged home on insulin therapy. Mean hospital stay was 60 days (10–202 days). Mortality was 50% (n=5).

Conclusions: One-third of pediatric HLH patients required insulin during their hospitalization for severe hyperglycemia likely secondary to multiple factors including glucocorticoid use, parenteral nutrition, inflammation, and severe illness. Insulin is typically started within 5 days of initiating steroid therapy, limited to IV infusions, and often is not needed by the time of discharge. Risk of mortality is very high.
An Unusual Form of Type 1 Diabetes With an Elevated Proinsulin Level
Authors: Havranova Jana , Gallagher Thomas , Arastu Mohammad Ishaq
Published: May 2021

Introduction: Diabetes is one of the most prevalent diseases in the world. We recognize the three most common types of diabetes: type1, type2 and gestational diabetes. It is estimated that around 425 million of people worldwide have diabetes and about 90% of those represent type 2 diabetes. The most common types of diabetes are polygenic -- they are caused by a defect in multiple genes. Monogenic diabetes is caused by a mutation in a single gene. We currently have over 10 different types of monogenic diabetes called MODY (Maturity Onset Diabetes of the Young). Sun et al. states that over the past few years, 30 different insulin gene mutations were reported to cause a new syndrome called MIDY (Mutant INS-gene-induced Diabetes of Youth). Most of these mutations lead to proinsulin misfolding in the endoplasmic reticulum. We present a rare case of a young obese female with an elevated proinsulin level and low C-peptide level diagnosed with type 1 diabetes requiring therapy with insulin. Case Description: A 21 year old female with past medical history of chronic diarrhea initially presented with a complaint of dry mouth, dizziness, excessive urination, and thirst. She was found to have hyperglycemia of 203 mg/dL, A1C 8.3, and negative ketones. Patient had a strong family history of diabetes. She had a family history of: father with type 1 diabetes; mother with a past medical history of gestational diabetes who became diabetic postpartum; and three of the patient’s grandparents with a history of diabetes. Patient was started on the oral hypoglycemic agents metformin and glipizide, but she only had partial response to these medications. Because of her strong family history and incomplete response to oral hypoglycemic agents, additional testing was performed. Patient was found to have a low C-peptide level (1.6 ng/mL), elevated proinsulin (72.9 pmol/L), positive GAD antibody (10.3 units/mL) and negative islet cell autoantibody. Patient had a very good response to insulin and subsequently became insulin dependent. She is currently on an insulin pump. Conclusion: Sun et al. reports that proinsulin misfolding causes beta cell failure. Increased misfolding occurs under certain pathological conditions that are currently unknown. We think that there might be some increased proinsulin misfolding abnormality that might be occurring in this patient. There are most likely many epigenetic modifiers that would trigger certain individuals to be more prone to this phenomena of misfolded proinsulin. Future research in diabetes may one day yield antibodies that would specifically recognize misfolded proinsulin in the plasma. Further research is required to elucidate how defective proinsulin folding may lead to beta cell dysfunction and subsequent evolution of diabetes mellitus.
Chronic Kidney Disease Prevalence and Glomerular Filtration Rate Trends in Children With Type 1 Diabetes
Authors: Favel Kristen , Mammen Cherry , Panagiotopoulos Constadina
Published: May 2021

