A new protocol for rapid SPECT/CT blood pool imaging consisting of fewer image-angle acquisitions (fewer-angle SPECT/CT, or FASpecT/CT) was evaluated for localization of focal sites of soft-tissue inflammation, infection, and osteomyelitis. Methods: Immediately after dynamic flow and standard planar blood pool imaging with 99mTc-methylene diphosphonate, FASpecT/CT was performed with a dual-head γ-camera consisting of 6 steps over 360°, 12 total images with 30° of separation between angles, and 30 s per image, requiring a total imaging time of approximately 3 min. Images were reconstructed using iterative ordered-subset expectation maximization. Before use in a patient-care setting, various FASpecT/CT acquisition protocols were modeled using a phantom to determine the minimum number of stops and the stop duration required to produce a reliable image. Results: FASpecT/CT images provided excellent 3-dimensional localization of spine osteomyelitis, soft-tissue infection of the foot, and tendonitis of the hand and foot using a 3-min image acquisition time. The FASpecT/CT acquisition protocol required 1.3–3.5 min, including camera movement time. This was a reduction of 72%–90% from the time required for the standard 60-angle, 20-s SPECT/CT acquisition. Conclusion: The ability of FASpecT/CT blood pool images to help localize focal sites of hyperemia and inflammation can increase exam sensitivity and specificity. Additionally, using a FASpecT/CT protocol decreases imaging time by up to 90%.

OBJECTIVE To examine the effect of combination therapy with canagliflozin plus liraglutide on HbA1c, endogenous glucose production (EGP), and body weight versus each therapy alone. RESEARCH DESIGN AND METHODS Forty-five patients with poorly controlled (HbA1c 7–11%) type 2 diabetes mellitus (T2DM) on metformin with or without sulfonylurea received a 9-h measurement of EGP with [3-3H]glucose infusion, after which they were randomized to receive 1) liraglutide 1.2 mg/day (LIRA), 2) canagliflozin 100 mg/day (CANA), or 3) liraglutide 1.2 mg plus canagliflozin 100 mg (CANA/LIRA) for 16 weeks. At 16 weeks, the EGP measurement was repeated. RESULTS The mean decrease from baseline to 16 weeks in HbA1c was −1.67 ± 0.29% (P = 0.0001), −0.89 ± 0.24% (P = 0.002), and −1.44 ± 0.39% (P = 0.004) in patients receiving CANA/LIRA, CANA, and LIRA, respectively. The decrease in body weight was −6.0 ± 0.8 kg (P < 0.0001), −3.5 ± 0.5 kg (P < 0.0001), and −1.9 ± 0.8 kg (P = 0.03), respectively. CANA monotherapy caused a 9% increase in basal rate of EGP (P < 0.05), which was accompanied by a 50% increase (P < 0.05) in plasma glucagon-to-insulin ratio. LIRA monotherapy reduced plasma glucagon concentration and inhibited EGP. In CANA/LIRA-treated patients, EGP increased by 15% (P < 0.05), even though the plasma insulin response was maintained at baseline and the CANA-induced rise in plasma glucagon concentration was blocked. CONCLUSIONS These results demonstrate that liraglutide failed to block the increase in EGP caused by canagliflozin despite blocking the rise in plasma glucagon and preventing the decrease in plasma insulin concentration caused by canagliflozin. The failure of liraglutide to prevent the increase in EGP caused by canagliflozin explains the lack of additive effect of these two agents on HbA1c.

