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OBJECTIVE The risk of hypoglycemia in people with insulin-treated diabetes has debarred them from certain “safety-critical” occupations, including flying commercial aircraft. This report evaluates the effectiveness of a protocol enabling a large cohort of insulin-treated pilots to fly commercially. RESEARCH DESIGN AND METHODS This was an observational study of pilots with insulin-treated diabetes who were granted medical certification to fly commercial and noncommercial aircraft. Clinical details, pre- and in-flight (hourly and 30 min before landing) blood glucose values were correlated against the protocol-specified ranges: green (5–15 mmol/L), amber (low, 4–4.9 mmol/L; high, 15.1–20 mmol/L), and red (low, 20 mmol/L). RESULTS A total of 49 pilots with type 1 (84%) or type 2 (16%) diabetes who had been issued class 1 or class 2 certificates were studied. Median diabetes duration was 10.9 years. Mean HbA1c was 7.2% (55.0 mmol/mol) before certification and 7.2% (55.1 mmol/mol) after certification (P = 0.97). Blood glucose values (n = 38,621) were recorded during 22,078 flying hours. Overall, 97.69% of measurements were within the green range, 1.42% within the low amber range, and 0.75% within the high amber range. Only 0.12% of readings were within the low red range and 0.02% within the high red range. Out-of-range readings declined from 5.7% in 2013 to 1.2% in 2019. No episodes of pilot incapacitation occurred, and glycemic control did not deteriorate. CONCLUSIONS The protocol is practical to implement, and no events compromising safety were reported. This study represents what is, to our knowledge, the most extensive data set from people with insulin-treated diabetes working in a “safety-critical” occupation, which may be relevant when estimating risk in other safety-critical occupations.

OBJECTIVE To investigate the mechanism for increased ketogenesis following treatment with the SGLT2 inhibitor dapagliflozin in people with type 2 diabetes. RESEARCH DESIGN AND METHODS The design was a double-blind, placebo-controlled, crossover study with a 4-week washout period. Participants received dapagliflozin or placebo in random order for 4 weeks. After each treatment, they ingested 30 mL of olive oil containing [U-13C]palmitate to measure ketogenesis, with blood sampling for 480 min. Stable isotopes of glucose and glycerol were infused to measure glucose flux and lipolysis, respectively, at 450–480 min. RESULTS Glucose excretion rate was higher and peripheral glucose uptake lower with dapagliflozin than placebo. Plasma β-hydroxybutyrate (BOHB) concentrations and [13C2]BOHB concentrations were higher and glucose concentrations lower with dapagliflozin than placebo. Nonesterified fatty acids (NEFAs) were higher with dapagliflozin at 300 and 420 min, but lipolysis at 450–480 min was not different. Triacylglycerol at all time points and endogenous glucose production rate at 450–480 min were not different between treatments. CONCLUSIONS The increase in ketone enrichment from the ingested palmitic acid tracer suggests that meal-derived fatty acids contribute to the increase in ketones during treatment with dapagliflozin. The increase in BOHB concentration with dapagliflozin occurred with only minimal changes in plasma NEFA concentration and no change in lipolysis. This finding suggests a metabolic switch to increase ketogenesis within the liver.

OBJECTIVE To determine the effect of the sodium–glucose cotransporter 2 inhibitor dapagliflozin on glucose flux, lipolysis, and ketone body concentrations during insulin withdrawal in people with type 1 diabetes. RESEARCH DESIGN AND METHODS A double-blind, placebo-controlled crossover study with a 4-week washout period was performed in 12 people with type 1 diabetes using insulin pump therapy. Participants received dapagliflozin or placebo in random order for 7 days. Stable isotopes were infused to measure the glucose Ra, Rd, and lipolysis. At isotopic steady state, insulin was withdrawn, and the study was terminated after 600 min or earlier if blood glucose reached 18 mmol/L, bicarbonate 5.0 mmol/L. RESULTS At baseline, glucose Ra was significantly higher for the dapagliflozin group than the placebo group. Following insulin withdrawal, plasma glucose concentrations at the end point were significantly lower with dapagliflozin than placebo and glucose Rd area under the curve (AUC)0–180 min and β-hydroxybutyrate (BOHB) AUC0–180 min were significantly higher. There was a small but significantly higher glycerol Ra (measure of lipolysis) AUC0–180 min with dapagliflozin. Nonesterified fatty acid concentrations were not different between treatments. When divided by BMI >27 and CONCLUSIONS During insulin withdrawal, the increase in BOHB with dapagliflozin may be partially due to increased lipolysis. However, reduced renal excretion, reduced BOHB uptake by peripheral tissues, or a metabolic switch to increased ketogenesis within the liver may also play a role.

