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The importance of glucose metabolic changes and inflammatory responses to these changes connect diabetes and Alzheimer’s disease (AD). The role intracellular insulin may have in this process could provide for alternative therapeutic approaches. In this study a novel cholesteryl ester based vesicle called a CholestosomeTM, that encapsulates payloads at a high drug to lipid ratio has been used to study the effect of intracellular delivery of insulin on the expression of AD and inflammatory markers in neural cell lines. CholestosomeTM-encapsulated molecules, including insulin, have been delivered to a number of different cell types in vitro and in vivo. Prior studies in rodents have shown the potential for oral delivery of insulin using cholestosomeTM technology with a high tissue to plasma ratio in several tissues, including brain. The present study measured the relative expression of AD (APP, BACE, presenilin 1 and 2, clusterin and GSK3B) and inflammatory (MMP-9, TLR-4, IL-1beta and TNF-alpha) markers determined after delivery of Insulin (I) and CholestosomeTM encapsulated insulin (CHI) to several neural cell lines. In this preliminary comparative study the impact of insulin (I) versus CHI on RNA expression of these markers differed depending on neural subtype and marker type. Disclosure M. McCourt: None. L. Mielnicki: None. J. Hughes: None. M.Q. Irving: None. J. Schentag: Stock/Shareholder; Self; TheraSyn. H. Ghanim: None. P. Dandona: Research Support; Self; JDRF. Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk Inc.

Since liraglutide suppresses plasma glucagon concentrations and dapagliflozin increases glucagon concentrations, although both improve glycemia in patients with type 1 diabetes, we have now investigated whether they alter the concentrations of the two other products of the proglucagon gene, GLP-1 and GLP-2. Thirty patients with type 1 diabetes, treated with liraglutide for 26 weeks were randomized into receiving dapagliflozin 10 mg daily (n=20) or placebo (n=10) for 12 weeks. Fasting blood samples were obtained prior to liraglutide treatment, at the onset of dapagliflozin treatment and at the end of dapagliflozin treatment. At the end of 26 weeks liraglutide treatment and then 12 weeks of dapagliflozin therapy, mean HbA1c fell by 0.31±0.19% (NS) and 0.66±0.22% (p=0.0004), respectively. There was a significant increase in the plasma concentrations of GLP-1 (by 89±24%, from 30.4±5.1pM to 48.6±8.2pM, P=0.001) but not GLP-2 after 26 weeks of liraglutide treatment with a fall in glucagon levels. Dapagliflozin treatment induced a further significant increase in plasma GLP-1 (by 72±24%, from 48.6±8.2pM to 70.8±9.2pM, P=0.001) and caused an increase in GLP-2 concentrations (by 48±18%, from 2.01±0.42ng/ml to 2.97±0.51pM, P=0.01) along with an increase in glucagon concentrations. We conclude that while liraglutide suppresses glucagon, it induces an increase in GLP-1 concentrations. In addition, dapagliflozin increases both GLP-1 and GLP-2 concentrations while also increasing glucagon. Disclosure H. Ghanim: None. K. Green: None. P. Dandona: Advisory Panel; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi.

DEPICT-1 and -2 (NCT02268214, NCT02460978) were near identical studies assessing DAPA 5 and 10 mg as add-on to insulin (INS) in T1D. Here we present an analysis of the pooled population from the two studies. Safety data were available for 548, 566 and 532 patients (pts) in the DAPA 5 mg, 10 mg and placebo (PBO) groups, respectively and efficacy data for 530, 529 and 532 pts in each group, respectively. Baseline characteristics were similar between groups. Overall mean (SD) age was 43 (14) years, BMI 28 (5) kg/m2, duration of T1D 20 (12) years and HbA1c 8.5 (0.7)%. At week (week) 24 and 52 DAPA decreased HbA1c, systolic blood pressure (BP) and weight vs. PBO (Table). At week 24, INS dose was decreased with DAPA 5 mg (−8.3%) and 10 mg (−10.5%) but increased with PBO (+1.4%); this pattern was also seen up to week 52. More DAPA vs. PBO pts achieved HbA1c reduction ≥0.5% without severe hypoglycemia (hypo; Table). Safety of DAPA was consistent with previous observations in T1D and T2D. Severe hypo was balanced across groups. Events adjudicated as definite diabetic ketoacidosis (DKA) occurred more frequently with DAPA vs. PBO (in 3.8 vs. 1.1% of pts after 52 weeks); most were of mild or moderate intensity. In conclusion, over 52 weeks in this large group of pts with T1D, DAPA provided glycemic, weight and BP benefits along with reductions in INS, increased DKA events, but with a low frequency of severe hypo. Disclosure P. Dandona: Advisory Panel; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. C. Mathieu: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Speaker's Bureau; Self; AstraZeneca, Novartis AG, Novo Nordisk A/S, Sanofi. M. Phillip: Consultant; Self; Qulab Medical, RSP Systems A/S. Research Support; Self; Bristol-Myers Squibb Company, Dexcom, Inc., JDRF, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., OPKO. Stock/Shareholder; Self; DreaMed Diabetes, Ltd., NG Solutions Ltd., Nutriteen Professional Ltd. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Insulet Corporation, Medtronic MiniMed, Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. L. Hansen: Employee; Self; AstraZeneca, MedImmune. Stock/Shareholder; Self; Bristol-Myers Squibb Company, Novo Nordisk A/S. F.A. Thoren: Employee; Self; AstraZeneca. M.F. Scheerer: Employee; Self; AstraZeneca. J. Xu: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. Funding AstraZeneca

