Unsupervised Anomaly Detection to Characterize Heterogeneity in Type 2 Diabetes.

Diabetes is associated with heterogeneous behaviors affecting patients' clinical characteristics and trajectories. This study includes 21,288 patients with type 2 diabetes (women, ages 30 to 65). The cohort was filtered through a set of preprocessing heuristics in order to assure the cohort exhibited a similar clinical trajectory. Anomalous characteristics were then identified using dimensionality reduction and anomaly detection methods. Compared to the majority of the cohort, patients classified as anomalous were twice as likely to be admitted into the hospital (7.94[7.59 8.28] versus 3.12[3.06 3.17] times), have a higher incidence of comorbidities (2[1.64 2.36] times more), and be prescribed more insulin and less new and more expensive diabetes medications (such as Sodium glucose co-transporter 2 inhibitors). Patients with these anomalous characteristics may benefit from additional or specialized interventions to avert their risk for adverse outcomes.

Effects of Sotagliflozin Combined with Intensive Insulin Therapy in Young Adults with Poorly Controlled Type 1 Diabetes: The JDRF Sotagliflozin Study.

Background: Young adults with type 1 diabetes (T1D) tend to have higher A1C than older adults and are at increased risk for diabetic ketoacidosis (DKA). Oral adjuncts to insulin have not been previously studied in this population. Methods: In this phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, adults aged 18-30 years with T1D and A1C ≥9.0% were randomly assigned to placebo (n = 42) or sotagliflozin 400 mg (n = 43), in addition to insulin for 12 weeks. Insulin doses were adjusted to meet glucose targets (preprandial 80-130 mg/dL, postprandial <180 mg/dL). The primary endpoint was change from baseline in A1C at week 12. Results: From a baseline of 9.8%, mean A1C decreased by 1.0% with placebo and 1.3% with sotagliflozin (-0.4% [95% confidence interval (CI): -0.8 to 0.1]; P = 0.10 vs. placebo). In the prespecified A1C ≤10.0% subgroup, the treatment difference was -0.8% (-1.3 to -0.2; P = 0.006), favoring sotagliflozin. Overall, relative to placebo, postprandial glucose (PPG) decreased by 56.6 mg/dL (-89.7 to -23.6; P < 0.001) and weight decreased by 2.37 kg (-3.5 to -1.2; P < 0.001). More patients achieved an A1C <7.0% with sotagliflozin (16.3%) than placebo (2.4%; P = 0.026). Rates of documented hypoglycemia and severe hypoglycemia were similar between groups. One DKA event occurred with placebo, and none occurred with sotagliflozin. Conclusions: In young adults with T1D and suboptimal glycemic control, sotagliflozin plus insulin for 12 weeks numerically improved A1C and significantly improved A1C goal attainment, PPG, and body weight. Sotagliflozin plus insulin was generally well tolerated without any episodes of DKA (NCT02383940).

Diabetic Ketoacidosis and Related Events With Sotagliflozin Added to Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of the inTandem 1 and 2 Studies.

OBJECTIVE: To evaluate the incidence and risk factors for diabetic ketoacidosis (DKA) and related adverse events (AEs) in adults with type 1 diabetes treated with sotagliflozin adjunctive to insulin. RESEARCH DESIGN AND METHODS: Data from two identically designed, 52-week, randomized studies were pooled and analyzed for DKA, changes in ß-hydroxybutyrate (BHB), and percentage of patients with BHB >0.6 and >1.5 mmol/L. The patients were administered placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg once daily. RESULTS: A total of 191 ketosis-related AEs were reported, and 98 underwent adjudication. Of these, 37 events (36 patients) were adjudicated as DKA, with an exposure-adjusted incidence rate of 0.2, 3.1, and 4.2 events per 100 patient-years for placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively. No patient died of a DKA event. From a baseline BHB of ∼0.13 mmol/L, sotagliflozin treatment led to a small median increase over 52 weeks (≤0.05 mmol/L at all time points). Of sotagliflozin-treated patients, approximately 47% and 7% had ≥1 BHB measurement >0.6 mmol/L and >1.5 mmol/L, respectively (vs. 20% and 2%, respectively, of placebo-treated patients). Subsequent to the implementation of a risk mitigation plan, annualized DKA incidence was lower versus preimplementation in both the sotagliflozin 200 and 400 mg groups. CONCLUSIONS: In patients with type 1 diabetes, confirmed DKA incidence increased when sotagliflozin was added to insulin compared with insulin alone. A lower incidence of DKA was observed following the implementation of an enhanced risk mitigation plan, suggesting that this risk can be managed with patient education.