AIM To examine the effect of combination therapy with canagliflozin plus liraglutide versus each agent alone on beta cell function in type 2 diabetes mellitus (T2DM) patients. RESEARCH DESIGN AND METHODS 45 poorly controlled (HbA1c=7-11%) T2DM patients received oral glucose tolerance test (OGTT) before and after 16 weeks of treatment with: (1) liraglutide (LIRA); (2) canagliflozin (CANA); (3) liraglutide plus canagliflozin (CANA/LIRA). RESULTS Both liraglutide and canagliflozin significantly lowered HbA1c with no significant additive effect of the combination on HbA1c (0.89%, 1.43%, and 1.67% respectively). Insulin secretion during the OGTT, measured with (∆C-Pep/∆G)0-120, increased in the three groups (from 0.30±0.06 to 0.48±0.10; 0.29±0.05 to 0.98±0.23; and 0.24±0.06 to 1.09±0.12 in subjects receiving CANA, LIRA and CANA/LIRA respectively, p=0.02 for CANA Vs LIRA, p<0.0001, CANA/LIRA Vs CANA), and the increase in insulin secretion was associated with an increase in beta cell glucose sensitivity (29±5 to 55±11; 33±6 to 101±16; and 28±6 to 112±12, respectively, p=0.01 for CANA Vs LIRA, p<0.0001, CANA/LIRA Vs CANA). No significant difference in the increase in insulin secretion or beta cell glucose sensitivity was observed between subjects in LIRA or CANA/LIRA groups. The decrease in HbA1c strongly and inversely correlated with the increase in beta cell glucose sensitivity (r=0.71, p<0.001). In multivariate regression model, improved beta cell glucose sensitivity was the strongest predictor of HbA1c decrease with each therapy. CONCLUSION Improved beta cell glucose sensitivity with canagliflozin monotherapy and liraglutide monotherapy or in combination is major factor responsible for the HbA1c decrease. Canagliflozin failed to produce an additive effect to improve beta cell glucose sensitivity above that observed with liraglutide.

Sodium–glucose cotransport 2 inhibitors (SGLT2i) lower plasma glucose but stimulate endogenous glucose production (EGP). The current study examined the effect of dapagliflozin on EGP while clamping plasma glucose, insulin, and glucagon concentrations at their fasting level. Thirty-eight patients with type 2 diabetes received an 8-h measurement of EGP ([3-3H]-glucose) on three occasions. After a 3-h tracer equilibration, subjects received 1) dapagliflozin 10 mg (n = 26) or placebo (n = 12); 2) repeat EGP measurement with the plasma glucose concentration clamped at the fasting level; and 3) repeat EGP measurement with inhibition of insulin and glucagon secretion with somatostatin infusion and replacement of basal plasma insulin and glucagon concentrations. In study 1, the change in EGP (baseline to last hour of EGP measurement) in subjects receiving dapagliflozin was 22% greater (+0.66 ± 0.11 mg/kg/min, P < 0.05) than in subjects receiving placebo, and it was associated with a significant increase in plasma glucagon and a decrease in the plasma insulin concentration compared with placebo. Under glucose clamp conditions (study 2), the change in plasma insulin and glucagon concentrations was comparable in subjects receiving dapagliflozin and placebo, yet the difference in EGP between dapagliflozin and placebo persisted (+0.71 ± 0.13 mg/kg/min, P < 0.01). Under pancreatic clamp conditions (study 3), dapagliflozin produced an initial large decrease in EGP (8% below placebo), followed by a progressive increase in EGP that was 10.6% greater than placebo during the last hour. Collectively, these results indicate that 1) the changes in plasma insulin and glucagon concentration after SGLT2i administration are secondary to the decrease in plasma glucose concentration, and 2) the dapagliflozin-induced increase in EGP cannot be explained by the increase in plasma glucagon or decrease in plasma insulin or glucose concentrations.