The DEPICT-2 trial (NCT02460978) evaluated the efficacy and safety of dapagliflozin (DAPA) as add-on to adjustable insulin (INS) in patients (pts) with inadequately controlled T1D (A1c 7.5-10.5%) over 24 weeks. This phase 3 study randomized pts 1:1:1 to DAPA 5 mg (n=271), 10 mg (n=270) or placebo (PBO; n=272) plus INS. INS dose could be adjusted by the investigator according to self-monitored blood glucose readings, local guidance and individual circumstances. At Week 24, DAPA 5 and 10 mg significantly decreased A1c (0.37% and 0.42% reductions in the DAPA 5 mg and 10 mg groups respectively), total daily insulin dose (TDD), and body weight (Table). As measured by masked continuous glucose monitoring (CGM), mean interstitial glucose, mean amplitude of glucose excursion (MAGE) and mean percent of readings within target glycemic range (>70-≤180 mg/dL) vs. PBO were improved. There was an increase in pts who reduced their A1c by ≥0.5% without severe hypoglycemia (odds ratios [95% CI]: 2.71 [1.81, 4.06] and 3.07 [2.05, 4.60] for DAPA 5 and 10 mg respectively). Hypoglycemic events, including severe hypoglycemia were balanced between treatment groups. There were more adjudicated definite diabetic ketoacidosis (DKA) events on DAPA. In conclusion, DAPA vs. PBO as add-on to INS in pts with T1D was well tolerated, improved glycemic control and decreased variability without increasing hypoglycemia but with more DKA events. Week 24 outcomesDAPA 5 mg + INS (n=271)DAPA 10 mg + INS (n=270)Placebo + INS (n=272)HbA1c, % Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 8.45 (0.69) −0.34 (0.05) −0.37 (−0.49, −0.26) 70-≤180 mg/dL, % Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 43.50 (12.43) 5.92 (0.82) 9.02 (6.97, 11.06) Disclosure C. Mathieu: Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novartis AG. Advisory Panel; Self; Novartis AG, Bristol-Myers Squibb Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca, Pfizer Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Hanmi Pharmaceutical. Research Support; Self; Roche Diagnostics Corporation. Advisory Panel; Self; Roche Diagnostics Corporation. Research Support; Self; Medtronic. Advisory Panel; Self; Medtronic, MannKind Corporation. Research Support; Self; Intrexon. Advisory Panel; Self; Intrexon, Dianax, UCB, Inc.. Research Support; Self; Abbott. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. P. Gillard: None. P.A. Senior: Consultant; Self; Abbott, AstraZeneca. Research Support; Self; AstraZeneca, Prometic Life Sciences Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc., Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., Abbott. Research Support; Self; Viacyte, Inc.. C. Hasslacher: None. E. Araki: Speaker's Bureau; Self; Astellas Pharma US, Inc., MSD K.K., Kowa Pharmaceuticals America, Inc., Sanofi, Novo Nordisk Inc.. Research Support; Self; Astellas Pharma US, Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Takeda Pharmaceuticals U.S.A., Inc., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Sanofi, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama?Pharmaceutical Co. M. Lind: Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eli Lilly and Company. Advisory Panel; Self; MSD K.K.. Research Support; Self; Pfizer Inc.. Consultant; Self; Medtronic. S.C. Bain: Research Support; Self; Novo Nordisk Inc., AstraZeneca. S. Jabbour: None. N. Arya: Employee; Self; AstraZeneca. F.A. Thoren: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca.

We have previously demonstrated that a 12-week addition of liraglutide to insulin therapy in patients with type 1 diabetes (T1D) results in an improvement in glycemic control, weight loss and a reduction in systolic blood pressure (SBP). We have now conducted a 1 year randomized study investigating effects of liraglutide in patients with T1DM. All patients had T1D for at least one year, were on insulin therapy and had no detectable c-peptide in plasma (mean BMI: 28.9±1.4kg/m2, mean HbA1c: 7.82±0.16%, mean age: 46.7±1.9 years, mean age of T1D diagnosis: 22.3±1.7 years). They were randomized to receive placebo, (n=20) or 1.8mg Liraglutide (n= 26) daily for 52 weeks. Continues glucose monitoring (CGM) was performed for 4 weeks before and at end of treatment. At the end of 52 weeks treatment with liraglutide, placebo adjusted HbA1c fell significantly by 0.57±0.17% (p=0.006 vs. placebo) from 7.920.15± to 7.45±0.12% (p=0.009). Weekly placebo adjusted average blood glucose fell by 15±4mg/dl (p=0.014 vs. placebo) from 174±5 to 156±6mg/dl (p=0.021) and fasting weekly glucose fell by 8±7mg/dl (p=0.075 vs. placebo) from 165±7 to 153±9mg/dl (p=0.032). There was no change in reported incidences of hypoglycemia and no change in percent time spent below 70mg/dl based on CGM. Total insulin dose did not alter. There was a significant weight loss by 2.5±0.9kg (placebo adjusted, p=0.041 vs. placebo) from 83.6±4.1 to 80.5±4.0kg (p=0.01) in the liraglutide group. Placebo corrected SBP also fell following liraglutide treatment by 9±3mmHg (p=0.031) from 128±3 to 122±3 mmHg while placebo adjusted diastolic BP fell by 5±1mmHg from (79±2 to 75±2mmHg). We conclude that the addition of liraglutide to insulin treatment in type 1 diabetes significantly reduced HbA1c, mean and fasting blood glucose, blood pressure and body weight without significant increase in hypoglycemia. Disclosure P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. H. Ghanim: None. N.D. Kuhadiya: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S, Janssen Scientific Affairs, LLC.. Advisory Panel; Self; AstraZeneca. Consultant; Self; Dexcom, Inc.. T. Shah: None. J.M. Hejna: None. A. Makdissi: Speaker's Bureau; Self; Eli Lilly and Company. M. Batra: Speaker's Bureau; Self; Eli Lilly and Company. A. Chaudhuri: Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc..