Letter to the Editor Re: Scott S.N., et al. Nutrients 2019, 11(5), 1022.

I read with great interest the thoughtful review concerning the potential impact of carbohydrate restriction in type 1 diabetes on glycaemic parameters and athletic performance [...].

Tamoxifen suppresses pancreatic ß-cell proliferation in mice.

Tamoxifen is a mixed agonist/antagonist estrogen analogue that is frequently used to induce conditional gene deletion in mice using Cre-loxP mediated gene recombination. Tamoxifen is routinely employed in extremely high-doses relative to typical human doses to induce efficient gene deletion in mice. Although tamoxifen has been widely assumed to have no influence upon ß-cells, the acute developmental and functional consequences of high-dose tamoxifen upon glucose homeostasis and adult ß-cells are largely unknown. We tested if tamoxifen influences glucose homeostasis in male mice of various genetic backgrounds. We then carried out detailed histomorphometry studies of mouse pancreata. We also performed gene expression studies with islets of tamoxifen-treated mice and controls. Tamoxifen had modest effects upon glucose homeostasis of mixed genetic background (F1 B6129SF1/J) mice, with fasting hyperglycemia and improved glucose tolerance but without overt effects on fed glucose levels or insulin sensitivity. Tamoxifen inhibited proliferation of ß-cells in a dose-dependent manner, with dramatic reductions in ß-cell turnover at the highest dose (decreased by 66%). In sharp contrast, tamoxifen did not reduce proliferation of pancreatic acinar cells. ß-cell proliferation was unchanged by tamoxifen in 129S2 mice but was reduced in C57Bl6 genetic background mice (decreased by 59%). Gene expression studies revealed suppression of RNA for cyclins D1 and D2 within islets of tamoxifen-treated mice. Tamoxifen has a cytostatic effect on ß-cells, independent of changes in glucose homeostasis, in mixed genetic background and also in C57Bl6 mice. Tamoxifen should be used judiciously to inducibly inactivate genes in studies of glucose homeostasis.

Dose-dependent glycometabolic effects of sotagliflozin on type 1 diabetes over 12 weeks: The inTandem4 trial.

AIMS: To assess the dose-related effects of sotagliflozin, a novel dual inhibitor of sodium-glucose co-transporters-1 and -2, in type 1 diabetes (T1D). MATERIALS AND METHODS: In this 12-week, multicentre, randomized, double-blind, placebo-controlled dose-ranging trial, adults with T1D were randomized to once-daily placebo (n = 36) or sotagliflozin 75 mg (n = 35), 200 mg (n = 35) or 400 mg (n = 35). Insulin was maintained at baseline doses. The primary endpoint was least squares mean (LSM) change in glycated haemoglobin (HbA1c) from baseline. Other endpoints included proportion of participants with ≥0.5% HbA1c reduction and assessments of 2-hour postprandial glucose (PPG), weight, and urinary glucose excretion (UGE). RESULTS: From a mean baseline of 8.0% ± 0.8% (full study population), placebo-adjusted LSM HbA1c decreased by 0.3% (P = .07), 0.5% (P < .001) and 0.4% (P = .006) with sotagliflozin 75 mg, 200 mg and 400 mg, respectively, at week 12. In the placebo and sotagliflozin 75 mg, 200 mg and 400 mg groups, 33.3%, 37.1%, 80.0% and 65.7% of participants achieved an HbA1c reduction ≥0.5%. Placebo-adjusted PPG decreased by 22.2 mg/dL (P = .28), 28.7 mg/dL (P = .16) and 50.2 mg/dL (P = .013), UGE increased by 41.8 g/d (P = .006), 57.7 g/d (P < .001) and 70.5 g/d (P < .001), and weight decreased by 1.3 kg (P = .038), 2.4 kg (P < .001) and 2.6 kg (P < .001) with sotagliflozin 75 mg, 200 mg and 400 mg, respectively. One case of severe hypoglycaemia occurred in each sotagliflozin group and one case of diabetic ketoacidosis (DKA) occurred with sotagliflozin 400 mg. CONCLUSIONS: Combined with stable insulin doses, sotagliflozin 200 mg and 400 mg improved glycaemic control and weight in adults with T1D. Sotagliflozin 400 mg reduced PPG levels. UGE increased with all sotagliflozin doses. Rates of severe hypoglycaemia and DKA were low (NCT02459899).