Objective: To determine the effect of SGLT2 inhibitor dapagliflozin on glucose flux, lipolysis and ketone body concentrations during insulin withdrawal in people with type 1 diabetes. Research Design and Methods: A double-blind placebo controlled crossover study with a 4-week wash out period was performed in 12 people with type 1 diabetes using insulin pump therapy. Participants received dapagliflozin or placebo in random order for 7 days. Stable isotopes were infused to measure the rate of glucose production (Ra), disappearance (Rd) and lipolysis. At isotopic steady state insulin was withdrawn and the study terminated after 600 minutes or earlier if blood glucose reached 18mmol/L, bicarbonate 5.0 mmol/L. Results: At baseline, glucose Ra was significantly higher with dapagliflozin than placebo. Following insulin withdrawal, plasma glucose concentrations at the end point were significantly lower with dapagliflozin than placebo and AUC0-180min glucose Rd and AUC0-180min β-hydroxybutyrate (BOHB) were significantly higher. There was a small but significantly higher AUC0-180min glycerol Ra (measure of lipolysis) with dapagliflozin. Non-esterified fatty acid concentrations were not different between treatments.When divided by BMI>27 and

OBJECTIVE This multicenter, treat-to-target, phase 3 trial evaluated the efficacy and safety of fast-acting insulin aspart (faster aspart) versus conventional insulin aspart (IAsp) in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS The primary end point was change from baseline in HbA1c after 26 weeks. After an 8-week run-in, subjects were randomized (1:1:1) to double-blind mealtime faster aspart (n = 381), IAsp (n = 380), or open-label postmeal faster aspart (n = 382)—each with insulin detemir. RESULTS HbA1c was reduced in both treatment groups, and noninferiority to IAsp was confirmed for both mealtime and postmeal faster aspart (estimated treatment difference [ETD] faster aspart–IAsp, mealtime, –0.15% [95% CI –0.23; –0.07], and postmeal, 0.04% [–0.04; 0.12]); mealtime faster aspart statistically significantly reduced HbA1c versus IAsp (P = 0.0003). Postprandial plasma glucose (PPG) increments were statistically significantly lower with mealtime faster aspart at 1 h (ETD –1.18 mmol/L [95% CI –1.65; –0.71], –21.21 mg/dL [–29.65; –12.77]; P < 0.0001) and 2 h (–0.67 mmol/L [–1.29; –0.04], –12.01 mg/dL [–23.33; –0.70]; P = 0.0375) after the meal test; superiority to IAsp for the 2-h PPG increment was confirmed. The overall rate of severe or blood glucose–confirmed (plasma glucose CONCLUSIONS Faster aspart effectively improved HbA1c, and noninferiority to IAsp was confirmed, with superior PPG control for mealtime faster aspart versus IAsp. Subjects randomized to postmeal faster aspart for all meals maintained HbA1c noninferior to that obtained with mealtime IAsp.

Many people with T2DM do not achieve HbA1c goals in clinical practice, owing in part to sub-optimal basal insulin titration. TAKE CONTROL, a 24-week, multicenter, randomized, open-label, parallel-group study, compared the efficacy and safety of a Gla-300 titration algorithm (fasting self-monitored plasma glucose >130 mg/dL, +3 U; Disclosure E. Delgado: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S. Advisory Panel; Self; Sanofi-Aventis. Speaker's Bureau; Self; Sanofi-Aventis. Research Support; Self; Sanofi-Aventis. Speaker's Bureau; Self; Esteve, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Lilly. Research Support; Self; Menarini Group. M. Bonnemaire: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. A. Dauchy: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. V. Donicova: None. M. Kvapil: None. N. Tentolouris: Advisory Panel; Self; MSD K.K., AstraZeneca, Sanofi, Novo Nordisk A/S, Elpen Pharmaceutical Co. Inc., Eli Lilly and Company, Boehringer Ingelheim GmbH, Novartis AG. Research Support; Self; MSD K.K., Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Pfizer Inc., AstraZeneca, Janssen-Cilag Pty Limited, GlaxoSmithKline plc., Novartis AG. L. Popescu: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. D. Russell-Jones: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim, Cellnovo, Eli Lilly and Company, Novartis, Novo Nordisk, Sanofi.