Background and Objectives: Children with type 1 diabetes (T1D) are at risk for acute kidney injury (AKI) secondary to diabetic ketoacidosis, as well as chronic kidney disease (CKD) from diabetic nephropathy. The primary objective of this study was to assess the prevalence of abnormalities in estimated glomerular filtration rate (eGFR) in children with T1D. As a secondary objective, we sought to explore the relationship between clinical characteristics and trends in eGFR. Design, Setting, Participants, and Measurements: This ambispective cohort study involved children aged 18 years or younger with T1D (n = 420), followed in the diabetes clinic at British Columbia Children’s Hospital (BCCH), the tertiary pediatric hospital in Vancouver, British Columbia, Canada. Data was collected from the BCCH paper and electronic health records. CKD was defined as eGFR less than 60 mL/min/1.73 m2. Being at risk of CKD was defined as having a mildly decreased eGFR (60-<90 mL/min/1.73 m2) and/or hyperfiltration (eGFR ≥140 mL/min/1.73 m2). eGFR was calculated using the modified Schwartz formula (36.5 x height in cm / serum creatinine in μmol/L). Linear regression analysis was used to describe the relationship between eGFR and duration of T1D. Covariates included in the analysis included sex, history of DKA, A1c, and BMI. Results: Of the 420 participants, 225 (54%) were male, with a median age at T1D diagnosis of 6.1 years and T1D duration of 4.8 years (range <1.0–15.0 years). One-hundred and eighty-six (44%) children were hospitalized for DKA, of which 89 (48%) developed AKI. No participants had an eGFR < 60 ml/min/1.73m2, and 317 (76%) had normal renal function. Fifty-one participants (12%) had an eGFR < 90 ml/min/1.73 m2, and 52 (12%) demonstrated hyperfiltration. When analyzed as a cohort cross-sectionally based on duration of T1D, there was a significant linear decline in eGFR of 1.4 ml/min/1.73 m2 per year (95% CI -1.95, -0.87 ml/min/1.73 m2). Conclusion: In a large group of pediatric patients with type 1 diabetes, 24% were at risk for chronic kidney disease based on a mildly decreased GFR and/or hyperfiltration. The pattern of eGFR decline over time is concerning and relevant, as this cohort is at risk for CKD secondary to diabetic kidney disease. Strategies are needed to improve the follow-up and management of early CKD in children with type 1 diabetes to maintain their renal function into adulthood, and more studies are needed to quantify further change in eGFR in the young adult population.
Effects of Treatment With Continuous Subcutaneous Insulin Infusion on Arterial Stiffness and Endothelial Glycocalyx Compared to MDI Intensification in Patients With Type 1 Diabetes: Improvement After a Six-Month Pump Treatment
Authors: Kountouri Aikaterini , Thymis John , Kousathana Foteini , Balampanis Konstantinos , Pliouta Loukia , Prentza Vasiliki , Katogiannis Konstantinos , Kostelli Gavriela , Barmpagianni Aikaterini , Liatis Stavros , Lambadiari Vaia , Ikonomidis Ignatios
Published: May 2021

Patients with type 1 diabetes mellitus (T1DM) present signs of atherosclerosis and endothelial dysfunction earlier compared to healthy individuals. The evidence regarding the efficacy of continuous subcutaneous insulin infusion (CSII) in vascular function in T1DM are scarce. The aim of this study is to determine whether insulin intensification with CSII improves arterial stiffness and endothelial function in T1DM compared to multiple daily insulin (MDI) injections. Thirty patients with T1DM were included in our study. Fifteen patients with poor glycemic control were transitioned from MDI to CSII and were reviewed immediately prior (baseline) and six months after the initiation of CSII. Fifteen patients, matched for sex, age and glycemic control, remained on intensified treatment with MDI (control group). In all patients at each visit we measure a) Carotid-femoral PWV b) central systolic blood pressure (cSBP) c) perfused boundary region (PBR) of the sublingual arterial microvessels. Both groups had similar cardiovascular markers and HbA1c at baseline (p>0.05). After a six month treatment period, patients on CSII improved HbA1c (7.9±1.5% vs 7.35±0.7%, p<0.05), PBR (2.1±0.2 vs. 2±0.2 μm, p<0.05), PWV (7.5±0.3 vs. 7.4±1.1m/s, p<0,05) and cSBP (114.6±12.5 vs. 112±5.4 mmHg, p<0.05). There were no statistically significant differences in PBR (2±0.3 vs. 2±0.3 μm, p>0.05), PWV (8±2.3 vs. 8±1.9m/s, p>0.05) and cSBP (115±15.2 vs. 115.7±15.4 mmHg, p>0.05) in patients who remained on MDI, despite improvement of HbA1c (8±1.1% vs 7.36±0.8%, p<0.05). The use of CSII improves the thickness of endothelial glycocalyx and decreases arterial stiffness after six months treatment in patients with T1DM.
Improving Care Delivery for Young Adults With Type 1 Diabetes via a Multi-Faceted Quality Improvement Interdisciplinary Intervention
Authors: Chan Alvita Justine , Gomer Stephanie , Dimaraki Eleni V , Lipscombe Lorraine Lucille , Mukerji Geetha
Published: May 2021

Background: The transition from pediatric to adult type 1 diabetes (TID) care represents a vulnerable period for young adults (YA), and many are eventually lost to follow up. This can result in lost opportunities for patient education, worsened glycemic control and increased rates of acute diabetes complications. To address this, a multi-faceted quality improvement (QI) intervention was implemented at a YA T1D program with the goal of improving patient attendance and care delivery amongst YA with T1D.