Adjunct Therapy in Type 1 Diabetes: A Survey to Uncover Unmet Needs and Patient Preferences Beyond HbA1c Measures.

Background: Adjunct therapy can help patients with type 1 diabetes achieve glycemic goals while potentially mitigating some of the side effects of insulin. In this study, we used a patient survey to identify the unmet needs in type 1 diabetes therapy, patient views of treatment benefit-risk trade-offs, and patient preferences for the use of an adjunct therapy. Methods: A quantitative survey was sent to 2084 adults with type 1 diabetes in November 2017. "Jobs-to-be-done" and conjoint analyses were performed on survey responses to identify unmet needs and the importance of treatment-associated benefits and risks to patients. A 5-point Likert scale measured the importance and satisfaction with patients' current therapy, and with gaps relating to unmet needs. In the conjoint analysis, patients were asked to choose between "packages" of attributes of two doses of adjunct therapy (200 and 400 mg) and placebo, based on established benefits and side effects. Results: A total of 1313 patients (63%) responded. The greatest unmet needs identified were simplifying treatment, lowering/maintaining glycated hemoglobin (HbA1c), reducing mental effort, and increasing time in range (TIR). Conjoint analysis showed that reductions in body weight and TIR had the highest attribute importance (25% and 18%, respectively). The majority (93%) of patients had a preference for the adjunct therapy (either dose) over placebo. Conclusions: This survey highlights the importance of measures beyond HbA1c, such as treatment simplification and TIR, and patient preference for adjunct therapies that help address unmet needs in type 1 diabetes treatment.

Outcomes, care utilization, and expenditures in adolescent pregnancy complicated by diabetes.

BACKGROUND AND OBJECTIVE: Adolescence and pregestational diabetes separately increase risks of adverse pregnancy outcomes, but little is known about their combined effect. To analyze pregnancy outcomes, healthcare utilization, and expenditures in adolescent pregnancies with and without pregestational diabetes using a national claims database. METHODS: Retrospective study using Truven Health MarketScan Commercial Claims and Encounters Database, 2011 to 2015. Females 12 to 19 years old, continuously enrolled for at least 12 months before a livebirth until 2 months after, were included. Pregestational diabetes, diabetes complications (ketoacidosis, retinopathy, neuropathy, nephropathy), comorbidities, and pregnancy outcomes (preeclampsia, preterm delivery, high birthweight, cesarean delivery) were identified using claims data algorithms. Healthcare utilization and payer expenditure were tabulated per enrollee. Multivariate logistic regressions assessed pregnancy outcomes; multivariate OLS regression assessed payer expenditures. RESULTS: About 33 502 adolescents were included. Adolescents without diabetes had pregnancy outcomes consistent with national estimates. Adolescents with uncomplicated diabetes had increased odds of preeclampsia adjusted odds ratios 2.41 (95% confidence interval 1.93-3.02), preterm delivery 1.50 (1.21-1.87), high birthweight 1.84 (1.50-2.27), and cesarean delivery 1.81 (1.52-2.15). Diabetes with ketoacidosis and/or end-organ damage had higher odds of preeclampsia 5.62 (2.77-11.41), preterm delivery 5.81 (3.00-11.25), high birthweight 2.38 (1.08-5.24), and cesarean delivery 3.43 (1.78-6.64). Adolescents with diabetes utilized significantly more outpatient and inpatient care during pregnancy. Payer expenditures increased by 45.3% (34.8-55.9%) among adolescents with diabetes and by 82.6% (49.1-116.0%) among adolescents with diabetes complicated by ketoacidosis and/or end-organ damage. CONCLUSION: Compared with normal adolescent pregnancies, pregestational diabetes significantly increases risks of adverse pregnancy outcomes and significantly escalates healthcare utilization and cost.

