Introduction Evidence supporting use of continuous glucose monitoring in type 2 diabetes treated with basal insulin is unclear. This real-world study aimed to assess the impact on glycated hemoglobin (HbA1c) of flash glucose monitoring use in adults with type 2 diabetes managed with basal insulin. Research design and methods Medical records were reviewed for adult individuals with type 2 diabetes using basal insulin for ≥1 year with or without additional antihyperglycemic medication, HbA1c 8.0%–12.0% prior to FreeStyle Libre Flash Glucose Monitoring use for ≥90 days and an HbA1c measurement recorded between 90 and 194 days after device use. Exclusion criteria included utilization of bolus insulin. Meta-analysis data are from the current study (USA) and a similar Canadian cohort. Results Medical record analysis (n=100) from 8 USA study sites showed significant HbA1c decrease of 1.4%±1.3%, from 9.4%±1.0% at baseline to 8.0%±1.2% after device use, p<0.0001 (mean±SD). Meta-analysis of medical records from USA and Canada sites (n=191) showed HbA1c significantly decreased by 1.1%±0.14% (mean±SE), from baseline 9.2%±1.0% to 8.1%±1.1%, p≤0.0001, with moderate to high heterogeneity between sites (Q=43.9, I2=74.9, p<0.0001) explained by differences in baseline HbA1c between sites. The HbA1c improvement in both groups was observed by age group, body mass index, duration of insulin use and sex at birth. Conclusions In a real-world retrospective USA study and a meta-analysis of a larger USA and Canada cohort, HbA1c significantly reduced in basal insulin-treated type 2 diabetes, without bolus insulin initiation and following the commencement of flash glucose monitoring technology.

Introduction Evidence supporting use of continuous glucose monitoring in type 2 diabetes treated with basal insulin is unclear. This real-world study aimed to assess the impact on glycated hemoglobin (HbA1c) of flash glucose monitoring use in adults with type 2 diabetes managed with basal insulin. Research design and methods Medical records were reviewed for adult individuals with type 2 diabetes using basal insulin for >= 1 year with or without additional antihyperglycemic medication, HbA1c 8.0%-12.0% prior to FreeStyle Libre Flash Glucose Monitoring use for >= 90 days and an HbA1c measurement recorded between 90 and 194 days after device use. Exclusion criteria included utilization of bolus insulin. Meta-analysis data are from the current study (USA) and a similar Canadian cohort. Results Medical record analysis (n=100) from 8 USA study sites showed significant HbA1c decrease of 1.4%+/- 1.3%, from 9.4%+/- 1.0% at baseline to 8.0%+/- 1.2% after device use, p<0.0001 (mean +/- SD). Meta-analysis of medical records from USA and Canada sites (n=191) showed HbA1c significantly decreased by 1.1%+/- 0.14% (mean +/- SE), from baseline 9.2%+/- 1.0% to 8.1%+/- 1.1%, p <= 0.0001, with moderate to high heterogeneity between sites (Q=43.9, I-2=74.9, p<0.0001) explained by differences in baseline HbA1c between sites. The HbA1c improvement in both groups was observed by age group, body mass index, duration of insulin use and sex at birth. Conclusions In a real-world retrospective USA study and a meta-analysis of a larger USA and Canada cohort, HbA1c significantly reduced in basal insulin-treated type 2 diabetes, without bolus insulin initiation and following the commencement of flash glucose monitoring technology.

