OBJECTIVE-We sought to determine whether alterations in meal absorption and gastric emptying contribute to the mechanism by which inhibitors of dipeptidyl peptidase-4 (DPP-4) lower postprandial glucose concentrations.RESEARCH DESIGN AND METHODS-We simultaneously measured gastric emptying, meal appearance, endogenous glucose production, and glucose disappearance in 14 subjects with type 2 diabetes treated with either vildaglipitin (50 mg b.i.d.) or placebo for 10 days using a double-blind, placebo-controlled, randomized, crossover design.RESULTS-Fasting (7.3 Ϯ 0.5 vs. 7.9 Ϯ 0.5 mmol/l) and peak postprandial (14.1 Ϯ 0.6 vs. 15.9 Ϯ 0.9 mmol/l) glucose concentrations were lower (P Ͻ 0.01) after vildagliptin treatment than placebo. Despite lower glucose concentrations, postprandial insulin and C-peptide concentrations did not differ during the two treatments. On the other hand, the integrated (area under the curve) postprandial glucagon concentrations were lower (20.9 Ϯ 1.6 vs. 23.7 Ϯ 1.3 mg/ml per 5 h, P Ͻ 0.05), and glucagon-like peptide 1 (GLP-1) concentrations were higher (1,878 Ϯ 270 vs. 1,277 Ϯ 312 pmol/l per 5 h, P ϭ 0.001) during vildagliptin administration compared with placebo. Gastric emptying and meal appearance did not differ between treatments.CONCLUSIONS-Vildagliptin does not alter gastric emptying or the rate of entry of ingested glucose into the systemic circulation in humans. DPP-4 inhibitors do not lower postprandial glucose concentrations by altering the rate of nutrient absorption or delivery to systemic circulation. Alterations in islet function, secondary to increased circulating concentrations of active GLP-1, are associated with the decreased postprandial glycemic excursion observed in the presence of vildagliptin.

Vildagliptin improves islet function in T2DM and improves glucose metabolism in peripheral tissues.

895The purpose of this double-blind, placebo-controlled study was to measure the effects of FTY720, a novel immunomodulator, on heart rate and rhythm in healthy volunteers. Subjects (n = 66) FTY720 is a novel immunomodulator that acts as a sphingosine-1-phosphate (S1P) receptor agonist, thereby reducing the recirculation of lymphocytes to blood and peripheral tissues, including inflammatory lesions and graft sites. [1][2][3][4] In contrast to classic immunosuppressants, FTY720 does not impair cellular or humoral immunity to systemic viral infection and does not affect the activation, expansion, or proliferation of T lymphocytes or immunological memory in preclinical models. 5FTY720 was effective in prolonging allograft survival in preclinical models of cardiac, renal, and hepatic transplantation. 4 Furthermore, a synergistic effect was noted when FTY720 was used in combination with subtherapeutic or therapeutic doses of cyclosporine in a number of different allograft models. 4 The results of phase II clinical studies demonstrated that FTY720 can be used effectively and safely in combination with classic immunosuppressive agents, including cyclosporine 6 and everolimus. 7 FTY720 has been well tolerated in comparative studies conducted in renal transplant recipients to date. However, a recurring finding in these trials has been a reduction in heart rate with initiation of FTY720 treatment. [6][7][8][9] This negative chronotropic effect appears to be temporally associated with the first dose of FTY720. A nadir in heart rate is observed within 4 to 12 hours of drug administration, with heart rate recovering close to baseline within 48 hours after a single dose of FTY720.6-9 The mechanism underlying the effect of FTY720 on heart rate appears to be mediated by its capacity to agonize S1P

Background & Aims Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that predominantly affects young adults with no underlying liver disease. A somatic, 400 Kb deletion on chromosome 19 that fuses part of the DnaJ heat shock protein family (Hsp40) member B1 gene (DNAJB1) to the protein kinase cAMP-activated catalytic subunit alpha gene (PRKACA) has been repeatedly identified in patients with FL-HCC. However, the DNAJB1–PRKACA gene fusion has not been shown to induce liver tumorigenesis. We used the CRISPR/Cas9 technique to delete in mice the syntenic region on chromosome 8 to create a Dnajb1–Prkaca fusion and monitored the mice for liver tumor development. Methods We delivered CRISPR/Cas9 vectors designed to juxtapose exon 1 of Dnajb1 with exon 2 of Prkaca to create the Dnajb1–Prkaca gene fusion associated with FL-HCC, or control Cas9 vector, via hydrodynamic tail vein injection to livers of 8 week-old female FVB/N mice. These mice did not have any other engineered genetic alterations and were not exposed to liver toxins or carcinogens. Liver tissues were collected 14 months after delivery; genomic DNA was analyzed by PCR to detect the Dnajb1–Prkaca fusion, and tissues were characterized by histology, immunohistochemistry, RNA sequencing, and whole-exome sequencing. Results Livers from 12 of the 15 mice given the vectors to induce the Dnajb1–Prkaca gene fusion, but none of the 11 mice given the control vector, developed neoplasms. The tumors contained the Dnajb1–Prkaca gene fusion and had histologic and cytologic features of human FL-HCCs: large polygonal cells with granular, eosinophilic, and mitochondria-rich cytoplasm, prominent nucleoli, and markers of hepatocytes and cholangiocytes. In comparing expression levels of genes between the mouse tumor and non-tumor liver cells, we identified changes similar to those detected in human FL-HCC, which included genes that affect cell cycle and mitosis regulation. Genomic analysis of mouse neoplasms induced by the Dnajb1–Prkaca fusion revealed a lack of mutations in genes commonly associated with liver cancers, as observed in human FL-HCC. Conclusions Using CRISPR/Cas9 technology, we found generation of the Dnajb1–Prkaca fusion gene in wild-type mice to be sufficient to initiate formation of tumors that have many features of human FL-HCC. Strategies to block DNAJB1–PRKACA might be developed as therapeutics for this form of liver cancer.