Objectives and Methods: To examine changes in endogenous glucose production (EGP). Tissue glucose disappearance (Rd) and urinary glucose excretion (UGE) after SGLT2i alone and combined with DPP-4i. We randomized (2:2:1) 56 T2D patients (A1c=8.9±0.2, FPG=178±10, BMI=34±1.3) to receive dapagliflozin 10 mg [n=22, D], dapagliflozin/saxagliptin 10/5 mg [n=22, D/S], placebo [n=12, P]. Subjects received 75 g OGTT (240 min) with [3H-glu] IV and [14C-glu ] orally pre and post treatment (Tx) for 4 months. Results: Post-Tx, A1c increased by 0.1±0.4% in P and decreased (p<001) by 1.4±0.2% in (D) and 1.9±0.3% in (D/S) (p<0.001). FPG decreased by 44 (D) and 56 (D/S) mg/dl (p <0.001) and was unchanged with (P). During OGTT, increment in PG was reduced by 21 (D) and 29 (D/S) (p<0.001) and increased by 12 mg/dl in (P).Pre-Tx, basal EGP was similar in 3 groups (~2.4 mg/kg.min) and decreased by ~50% during OGTT. Post-Tx, despite the marked decrease in FPG, basal EGP increased in both D and D/S; EGP suppression ~50% during OGTT was unchanged in D and D/S. Pre-Tx, UGE (mg/kg.min) during OGTT was negligible in 3 groups: Post-Tx, UGE increased to 1.0±0.1 (D) and 1.1±0.1 (D/S) (p<0.01) but not in P. Pre-Tx, Tissue Rd (mg/kg.min) increased similarly during OGTT in all 3 groups by ~ 40%; Post-Tx, the increase in Tissue Rd was greater (p<0.05) in D (∆1.7±0.3) and D/P (∆3.8±0.3) vs. P (∆1.4±0.2). Pre-Tx, basal glucose clearance (GC) was similar in all 3 groups (~1.4 ml/kg.min) and did not change during OGTT. Post-Tx, both basal GC and GC during OGTT increased (p<0.05-0.01) in D and D/S, without change in plasma insulin/C-peptide conc. Conclusions: D and D/S treatment improved glycemic control by (i) increasing UGE and (ii) augmenting Tissue glucose clearance by ameliorating glucotoxicity, Saxa addition to dapa produced only modest further A1c reduction because it failed to block dapagliflozin-induced stimulation of EGP, even though it increased insulin and decreased glucagon secretion. Disclosure Y. Qin: None. A. Gastaldelli: Consultant; Self; A. Menarini Diagnostics, Eli Lilly and Company, Genentech, Inc., Gilead Sciences, Inc., Inventiva Pharma. M. Abdul-Ghani: None. J.M. Adams: None. A.M. Ali: None. M.M. Eletrebi: None. R.A. Martinez: None. C.L. Triplitt: Consultant; Self; Abbott. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker&s Bureau; Self; AstraZeneca, Novo Nordisk Inc. E. Cersosimo: None. Funding AstraZeneca

To investigate mechanisms responsible for the clinical and metabolic benefits observed with SGLT2i plus DPP-4i therapy, we randomized 30 T2D patients (A1c=8.6±0.2%, BMI=33.1±1.9) to receive dapagliflozin 10 mg [DAPA], dapagliflozin/saxagliptin 10/5 mg [DAPA/SAXA] or placebo [PCB]. Baseline OGTT, glucose kinetics (3-3H-glucose), indirect calorimetry, HbA1c, FPG, FFA, insulin, and glucagon were repeated after 16 weeks of therapy. Results: Insulin secretion (δI/δG)0-120 min during OGTT increased (p<0.05) in DAPA (+0.6±0.1) and DAPA/SAXA (+0.6±0.1), but not in PCB (-0.4±0.20). The Matsuda Index improved (p<0.01) in DAPA (+0.6±0.20) and DAPA/SAXA (+0.7±0.1), but not in PCB (-0.1±0.2). The Disposition Index [IS/IR] increased (p<0.05) in DAPA (δ0.23±0.03) and DAPA/SAXA (δ 0.2±0.02), but not in PCB (δ0.03±0.04). The increase in fasting plasma glucagon in PCB (+37±4) and DAPA (+20±2) was blunted (p<0.05) in combo (-7±4 pg/ml). There were no significant changes in fasting plasma FFA. Conclusion: DAPA/SAXA combination therapy was associated with improved glycemic control vs. DAPA due to the attenuation of the rise in EGP. Further, the increase in glucose Ox in combination with inhibition of lipid Ox and glucagon secretion inhibit ketone production which may reduce the risk of DKA. Addition of SAXA improves insulin secretion and prevents the glucagon elevation induced by DAPA. CharacteristicsPCBDAPADAPA/SAXAp-valueδ BMI (Kg/m2)+0.16±0.27-0.58±0.42-0.77±0.01*<0.05δ HbA1c (%)+0.6±0.2-1.4±0.1-1.7±0.2*<0.01δ FPG (mg/dl)+35±3-59±6-68±8*<0.001Mean OGTT Glu (mg/dl)+41±6-73±8-86±7*<0.001δ Basal EGP (mg/kg.min)+0.26±0.04+0.19±0.04-0.06±0.05**<0.01δ Lipid Ox (%)-8±6+16±3+10±2*<0.001 & ***<0.05δ Glucose Ox (%)+5±4-31±3-17±2*<0.001 &***<0.001*= DAPA & DAPA/SAXA vs. PCB; **=DAPA/SAXA vs. DAPA & PCB; ***=DAPA vs. DAPA/SAXA EGP=Endogenous Glucose Production; Ox: Oxidation Disclosure Y. Qin: None. J.M. Adams: None. R.A. Martinez: None. A. Di Pino: None. H. Al Jobori: None. A.M. Ali: None. C.L. Triplitt: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Sanofi, Novo Nordisk Inc. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc. E. Cersosimo: Research Support; Self; AstraZeneca, VeroScience, LLC.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Janssen Pharmaceuticals, Inc., Eli Lilly and Company.

The decrement in plasma glucose concentration with SGLT2 inhibitors (SGLT2i) is blunted by a rise in endogenous glucose production (EGP). We investigated the ability of incretin treatment to offset the EGP increase. Subjects with type 2 diabetes (n = 36) were randomized to 1) canagliflozin (CANA), 2) liraglutide (LIRA), or 3) CANA plus LIRA (CANA/LIRA). EGP was measured with [3-3H]glucose with or without drugs for 360 min. In the pretreatment studies, EGP was comparable and decreased (2.2 ± 0.1 to 1.7 ± 0.2 mg/kg ⋅ min) during a 300- to 360-min period (P < 0.01). The decrement in EGP was attenuated with CANA (2.1 ± 0.1 to 1.9 ± 0.1 mg/kg ⋅ min) and CANA/LIRA (2.2 ± 0.1 to 2.0 ± 0.1 mg/kg ⋅ min), whereas with LIRA it was the same (2.4 ± 0.2 to 1.8 ± 0.2 mg/kg ⋅ min) (all P < 0.05 vs. baseline). After CANA, the fasting plasma insulin concentration decreased (18 ± 2 to 12 ± 2 μU/mL, P < 0.05), while it remained unchanged in LIRA (18 ± 2 vs. 16 ± 2 μU/mL) and CANA/LIRA (17 ± 1 vs. 15 ± 2 μU/mL). Mean plasma glucagon did not change during the pretreatment studies from 0 to 360 min, while it increased with CANA (69 ± 3 to 78 ± 2 pg/mL, P < 0.05), decreased with LIRA (93 ± 6 to 80 ± 6 pg/mL, P < 0.05), and did not change in CANA/LIRA. LIRA prevented the insulin decline and blocked the glucagon rise observed with CANA but did not inhibit the increase in EGP. Factors other than insulin and glucagon contribute to the stimulation of EGP after CANA-induced glucosuria.