Improved glycemic control and weight loss, without increased hypoglycemia, were demonstrated in two short-term, 24-week, Phase 3 studies of the SGLT2 inhibitor dapagliflozin (DAPA) as adjunct to adjustable insulin in patients with inadequately controlled T1D (DEPICT-1 and 2). In this post-hoc analysis we pooled continuous glucose monitoring (CGM) data at baseline and week 24 from both studies. In total, 1591 patients were included (DAPA 5 mg N=530; DAPA 10 mg N=529; placebo N=532). Baseline characteristics were comparable between the study groups. DAPA treatment significantly reduced mean interstitial glucose, mean amplitude of glucose excursions (MAGE), and postprandial glucose, while expanding the time in glycemic target range (>70 mg/dL to ≤180 mg/dL)(Table). In addition, DAPA treatment did not increase the percent of glucose readings ≤70 mg/dL or ≤54 mg/dL, or the percent of readings ≤70 mg/dL in the nocturnal period (00:00 to 05:59). These results demonstrate that DAPA as adjunct to insulin in patients with T1D reduced glycemic variability without increasing time in the hypoglycemia range.Table. Pooled CGM parametersCGM parameterTreatment armMean baseline value (SD)Mean Week 24 value (SD)Adjusted mean change from baseline (SE)Difference vs. placebo (95% CI)Mean 24-hour glucose readings (mg/dL)DAPA 5 mg193.00 (28.78)179.93 (32.41)-8.40 (1.30)−15.48 (−18.82, −12.13)DAPA 10 mg191.00 (28.11)174.87 (26.59)–11.82 (1.32)−18.90 (−22.25, − 15.54)Placebo191.64 (29.04)194.34 (32.62)7.07 (1.33)MAGE (mg/dL)DAPA 5 mg170.53 (30.55)154.67 (34.21)–12.48 (1.37)−13.36 (−16.89, −9.83)DAPA 10 mg171.01 (31.59)154.52 (34.52)–13.06 (1.39)−13.94 (−17.48, −10.40)Placebo168.99 (31.46)166.94 (31.62)0.88 (1.40)Percent of 24-hour glucose values within >70 – ≤180 mg/dL (%)DAPA 5 mg43.38 (12.22)51.69 (14.49)6.48 (0.60)9.07 (7.55, 10.59)DAPA 10 mg43.98 (12.32)53.89 (13.26)8.08 (0.60)10.67 (9.15, 12.20)Placebo43.66 (12.64)43.10 (13.97)–2.59 (0.61)Percent of glucose readings ≤70 mg/dL over 24-hours (%)DAPA 5 mg4.96 (4.64)4.85 (4.89)–0.43 (0.21)0.06 (–0.47, 0.59)DAPA 10 mg5.30 (4.90)5.10 (4.44)–0.33 (0.21)0.16 (–0.38, 0.69)Placebo5.14 (5.56)4.83 (4.72)–0.49 (0.21)Percent of glucose readings ≤54 mg/dL (%)DAPA 5 mg2.22 (2.87)2.02 (2.83)–0.32 (0.13)–0.14 (–0.47, 0.19)DAPA 10 mg2.34 (3.13)2.05 (2.63)–0.34 (0.13)–0.16 (–0.48, 0.17)Placebo2.28 (3.82)2.15 (3.15)–0.19 (0.13)Postprandial glucose readings by CGM (mg/dL)DAPA 5 mg199.42 (40.51)192.97 (43.90)–0.85 (1.99)–8.55 (–13.70, –3.41)DAPA 10 mg196.61 (38.57)186.93 (36.21)–5.05 (2.02)–12.76 (–17.93, –7.58)Placebo197.35 (42.32)199.68 (44.36)7.70 (2.03)Percent of nocturnal (00:00–05:59) glucose values ≤70 mg/dL (%)DAPA 5 mg5.94 (7.64)5.95 (8.26)–0.38 (0.36)–0.15 (–1.07, 0.78)DAPA 10 mg5.52 (7.22)6.00 (7.60)–0.18 (0.37)0.06 (–0.87, 0.99)Placebo5.83 (7.74)5.85 (7.64)–0.24 (0.37) Disclosure C. Mathieu: Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novartis AG. Advisory Panel; Self; Novartis AG, Bristol-Myers Squibb Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca, Pfizer Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Hanmi Pharmaceutical. Research Support; Self; Roche Diagnostics Corporation. Advisory Panel; Self; Roche Diagnostics Corporation. Research Support; Self; Medtronic. Advisory Panel; Self; Medtronic, MannKind Corporation. Research Support; Self; Intrexon. Advisory Panel; Self; Intrexon, Dianax, UCB, Inc.. Research Support; Self; Abbott. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. M. Phillip: Other Relationship; Self; Sanofi, Medtronic MiniMed, Inc., Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Merck & Co., Inc., Bristol-Myers Squibb Company, Kamada, Lexicon Pharmaceuticals, Inc.. Other Relationship; Self; DreaMed Diabetes, Ltd.. Speaker's Bureau; Self; Abbott. T. Oron: None. L. Hansen: Employee; Self; MedImmune. F.A. Thoren: Employee; Self; AstraZeneca. J. Xu: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca.