Methods: The intervention consisted of three main components: a transitional navigator, an interdisciplinary diabetes assessment flowsheet and virtual care via phone or video conference. These components were implemented at the YA T1D program using a stepwise approach beginning in 2019. The attendance of all patients seen between January 2017 and August 2020 were tracked monthly on a run chart to identify any shifts after each component was implemented. A pre-post analysis was also performed in new patients with a minimum follow up period of 12 months to compare secondary outcomes including A1c reduction at 12 months, incidence of diabetes-related ED visits/hospitalizations, incidence of severe hypoglycemia and psychosocial counselling rates.

Results: A total of 2240 scheduled appointments was included in the primary analysis. Patient attendance improved from 59% to 79% (p<0.01) with virtual care, demonstrated by a shift in attendance sustained over 6 months after its implementation. Virtual care was utilized in 81.3% of appointments in the post-intervention period. Subgroup analysis showed the improvement in attendance was significant in follow up appointments (80% vs 59%, p<0.01), but there was no difference in attendance for initial consultations (67% vs 58%, p=0.45).

Forty-two patients were included in the pre-post analysis (n=27 in the pre-intervention and n=15 in the post-intervention period). There were with no significant difference in baseline characteristics of the two groups. Mean patient age was 20.2±2.9 years. Males comprised of 28.5% of the study population. Mean duration of diabetes was 11.1±5.3 years, and baseline average A1c was 8.6±1.7%. Preliminary analysis demonstrated there was significant improvement in preconception counselling rate (76% vs 100%, p=0.048) following the intervention. There was no significant difference in A1c reduction at 12 months, incidence of diabetes-related ED visits/hospitalizations or incidence of severe hypoglycemia.

Conclusion: Virtual care was effective in improving attendance for follow up appointments at a YA T1D clinic. Further data analysis for patients assessed in September to December 2020 is currently underway.
Trends in Type 1 Diabetes Mortality and Disability-Adjusted Life-Years in 27 European Countries and the United Kingdom: 1990–2017
Authors: Kudzinskas Aurimas , Alazawi Andrew , Hughes Will , Goodall Richard , Harbinson Eleanor , Salciccioli Justin , Marshall Dominic , Bravis Vassiliki , Shalhoub Joseph
Published: May 2021

Background: Type 1 diabetes mellitus (T1DM) is a prevalent condition with significant morbidity and financial implications. This study aims to compare the temporal trends in T1DM mortality and morbidity across 27 European Union (EU) countries and the United Kingdom between 1990 and 2017. Methods: The Global Burden of Disease Study database was used to extract T1DM age-standardized mortality rates (ASMR) and disability-adjusted life-years rates (DALYs) per 100,000 for 27 EU countries and the United Kingdom. Joinpoint regression analysis was used to interpret trends. Results: All countries, excluding males from the Czech Republic (+28.5%), had relative reductions in ASMR between 1990 and 2017. The largest relative reductions in ASMR between 1990 and 2017 were observed in Slovenia for both males and females (-75.9% and -87.9%, respectively). The smallest relative reductions in ASMR between 1990 and 2017 were seen in Malta for males (-5.9%) and Czech Republic for females (-12.5%). For all years from 1999 to 2017, males in all countries had higher T1DM ASMRs compared to females. Similarly, T1DM DALYs have decreased across all countries excluding males from the Czech Republic and Malta (+10.4% and +5.3%, respectively). The largest relative reductions in DALYs between 1990 and 2017 were observed in Poland for both males and females (-46.4% and -70.4%, respectively). The smallest relative reductions in DALYs were seen in Greece for both males and females (-4.1% and -17.0%, respectively). From all years from 2006 to 2017, males in all countries had higher T1DM DALYs compared to females. Joinpoint regression analysis demonstrated that over the time period covered by the most recent trends (2013/14–2017), small increases in T1DM ASMRs were observed in Malta, Germany, and Denmark, for males, and in the UK, Netherlands, Germany, and Denmark for females. Furthermore, the UK also observed increases in DALY rates for both males and females between 2013 and 2017 (estimated annual percentage increases: males +0.6%, females +0.5%). Discussion: We identified improvements in both the mortality and morbidity from T1DM in European Union Countries between 1990 and 2017. Both the incidence and prevalence of T1DM is known to be increasing, therefore the observed improvements in mortality and morbidity reflect continent wide improvements in disease management. Our data do suggest, however, that the improvements in mortality and DALYs appear to be plateauing in the UK over the time periods covered by the most recent trends.
A Pilot Study of External Counterpulsation on Reactive Hyperemia, Levels of Glycemia and Metabolic Parameters in Type 2 Diabetes Mellitus
Authors: Shan Hoong Caroline Wei , Tan Maudrene , Kao Shih Ling , Khoo Eric Yin Hao
Published: May 2021

