One year of sitagliptin treatment protects against islet amyloid-associated β-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice

The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin is an attractive therapy for diabetes, as it increases insulin release and may preserve β-cell mass. However, sitagliptin also increases β-cell release of human islet amyloid polypeptide (hIAPP), the peptide component of islet amyloid, which is cosecreted with insulin. Thus, sitagliptin treatment may promote islet amyloid formation and its associated β-cell toxicity. Conversely, metformin treatment decreases islet amyloid formation by decreasing β-cell secretory demand and could therefore offset sitagliptin's potential proamyloidogenic effects. Sitagliptin treatment has also been reported to be detrimental to the exocrine pancreas. We investigated whether long-term sitagliptin treatment, alone or with metformin, increased islet amyloid deposition and β-cell toxicity and induced pancreatic ductal proliferation, pancreatitis, and/or pancreatic metaplasia/neoplasia. hIAPP transgenic and nontransgenic littermates were followed for 1 yr on no treatment, sitagliptin, metformin, or the combination. Islet amyloid deposition, β-cell mass, insulin release, and measures of exocrine pancreas pathology were determined. Relative to untreated mice, sitagliptin treatment did not increase amyloid deposition, despite increasing hIAPP release, and prevented amyloid-induced β-cell loss. Metformin treatment alone or with sitagliptin decreased islet amyloid deposition to a similar extent vs untreated mice. Ductal proliferation was not altered among treatment groups, and no evidence of pancreatitis, ductal metaplasia, or neoplasia were observed. Therefore, long-term sitagliptin treatment stimulates β-cell secretion without increasing amyloid formation and protects against amyloid-induced β-cell loss. This suggests a novel effect of sitagliptin to protect the β-cell in type 2 diabetes that appears to occur without adverse effects on the exocrine pancreas.

Colon cancer surveillance in inflammatory bowel disease: unclear gain but no psychological pain?

BACKGROUND: Surveillance for colorectal neoplasia in inflammatory bowel disease (IBD) is widely practised despite a lack of convincing mortality reduction. The psychological impact of this approach is largely unexplored. AIM: To examine psychological well-being among IBD subjects undergoing colonoscopic surveillance for colorectal cancer (CRC). METHODS: A cross-sectional study was performed by interrogating an IBD database for subjects currently enrolled in colonoscopic surveillance programmes. Identified surveillance subjects were age- and gender-matched with IBD control subjects not meeting surveillance criteria. Subjects were mailed a questionnaire including demographic details, the Short Form 36 (SF-36) survey to assess quality of life, the Spielberger State-Trait Personality Inventory, the Multidimensional Health Locus of Control, and a Risk Perception Questionnaire. RESULTS: One hundred and thirty-nine of 286 (49%) subjects responded, 53% male, 46% Crohn disease. Fifty-six per cent respondents were in the surveillance group. Surveillance subjects were older (55.4 vs 51.1 years; P = .048) with longer disease duration, but otherwise had comparable demographics with controls. Overall, quality of life was not significantly different between cohorts (mean SF-36 63.82 vs 65.48; P = 0.70). Groups did not differ on any locus of control classification (P = 0.52), nor was there any difference between mean scores on 'state' subscales of the Spielberger State-Trait Personality Inventory: anxiety (P = 0.91), curiosity (P = 0.12), anger (P = 0.81) or depression (P = 0.70). Both groups grossly overestimated their perceived lifetime risk of CRC at 50%, with no difference between surveillance and control subjects (P = 1.0). CONCLUSIONS: Enrolment in colonoscopic colon cancer surveillance does not appear to impair psychological well-being in individuals with IBD despite longer disease duration. IBD patients overestimate their risk of CRC.

Cancer and life-history traits: lessons from host-parasite interactions

Despite important differences between infectious diseases and cancers, tumour development (neoplasia) can nonetheless be closely compared to infectious disease because of the similarity of their effects on the body. On this basis, we predict that many of the life-history (LH) responses observed in the context of host-parasite interactions should also be relevant in the context of cancer. Parasites are thought to affect LH traits of their hosts because of strong selective pressures like direct and indirect mortality effects favouring, for example, early maturation and reproduction. Cancer can similarly also affect LH traits by imposing direct costs and/or indirectly by triggering plastic adjustments and evolutionary responses. Here, we discuss how and why a LH focus is a potentially productive but under-exploited research direction for cancer research, by focusing our attention on similarities between infectious disease and cancer with respect to their effects on LH traits and their evolution. We raise the possibility that LH adjustments can occur in response to cancer via maternal/paternal effects and that these changes can be heritable to (adaptively) modify the LH traits of their offspring. We conclude that LH adjustments can potentially influence the transgenerational persistence of inherited oncogenic mutations in populations.