In the short term (24-week) period of the Phase 3 study DEPICT-1, treatment with the SGLT2 inhibitor dapagliflozin (DAPA) as adjunct to adjustable insulin (INS) improved glycemic control and was well-tolerated in patients with inadequately controlled T1D (HbA1c 7.5-10.5%) (Lancet Diabetes Endocrinol. 2017;5:864-76). Here we describe the 28-week extension of DEPICT-1, assessing the 52-week efficacy and safety of DAPA in patients who completed the 24-week period. 747 patients in the DAPA 5 mg (n=250), 10 mg (n=270), or placebo (PBO; n=227) plus INS groups entered the long-term period (90% of the randomized patients); 85% completed the study. Reductions in HbA1c and body weight were maintained in the DAPA groups vs. PBO over 52 weeks (Table). The moderate decrease in HbA1c with DAPA was accompanied by a more substantial dose-dependent reduction in body weight. Total events of adjudicated definite DKA increased in the long-term period, with more in the DAPA groups vs. PBO at Week 52. Most were mild or moderate, with the primary cause related to missed insulin doses or pump failure. Adverse events (AEs), serious AEs, and hypoglycemic events were balanced between groups (Table). In conclusion, DAPA plus INS provided a sustained reduction in HbA1c and body weight, and was well-tolerated, but increased events of DKA over 52 weeks in patients with inadequately controlled T1D.Efficacy outcomes at Week 52DAPA 5 mg + INS n=259*DAPA 10 mg + INS n=259*Placebo + INS n=260*A1c, % Week 52 adjusted mean change from baseline (SE) Difference vs PBO (95% CI). -0.27 (0.06) -0.33 (-0.49, -0.17). -0.31 (0.06) -0.36 (-0.53, -0.20). 0.06 (0.06) -Total body weight Week 52 adjusted mean percent change from baseline (SE) Difference vs PBO (95% CI). -2.80 (0.32) -2.95 (-3.83, -2.06). -4.39 (0.31) -4.54 (-5.40, -3.66). 0.15 (0.33) -Safety outcomes at Week 52, n (%)n=277†n=296†n=260†≥1 AE ≥1 SAE ≥1 related SAE ≥1 event of any hypoglycaemia ≥1 event of severe hypoglycaemia Events adjudicated as definite DKA ...Mild ...Moderate ...Severe215 (77.6) 37 (13.4) 8 (2.9) 227 (81.9) 29 (10.5) 12 (4.3) ...5 (1.8) ...3 (1.1) ...4 (1.4)236 (79.7) 40 (13.5) 13 (4.4) 241 (81.4) 25 (8.4) 10 (3.4) ...2 (0.7) ...6 (2.0) ...2 (0.7)189 (72.7) 30 (11.5) 2 (0.8) 212 (81.5) 30 (11.5) 5 (1.9) ...3 (1.2) ...1 (0.4) ...1 (0.4)AE, adverse event; CI, confidence interval; DAPA, dapagliflozin; PBO, placebo; INS, insulin; SAE, serious adverse event; SE, standard error. *n is the number of patients who received 52 weeks of treatment in the full analysis set (excludes the first 55 patients allocated to only DAPA groups due to an interactive voice response system randomization system error). †n is the number of patients who initiated the 24-week period in the safety analysis set (includes the first 55 patients incorrectly randomized to only DAPA groups). ‡Includes events monitored in both 24-week short-term period and 28-week extension. Disclosure P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. C. Mathieu: Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novartis AG. Advisory Panel; Self; Novartis AG, Bristol-Myers Squibb Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca, Pfizer Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Hanmi Pharmaceutical. Research Support; Self; Roche Diagnostics Corporation. Advisory Panel; Self; Roche Diagnostics Corporation. Research Support; Self; Medtronic. Advisory Panel; Self; Medtronic, MannKind Corporation. Research Support; Self; Intrexon. Advisory Panel; Self; Intrexon, Dianax, UCB, Inc.. Research Support; Self; Abbott. M. Phillip: Other Relationship; Self; Sanofi, Medtronic MiniMed, Inc., Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Merck & Co., Inc., Bristol-Myers Squibb Company, Kamada, Lexicon Pharmaceuticals, Inc.. Other Relationship; Self; DreaMed Diabetes, Ltd.. Speaker's Bureau; Self; Abbott. L. Hansen: Employee; Self; MedImmune. D. Tschoepe: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc.. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Servier. Speaker's Bureau; Self; Servier, Sanofi, Novartis Pharmaceuticals Corporation. Research Support; Self; AstraZeneca, Bayer AG, Eli Lilly and Company, Novo Nordisk A/S, Novartis Pharmaceuticals Corporation, Sanofi. F.A. Thoren: Employee; Self; AstraZeneca. J. Xu: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca.