Introduction: External counter-pulsation (ECP) involves cuff inflation over the lower extremities to generate sheer stress, thereby improving endothelial function and anginal symptoms in coronary artery disease. Endothelial dysfunction is also involved in the pathogenesis of T2DM. We hypothesized that 1) ECP will be associated with an improvement in endothelial function in T2DM as measured by peripheral artery tonometry, and 2) explored whether this would vary with different dose and frequency regimens. A shorter or less intensive regimen could potentially reduce cost and improve patient compliance if a similar therapeutic response is achieved.

Methods: This single-center prospective study in a tertiary institute in Singapore involving 46 adults with T2DM of HbA1c between 7 to 10%, who were randomly assigned to receive 35 sessions of ECP at different regimens and duration. Subjects in arm 1 received 1-hour daily sessions 5x per week for 7 consecutive weeks, subjects in arm 2 received 0.5-hour sessions 5x per week for 7 consecutive weeks, and subjects in arm 3 received 1-hour sessions 3x per week for 12 consecutive weeks. Endothelial function was evaluated by reactive hyperemia index (RHI) via peripheral arterial tonometry measured at the start, midpoint and end of study. Other secondary outcomes included fasting glucose, homeostatic model assessment of insulin resistance (HOMA-IR), HbA1c, blood pressure, lipid profile, weight and vibration sense.

Results: 42 subjects completed the 35-session course of ECP. Mean age was 56.1±9.3 years, duration of diabetes 8.8±4.7 years, baseline RHI 2.0 (1.3–3.7) and baseline HOMA-IR was 3.1 (0.5–18.7). All regimes of ECP were well-tolerated. There was no change in RHI across all 3 regimens of ECP individually or collectively at the end of the study (ΔRHI +0.01%, p=0.458). Glycaemic markers of fasting glucose, HbA1c and HOMA-IR, as well as blood pressure, lipid profile, weight and vibration sense also remained unchanged at endpoint. Subgroup analysis showed a significant improvement in RHI (ΔRHI +20.6%, p=0.0178) in 7 subjects with more severe endothelial dysfunction (defined by RHI<1.67) at baseline who had a trend to having a longer duration of diabetes, however there was no improvement in fasting glucose, HbA1c, HOMA-IR or metabolic parameters in this group.

Conclusion: ECP did not show a beneficial effect on endothelial function, glycemic control or metabolic parameters in this South-East Asian population with T2DM at any of the three regimens. This may partly be explained by less severe endothelial dysfunction and less insulin resistance in our population at baseline. Future studies of ECP may investigate its potential benefits in a larger population of T2DM with more severe endothelial dysfunction, higher insulin resistance and/or longer duration of diabetes at baseline.
Association of NOS3 Genetic Polymorphism With the Predisposition to Diabetes and Pre-Diabetes, Retrospective Study
Authors: Ayesh Hazem , Ayesh Sajida S , Beran Azizullah , Ayesh Suhail
Published: May 2021

Background: Endothelial nitric oxide synthetase (eNOS) encoded by NOS3 gene has an important role in modulating vascular endothelial function. Many studies reported a possible role of NOS3 in the pathogenesis of diabetes mellitus (DM). This study investigated the association of NOS3 (G>T) rs1799983 genetic polymorphism with DM, pre-diabetes (pre-DM), and insulin resistance (IR).

Methods: A random sample of 220 subjects (DM & pre-DM) compared with 220 healthy subjects. Sample obtained from Palestinian adults who consented to genetic and biochemical testing. All subjects genotyped for NOS3 (G > T) rs1799983 SNP using ARMS PCR. Fasting blood sugar (FBS) and triglyceride (TGA) levels were obtained for all subjects. Triglyceride glucose index (TyG) was used as a surrogate marker for IR. Regression analysis adjusted for age and body mass index (BMI) was performed to investigate the association between DM & Pre-DM status, FBS, and TyG with NOS3 genetic polymorphism.

Results: NOS3 minor allele frequency positively correlated with FBS levels after controlling for age and BMI (P-value 0.006). DM & pre-DM were more frequent in homozygous NOS3 subjects with an odds ratio of 2.04 (P = 0.05). NOS3 minor allele frequency positively correlated with TyG but not statistically significant association (P = 0.061).