Improving the scientific rigour of nutritional recommendations for adults with type 2 diabetes: A comprehensive review of the American Diabetes Association guideline-recommended eating patterns.

AIMS: The global rate of type 2 diabetes (T2D) continues to rise. Guidelines that influence the worldwide treatment of this disease are central to changing this trajectory. We sought in this review to evaluate the appropriateness of sources cited in the American Diabetes Association's (ADA) guidelines on eating patterns for T2D management, identify additional relevant sources, and evaluate the evidence. MATERIALS AND METHODS: We reviewed the evidence behind the ADA's recommendations on eating patterns in the 2018 and 2019 ADA Standards of Care and the 2014 ADA Nutrition Therapy Recommendations for Adults with Diabetes. Additionally, we conducted a comprehensive search to identify any additional studies not included in the cited evidence. To determine appropriateness of inclusion in the guidelines, the following criteria were applied: 1) it was a clinical trial or systematic review/meta-analysis of clinical trials; 2) it involved persons with T2D; 3) one of the study arms followed one of the eating patterns currently recommended; 4) its reported outcomes included glycaemic control; 5) outcomes were reported separately for persons with T2D. RESULTS: We found a wide variation in the evidence for each eating pattern. Issues that have hampered the guideline process include: lack of a rigorous literature review, resulting in the omission of pertinent studies; an overreliance on prospective cohort studies; inconsistent standards for evidence; inclusion of studies not on persons with T2D; and bias. CONCLUSIONS: The ADA Guidelines recommended eating patterns fall short of rigorous standards of scientific review according to state-of-the-art systematic review and guideline creation practices.

Improved Time in Range and Glycemic Variability With Sotagliflozin in Combination With Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of 24-Week Continuous Glucose Monitoring Data From the inTandem Program.

OBJECTIVE: To evaluate effects of the dual sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibitor sotagliflozin in combination with insulin on glucose time in range (TIR) and glucose excursions, postprandial glucose (PPG), and other glycemic metrics in adults with type 1 diabetes using masked continuous glucose monitoring (CGM). RESEARCH DESIGN AND METHODS: Data sets from the inTandem1 (clinical trial reg. no. NCT02384941) and inTandem2 (clinical trial reg. no. NCT02421510) double-blind randomized trials evaluating sotagliflozin versus placebo in adults with type 1 diabetes treated with optimized insulin were pooled for analyses of masked CGM data from a subset of participants in each trial. The pooled cohort included patients randomized to receive placebo (n = 93), sotagliflozin 200 mg (n = 89), or sotagliflozin 400 mg (n = 96). The primary outcome was change from baseline to week 24 in glucose TIR (3.9-10.0 mmol/L [70-180 mg/dL]). Secondary end points included time below and above the target range and 2-h PPG level assessed after a standardized mixed meal. RESULTS: Mean percentage of glucose TIR/percentage time spent at <3.9 mmol/L (<70 mg/dL) during week 24 was 51.6%/5.9%, 57.8%/5.5%, and 64.2%/5.5% with placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively, which corresponded to a placebo-adjusted change from a baseline of +5.4%/-0.3% (P = 0.026; +1.3/-0.1 h/day) for sotagliflozin 200 mg and +11.7%/-0.1% (P < 0.001; +2.8/-0.02 h/day) for sotagliflozin 400 mg. Placebo-adjusted PPG reductions were 1.9 ± 0.7 mmol/L (35 ± 13 mg/dL; P = 0.004) and 2.8 ± 0.7 mmol/L (50 ± 13 mg/dL; P < 0.001) with sotagliflozin 200 and 400 mg, respectively. CONCLUSIONS: Combined with optimized insulin in type 1 diabetes, sotagliflozin significantly increased glucose TIR without increasing time spent at <3.9 mmol/L and reduced PPG, thereby improving glycemic control.

Glucagon Receptor Antagonist-Stimulated α-Cell Proliferation Is Severely Restricted With Advanced Age.