Empowering individuals to self-titrate their basal insulin may help to reduce rates of sub-optimal titration often observed in clinical practice and help more people achieve HbA1c goals. Here we compare the results from the recently completed TAKE CONTROL study, which evaluated self-titration and physician-led titration of insulin glargine 300 U/mL (Gla-300) in people with T2DM, with comparable studies (AT.LANTUS and ATLAS) of insulin glargine 100 U/mL (Gla-100). All 3 studies were 24-week, multicenter, randomized, open-label, parallel-group studies. Fasting blood glucose targets were 80-130 mg/dL (4.4-7.2 mmol/L) in TAKE CONTROL, ≤100 mg/dL (5.5 mmol/L) in AT.LANTUS and ≤110 mg/dL (6.1 mmol/L) in ATLAS. Mean baseline HbA1c was between 8.4 and 8.9% (Table). Self-titration statistically significantly lowered mean HbA1c by 0.97 to 1.40% vs. physician-led titration (0.84 to 1.25%; p Disclosure M. Davies: Advisory Panel; Self; AstraZeneca. Board Member; Self; AstraZeneca. Consultant; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Board Member; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Eli Lilly and Company. Board Member; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Board Member; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Board Member; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Board Member; Self; Sanofi-Aventis. Consultant; Self; Sanofi-Aventis. Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Sanofi-Aventis. Speaker's Bureau; Self; Sanofi-Aventis. Advisory Panel; Self; Servier. Consultant; Self; Intarcia Therapeutics, Inc.. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. E. Boelle-Le Corfec: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. M. Bonnemaire: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. M. Odawara: Speaker's Bureau; Self; Sanofi, Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Eli Lilly and Company. Advisory Panel; Self; Sanofi, Novo Nordisk Inc., Eli Lilly and Company. L. Popescu: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. J. Sieber: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. D. Russell-Jones: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim, Cellnovo, Eli Lilly and Company, Novartis, Novo Nordisk, Sanofi. K. Strojek: Research Support; Self; AstraZeneca. Other Relationship; Self; Sanofi-Aventis, Novo Nordisk A/S. Speaker's Bureau; Self; Servier, Eli Lilly and Company, MSD K.K., Boehringer Ingelheim GmbH. Research Support; Self; Pfizer Inc., Amgen Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc. N. Tentolouris: Advisory Panel; Self; MSD K.K., AstraZeneca, Sanofi, Novo Nordisk A/S, Elpen Pharmaceutical Co. Inc., Eli Lilly and Company, Boehringer Ingelheim GmbH, Novartis AG. Research Support; Self; MSD K.K., Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Pfizer Inc., AstraZeneca, Janssen-Cilag Pty Limited, GlaxoSmithKline plc., Novartis AG.

OBJECTIVE To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Patients were randomized to subcutaneous (SC) EQW 2.0 mg + oral placebo (n = 248), MET 2,000 mg/day + SC placebo (n = 246), PIO 45 mg/day + SC placebo (n = 163), or SITA 100 mg/day + SC placebo (n = 163) for 26 weeks. MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW or placebo were administered weekly, while oral medication or placebo was administered daily. RESULTS Baseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 years, HbA1c 8.5%, fasting serum glucose 9.9 mmol/L, body weight 87.0 kg, and diabetes duration 2.7 years. HbA1c reductions (%) at 26 weeks (least-squares means) with EQW versus MET, PIO, and SITA were −1.53 vs. −1.48 (P = 0.620), −1.63 (P = 0.328), and −1.15 (P < 0.001), respectively. Weight changes (kg) were −2.0 vs. −2.0 (P = 0.892), +1.5 (P < 0.001), and −0.8 (P < 0.001), respectively. Common adverse events were as follows: EQW, nausea (11.3%) and diarrhea (10.9%); MET, diarrhea (12.6%) and headache (12.2%); PIO, nasopharyngitis (8.6%) and headache (8.0%); and SIT, nasopharyngitis (9.8%) and headache (9.2%). Minor (confirmed) hypoglycemia was rarely reported. No major hypoglycemia occurred. CONCLUSIONS EQW was noninferior to MET but not PIO and superior to SITA with regard to HbA1c reduction at 26 weeks. Of the agents studied, EQW and MET provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia.