AMP kinase is a key enzyme involved with energy regulation, the intake of macronutrients, the uptake of glucose and fatty acids by cells and the metabolic combustion of fatty acids. We hypothesized that in patients with hypogonadism associated with diabetes, its expression and activity are diminished since there is a quantitative and qualitative loss of skeletal muscle function. Twenty-two men with HH and T2DM were compared with 20 eugonadal men with T2DM at baseline. From the HH patients, 12 were treated with testosterone 200mg every 2 weeks injected intramuscularly for 24 weeks, during which their plasma concentrations were maintained in the physiological range. Hyperinsulinemic, euglycemic clamps (HEC) were carried out prior to and after testosterone replacement and fat (abdomen) and muscle (quadriceps) biopsies were carried out prior to and after HEC procedure on each occasion. In the hypogonadal state, the expression and the activity (measured as phoso-T172-AMPK-α) of AMP kinase-α was significantly lower in HH patients than eugonadal diabetics both in adipose tissue and skeletal muscle by 37% and 29%, respectively, for expression and by 22.1% and 28%, respectively for activity. Following testosterone, there was no change in expression but there was a significant increase in AMP kinase activity by 69±31% (from 14.9±2.8 to 22.8±2.2U/ml, p Disclosure S. Dhindsa: None. H. Ghanim: None. M. Batra: Speaker's Bureau; Self; Eli Lilly and Company. A. Chaudhuri: Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc.. S. Abuaysheh: None. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca.

Aim: To investigate whether the intake of a meal suppresses ketogenesis in patients with type 1 diabetes. Methods: 30 patients with type 1 diabetes with no C-peptide, fasted overnight, were divided into 3 groups of 10 patients each. The first (group 1) continued the fast for 5 hours after arrival in our clinical research unit while the second (group 2) was administered a high fat high calorie (HFHC) meal without preprandial insulin and the third (group 3) was administered the meal with preprandial insulin. Blood samples were obtained prior to and after the meal at hourly intervals for 5 hours. Results: In group 1, glucose and glucagon concentrations remained unchanged while FFA concentrations increased (by 74±16%) as did acetoacetate (AcAc) and beta-hydroxybutyrate (BHB) concentrations (by 52±13% and 64±16%, respectively). In group 2, the intake of the meal without preprandial insulin induced marked increase in glucose, glucagon and FFAs (by 235±32%, 81±18% and 75±17%, respectively) concentrations. However, the meal induced significantly lower increase in AcAc or BHB concentrations (increased by 29±9% and 35±11%, respectively) compared to group 1. In group 3, given preprandial insulin before the meal, there was a significant reduction in glucose and glucagon concentrations as compared to group 2 and a fall in FFA concentrations (by 41±12%) below baseline levels. There was no significant increase in AcAc and BHB. Conclusions: While a prolonged fast was associated with maintenance of glucose and increases in FFA, AcAc and BHB concentrations, the intake of the meal prevented increases in AcAc and BHB in spite of increases in glucose, glucagon and FFA concentrations. These actions are consistent with an anti-ketogenic effect of the meal intake even in type 1 diabetes with an absence of β cell function. Disclosure H. Ghanim: None. K. Green: None. J.M. Hejna: None. N.D. Kuhadiya: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S, Janssen Scientific Affairs, LLC.. Advisory Panel; Self; AstraZeneca. Consultant; Self; Dexcom, Inc. M. Batra: Speaker's Bureau; Self; Eli Lilly and Company. A. Chaudhuri: Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca.

Objective: Since morbid obesity is associated with congestive cardiac failure and hypertension, and gastric bypass surgery is followed by a reduction in blood pressure and a reduction in the risk of congestive cardiac failure, we hypothesized that weight loss following bariatric surgery in morbidly obese patients is associated with a decrease in plasma concentrations of neprilysin, mediators of renin angiotensin system, catecholamines and endothelin-1 with an increase in the concentrations of vasodilators. Method: Fasting blood samples were obtained from fourteen patients with morbid obesity and diabetes prior to and 6 months after Roux-en-Y gastric bypass (RYGB) surgery. Plasma and serum were separated for the measurement of neprilysin; vasoconstrictors, angiotensinogen, renin, angiotensin II, endothelin-1, epinephrine and norepinephrine; and vasodilators, ANP, BNP, cGMP, and cAMP. The mRNA expression of angiotensin converting enzyme (ACE) and adenylate and guanylate cyclases in circulating mononuclear cells (MNC) was also measured. Results: Six months after RYGB, BMI fell from 52.1±4.8 to 40.4±4.0 kg/m2 and there were significant improvements in the HbA1c. Plasma concentrations of neprilysin, angiotensinogen, angiotensin II, renin and endothelin-1 fell significantly by 27±16%, 22±10% 22±8%, 35±13% and 17±6% (p Conclusion: RYGB suppressed neprilysin concentrations, which may contribute the observed increase in plasma ANP concentrations. In addition, RYGB resulted in a reduction in plasma angiotensinogen, angiotensin II, renin and endothelin-1 concentrations. These changes may contribute to the reduction in the risk of congestive cardiac failure and blood pressure after RYGB. Disclosure P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. H. Ghanim: None. S. Monte: Stock/Shareholder; Self; Mobile Pharmacy Solutions (Community Pharmacy). Employee; Self; Synergy Bariatrics, a Department of ECMC. K. Green: None. J.A. Caruana: None.