This retrospective, real-world, chart review study determined the effectiveness of the FreeStyle Libre® Flash Glucose Monitoring System on HbA1c when used by adults with type 2 diabetes (T2D) in a real-world setting between 3 months to 6 months after starting FreeStyle Libre. The study population included adults on a basal insulin regimen for at least 1 year, with HbA1c between 8.0 and 12.0% (64 to 108 mmol/mol), using FreeStyle Libre regularly for at least 3 months. Pregnant patients were excluded, as were patients on dialysis. A total of 100 records from basal insulin using patients with T2D from 8 clinical sites in the US were included in this chart review. Mean HbA1c was 9.4±1.0% (79.2±11.1 mmol/mol), prior to FreeStyle Libre use, age was 56.0±10.3 years, BMI was 36.1±7.8 kg/m2 and average duration of insulin use 4.5±3.5 years (mean±SD); 96.0% of patients were on oral anti-diabetic medications in addition to basal insulin and 52.0% were male. HbA1c results were recorded between 90 to 194 days from the start of use of FreeStyle Libre, between December 2017 and March 2020. To minimise selection bias records were selected on a systematic basis. After at least 3 months of using FreeStyle Libre in addition to their usual clinical care, HbA1c (primary outcome) was significantly reduced by 1.4±1.3% (mean±SD); p<0.0001. Sub-group analysis by baseline HbA1c (<9.0%, ≥9.0%) showed both groups significantly reduced HbA1c; with reductions of 0.8±0.7%, p<0.0001 and 1.7±1.4%, p<0.0001, respectively. This real-world, chart review study concluded that people with T2D on basal insulin therapy, using FreeStyle Libre for between 3 to 6 months significantly reduced HbA1c. Disclosure A. L. Carlson: Board Member; Self; JDRF, Other Relationship; Self; Medtronic, Research Support; Self; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Omnipod, Sanofi, UnitedHealth Group. T. D. Daniel: Advisory Panel; Self; Abbott Diabetes, Bayer Healthcare Pharmaceuticals Inc. A. Desantis: None. S. Jabbour: None. E. Karslioglu-french: None. D. F. Kruger: Advisory Panel; Self; Abbott Diabetes, Novo Nordisk, Sanofi US, Research Support; Self; Abbott Diabetes, Dexcom, Inc., Novo Nordisk, Speaker’s Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Stock/Shareholder; Self; Pendulum Therapeutics. E. Miller: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk Inc., Research Support; Self; Pendulum Therapeutics, Research Support; Spouse/Partner; Abbott Diabetes. K. Ozer: Research Support; Self; Abbott Diabetes, AbbVie Inc., Eli Lilly and Company, Novo Nordisk, Senseonics, Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk. Funding Abbott Diabetes Care

Two retrospective chart review studies evaluated the effectiveness of the FreeStyle Libre® Flash Glucose Monitoring System on HbA1c when used by adults with type 2 diabetes (T2D) in a real-world setting. Each study aimed to determine the effect of FreeStyle Libre when used for between 3 months to 6 months on HbA1c. Each study population included adults on a basal insulin regimen for at least 1 year who had been using FreeStyle Libre regularly for at least 3 months and with HbA1c between 8.0 and 12.0% (64 to 108 mmol/mol). Pregnant patients were excluded, as were patients on dialysis. This meta-analysis comprised of a total of 191 records from basal insulin using patients with T2D from 14 medical centers across Canada and the US. On average, HbA1c was 9.2±1.0% (76.8±10.7 mmol/mol) prior to FreeStyle Libre use, age was 60.0±11.3 years and average duration of insulin use 4.3±3.3 years (mean±SD), 95.8% of patients were on oral antidiabetic medications and 60.2% were male. Renal and CVD complications were reported by 31.4% and 28.3% of patients, respectively. HbA1c results were recorded between 90 and 194 days from the start of use of FreeStyle Libre, between December 2017 and March 2020. Overall mean change in HbA1c, after at least 3 months of using FreeStyle Libre, was significantly reduced by 1.1±0.14% (mean±SE); p<0.0001, with moderate to high heterogeneity between centers (Q=43.9, I2=74.9, p<0.0001) explained by differences in initial HbA1c between centers. No significant differences were detected between: age group, sex, BMI or duration of insulin use. This meta-analysis of two real-world, chart review studies concludes that people with T2D on basal insulin therapy, using FreeStyle Libre for between 3 to 6 months significantly reduced HbA1c. Disclosure A. L. Carlson: Board Member; Self; JDRF, Other Relationship; Self; Medtronic, Research Support; Self; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Omnipod, Sanofi, UnitedHealth Group. T. D. Daniel: Advisory Panel; Self; Abbott Diabetes, Bayer Healthcare Pharmaceuticals Inc. A. Desantis: None. S. Jabbour: None. E. Karslioglu-french: None. D. F. Kruger: Advisory Panel; Self; Abbott Diabetes, Novo Nordisk, Sanofi US, Research Support; Self; Abbott Diabetes, Dexcom, Inc., Novo Nordisk, Speaker’s Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Stock/Shareholder; Self; Pendulum Therapeutics. E. Miller: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk Inc., Research Support; Self; Pendulum Therapeutics, Research Support; Spouse/Partner; Abbott Diabetes. K. Ozer: Research Support; Self; Abbott Diabetes, AbbVie Inc., Eli Lilly and Company, Novo Nordisk, Senseonics, Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk. T. Elliott: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk, Other Relationship; Self; Abbott Diabetes. Funding Abbott Diabetes Care