OBJECTIVE Insulin detemir lacks the usual propensity for insulin to cause weight gain. We investigated whether this effect was a result of reduced energy intake and/or increased energy expenditure. RESEARCH DESIGN AND METHODS A 32-week, randomized crossover design trial was undertaken in 23 patients with type 1 diabetes. Patients on a basal-bolus regimen (with insulin aspart as the bolus insulin) were randomly assigned to insulin detemir or NPH insulin as a basal insulin for 16 weeks, followed by the other basal insulin for 16 weeks. At the end of each 16-week period, total energy expenditure, resting energy expenditure, diet-induced thermogenesis, activity energy expenditure, energy intake, weight change, glycemic control, hypoglycemic episodes, and hormones that affect satiety and fuel partitioning were measured. RESULTS After 16 weeks, weight change was −0.69 ± 1.85 kg with insulin detemir and +1.7 ± 2.46 kg with NPH insulin (P < 0.001). Total energy intake was significantly less with insulin detemir (2,016 ± 501 kcal/day) than with NPH insulin (2,181 ± 559 kcal/day) (P = 0.026). There was no significant difference in any measure of energy expenditure, HbA1c percentage, or number of hypoglycemic episodes. Leptin was lower and resistin was higher with insulin detemir compared with NPH insulin (P = 0.039, P = 0.047). After the meal, ghrelin and pancreatic polypeptide levels (P = 0.002, P = 0.001) were higher with insulin detemir. CONCLUSIONS The reduced weight gain with insulin detemir compared with NPH insulin is attributed to reduced energy intake rather than increased energy expenditure. This may be mediated by a direct or indirect effect of insulin detemir on the hormones that control satiety.

OBJECTIVE—Insulin detemir is a soluble long-acting basal insulin analog designed to overcome the limitations of conventional basal insulin formulations. Accordingly, insulin detemir has been compared with NPH insulin with respect to glycemic control (HbA1c, prebreakfast glucose levels and variability, and hypoglycemia) and timing of administration. RESEARCH DESIGN AND METHODS—People with type 1 diabetes (n = 408) were randomized in an open-label, parallel-group trial of 16-week treatment duration using either insulin detemir or NPH insulin. Insulin detemir was administered twice daily using two different regimens, either before breakfast and at bedtime (IDetmorn+bed) or at a 12-h interval (IDet12h). NPH insulin was administered before breakfast and at bedtime. Mealtime insulin was given as the rapid-acting insulin analog insulin aspart. RESULTS—With both insulin detemir groups, clinic fasting plasma glucose was lower than with NPH insulin (IDet12h vs. NPH, −1.5 mmol/l [95% CI −2.51 to −0.48], P = 0.004; IDetmorn+bed vs. NPH, −2.3 mmol/l (−3.32 to −1.29), P < 0.001), as was self-measured prebreakfast plasma glucose (P = 0.006 and P = 0.004, respectively). The risk of minor hypoglycemia was lower in both insulin detemir groups (25%, P = 0.046; 32%, P = 0.002; respectively) compared with NPH insulin in the last 12 weeks of treatment, this being mainly attributable to a 53% reduction in nocturnal hypoglycemia in the IDetmorn+bed group (P < 0.001). Although HbA1c for each insulin detemir group was not different from the NPH group, HbA1c for the pooled insulin detemir groups was significantly lower than for the NPH group (mean difference −0.18% [−0.34 to −0.02], P = 0.027). Within-person between-day variation in self-measured prebreakfast plasma glucose was lower for both detemir groups (both P < 0.001). The NPH group gained weight during the study, but there was no change in weight in either of the insulin detemir groups (IDet12h vs. NPH, −0.8 kg [−1.44 to −0.24], P = 0.006; IDetmorn+bed vs. NPH, −0.6 kg [−1.23 to −0.03], P = 0.040). CONCLUSIONS—Overall glycemic control with insulin detemir was improved compared with NPH insulin. The data provide a basis for tailoring the timing of administration of insulin detemir to the individual person’s needs.