Dapagliflozin and other SGLT2 inhibitors are known to increase hematocrit. One possible mechanism is glycosuria and polyuria and the loss of fluid from the vascular compartment. However, since type 2 diabetes is a pro-inflammatory state and since hepcidin, a known suppressor of erythropoiesis, is increased in pro-inflammatory states, we investigated the possibility that dapagliflozin suppresses hepcidin concentrations and thus increases erythropoiesis. Twenty-two patients with type 2 diabetes and normal renal function (mean age: 62.1±1.7 years) were randomly treated with placebo or dapagliflozin 10 mg daily for 12 weeks. In the dapagliflozin group, there was a fall in HbA1c from 7.1±0.2% to 6.7±0.2% (p Disclosure H. Ghanim: None. J.M. Hejna: None. S. Abuaysheh: None. T. Shah: None. J. Kumar: None. M. Batra: Speaker's Bureau; Self; Eli Lilly and Company. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca.

Hypothesis. In view of the reduction in post prandial glucose concentrations and an increase in insulin concentrations and the inhibition of post prandial endotoxemia and increases in TLR-4 and TLR-2 expression following the intake of fiber with a high fat high calorie meal (HFHC) in normal subjects, we hypothesized that a similar effect would be observed following the intake with such a meal in patients with type 2 diabetes. Methods. Ten patients with type diabetes were included in the study and were administered the HFHC meal alone on one day and with dietary fiber (28gram of mainly insoluble fiber) a week later. Fasting premeal and post meal samples were obtained sequentially at hourly intervals for 5 hours. Blood samples were processed for preparation of peripheral blood mononuclear cells (MNC), plasma and serum. Results. Post meal glucose concentrations were not altered significantly but the peak increase in post meal insulin concentrations was greater after fiber (34±6 vs. 26±4µU/ml, p Conclusions. The intake of fiber resulted in an early peak of GLP-1 and a greater increase in insulin concentrations but the increase in glucose was not altered. Fiber intake also suppressed ROS generation and NFκB binding while reducing the magnitude of endotoxemia and the receptor to endotoxin. Thus, the intake of fiber increases insulinogenesis and reduces oxidative and inflammatory stress in patients with type 2 diabetes. Disclosure C. Tang: None. H. Ghanim: None. K. Green: None. A. Makdissi: Speaker's Bureau; Self; Eli Lilly and Company. M. Batra: Speaker's Bureau; Self; Eli Lilly and Company. A. Chaudhuri: Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca.

PCSK9 is a major modulator of LDLc through internalization and endosomal degradation of LDL receptor. It has been shown that PCSK9 plasma levels predict CVD risk. Bariatric surgery is known to reduce both LDLc and CVD. However, its exact effect on circulating PCSK9 levels has not been fully investigated. We have now investigated the effect of strict caloric restriction and Roux-en-Y bariatric surgery (RYGB) in 15 morbidly obese patients on plasma PCSK-9 levels. Subjects were instructed to follow a regimen of 4 liquid shakes (up to 16g carbohydrate, 0g fat, and 33g of protein, total daily intake was 550-785 calories) during the 2-weeks strict caloric restriction period prior to surgery and the usual dietary regime after surgery. Blood samples were obtained at 2 weeks before, at the time of surgery and 6 months after RYGB. There was a significant weight loss of 7.8±2.4 Kg during the 2 weeks prior to surgery and of additional 26.6±5.3 Kg 6 months after surgery. At completion of strict caloric restriction, subjects had a significant reductions in glucose, insulin and HOMA-IR (7.1±1.1 to 4.5± 1.0) which continued following surgery (HOMA-IR (4.5±1.0 to 2.1± 0.3). LDL(c) fell significantly by 11±7% (from 120±6 to 109±7mg/dl) following the strict caloric restriction and by 15±8% (from 109±7 to 95±6mg/dl) following surgery. There was a reduction of 38±11% (from 227±25 to 139±15 ng/ml) in plasma PCSK9 concentration in the 2 weeks of caloric restriction. Thereafter, PCSK9 levels increased to 166±22ng/ml over the next 6 months. Our data show that there is an impressive and concurrent fall in PCSK9, LDL(c) concentrations and insulin resistance following strict caloric restriction. The marked weight loss over 6 months has only a marginal effect on PCSK9 concentrations while metabolic improvements persisted. This reduction in PCSK9 may contribute to the known benefit in cardiovascular outcomes following bariatric surgery. Disclosure H. Ghanim: None. S. Abuaysheh: None. S. Monte: Stock/Shareholder; Self; Mobile Pharmacy Solutions (Community Pharmacy). Employee; Self; Synergy Bariatrics, a Department of ECMC. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca.

We have previously demonstrated that the addition of liraglutide to insulin significantly improves the glycemic control in patients with type 1 diabetes (T1D) with undetectable c-peptide. We have now investigated whether the addition of GLP-1 therapy to insulin in c-peptide positive patients with T1D will increase the c-peptide concentrations and improve the glycemia further with reduced insulin requirements. We conducted a retrospective analysis of 11 Caucasian patients with detectable c-peptide and positive GAD-65 antibodies treated with GLP-1 therapy for 12±1 weeks (baseline c-peptide: 0.43±0.09 ng/ml; baseline HbA1c: 10.63±0.87%; mean age: 43±5 years; mean age of diabetes diagnosis: 37±5 years; mean duration of diabetes: 6±2 years; mean BMI: 23± 1Kg/m2; mean body weight: 71±2 kg; 6 females, 5 males). At the end of 12± 1 weeks of GLP-1 therapy; c-peptide concentrations increased significantly from 0.43±0.09 to 1.42±0.42ng/ml(p=0.01); HbA1c fell from 10.63± 0.87% to 7.45± 0.52%(p Disclosure N.D. Kuhadiya: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S, Janssen Scientific Affairs, LLC.. Advisory Panel; Self; AstraZeneca. Consultant; Self; Dexcom, Inc.. B. Prohaska: None. H. Ghanim: None. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca.