Mitochondrial function has been examined in insulin-resistant (IR) states including type 2 diabetes mellitus (T2DM). Previous studies using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) in T2DM reported results as relative concentrations of metabolite ratios, which could obscure differences in phosphocreatine ([PCr]) and adenosine triphosphate concentrations ([ATP]) between T2DM and normal glucose tolerance (NGT) individuals. We used an image-guided 31P-MRS method to quantitate [PCr], inorganic phosphate [Pi], phosphodiester [PDE], and [ATP] in vastus lateralis (VL) muscle in 11 T2DM and 14 NGT subjects. Subjects also received oral glucose tolerance test, euglycemic insulin clamp, 1H-MRS to measure intramyocellular lipids [IMCL], and VL muscle biopsy to evaluate mitochondrial density. T2DM subjects had lower absolute [PCr] and [ATP] than NGT subjects (PCr 28.6 ± 3.2 vs. 24.6 ± 2.4, P < 0.002, and ATP 7.18 ± 0.6 vs. 6.37 ± 1.1, P < 0.02) while [PDE] was higher, but not significantly. [PCr], obtained using the traditional ratio method, showed no significant difference between groups. [PCr] was negatively correlated with HbA1c ( r = -0.63, P < 0.01) and fasting plasma glucose ( r = -0.51, P = 0.01). [PDE] was negatively correlated with Matsuda index ( r = -0.43, P = 0.03) and M/I ( r = -0.46, P = 0.04), but was positively correlated with [IMCL] ( r = 0.64, P < 0.005), HbA1c, and FPG ( r = 0.60, P = 0.001). To summarize, using a modified, in vivo quantitative 31P-MRS method, skeletal muscle [PCr] and [ATP] are reduced in T2DM, while this difference was not observed with the traditional ratio method. The strong inverse correlation between [PCr] vs. HbA1c, FPG, and insulin sensitivity supports the concept that lower baseline skeletal muscle [PCr] is related to key determinants of glucose homeostasis.

Background: We previously have shown that SGLT2 inhibitors cause an increase in HGP accompanied with an increase in plasma glucagon concentration. We hypothesized that the increase in plasma glucagon concentration is, at least in part, responsible for the increase in HGP. The aim of the present study was to examine whether inhibition of glucagon secretion by liraglutide can prevent the increase in HGP. Research Design and Methods: 51 T2DM patients (age=51±1 yr; 40% female; BMI=34.6±0.7; diabetes duration=6.8±0.8 yr; FPG=175±7; HbA1c=8.3±0.1%) were randomized to receive for 16 weeks: (i) canagliflozin 300 mg; (ii) liraglutide 1.8 mg; or (iii) canagliflozin 300 mg plus liraglutide 1.8 mg. HGP (measured with 3-3H-glucose infusion) and plasma glucagon concentration were measured before and after 16 weeks of treatment. Results: Canagliflozin monotherapy caused a significant reduction in HbA1c (-1.1±0.2%, p<0.01) accompanied with an increase in plasma glucagon concentration (by 28%, p<0.05) and HGP (by 15%, p<0.05) which lasted for 16 weeks. Conversely, liraglutide monotherapy caused a 1.6±0.5% (p<0.01) reduction in HbA1c accompanied by a small (6%) reduction in HGP (P=NS) without significant change in fasting plasma glucagon concentration. The combination of canagliflozin plus liraglutide caused a greater reduction in HbA1c (1.9±0.5%, p<0.vs. canagliflozin and p=NS vs. liraglutide) and attenuated the increase in fasting plasma glucagon and basal HGP at 16 weeks. Conclusion: These results: (1) support a possible role for increased plasma glucagon levels in the long term maintenance of increase in HGP caused by SGLT2i, and (2) suggest that factors other than/in addition to glucagon contribute to the initiation of the increase in HGP. Disclosure M. Abdul-Ghani: None. A.M. Ali: None. R.A. Martinez: None. J.M. Adams: None. E. Cersosimo: Research Support; Self; AstraZeneca, VeroScience, LLC.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Janssen Pharmaceuticals, Inc., Eli Lilly and Company. C.L. Triplitt: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Sanofi, Novo Nordisk Inc. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..