Type 1 diabetes is associated with abnormalities of the growth hormone (GH)-IGF-I axis. Such abnormalities include decreased circulating levels of IGF-I. We studied the effects of IGF-I therapy (40 microg x kg(-1) x day(-1)) on protein and glucose metabolism in adults with type 1 diabetes in a randomized placebo-controlled trial. A total of 12 subjects participated, and each subject was studied at baseline and after 7 days of treatment, both in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. Protein and glucose metabolism were assessed using infusions of [1-13C]leucine and [6-6-2H2]glucose. IGF-I administration resulted in a 51% rise in circulating IGF-I levels (P < 0.005) and a 56% decrease in the mean overnight GH concentration (P < 0.05). After IGF-I treatment, a decrease in the overnight insulin requirement (0.26+/-0.07 vs. 0.17+/-0.06 U/kg, P < 0.05) and an increase in the glucose infusion requirement were observed during the hyperinsulinemic clamp (approximately 67%, P < 0.05). Basal glucose kinetics were unchanged, but an increase in insulin-stimulated peripheral glucose disposal was observed after IGF-I therapy (37+/-6 vs. 52+/-10 micromol x kg(-1) x min(-1), P < 0.05). IGF-I administration increased the basal metabolic clearance rate for leucine (approximately 28%, P < 0.05) and resulted in a net increase in leucine balance, both in the basal state and during the hyperinsulinemic amino acid clamp (-0.17+/-0.03 vs. -0.10+/-0.02, P < 0.01, and 0.25+/-0.08 vs. 0.40+/-0.06, P < 0.05, respectively). No changes in these variables were recorded in the subjects after administration of placebo. These findings demonstrated that IGF-I replacement resulted in significant alterations in glucose and protein metabolism in the basal and insulin-stimulated states. These effects were associated with increased insulin sensitivity, and they underline the major role of IGF-I in protein and glucose metabolism in type 1 diabetes.

IDDM is associated with elevated circulating levels of growth hormone (GH) and reduced insulin-like growth factor I (IGF-I). GH antagonizes the action of insulin-increasing insulin requirements in IDDM. The effects of subcutaneously administered rhIGF-I on glycemie control, insulin requirements, and GH secretion were studied in eight adults with IDDM. Patients received either placebo or rhIGF-I (50 pg/kg b.i.d.) for 19 days in a randomized, double-blind, parallel-design, placebo-controlled trial. Overnight GH, plasma glucose, free insulin, IGF-I, fructosamine, and lipid profiles were assessed during this period. rhIGF-I therapy increased IGF-I concentration from 117.1 ± 14.2 (mean ± SE) ng/ml (baseline) to 310.5 ± 40.6 and 257.1 ± 41.2 ng/ml on day 5 (P < 0.01 vs. baseline) and day 20 (P < 0.01 vs. baseline), respectively. After 19 days of rhIGF-I treatment, fructosamine concentrations were unchanged compared with baseline (439 ± 32 vs. 429 ± 35 μmol/l, day –1 vs. day 20, respectively), yet insulin requirements were decreased by ∼45% (0.67 ± 0.08 vs. 0.36 ± 0.07 U · kg−1 · day−1, day –1 vs. day 19, respectively, P < 0.005). After 4 days of rhIGF-I therapy, there was a decrease in free insulin levels (8.38 ± 1.47 vs. 4.98 ± 0.84 mU/l, P < 0.05), mean overnight GH concentration (12.6 ± 3.3 vs. 3.8 ± 2.1 mU/l, P = 0.05), and total cholesterol and triglycerides (4.68 ± 0.31 vs. 4.25 ± 0.35 mmol/l, P < 0.05, 1.27 ± 0.19 vs. 0.95 ± 0.21 mmol/l, P < 0.001, respectively). There was no change in any variable in the placebo-treated patients. This study demonstrates that subcutaneous administration of rhIGF-I decreases insulin requirements and improves the plasma lipid profile while maintaining glycemie control in adults with IDDM. The excess nocturnal release of GH, characteristic of IDDM, is also decreased by rhIGF-I therapy. Exogenous rhIGF-I therapy may have a role in the treatment of adults with IDDM, particularly in the setting of abnormal lipids and a high insulin requirement.

To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes. ispartof: Diabetes Care vol:35 issue:2 pages:252-258 ispartof: location:United States status: published