Galectin-3 (gal-3) has recently been shown to mediate insulin resistance in mice. Its deletion leads to insulin sensitization while its excess is associated with insulin resistance. We, thus, undertook an investigation into its role in the reversal of insulin resistance in three human models of insulin sensitization: (1) 6 months following bariatric surgery (RYGB) and weight loss in patients with morbid obesity; there was a reduction in BMI from 52.1±4.8 to 40.4±4.0 kg/m2 (p Disclosure P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. H. Ghanim: None. M.S. Shah: None. K. Green: None. A. Makdissi: Speaker's Bureau; Self; Eli Lilly and Company. A. Chaudhuri: Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc..

Subjects with diabetes have a 1.8 times greater risk of having a heart attack than subjects without diabetes. Although cardiovascular mortality has decreased by 30.8% in the last decade, it is still responsible for 1 in 3 deaths in the U.S. (1). In spite of targeting the common risk factors, there is still a residual burden for atherosclerotic cardiovascular disease (ASCVD) (2). As inflammatory processes are involved in every stage of atherosclerosis, targeting inflammation has become an attractive strategy for further reducing the incidence of ASCVD (3). AMP activated kinase (AMPK) is an enzyme that increases cellular ATP generation and diminishes ATP use for less critical processes (4). It regulates the transport of glucose, the synthesis of lipids and proteins, and the rate of fuel metabolism. It is also involved in regulating inflammation and oxidative and ER stress (5). AMPK may thus provide the link between nutrient, metabolic, and inflammatory stimuli. Dysregulation of AMPK may therefore play a role in the pathogenesis of diabetes, hypertension, and ASCVD. On the basis of the information cited above, activation of AMPK could prevent or treat these conditions. Although there is evidence that AMPK activation is atheroprotective, the specific mechanism responsible for this effect is unclear (6). To explore the hypothesis that the atheroprotective effect of AMPK is …

It has been known for five decades that nonesterified fatty acids (NEFAs) have a role in the activation of platelets and thrombosis. Thus, the infusion of NEFAs leads to massive thrombosis and platelet activation (1–4). It has also been shown that their binding to albumin protects the platelets from activation (5). Thus, it follows that a fall in the concentrations of albumin, as in the nephrotic syndrome, would potentially lead to platelet activation. This has been demonstrated in several studies (6). Similarly, any condition that leads to an increase in NEFAs or a decrease in plasma albumin concentrations or a combination of the two would contribute to platelet hyperactivity. Insulin is a potent antilipolytic hormone and thus insulin-resistant states are characterized by accelerated lipolysis and increased NEFA concentrations. This promotes platelet aggregation. In addition, elevated NEFA concentrations interfere with insulin signal transduction and induce insulin resistance (7). NEFAs also induce oxidative and inflammatory stress (8) and thus activate monocytes, which express the prothrombotic tissue factor (TF) on their cell membranes (9). TF activates the extrinsic pathway of thrombin generation and hence may precipitate thrombosis. Activated platelets in patients with diabetes and …

In a recent issue of Diabetes , Vandal et al. (1) showed that the administration of a high-fat diet induced the deposition of β-amyloid in the brains of mice. They also showed that the deposition of amyloid was prevented or reversed by the administration of insulin. These observations are consistent with our previous observation that morbid obesity in the human is …

To test the possible acute proinflammatory effects of fatty acids, we induced an increase in plasma free fatty acid (FFA) concentrations after a lipid and heparin infusion for 4 h in 10 healthy subjects. We determined the nuclear factor-κB (NF-κB) binding activity in mononuclear cells (MNCs), the p65 subunit of NF-κB, reactive oxygen species (ROS) generation by MNC, and polymorphonuclear leukocytes (PMN). Brachial artery reactivity, using postischemic flow-mediated dilation, was also measured. NF-κB binding activity in the MNC nuclear extracts increased to 163 ± 17% and 144 ± 14% as compared with basal levels at 2 and 4 h (P < 0.005) and remained elevated (P < 0.05) at 6 h (2 h after cessation of lipid infusion). NF-κB p65 subunit protein expression in MNC homogenates also increased at 2, 4, and 6 h (P < 0.05). ROS generation by PMNs increased significantly at 2 and 4 h (P < 0.005), whereas that by MNCs increased at 4 h (P < 0.05). Plasma macrophage migration inhibitory factor increased at 2 (P < 0.05) and 4 h (P < 0.005), respectively, and declined to baseline at 6 h. The postischemic flow-mediated dilation of brachial artery decreased from 6.3 ± 1.1% at baseline to 4.3 ± 1.9% and 2.7 ± 2.1% (P < 0.01) at 2, 4, and 6 h, respectively. We conclude that an increase in FFA concentration induces oxidative stress and has a proinflammatory effect; it also impairs postischemic flow-mediated vasodilation of the brachial artery.