Glucagon-containing α-cells potently regulate glucose homeostasis, but the developmental biology of α-cells in adults remains poorly understood. Although glucagon receptor antagonists (GRAs) have great potential as antidiabetic therapies, murine and human studies have raised concerns that GRAs might cause uncontrolled α-cell growth. Surprisingly, previous rodent GRA studies were only performed in young mice, implying that the potential impact of GRAs to drive α-cell expansion in adult patients is unclear. We assessed adaptive α-cell turnover and adaptive proliferation, administering a novel GRA (JNJ-46207382) to both young and aged mice. Basal α-cell proliferation rapidly declined soon after birth and continued to drop to very low levels in aged mice. GRA drove a 2.4-fold increase in α-cell proliferation in young mice. In contrast, GRA-induced α-cell proliferation was severely reduced in aged mice, although still present at 3.2-fold the very low basal rate of aged controls. To interrogate the lineage of GRA-induced α-cells, we sequentially administered thymidine analogs and quantified their incorporation into α-cells. Similar to previous studies of ß-cells, α-cells only divided once in both basal and stimulated conditions. Lack of contribution from highly proliferative "transit-amplifying" cells supports a model whereby α-cells expand by self-renewal and not via specialized progenitors.

The Autoimmune Disorder Susceptibility Gene CLEC16A Restrains NK Cell Function in YTS NK Cell Line and Clec16a Knockout Mice.

CLEC16A locus polymorphisms have been associated with several autoimmune diseases. We overexpressed CLEC16A in YTS natural killer (NK) cells and observed reduced NK cell cytotoxicity and IFN-γ release, delayed dendritic cell (DC) maturation, decreased conjugate formation, cell-surface receptor downregulation and increased autophagy. In contrast, siRNA mediated knockdown resulted in increased NK cell cytotoxicity, reversal of receptor expression and disrupted mitophagy. Subcellular localization studies demonstrated that CLEC16A is a cytosolic protein that associates with Vps16A, a subunit of class C Vps-HOPS complex, and modulates receptor expression via autophagy. Clec16a knockout (KO) in mice resulted in altered immune cell populations, increased splenic NK cell cytotoxicity, imbalance of dendritic cell subsets, altered receptor expression, upregulated cytokine and chemokine secretion. Taken together, our findings indicate that CLEC16A restrains secretory functions including cytokine release and cytotoxicity and that a delicate balance of CLEC16A is needed for NK cell function and homeostasis.

International Consensus on Risk Management of Diabetic Ketoacidosis in Patients With Type 1 Diabetes Treated With Sodium-Glucose Cotransporter (SGLT) Inhibitors.

Sodium-glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes.

Low-Level Insulin Content Within Abundant Non-ß Islet Endocrine Cells in Long-standing Type 1 Diabetes.

Although most patients with type 1 diabetes (T1D) continue to produce small amounts of insulin decades after disease onset, very few ß-cells persist within their pancreata. Consequently, the source of persistent insulin secretion within T1D remains unclear. We hypothesized that low-level insulin content within non-ß-cells could underlie persistent T1D insulin secretion. We tested for low levels of insulin (insulinlow) within a large cohort of JDRF Network for Pancreatic Organ Donors With Diabetes (nPOD) human pancreata across a wide range of ages and T1D disease durations. Long exposures, high-throughput imaging, and blinded parallel examiners allowed precise quantification of insulinlow cells. Of note, abundant islet endocrine cells with low quantities of insulin were present in most T1D pancreata. Insulinlow islet abundance and composition were not influenced by age, duration of diabetes, or age of onset. Insulinlow islets also contained ß-cell markers at variable levels, including Pdx1, Nkx6.1, GLUT1, and PC1/3. Most insulinlow cells contained abundant glucagon and other α-cell markers, suggesting that α-cells drive much of the insulinlow phenotype in T1D. However, pancreatic polypeptide, somatostatin, and ghrelin cells also contributed to the insulinlow cell population. Insulinlow cells represent a potential source of persistent insulin secretion in long-standing T1D and a possible target for regenerative therapies to expand ß-cell function in disease.

Identifying and addressing gaps in reproductive health education for adolescent girls with type 1 diabetes.