This is a single-center randomized open label active-controlled crossover trial comparing efficacy and safety of fast acting insulin aspart (FA) (FIASP(R)) versus insulin aspart (IAsp) (NovoLog(R)) when used in the Medtronic 670G system in auto mode in patients with type 1 diabetes. Forty patients were randomized to either IAsp or FA. Each treatment period was 7 weeks and a standardized meal test was administered 6 weeks after the start of each treatment period. The primary endpoint was postprandial glucose (PPG) increment after the meal test at 1 h. Treatment with FA using the MiniMed 670G hybrid closed loop (HCL) led to a greater reduction in 1-h postprandial glucose increase compared with treatment with IAsp during the standardized mixed meal test. Change in glucose: [estimated treatment difference (ETD +/- standard deviation [SD]); 95% confidence interval]: 70.27 (+/- 17.36) mg/dL (3.9 +/- 1.0 mmol/L) with FA versus 98.42 (+/- 17.36) mg/dL (5.5 +/- 1.0 mmol/L) with IAsp (P = 0.008). Patients spent 1.81% (P = 0.016) more time (equivalent to 26 min per day) in the 70-180 mg/dL (3.89-9.99 mmol/L) range with FA than with IAsp. The entire sample spent only 0.5% of time <54 mg/dL (<3.0 mmol/L) range. The increment in the 1 h postmeal test glucose was significantly lower with FA versus IAsp. FA in a HCL setting is safe and effective with patients spending more time in the 70-180 mg/dL (3.89-9.99 mmol/L) target range than with IAsp. Trial registration: Clinicaltrials.gov identifier: NCT03977727.

On March 18, as the COVID 19 crisis accelerated, we converted overnight to seeing our patients by video. Our journey into telemedicine was abrupt, and there was a steep learning curve.

Context: Hashimoto's thyroiditis is less prevalent in tobacco smokers. Anatabine, an alkaloid found in Solanaceae plants including tobacco, has been reported to ameliorate a mouse model of Hashimoto's thyroiditis.Objective: The effects of anatabine in patients with Hashimoto's thyroiditis were studied.Design, Setting, Patients, and Intervention: This was a double-blind, randomized, placebo-controlled multisite study. A total of 146 patients (70 treated with anatabine and 76 with placebo) completed the study. Approximately 50% of patients in each group were taking levothyroxine. Anatabine lozenges (9-24 mg/d) or placebo, each containing vitamins A and D-3, were administered orally 3 times a day for 3 months.Main Outcome Measures: Serum thyroperoxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) levels were assessed. Safety was assessed through adverse events, clinical laboratory evaluations, and vital sign measurements.Results: Anatabine-treated patients had a significant reduction in absolute serum TgAb levels from baseline by study end relative to those receiving placebo (P = .027); however, there were no significant changes or differences in treatment group means for TPOAb or TgAb levels. Mean +/- SD TgAb values decreased by 46.2 +/- 101.1 and 3.9 +/- 83.9 World Health Organization units for the anatabine and placebo groups, respectively. Significantly more patients had a >20% drop in TgAb levels in the anatabine than placebo group (P = .023). Overall, the anatabine supplement was safe and well tolerated, although significantly (P < .05) more patients in the anatabine group reported adverse events.Conclusions: These results demonstrate an immunological effect of anatabine on TgAb levels. Further studies are warranted to determine the longer-term effects and possible actions of anatabine on the course of Hashimoto's thyroiditis.