Discussion: Many studies reported a potential role of NOS3 genetic polymorphism in DM and IR pathogenesis. In this study, NOS3 minor allele frequency positivity correlated with FBS levels. Homozygous NOS3 was associated with a 2-fold increase in the prevalence of DM & pre-DM. NOS3 genetic polymorphism didn’t show a statistically significant correlation with TyG (P = 0.061). With the increasing availability of genetic testing, NOS3 may serve as an early screening tool to identify subjects with a high risk for elevated FBS. Further studies are required to understand the exact role of NOS3 genetic polymorphism in the pathogenesis of DM, and to evaluate the clinical efficacy and cost-effectiveness of genetic testing.

Conclusion: NOS3 genetic polymorphism has a statistically significant relationship with the FBS level. Further studies are required to confirm the association between NOS3 and DM.
Clinical And Biochemical Outcomes Of Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors In Type 2 Diabetes Mellitus Patients
Authors: Saleem Muhammad , Ram Nanik , Khan Sajjad Ali , Suchal Zafar Aleem , Mehdi Khan Muhammad Mustansir
Published: May 2021

Background: SGLT-2 inhibitors are a group of oral medications that work independently of insulin working as anti-diabetics by enhancing the excretion of glucose. The purpose of our study was to assess the improvement in terms of HbA1c, weight, blood pressure and BMI and the hepatics and renal effect in terms of SGPT and Creatinine in patients already on three oral glucose lowering agents when SGLT-2 inhibitor was added to their medications. Methods: This retrospective, real world, single center study included 99 patients (mean age [Standard Deviation]: 53.8 [9.63] years) with poorly control type 2 diabetes. Data was recorded at three times, before the addition of SGLT-2 inhibitor and then at 3 and 6 month follow up after the drug had been added in patient’s medications. Physical parameters namely weight, BMI and blood pressure were recorded in the clinic while HbA1c, SGPT and Creatinine were checked by laboratory. Results: Improvement was seen in all parameters at both 3 and 6 month follow up interval. The reduction in HbA1c was statistically significant (P-value < 0.001) with (Mean Reduction [Standard Deviation)) 0.81[1.02] % at 3 months and 1.07[1.11] % at 6 months. Weight was also significantly reduced (P-value < 0.001) with (MR [SD]) 1.83[2.32] kg at 3 and 4.02[6.04] kg at 6 months. Statistically significant reduction (P-value < 0.001) in BMI was also seen with 0.69[0.95] kgm-2 at 3 months and 2.13[3.41] kgm-2 at 6 months of follow up. The systolic blood pressure showed significant reduction (P-value < 0.05) of 5.9[15.76] mmHg at 3 months and 6.37[18.33] mmHg at 6 months. The creatinine and SGPT values of the patient showed minimal variation over the course of these 6 months of follow up. Conclusion: Our study showed that SGPT-2 can be reliably used in patients in which diabetes is not being controlled by other glucose lowering agents and is safe for use in patients in which hepatic and renal function needs to be preserved. Keywords: SGLT-2 inhibitors, Type 2 Diabetes Mellitus, Pakistan
HbA1c Is Not Potent Glucose Control Assessment Tool in Type 2 Diabetes Patients Treated With Insulin
Authors: Totomirova Tzvetelina , Arnaudova Mila
Published: May 2021

