Involvement of Amino Acid 36 in TM1 in Voltage Sensitivity in Mouse Na<Superscript>+</Superscript>/Glucose Cotransporter SGLT1

Human SGLT1 protein is an established sodium-glucose cotransporter. Despite widespread use of the mouse as a model organism, the mouse SGLT1 homologue has yet to be functionally characterized. Additionally, the crystal structure of a sugar transporter homologue, Vibrio SGLT, has recently been described, however, it offers limited information about the role of transmembrane segments outside of the core ligand binding domains. In particular, the amino acids in TM1 were not assigned in the structure. To examine the contribution of TM1 to the function of SGLT1, we have cloned and characterized the biophysical properties of SGLT1 from mouse, mSGLT1, and compared it to a clone containing an amino acid substitution in TM1, F36S. As predicted, both proteins formed functional Na⁺/sugar cotransporters, but F36S-mSGLT1 showed decreased rates of sugar uptake and decreased apparent affinities for both Na⁺ and sugar compared to mSGLT1. Analysis of pre-steady-state currents and comparison with the crystal structure of Vibrio SGLT provide plausible mechanisms to explain the differences in function of these two proteins. Our data suggest that amino acids in TM1, which are not involved in ligand binding and translocation pathways, significantly influence the functional properties of sodium-glucose carrier proteins.     

Pharmacokinetic evaluation of medicinally important synthetic N,N′ diindolylmethane glucoside: Improved synthesis and metabolic stability

An improved route for the synthesis of N,N′-diindolyl methane (DIM) glycosides has been developed by using Fe/Al pillared clay catalyst. In-silico pharmacokinetics followed by in-vitro studies like aqueous solubility, lipophilicity, P-glycoprotein (P-gp) dependent ATPase activity, permeability, plasma protein binding, RBC partitioning, metabolic stability in different liver microsomes and its in-vitro-in-vivo extrapolation were conducted for the most potent derivative namely NGD16. The compound was found to have low solubility, optimum lipophilicity, no P-gp inhibitory activity, intermediate permeability, high plasma protein binding, low RBC partitioning, acceptable metabolic stability in rat liver microsomes (RLM) as well as human liver microsomes (HLM) with intermediate hepatic extraction ratio.     

Inpatient Perioperative Euglycemic Diabetic Ketoacidosis Due to Sodium-Glucose Cotransporter-2 Inhibitors – Lessons From a Case Series and Strategies to Decrease Incidence

ObjectiveTo identify clinical characteristics and factors associated with the development of euglycemic diabetic ketoacidosis (eDKA), and develop suitable strategies to reduce such events.MethodsElectronic health record (EHR) data were extracted to identify all patients between December 1, 2013, and March 30, 2021, who underwent surgical procedures and had been prescribed a sodium-glucose cotransporter 2 inhibitor (SGLT2i) before these procedures. The resulting list was streamlined to a subset of patients who either had diabetic ketoacidosis (DKA) listed as a hospital diagnosis, postoperative serum bicarbonate ≤ 16 mmol/L, or postoperative serum pH ≤ 7.20. Clinical documentation and laboratory data were reviewed to determine the patients with eDKA.ResultsA total of 2183 procedures conducted on 1307 patients, met the inclusion criteria with the majority (1726, 79.1%) being nonemergent patients. Among 1307 patients, 625 (47.8%) were prescribed empagliflozin, 447 (34.2%) canagliflozin, 214 (16.4%) dapagliflozin, and 21 (1.6%) ertugliflozin, respectively. A total of 8 incidences pertaining to eDKA were noted for 8 unique patients; 5 had undergone emergency surgery whereas 3 had undergone nonemergent procedures. In the 3 nonemergent cases, only 1 patient had received counseling to stop the SGLT2i 3 days before the procedure. In perioperative patients who were prescribed an SGLT2i over 6 years, the incidence of eDKA was 0.17% and 1.1% for nonemergent and emergent procedures, respectively.ConclusionEuglycemic DKA was rare in patients undergoing nonemergent procedures, likely because of preoperative instructions to stop their SGLT2i 3 days before the procedure. Euglycemic DKA was more likely to occur in patients undergoing emergency surgery when the SGLT2i could not be prophylactically stopped.     