OBJECTIVE:Reports of concomitant diabetic ketoacidosis (DKA) and acute pancreatitis (AP) are lacking among emerging forms of diabetes. This longitudinal study characterized ketosis-prone diabetes (KPD) in patients presenting with concomitant AP and DKA.METHODS:Multi-ethnic KPD patients (N = 755) were followed prospectively for 1 year from the time of index DKA using repeated metabolic and beta cell functional reserve measures. Baseline and longitudinal characteristics were compared between KPD patients whose index DKA was associated with (n = 54) or without (n = 701) AP.RESULTS:The AP group had significantly higher baseline serum amylase, lipase, and triglyceride levels and significantly lower bicarbonate levels than the non-AP group. AP patients had significantly greater C-peptide area-under-the-curve with glucagon stimulation shortly after the index DKA, and higher fasting C-peptide (FCP) levels 6 to 12 months later. Using the validated "Aβ" KPD classification, 85% of AP patients had β+ status (preserved beta cell functional reserve), compared to 60% of non-AP patients (P = .04). Multivariate analysis revealed that among the β+ KPD subgroup with an identifiable precipitating factor for DKA ("provoked" DKA), patients with AP had worse long-term glycemic outcomes than patients whose DKA was associated with other factors.CONCLUSION:Despite greater clinical severity at presentation, KPD patients with AP have better preserved beta cell function than those without AP. β+ KPD patients presenting with AP have worse long-term glycemic control than those with other causes of provoked DKA. Factors other than beta cell function negatively impact glycemic control in KPD patients presenting with AP.

OBJECTIVEdKetosis-prone diabetes (KPD) is characterized by diabetic ketoacidosis (DKA) in patients lacking typical features of type 1 diabetes. A validated classification scheme for KPD includes two autoantibody-negative (“A2”) phenotypic forms: “A2b2” (lean, early onset, lacking b-cell functional reserve), and “A2b+” (obese, late onset, with substantial b-cell functional reserve after the index episode of DKA). Recent longitudinal analysis of a large KPD cohort revealed that the A2b+ phenotype includes two distinct subtypes distinguished by the index DKA episode having a defined precipitant (“provoked,”with progressive b-cell function loss over time) or no precipitant (“unprovoked,” with sustained b-cell functional reserve). These three A2 KPD subtypes are characterized by absence of humoral islet autoimmune markers, but a role for cellular islet autoimmunity is unknown.

A−β+ ketosis-prone diabetes (KPD) is an emerging syndrome of obesity, unprovoked ketoacidosis, reversible β-cell dysfunction, and near-normoglycemic remission. We combined metabolomics with targeted kinetic measurements to investigate its pathophysiology. Fasting plasma fatty acids, acylcarnitines, and amino acids were quantified in 20 KPD patients compared with 19 nondiabetic control subjects. Unique signatures in KPD—higher glutamate but lower glutamine and citrulline concentrations, increased β-hydroxybutyryl-carnitine, decreased isovaleryl-carnitine (a leucine catabolite), and decreased tricarboxylic acid (TCA) cycle intermediates—generated hypotheses that were tested through stable isotope/mass spectrometry protocols in nine new-onset, stable KPD patients compared with seven nondiabetic control subjects. Free fatty acid flux and acetyl CoA flux and oxidation were similar, but KPD had slower acetyl CoA conversion to β-hydroxybutyrate; higher fasting β-hydroxybutyrate concentration; slower β-hydroxybutyrate oxidation; faster leucine oxidative decarboxylation; accelerated glutamine conversion to glutamate without increase in glutamate carbon oxidation; and slower citrulline flux, with diminished glutamine amide–nitrogen transfer to citrulline. The confluence of metabolomic and kinetic data indicate a distinctive pathogenic sequence: impaired ketone oxidation and fatty acid utilization for energy, leading to accelerated leucine catabolism and transamination of α-ketoglutarate to glutamate, with impaired TCA anaplerosis of glutamate carbon. They highlight a novel process of defective energy production and ketosis in A−β+ KPD.