Glycated haemoglobin (HbA1c) is used for defining of glucose control in diabetic patients nevertheless its insufficiency to present overall control in some specific cases. Continuous Glucose Monitoring (CGM) is usually used for adjustment of insulin doses but the derived data are helpful for exact glucose control. We assess the potency of HbAc for defining of real glucose control in subgroup of type 2 diabetes patients treated with different insulin regimens. We studied 54 diabetic patients (33 men, 21 women; age 60.23±5.99 years, disease duration 12.64±5.02 years) - 33 with type 2 diabetes on pre-mixed insulin, 21 with type 2 on multiple insulin injection (MII). Patients performed multiple daily blood glucose measurements of fasting and prandial blood glucose for three months period. HbA1c was measured and CGM by using iProTM for seven days was performed at the end of this period. In pre-mixed insulin treated group and in intensified regimen group, moderate positive correlation was found between HbA1c and mean blood glucose derived from CGM (7.64±1.40% and 7.69±1.23%, respectively 7.64±1.48mmol/l and 7.60±1.30mmol/l), with r1=0.642 (p<0.01) and r2=0.570 (p<0.05). Even lower was correlation between HbA1c and time-in-range (r1=0.431 and r2 =0.401). There were no correlations between HbA1c and percentage of time spent below the target and number of hypoglycemic episodes in each group. Same trend of correlations was found comparing HbA1c and mean BG level in eight-point profile. Based on HbA1c assessment 36.36% of patients on premixed insulin, 19.05% of type 2 patients on MII were with good control. After estimation of results from SMBG these percentage were respectively 28.14% and 12.11%. CGM defined 27.27% of patients on premixed insulin, 13.80% of type 2 patients on MII as well controlled. We conclude that in insulin treated type 2 patients HbA1c gives relative information about overall control with no precise presenting of glucose fluctuations and out-of-range values of blood glucose with no information about hypoglycemic episodes. Nevertheless, short observed period CGM data could give much information that is comparable to three months blood glucose measurement and could replace the use of HbA1c for assessment of overall control. Reference: (1) Chehregosha H, et al. Diabetes Ther. 2019; 10, 853–863 (2) Beyond A1c Writing Group. Diab Care. 2018; 41: e92-e94 (3) Hirsch I et al. Diabetes Tech Ther 2017, 19 (3): S38-S48
Online Education Improves Knowledge and Confidence Related to CGM and the AGP
Authors: Larkin Amy , LaCouture Michael , Le Anne
Published: May 2021

We sought to determine if online continuing medical education (CME) could improve the knowledge and confidence of primary care physicians (PCPs) and diabetologists/endocrinologists (D/Es) related to CGM and AGP. The CME activity was a 30-minute online video panel discussion with synchronized slides. A repeated pairs pre-/post-assessment study design and chi-square test (P <.05 is considered significant) assessed educational effect. The activity launched March 23, 2020 and data were collected through May 19, 2020. In total, 338 PCPs and 189 D/Es were included in the analysis. Overall, there were knowledge and confidence improvements seen among all groups from pre- to post-assessment: • 14% of PCPs (P=.NS) 14% of D/Es (P<.05) improved at identifying benefits of an AGP report • 20% of PCPs (P<.01) 11% of D/Es (P=.NS) improved at recognizing importance of time in range in diabetes management • 13% of PCPs (P<.05) 3% of D/Es (P=.NS) improved at recognizing target blood glucose levels for time in range • 43% of PCPs and 36% of D/Es had a measurable increase in confidence in ability to explain results from an AGP to patients Continued educational gaps: • 60% of PCPs and 47% of D/Es failed to identify benefits of an AGP report • 35% of PCPs and 12% of D/Es failed to recognize importance of time in range in diabetes management This study demonstrates the success of online 30-minute video panel discussion CME on improving knowledge and confidence of PCPs and D/Es related to CGM and the AGP. Continued gaps were identified for future educational targets.
Racial/Ethnic Differences in Leisure-Time Physical Activity Among United States Adults With and Without Diabetes
Authors: Visaria Aayush , Kethidi Nikhit , Chilakapati Rachana , Shahani Jai , Modak Anurag , Shah Megh
Published: May 2021

Background: Physical activity (PA) is a key lifestyle recommendation for diabetes mellitus (DM) prevention and management. The purpose of this study was to describe the patterns of leisure-time, aerobic & muscle-strengthening PAs across races/ethnicities and DM status.

Methods: We included 91,386 adults ≥18 years from the 2011–2018 National Health Interview Surveys who were able to participate in light-moderate PA. Aerobic PA was classified per 2008 guidelines as inactive (0 minutes/week [min/wk] of moderate or vigorous activity), insufficiently active (0–150 moderate-equivalent min/wk, defined as sum of moderate-level and 2*vigorous-level PA), sufficiently active (150–300 moderate-equivalent min/wk), and highly active (>300 min/wk of moderate-level PA, >150 min/wk of vigorous-level PA, or >300 moderate-equivalent min/wk). We also classified aerobic PA continuously in terms of metabolic equivalents (METs; 4 METs for moderate and 8 METs for vigorous PA). Muscle-strengthening PA was dichotomized into ≥3 times/wk (adequate) and <3 times/wk (inadequate). Race/ethnicity was categorized as non-Hispanic White (NHW), non-Hispanic Black (NHB), Asian Indian (AI), Other Asian (OA), and Hispanic/Other (H/O). We used self-reported DM-stratified multivariable logistic and linear regression to assess racial/ethnic differences in PA. All analyses accounted for the survey design and weights to obtain nationally representative estimates.