Prevalence and Clinical Determinants of Obesity in Adults With Type 1 Diabetes Mellitus: A Single-Center Retrospective Observational Study

ObjectiveTo determine the prevalence of obesity and assess the cardiometabolic risk profile and treatments associated with obesity management in the type 1 diabetes mellitus adult population.MethodsWe reviewed the records of all patients with type 1 diabetes mellitus seen in our institution’s outpatient endocrinology clinic between 2015 and 2018. We stratified the patients into 4 weight categories on the basis of body mass index (BMI) (normal, overweight, obesity class I, and combined obesity class II and III) and evaluated their associated clinical characteristics and relevant medications.ResultsOf 451 patients, 64% had a BMI of >25 kg/m², and 25% had a BMI of ≥30 kg/m². Over 40% of patients with a BMI of >30 kg/m² had a history of cardiovascular disease. The off-label use of the glucagon-like peptide 1 receptor agonist was 12% and the sodium glucose cotransporter 2 inhibitor use was 5% in those with obesity. Only 2 patients were prescribed phentermine and 3 had undergone bariatric surgery. Hemoglobin A1C and low-density lipoprotein did not significantly differ between the normal weight and obesity groups. The obesity groups had significantly higher levels of median triglycerides and lower high-density lipoprotein than the normal weight group.ConclusionObesity was prevalent in a population of patients with type 1 diabetes mellitus seen in a specialty clinic. Those with obesity had a higher prevalence of cardiovascular disease than their normal weight counterparts. The use of weight loss medications was scarce. Studies exploring the safety and efficacy of obesity-targeted therapy in the type 1 diabetes mellitus population are needed.     

Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies

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Different Sodium-Glucose Cotransporter-2 Inhibitors: Can They Prevent Death?

ObjectiveSodium-glucose cotransporter-2 inhibitors (SGLT2is) in cardiovascular outcome trials (CVOTs) demonstrate cardiovascular (CV) safety and benefits. Some dedicated randomized controlled trials (RCTs) demonstrate benefit in terms of renal outcomes and hospitalization due to heart failure (HF). RCTs report differences in the secondary outcomes with respect to mortality (CV and/or all-cause). We undertook a meta-analysis of all SGLT2is for which in addition to CVOT, HF outcome/renal outcome studies are available to establish whether individual SGLT2is were able to prevent death.MethodsWe included available event-driven randomized, placebo-controlled CVOTs and dedicated RCTs of SGLT2is exploring renal outcomes and HF. We included 3 trials of empagliflozin, 3 of dapagliflozin, 2 of canagliflozin, and 2 of sotagliflozin. The efficacy outcomes included all-cause mortality and CV mortality. Hazard ratios (HRs) with 95% CIs were pooled for individual molecules.ResultsThe HR for all-cause mortality including all trials was 0.86 (0.80-0.93). The HRs for all-cause mortality in empagliflozin (N = 16 738), dapagliflozin (N = 26 208), canagliflozin (N = 14 543), and sotagliflozin (N = 11 806) were 0.86 (0.69-1.08), 0.83 (0.72-0.97), 0.86 (0.75-0.97), and 0.95 (0.81-1.11), respectively. The HR for CV mortality including all trials was 0.85 (0.78-0.92). The HRs for CV mortality in empagliflozin, dapagliflozin, sotagliflozin, and canagliflozin were 0.81 (0.63-1.03), 0.88 (0.78-1.00), 0.89 (0.74-1.07), and 0.84 (0.72-0.98), respectively.ConclusionSGLT2is as a class reduce both all-cause mortality and CV mortality. Canagliflozin possibly reduces both all-cause mortality and CV mortality, whereas dapagliflozin may reduce all-cause mortality but not CV mortality. Empagliflozin and sotagliflozin may reduce neither.     

Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular mortality in patients with diabetes mellitus but the protective mechanism remains elusive. Here we demonstrated that the SGLT2 inhibitor, Empagliflozin (EMPA), suppresses cardiomyocytes autosis (autophagic cell death) to confer cardioprotective effects. Using myocardial infarction (MI) mouse models with and without diabetes mellitus, EMPA treatment significantly reduced infarct size, and myocardial fibrosis, thereby leading to improved cardiac function and survival. In the context of ischemia and nutritional glucose deprivation where autosis is already highly stimulated, EMPA directly inhibits the activity of the Na⁺/H⁺ exchanger 1 (NHE1) in the cardiomyocytes to regulate excessive autophagy. Knockdown of NHE1 significantly rescued glucose deprivation-induced autosis. In contrast, overexpression of NHE1 aggravated the cardiomyocytes death in response to starvation, which was effectively rescued by EMPA treatment. Furthermore, in vitro and in vivo analysis of NHE1 and Beclin 1 knockout mice validated that EMPA’s cardioprotective effects are at least in part through downregulation of autophagic flux. These findings provide new insights for drug development, specifically targeting NHE1 and autosis for ventricular remodeling and heart failure after MI in both diabetic and non-diabetic patients.Electronic supplementary materialThe online version of this article (10.1007/s13238-020-00809-4) contains supplementary material, which is available to authorized users     