AIMS: Adolescent girls with diabetes are at risk for adverse pregnancy outcomes due to age, risk-taking behavior, poor glycemic control, and lack of knowledge. Our aims were to assess attitudes and behaviors related to reproductive health education (RHE) among diabetes healthcare providers and adolescent girls with diabetes, and to pilot a brief clinic-based RHE intervention. METHODS: We surveyed 29 providers and 50 adolescent girls with type 1 diabetes about RHE experiences, attitudes, and behaviors. We piloted the RHE intervention with 9 adolescent-parent dyads. RESULTS: 50% of providers were very uncomfortable discussing pregnancy or contraception. Most (72%) did not proactively initiate RHE; common barriers included insufficient time and subject knowledge. Fewer than 10% recommended long-acting reversible contraceptives. A minority (10%) of adolescents had discussed pregnancy or contraception with a provider. RHE sessions lasted a median of 16 (range 13-24) minutes, and there were promising trends for changes in adolescents' self-efficacy and intentions to use contraception and seek preconception counseling and in their knowledge of reproductive health. CONCLUSION: Adolescent girls with diabetes rarely receive education on pregnancy and contraception due to provider discomfort, limited knowledge, and limited time. RHE using easily-accessible materials with an educator may help address this gap in care.

CLEC16A regulates splenocyte and NK cell function in part through MEK signaling.

CLEC16A is implicated in multiple autoimmune diseases. We generated Clec16a inducible knockout (KO) mice to examine the functional link between CLEC16A auto-inflammation and autoimmunity. Clec16a KO mice exhibited weight loss and thymic and splenic atrophy. Mitochondrial potential was lowered in KO mice splenocytes resulting in aggregation of unhealthy mitochondria in B, T, and NK cells. In Clec16a KO mice we detected disrupted mitophagy in splenic B and T cells. NK cells from Clec16a KO mice exhibited increased cytotoxicity. Incomplete mitophagy was attenuated with PI3K and/or MEK inhibition in Clec16a KO mice. Our results demonstrate a functional link between CLEC16A and disrupted mitophagy in immune cells and show that incomplete mitophagy predisposes the KO mice to inflammation. Taken together, loss of function variants in CLEC16A that are associated with decreased CLEC16A expression levels may contribute to inflammation in autoimmunity through disrupted mitophagy. Drugs modulating mitophagy reverse the process and may be effective in treating and preventing autoimmunity in individuals with risk associated CLEC16A variants.

Sotagliflozin in Combination With Optimized Insulin Therapy in Adults With Type 1 Diabetes: The North American inTandem1 Study.

OBJECTIVE: Evaluate the efficacy and safety of the dual sodium-glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor sotagliflozin in combination with optimized insulin in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: The inTandem1 trial, a double-blind, 52-week phase 3 trial, randomized North American adults with T1D to placebo (n = 268), sotagliflozin 200 mg (n = 263), or sotagliflozin 400 mg (n = 262) after 6 weeks of insulin optimization. The primary end point was HbA1c change from baseline at 24 weeks. HbA1c, weight, and safety were also assessed through 52 weeks. RESULTS: From a mean baseline of 7.57%, placebo-adjusted HbA1c reductions were 0.36% and 0.41% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and 0.25% and 0.31% at 52 weeks (all P < 0.001). Among patients with a baseline HbA1c ≥7.0%, an HbA1c <7% was achieved by 15.7%, 27.2%, and 40.3% of patients receiving placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively (P ≤ 0.003 vs. placebo) at 24 weeks. At 52 weeks, mean treatment differences between sotagliflozin 400 mg and placebo were -1.08 mmol/L for fasting plasma glucose, -4.32 kg for weight, and -15.63% for bolus insulin dose and -11.87% for basal insulin dose (all P < 0.001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly by 2.5 points with sotagliflozin versus placebo (P < 0.001) at 24 weeks. Genital mycotic infections and diarrhea occurred more frequently with sotagliflozin. Adjudicated diabetic ketoacidosis (DKA) occurred in 9 (3.4%) and 11 (4.2%) patients receiving sotagliflozin 200 and 400 mg, respectively, and in 1 (0.4%) receiving placebo. Severe hypoglycemia occurred in 17 (6.5%) patients from each sotagliflozin group and 26 (9.7%) patients receiving placebo. CONCLUSIONS: In a 1-year T1D study, sotagliflozin combined with optimized insulin therapy was associated with sustained HbA1c reduction, weight loss, lower insulin dose, fewer episodes of severe hypoglycemia, improved patient-reported outcomes, and more DKA relative to placebo (ClinicalTrials.gov, NCT02384941).