OBJECTIVE Ketosis-prone diabetes (KPD) is characterized by diabetic ketoacidosis (DKA) in patients lacking typical features of type 1 diabetes. A validated classification scheme for KPD includes two autoantibody-negative (“A−”) phenotypic forms: “A−β−” (lean, early onset, lacking β-cell functional reserve) and “A−β+” (obese, late onset, with substantial β-cell functional reserve after the index episode of DKA). Recent longitudinal analysis of a large KPD cohort revealed that the A−β+ phenotype includes two distinct subtypes distinguished by the index DKA episode having a defined precipitant (“provoked,” with progressive β-cell function loss over time) or no precipitant (“unprovoked,” with sustained β-cell functional reserve). These three A− KPD subtypes are characterized by absence of humoral islet autoimmune markers, but a role for cellular islet autoimmunity is unknown. RESEARCH DESIGN AND METHODS Islet-specific T-cell responses and the percentage of proinflammatory (CD14+CD16+) blood monocytes were measured in A−β− (n = 7), provoked A−β+ (n = 15), and unprovoked A−β+ (n = 13) KPD patients. Genotyping was performed for type 1 diabetes–associated HLA class II alleles. RESULTS Provoked A−β+ and A−β− KPD patients manifested stronger islet-specific T-cell responses (P < 0.03) and higher percentages of proinflammatory CD14+CD16+ monocytes (P < 0.01) than unprovoked A−β+ KPD patients. A significant relationship between type 1 diabetes HLA class II protective alleles and negative T-cell responses was observed. CONCLUSIONS Provoked A−β+ KPD and A−β− KPD are associated with a high frequency of cellular islet autoimmunity and proinflammatory monocyte populations. In contrast, unprovoked A−β+ KPD lacks both humoral and cellular islet autoimmunity.

Ketosis-prone diabetes (KPD) is heterogeneous. Longitudinal follow-up revealed that patients with “A-β+” KPD (absent autoantibodies and preserved β-cell function) segregated into 2 subgroups with distinct evolution of β-cell function and glycemic control. Generalized linear analysis demonstrated that the variable that most significantly differentiated them was presence of a clinically evident precipitating event for the index diabetic ketoacidosis (DKA). Hence, we performed a comprehensive analysis of A-β+ KPD patients presenting with “provoked” compared with “unprovoked” DKA. Clinical, biochemical, and β-cell functional characteristics were compared between provoked and unprovoked A-β+ KPD patients followed prospectively for 1 to 8 years. Human leukocyte antigen class II allele frequencies were compared between these 2 groups and population controls. Unprovoked A-β+ KPD patients (n = 83) had greater body mass index, male preponderance, higher frequency of women with oligo-/anovulation, more frequent African American ethnicity, and less frequent family history of diabetes than provoked A-β+ KPD patients (n = 64). The provoked group had higher frequencies of the human leukocyte antigen class II type 1 diabetes mellitus susceptibility alleles DQB1*0302 (than the unprovoked group or population controls) and DRB1*04 (than the unprovoked group), whereas the unprovoked group had a higher frequency of the protective allele DQB1*0602. β-Cell secretory reserve and glycemic control improved progressively in the unprovoked group but declined in the provoked group. The differences persisted in comparisons restricted to patients with new-onset diabetes. “Unprovoked” A-β+ KPD is a distinct syndrome characterized by reversible β-cell dysfunction with male predominance and increased frequency of DQB1*0602, whereas “provoked” A-β+ KPD is characterized by progressive loss of β-cell reserve and increased frequency of DQB1*0302 and DRB1*04. Unprovoked DKA predicts long-term β-cell functional reserve, insulin independence, and glycemic control in KPD.

We thank Ozer, Abdelnour, and Alva (1) for the recognition of the importance in understanding the immediate metabolic effects of Roux-en-Y gastric bypass (RYGB) surgery. Although our study (2) was not designed to test the effects of type 2 diabetes or degree of obesity on glucose metabolism immediately post-RYGB, these questions are of considerable interest given the proposition that bariatric surgery be performed to treat type 2 diabetes in subjects with a BMI ≤35 kg/m2 (rev. in …