Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes

To assess the safety and efficacy of dual sodium–glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes

Panel II: Counter-terrorism

Appearing: Charles-Philippe David (University of Quebec at Montreal), chair ; Wesley Wark (University of Toronto), Dr. Philip Edelman (Health & Human Services), Christopher M. Sands (Center for Strategic & International Studies) and Ambassador Thomas E. McNamara (Department of State

Phosphorus Fractionation in Manure from Swine Fed Traditional and Low-Phytate Corn Diets

Traditional corn (Zea mays L.) (TC), the primary grain used in swine (Sus scrofa) diets, stores a majority of its P as phytate, which is largely unavailable for digestion by nonruminant animals. Low- phytate corn (LPC) contains similar amounts of total P but a smaller percentage of P as phytate. When fed to swine, LPC increases P utilization and reduces P content of manure. While differences in P content between manure from animals fed TC and LPC diets have been documented, solubility and lability of manure P have not been compared. Manure P was characterized in manure from swine fed either LPC or TC diets in 2000 and 2001. Total P was lower (20 vs. 34 g kg-1) and N to P ratio was higher (4.5 vs. 3.3) in LPC manure than in TC manure. Manures were sequentially extracted with deionized water, 0.5 M NaHCO3, 0.1 M NaOH, and 1.0 M HCl. Extracts were analyzed for inorganic and total P. Most P (approximately 80%) in the extracts was in the inorganic form. Concentration of P in the water-extractable fraction was lower for LPC manure (10.2 g kg-1 in 2000 and 9.7 g kg-1 in 2001) than for TC manure (13.6 g kg-1 in 2000 and 17.0 g kg-1 in 2001). Percentage of total P in each extract was in the order of: H2O (60%), HCl (22%), NaHCO3 (12%), NaOH (8%), and residue (\u3c1%). Total P and distribution of P in extracts indicates swine are able to utilize more P contained in LPC feed but the composition of P excreted in LPC manure is similar to TC manure. Solubility, crop availability, and lability of P in LPC manure should be similar to that of TC manure

Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes

OBJECTIVE: To assess the safety and efficacy of dual sodium–glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS: We treated 33 patients with sotagliflozin, an oral dual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial assessing safety, insulin dose, glycemic control, and other metabolic parameters over 29 days of treatment. RESULTS: In the sotagliflozin-treated group, the percent reduction from baseline in the primary end point of bolus insulin dose was 32.1% (P = 0.007), accompanied by lower mean daily glucose measured by continuous glucose monitoring (CGM) of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of 0.55% (5.9 mmol/mol) (P = 0.002) in HbA(1c) compared with the placebo group that showed 6.4% reduction in bolus insulin dose, a mean daily glucose of 170.3 mg/dL (9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA(1c). The percentage of time in target glucose range 70–180 mg/dL (3.9–10.0 mmol/L) increased from baseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = 0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 mmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002), for sotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with sotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group. CONCLUSIONS: As adjunct to insulin, dual SGLT1 and SGLT2 inhibition with sotagliflozin improved glycemic control and the CGM profile with bolus insulin dose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes

Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations

Potassium (K+) channels can regulate ionic conduction through their pore by a mechanism, involving the selectivity filter, known as C-type inactivation. This process is rapid in the hERG K+ channel and is fundamental to its physiological role. Although mutations within hERG are known to remove this process, a structural basis for the inactivation mechanism has yet to be characterized. Using MD simulations based on homology modeling, we observe that the carbonyl of the filter aromatic, Phe627, forming the S-0 K+ binding site, swiftly rotates away from the conduction axis in the wild-type channel. In contrast, in well-characterized non-inactivating mutant channels, this conformational change occurs less frequently. In the non-inactivating channels, interactions with a water molecule located behind the selectivity filter are critical to the enhanced stability of the conducting state. We observe comparable conformational changes in the acid sensitive TASK-1 channel and propose a common mechanism in these channels for regulating efflux of K+ ions through the selectivity filter

Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide

Serotonin produced by neuroendocrine tumors is believed to be a principal cause of the diarrhea in carcinoid syndrome. We assessed the safety and efficacy of telotristat etiprate, an oral serotonin synthesis inhibitor, in patients with diarrhea associated with carcinoid syndrome. In this prospective, randomized study, patients with evidence of carcinoid tumor and ≥4 bowel movements (BMs)/day despite stable-dose octreotide LAR depot therapy were enrolled in sequential, escalating, cohorts of four patients per cohort. In each cohort, one patient was randomly assigned to placebo and three patients to telotristat etiprate, at 150, 250, 350, or 500 mg three times a day (tid). In a subsequent cohort, one patient was assigned to placebo and six patients to telotristat etiprate 500 mg tid. Patients were assessed for safety, BM frequency (daily diary), 24 h urinary 5-hydroxyindoleacetic acid (u5-HIAA), and adequate relief of carcinoid gastrointestinal symptoms (using a weekly questionnaire). Twenty-three patients were treated: 18 received telotristat etiprate and five received placebo. Adverse events were generally mild. Among evaluable telotristat etiprate-treated patients, 5/18 (28%) experienced a ≥30% reduction in BM frequency for ≥2 weeks, 9/16 (56%) experienced biochemical response (≥50% reduction or normalization in 24-h u5-HIAA) at week 2 or 4, and 10/18 (56%) reported adequate relief during at least 1 of the first 4 weeks of treatment. Similar activity was not observed in placebo-treated patients. Telotristat etiprate was well tolerated. Our observations suggest that telotristat etiprate has activity in controlling diarrhea associated with carcinoid syndrome. Further studies confirming these findings are warranted