OBJECTIVE -The purpose of this study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations.RESEARCH DESIGN AND METHODS -We measured insulin secretion and action as well as glucose effectiveness in 14 subjects with type 2 diabetes who received vildagliptin (50 mg b.i.d.) or placebo for 10 days in random order separated by a 3-week washout. On day 9 of each period, subjects ate a mixed meal. Insulin sensitivity (S I ), glucose effectiveness, and ␤-cell responsivity indexes were estimated using the oral glucose and C-peptide minimal models. At 300 min 0.02 unit/kg insulin was administered intravenously.RESULTS -Vildagliptin reduced postprandial glucose concentrations (905 Ϯ 94 vs. 1,008 Ϯ 104 mmol/6 h, P ϭ 0.02). Vildagliptin did not alter net S I (7.71 Ϯ 1.28 vs. 6.41 Ϯ 0.84, P ϭ 0.13) or glucose effectiveness (0.019 Ϯ 0.002 vs. 0.018 Ϯ 0.002 dl ⅐ kg Ϫ1 ⅐ min Ϫ1 , P ϭ 0.65). However, the net ␤-cell responsivity index was increased (35.7 Ϯ 5.2 vs. 28.9 Ϯ 5.2 10 Ϫ9 min Ϫ1 , P ϭ 0.03) as was total disposition index (381 Ϯ 48 vs. 261 Ϯ 35 10Vildagliptin lowered postprandial glucagon concentrations (27.0 Ϯ 1.1 vs. 29.7 Ϯ 1.5 g ⅐ l Ϫ1 ⅐ 6 h Ϫ1 , P ϭ 0.03), especially after administration of exogenous insulin (81.5 Ϯ 6.4 vs. 99.3 Ϯ 5.6 ng/l, P ϭ 0.02).CONCLUSIONS -Vildagliptin lowers postprandial glucose concentrations by stimulating insulin secretion and suppressing glucagon secretion but not by altered insulin action or glucose effectiveness. A novel observation is that vildagliptin alters ␣-cell responsiveness to insulin administration, but the significance of this action is as yet unclear.

Vildagliptin is likely to be a useful therapy for patients with type 2 diabetes based on the inhibition of DPP-4 and the subsequent increase in incretin hormones, GLP-1 and GIP, and the decrease in glucose and glucagon levels.

SummaryObjectives-The incretin hormone glucagon-like peptide-1 (GLP-1) retards gastric emptying and decreases caloric intake. It is unclear whether increased GLP-1 concentrations achieved by inhibition of the inactivating enzyme dipeptidyl peptidase-4 (DPP-4) alter gastric volumes and satiation in people with type 2 diabetes.Methods-In a double-blind, placebo-controlled crossover design, 14 subjects with type 2 diabetes received vildagliptin (50 mg bid) or placebo for 10 days in random order separated by a 2-week washout. On day 7, fasting and postmeal gastric volumes were measured by a 99m Tc single-photon emission computed tomography (SPECT) method. On day 8, a liquid Ensure® meal was consumed at 30 ml/min, and maximum tolerated volume (MTV) and symptoms 30 min later were measured using a visual analogue scale (VAS) to assess effects on satiation. On day 10, subjects ingested water until maximum satiation was achieved. The volume ingested was recorded and symptoms similarly measured using a VAS.Results-Vildagliptin raised plasma GLP-1 concentrations. However, fasting (248 ± 21 vs. 247 ± 19 ml, P = 0·98) and fed (746 ± 28 vs. 772 ± 26 ml, P = 0·54) gastric volumes did not differ when subjects received vildagliptin or placebo. Treatment with vildagliptin did not alter the MTV of Ensure® (1657 ± 308 vs. 1389 ± 197 ml, P = 0·15) or water compared to placebo (1371 ± 141 vs. 1172 ± 156 ml, P = 0·23). Vildagliptin was associated with decreased peptide YY (PYY) concentrations 60 min after initiation of the meal (166 ± 27 vs. 229 ± 34 pmol/l, P = 0·01).Conclusions-Vildagliptin does not alter satiation or gastric volume in people with type 2 diabetes despite elevated GLP-1 concentrations. Compensatory changes in enteroendocrine secretion could account for the lack of gastrointestinal symptoms.

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