Results: Among the 91,386 participants, 45,676 (53%) were male, 11,835 (10%) were ≥65 years, and 5,106 (5.2%) had DM. Asian groups had lower adequate muscle-strengthening PA than others (%[SE]: NHW, 35[0.3]%; NHB, 35[0.7]%; AI, 27[1.6]%; OA, 30[1.3]%; H/O, 34[0.8]%; p<0.0001). AIs also had a lower proportion of ‘highly active’ individuals (%[SE]: NHW, 67[0.2]%; NHB, 65[0.7]%; AI, 57[1.8]%; OA, 61[1.5]%; H/O, 67[0.8]%; p<0.0001). Non-DM AIs had mean (SE) 622 (133) lower METs than NHWs (covariate adjusted mean METs [SE]: NHW, 3,568 [305]; NHB, 3,873 [309]; AI, 2,946 [333]; OA, 3,107 [321]; H/O, 3,736 [325]; p<0.001). This difference was also present in those with DM (adjusted mean METs [SE]: NHW, 2,231 [314]; NHB, 2,231 [379]; AI, 1,366 [456]; OA, 1,847 [495]; H/O, 2,454 [401]; p=0.013). Non-DM AIs and OAs had ~30% lower odds of being at least ‘sufficiently active’ relative to NHWs (aOR [95% CI]: AI, 0.70 [0.56, 0.87]; OA, 0.72 [0.61, 0.85]). All races/ethnicities had lower odds of adequate muscle-strengthening PA compared to NHWs (aOR [95% CI]: NHB, 0.94 [0.90, 0.99]; AI, 0.68 [0.60, 0.79]; OA, 0.75 [0.68, 0.84]; H/O, 0.73 [0.69, 0.77]). These inverse associations persisted in DM-diagnosed OAs, but not AIs.

Conclusion: Among those with and without DM, there exist racial/ethnic differences in strength-related and aerobic activities. Asian groups may benefit from aggressive counseling and PA interventions to both prevent and manage DM.
Study of the Effect of Early Insulin Therapy on Inflammation and Its Correlation With Glucotoxicity in Newly Diagnosed T2DM
Authors: Ramesh Jayanthy , Mudimela Madhubabu , Makineni Ashok Chakravarthy , Madhira Srivalli
Published: May 2021

Diabetes is a chronic metabolic and inflammatory disorder resulting in long term vascular complications. Glucotoxicity has been proposed to aggravate inflammatory stress. In this background,effect of early insulin therapy on inflammatory markers in relation to the glycemic status could be relevant in the newly diagnosed Type 2DM patients. Clinical studies highlighting this pathophysiologic aspect are sparse. Objective: To determine the effect of early insulin therapy in newly diagnosed patients with type 2 diabetes mellitus on inflammatory markers and glucotoxicity. Methods: 40 newly diagnosed type 2 diabetes patients, attending the endocrinology OPD at a tertiary teaching hospital were enrolled in this treatment related follow up study after institutional ethical committee clearance, conducted between May 2019 to February 2020. Patients with HbA1C > 8.5% to <12.5% were included in the study. Metabolic (FPG, PPG, HbA1c), and inflammatory parameters (Serum IL-6, Serum TNF alpha levels) were assessed both at baseline and after 9 months of insulin treatment. A simple,conventional twice daily premixed insulin was initiated at a starting dose of insulin at 0.5 U/kg/day and the dose was titrated according to FPG and 2 hr PPG in order to maintain glycemic goals as per ADA standards. Results: The study included 40 subjects with a mean age of 43.9 years and a mean BMI of 26.46 kg/m2. At the end of 9 months of the study, mean FPG, PPG, HbA1C were significantly reduced [FPG (118.45± 24.74mg/dl), PPG (152± 25 mg/dl), HbA1c (6.67± 0.42%)] as compared to baseline [FPG, (218.4± 37.84mg/dl), PPG (307±62mg/dl), HbA1C (9.95± 1.39%) (p <0.001). A statistically significant decrease in inflammatory markers like IL6, TNF alpha, from baseline to 9 months [.IL6 5.365±1.465 to 2.819±0.697 pg/ml, S.TNF alpha 36.476±16.902 to 11.274±3.712 pg/ml.] (p <0.001) was observed. Correlation studies revealed at 9 months, a highly significant positive correlation between FPG, PPG and IL6 and TNF alpha levels (p<0 .001), in comparison with baseline (p< 0.05). However IL6 levels significantly correlated with HBA1c both at baseline and at 9 months (p<0.05), whereas only a non significant positive correlation with TNF alpha was observed. Conclusion: Early Insulin treatment has beneficial effect on both Inflammation and glucotoxicity in newly diagnosed Type2 DM. Effective, simple and early insulin regimen offers a pathophysiologic based therapeutic perspective aiming at improving the natural course of diabetes.
Success of Online Education Related to New Data in T2D Management
Authors: Larkin Amy , Schrand Julie , Le Anne
Published: May 2021