Clinical Effects of Sodium-Glucose Transporter Type 2 Inhibitors in Patients With Partial Lipodystrophy

ObjectiveSevere insulin resistance syndromes, such as lipodystrophy, lead to diabetes, which is challenging to control. This study explored the safety and efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in a series of 12 patients with severe insulin resistance due to partial lipodystrophy.MethodsA retrospective chart review of the safety (N = 22) and efficacy (N = 12) of SGLT2is in patients with partial lipodystrophy was conducted at our institution. The efficacy outcomes included hemoglobin A1C level, insulin dose, fasting plasma glucose level, C-peptide level, lipid profile, 24-hour urinary glucose excretion, estimated glomerular filtration rate, and blood pressure before and after 12 months of SGLT2i treatment.ResultsThe hemoglobin A1C level decreased after SGLT2i treatment (at baseline: 9.2% ± 2.0% [77.0 ± 21.9 mmol/mol]; after 12 months: 8.4% ± 1.8% [68.0 ± 19.7 mmol/mol]; P = .028). Significant reductions were also noted in systolic (P = .011) and diastolic blood pressure (P = .013). There was a trend toward a decreased C-peptide level (P = .071). The fasting plasma glucose level, lipid level, and estimated glomerular filtration rate remained unchanged. The adverse effects included extremity pain, hypoglycemia, diabetic ketoacidosis (in a patient who was nonadherent to insulin), pancreatitis (in a patient with prior pancreatitis), and fungal infections.ConclusionSGLT2is reduced the hemoglobin A1C level in patients with partial lipodystrophy, with a similar safety profile compared with that in patients with type 2 diabetes. After individual consideration of the risks and benefits of SGLT2is, these may be considered a part of the treatment armamentarium for these rare forms of diabetes, but larger trials are needed to confirm these findings.     

Inpatient Hyperglycemia and Transitions of Care: A Systematic Review

ObjectiveThe transition of diabetes care from home to hospital, within the hospital, and upon discharge is fraught with gaps that can adversely affect patient safety and length of stay. We aimed to highlight the variability in care during these transitions and point out areas where research is needed.MethodsA PubMed search was performed with a combination of search terms that pertained to diabetes, hyperglycemia, hospitalization, locations in the hospital, discharge to home or a nursing facility, and diabetes medications. Studies with at least 50 patients that were written in the English language were included.ResultsWith the exception of transitioning from intravenous insulin infusion to subcutaneous insulin and perhaps admission to the regular floors, few studies pointedly focused on transitions of care, leading us to extrapolate recommendations based on data from disparate areas of care in the hospital. There is evidence at every stage of care, starting from the entry into the hospital and ending with discharge home or to a facility, that patients benefit from having protocols in place guiding overall care.ConclusionPockets of care exist in hospitals where methods of effective diabetes management have been studied and implemented. However, there is no sustained continuum of care. Protocols and care teams that follow patients from one physical location to the other may result in improved clinical outcomes during and following a hospital stay.     

Ultra Rapid-Acting Inhaled Insulin Improves Glucose Control in Patients With Type 2 Diabetes Mellitus

ObjectiveTo determine whether the use of an inhaled insulin would improve HbA1c.MethodsThis study was performed in 20 type 2 diabetes mellitus (T2DM) participants with HbA1c values ≥7.5 (58) to ≤11.5% (102 mmol/mol) on a variety of glucose-lowering regimens. Prandial Technosphere insulin (TI) was rapidly titrated based on a treatment algorithm using postprandial blood glucose to calculate premeal doses. A 2-week baseline period was followed by 12 weeks of active treatment with TI. The primary outcome was change in HbA1c. Secondary outcomes included glucose time in range (time in range: 70-180 mg/dL) obtained by a blinded continuous glucose monitoring during the baseline period and at the end of 12 weeks. Goals were to assess how to rapidly and safely initiate TI intensification, determine dosing requirements, and establish an effective dose range in uncontrolled T2DM.ResultsMean HbA1c decreased by −1.6% (−17 mmol/mol) from 9.0% (75 mmol/mol) at baseline to 7.4% (57 mmol/mol) at 12 weeks (P < .0001). Mean time in range increased from 42.2% to 65.7% (P < .0002). Mean prandial doses of TI were 18 or 19 units for all meals. Time below range was 1.1% baseline and 2.6% post treatment (P = .01).ConclusionTreatment with inhaled TI dosed using a simple algorithm improved glycemic control measured by both HbA1c and time in range, with low rates of hypoglycemia. These data add significantly to understanding TI in the management of T2DM patients for whom prandial insulin is a consideration.