HbA1c and Hypoglycemia Reductions at 24 and 52 Weeks With Sotagliflozin in Combination With Insulin in Adults With Type 1 Diabetes: The European inTandem2 Study.

OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of the dual sodium-glucose cotransporter 1 and 2 inhibitor sotagliflozin compared with placebo when combined with optimized insulin in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In a double-blind, 52-week, international phase 3 trial, adults with T1D were randomized to placebo (n = 258) or once-daily oral sotagliflozin 200 mg (n = 261) or 400 mg (n = 263) after 6 weeks of insulin optimization. The primary outcome was change in HbA1c from baseline to 24 weeks. The first secondary end point was a composite of the proportion of patients with HbA1c <7.0%, no episode of severe hypoglycemia, and no episode of diabetic ketoacidosis (DKA) at week 24. Fasting glucose, weight, insulin dose, and safety end points were assessed through 52 weeks. RESULTS: At 24 weeks, placebo-adjusted changes in HbA1c from baseline (7.8%) were -0.37% and -0.35% with sotagliflozin 200 and 400 mg, respectively (P < 0.001), and differences were maintained at 52 weeks. At 52 weeks, greater proportions of sotagliflozin-treated patients (200 mg: 25.67%; 400 mg: 26.62%) than placebo-treated patients (14.34%; P ≤ 0.001) met the composite end point, and sotagliflozin 400 mg reduced fasting plasma glucose (-0.87 mmol/L; P = 0.008), weight (-2.92 kg; P < 0.001), and total daily insulin dose (-8.2%; P = 0.001). In a 24-week continuous glucose monitoring (CGM) substudy, postprandial glucose decreased (P ≤ 0.009) and CGM demonstrated up to 3 h more time in the target range of 3.9-10.0 mmol/L with sotagliflozin. Treatment satisfaction increased and diabetes distress decreased with sotagliflozin (P < 0.05 vs. placebo). The frequency of documented hypoglycemia was lower with sotagliflozin, and severe hypoglycemia occurred by week 52 in 13 patients (5.0%), 13 patients (5.0%), and 6 patients (2.3%) treated with placebo and sotagliflozin 200 and 400 mg, respectively. DKA occurred in 0 of 258 patients, 6 of 261 patients (2.3%), and 9 of 263 patients (3.4%) in these respective groups. CONCLUSIONS: In a 1-year study, sotagliflozin was associated with statistically significant HbA1c reductions. More episodes of DKA and fewer episodes of documented and severe hypoglycemia were observed in patients using sotagliflozin relative to those receiving placebo (ClinicalTrials.gov, NCT02421510).

Highly Proliferative α-Cell-Related Islet Endocrine Cells in Human Pancreata.

The proliferative response of non-ß islet endocrine cells in response to type 1 diabetes (T1D) remains undefined. We quantified islet endocrine cell proliferation in a large collection of nondiabetic control and T1D human pancreata across a wide range of ages. Surprisingly, islet endocrine cells with abundant proliferation were present in many adolescent and young-adult T1D pancreata. But the proliferative islet endocrine cells were also present in similar abundance within control samples. We queried the proliferating islet cells with antisera against various islet hormones. Although pancreatic polypeptide, somatostatin, and ghrelin cells did not exhibit frequent proliferation, glucagon-expressing α-cells were highly proliferative in many adolescent and young-adult samples. Notably, α-cells only comprised a fraction (∼1/3) of the proliferative islet cells within those samples; most proliferative cells did not express islet hormones. The proliferative hormone-negative cells uniformly contained immunoreactivity for ARX (indicating α-cell fate) and cytoplasmic Sox9 (Sox9Cyt). These hormone-negative cells represented the majority of islet endocrine Ki67+ nuclei and were conserved from infancy through young adulthood. Our studies reveal a novel population of highly proliferative ARX+ Sox9Cyt hormone-negative cells and suggest the possibility of previously unrecognized islet development and/or lineage plasticity within adolescent and adult human pancreata.