An investigation into the possible effect of thyroid stimulating immunoglobulin G on lipogenesis by adipocytes led to the discovery that all human IgGs exerted an insulin-like stimulatory effect on lipogenesis by rat adipocytes in vitro. Highly purified polyclonal IgGs prepared from normal subjects had stimulatory potencies similar to those of monoclonal IgGs obtained from patients with IgG myeloma. However, whole sera from myeloma patients with elevated IgG concentrations had a significantly higher stimulatory effect on adipocyte lipogenesis than control sera. These observations provide the first evidence that human IgG has an insulin-like metabolic effect, and that this effect is probably exerted by a nonspecific nonvariable portion of the IgG molecule. IgG may thus contribute to the non-suppressible insulin-like activity in the serum.

SUMMARY In view of the known effect of zinc on the crystalline nature of insulin, we have investigated whether zinc alters the biologic potency of this hormone. Using the rate of lipogenesis by rat epididymal adipocytes as an index of the biologic potency of insulin, we have shown that zinc exerts a potent stimulatory effect upon lipogenesis in vitro similar to, but quite independently of, insulin and that it has an additive effect with that of insulin when both are incubated together. This effect of zinc on adipocytes and the biologic potency of insulin, hitherto unreported, is of significance at the biologic, pharmacologie, and clinical level.

Transcutaneous oxygen tension (tcPO2) of the legs and feet was measured at 37 and 44 degrees C in 21 patients with diabetes mellitus, 9 of whom had peripheral neuropathy. At 37 degrees C, tcPO2 in the legs and feet of diabetic patients with peripheral neuropathy was significantly higher (P less than .02) than in control subjects and diabetic patients without neuropathy. Whereas tcPO2 in the legs of control subjects and nonneuropathic diabetic patients was greater than in the feet (P less than .02), this leg-to-foot difference was absent in diabetic patients with neuropathy. After an increase in skin temperature to 44 degrees C, tcPO2 increased in the legs and feet of all three groups, but the increase was smallest in diabetic patients with neuropathy and greatest in control subjects. In neuropathic (P less than .02) and nonneuropathic (P less than .02) diabetic patients, tcPO2 was significantly lower than in control subjects. These data are consistent with a loss of vasoconstrictor tone in the blood vessels perfusing skin and subcutaneous tissue at 37 degrees C and an inability of these vessels to vasodilate and increase blood flow at 44 degrees C in diabetic patients in general and neuropathic diabetic patients in particular. This inability to increase tcPO2 after an increase in temperature and possibly other vasodilatory stimuli may contribute to the pathogenesis of nonhealing ulcers, protracted infections, and gangrene, which characterize the diabetic foot.

Vitamin E deficiency is associated with increased platelet aggregation, which can be normalized through vitamin E supplementation. In diabetes, increased platelet thromboxane A2 (TXA2) production is correlated with decreased platelet vitamin E content. We therefore investigated the effect of 400 mg DL-α-tocopherol acetate daily for 4 wk on ADP- and collagen-induced platelet aggregation and platelet TXA2 production in 22 type I (insulin-dependent) diabetic patients without macroangiopathy and with no or only minimal microangiopathy by a double-blind placebo-controlled crossover study. Platelet aggregation was induced in platelet-rich plasma by two or three different concentrations of ADP and collagen. TXA2 was measured by the stable spontaneous breakdown product thromboxane B2 by a specific radioimmunoassay. Whereas metabolic control remained unchanged during the study period, platelet TXA2 production was significantly (P < .05 and P < .01) reduced at each ADP concentration and at two of three collagen concentrations. Because increased TXA2 production of diabetic platelets is thought to play an important pathogenetic role in diabetic angiopathy, we conclude that vitamin E treatment could be beneficial with respect to platelet–vessel-wall interaction and thus might be promising for the prevention of diabetic angiopathy.

The effects of ethanol, acetaldehyde, and the two novel metabolites of ethanol 2,3-butanediol and 1,2-propanediol on basal and insulin-stimulated adipocyte lipogenesis and glucose oxidation in vitro were investigated. Whereas ethanol and acetaldehyde inhibited both processes at concentrations far greater than those found in alcoholic subjects, the two diols were extremely potent inhibitors of basal and insulin-stimulated adipocyte metabolism at concentrations far below those observed in alcoholic subjects. The incorporation of labeled glucose into the fatty acid moiety and glucose oxidation were inhibited at lower concentrations (0.25 μM) than those required to inhibit the incorporation of the labeled glucose into glycerol. The diols are therefore potent inhibitors of basal and insulin-stimulated adipocyte metabolism. This effect may be relevant to the pathogenesis of insulin resistance in alcoholic subjects.

To explain the contradictory data on the secretion of prostacyclin (PGI2) in clinical and experimental diabetes, we have investigated the effect of each of the major metabolic abnormalities in uncontrolled diabetes on vascular PGI2 synthesis. An increase in fatty acid concentrations caused a dose-dependent inhibition of PGI2 synthesis by rat aortic rings in vitro; linoleic and linolenic acids were consistently the most and palmitic the least inhibitory. Glucose had a stimulatory effect between 10 and 30 mmol/L, but a progressive fall in stimulation occurred at higher concentrations. Insulin was inhibitory at 10 and 50 mU/L; however, in combination with glucose (10 mmol/L) it was significantly stimulatory (at 10 mU/L) when the aortic rings were preincubated for 2 and 4 h. A pH of 7.0 or less was significantly inhibitory, whereas ketone bodies had no significant effect on PGI2 synthesis. These data show for the first time that altered metabolic factors in uncontrolled diabetes may have different effects on vascular PGI2 synthesis. These data help explain the variability of observations related to PGI2 synthesis and secretion in diabetes, and advocate a more detailed definition of the metabolic status of patients/animals used in such experiments.