We sought to determine if online continuing medical education (CME) could improve the knowledge and confidence of multiple specialties related to CVOT data for T2D therapies. The CME activity was a 30-minute online video panel discussion with synchronized slides focusing on new data at ADA 2020. A repeated pairs pre-/post-assessment study design and chi-square test (P <.05 is considered significant) assessed educational effect. The activity launched June 25, 2020 and data were collected through September 3, 2020. In total, 212 PCPs and 72 D/Es were included in the analysis. Overall, there were knowledge and confidence improvements seen among all groups from pre- to post-assessment: • 23% of PCPs (P<.01) and 24% of D/Es (P<.05) improved at recognizing the benefits of SGLT2 inhibitors across the class • 20% of PCPs (P=.NS) and 17% of D/Es (P<.05) improved at identifying new data presented at a conference • 15% of PCPs (P=.NS) and 13% of D/Es (P=.NS) improved at identifying class effect of SGLT2 inhibitors on hospitalizations for heart failure • 36% of PCPs and 25% of D/Es had measurable increases in confidence in treating patients with T2D and CVD Continued educational gaps: • 62% of PCPs and 39% of D/Es failed to identify benefits of SGLT2 inhibitors across the class • 45% of PCPs and 19% of D/Es failed to recognize new data presented at a conference • 58% of PCPs and 31% of D/Es failed to identify class effect of SGLT2 inhibitors on hospitalizations for heart failure This study demonstrates the success of online CME on improving knowledge and confidence of a multi-specialty group on CVOT data. Continued gaps were identified for future educational targets.
The Association Between Time in Range %, and Physical & Functional Indices Amongst Older People With Type 2 Diabetes: A Cross Sectional Study
Authors: Basson-Shleymovich Yamit , Cukierman-Yaffe Tali , Yahalom-Peri Tal , Azmon Michal
Published: May 2021

Diabetes is a major public health burden associated with high mortality, morbidity, hospitalization and health care services utilization rates. People with diabetes have an increased risk for mobility disability compared to those without diabetes, after controlling for age. People with diabetes also have a higher risk for falls and fractures. Data from the last several years suggests that this increased risk is not only due to diabetes co-morbidities but also due to an accelerated decline in physical capacity due to lower muscle quality and a more rapid decline in muscle mass (sarcopenia) and lower extremity strength over time. HBA1C is a measure of average glucose levels; however, it does not provide information about glycemic variability, or daily patterns of glycemia. In the last several years, several organizations have published consensus statements on the role of continuous glucose monitoring (CGM) in glucose control. The use of CGM has brought about the development of many glucose indices, amongst them is: Time In Range% (TIR) of 70–180 mg/dL (3.9–10 mmol/L). Less is known regarding the association between TIR and sarcopenia, muscle mass loss that leads to deterioration in mobility, disabilities and decline in physical indices in older people with diabetes. Aims: To assess among older people with diabetes type 2, the cross sectional association between: TIR and aerobic capacity, gait speed, strength, balance and frailty indices. Methods: A cross sectional study, conducted amongst people with diabetes over the age of 60. Participants were provided with a blinded CGM system- (I Pro2 carelink, Medtronic) for 1 week and underwent elaborate physical-functional assessment in the beginning and at the end of that week. The association between the % of time in range (Time in Range-TIR) and several physical indices was determined using linear regression.

Results: This analysis pertains to 55 men and women who completed the evaluation. After adjustment for age and gender, we found that 1% increase in TIR was associated with a 0.341 higher score on the 30 second Sit to Stand score (a measure of lower extremity strength) (P-value=0.02), a 0.351 higher score on the BERG scale (a measure of balance) (P-value=0.01), a 0.271 lower score on the timed up and go score (a measure of fall risk and balance) (P-value=0.008), a 0.289 higher score on the 6-minute walk score (a measure of aerobic capacity and endurance) (P-value=0.02) and a 0.261 lower score on the 360 turn test (a measure of dynamic balance) (P-value=0.0004). The same was not observed for the relationship between HGA1C & physical indices.