Patient-reported outcomes following islet cell or pancreas transplantation (alone or after kidney) in type 1 diabetes: a systematic review

Aims For selected individuals with complex Type 1 diabetes, pancreatic islet transplantation (IT) offers the potential of excellent glycaemic controlwithout significant hypoglycaemia, balanced by the need for ongoing systemic immunosuppression. Increasingly, patient-reported outcomes (PROs) are considered alongside biomedical outcomes as a measure of transplant success. PROs in IT have not previously been compared directlywith the closest alternate treatment option, pancreas transplant alone (PTA) or pancreas after kidney (PAK).

Methods We used a Population, Intervention, Comparisons, Outcomes (PICO) strategy to search Scopus and screened 314 references for inclusion.

Results Twelve studies [including PRO assessment of PAK, PTA, islet-after kidney (IAK) and islet transplant alone (ITA); n = 7–205] used a total of nine specified and two unspecified PRO measures. Results were mixed but identified some benefits which remained apparent up to 36 months post-transplant, including improvements in fear of hypoglycaemia, as well as some aspects of diabetes-specific quality of life (QoL) and general health status. Negative outcomes included short-term pain associated with the procedure, immunosuppressant side effects and depressed mood associated with loss of graft function.

Conclusions The mixed resultsmay be attributable to limited sample sizes. Also, some PROmeasures may lack sensitivity to detect actual changes, as they exclude issues and domains of life likely to be important forQoL post-transplantation and when patients may no longer perceive themselves to have diabetes. Thus, the full impact of islet ⁄ pancreas transplantation (alone or after kidney) on QoL is unknown. Furthermore, no studies have assessed patient satisfaction, which may highlight further advantages and disadvantages of transplantation.

Amyloid formation in human IAPP transgenic mouse islets and pancreas, and human pancreas, is not associated with endoplasmic reticulum stress

Aims/hypothesis Supraphysiological levels of the amyloidogenic peptide human islet amyloid polypeptide have been associated with beta cell endoplasmic reticulum (ER) stress. However, in human type 2 diabetes, levels of human IAPP are equivalent or decreased relative to matched controls. Thus, we sought to investigate whether ER stress is induced during amyloidogenesis at physiological levels of human IAPP.

Methods Islets from human IAPP transgenic mice that develop amyloid, and non-transgenic mice that do not, were cultured for up to 7 days in 11.1, 16.7 and 33.3 mmol/l glucose. Pancreases from human IAPP transgenic and non-transgenic mice and humans with or without type 2 diabetes were also evaluated. Amyloid formation was determined histologically. ER stress was determined in islets by quantifying mRNA levels of Bip, Atf4 and Chop (also known as Ddit3) and alternate splicing of Xbp1 mRNA, or in pancreases by immunostaining for immunoglobulin heavy chain-binding protein (BIP), C/EBP homologous protein (CHOP) and X-box binding protein 1 (XBP1).

Results Amyloid formation in human IAPP transgenic islets was associated with reduced beta cell area in a glucose- and time-dependent manner. However, amyloid formation was not associated with significant increases in expression of ER stress markers under any culture condition. Thapsigargin treatment, a positive control, did result in significant ER stress. Amyloid formation in vivo in pancreas samples from human IAPP transgenic mice or humans was not associated with upregulation of ER stress markers.

Conclusions/interpretation Our data suggest that ER stress is not an obligatory pathway mediating the toxic effects of amyloid formation at physiological levels of human IAPP.

Recent advances on the roles of NO in cancer and chronic inflammatory disorders

Nitric oxide (NO) is a short-life molecule produced by the enzyme known as the nitric oxide synthase (NOS), in a reaction that converts arginine and oxygen into citrulline and NO. There are three isoforms of the enzyme: neuronal NOS (nNOS, also called NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3). It is now known that each of these isoforms may be expressed in a variety of tissues and cell types. This paper is a review of the current knowledge of various functions of NO in diseases. We discuss in more detail its role in Cancer, the role of NO in myocardial pathophysiology, in central nervous system (CNS) pathologies. Other diseases such as inflammation, asthma, in chronic liver diseases, inflammatory bowel disease (IBD), arthritis, are also discussed. This review also covers the role of NO in cardiovascular, central nervous, pancreas, lung, gut, kidney, myoskeletal and chronic liver diseases (CLD). The ubiquitous role that the simple gas nitric oxide plays in the body, from maintaining vascular homeostasis and fighting infections to acting as a neurotransmitter and its role in cancer, has spurred a lot of interest among researchers all over the world. Nitric oxide plays an important role in the physiologic modulation of coronary artery tone and myocardial function. Nitric oxide from iNOS appears to be a key mediator of such glial-induced neuronal death. The high sensitivity of neurons to NO is partly due to NO causing inhibition of respiration, rapid glutamate release from both astrocytes and neurons, and subsequent excitotoxic death of the neurons.

B-cell loss and B-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition

Amyloid deposition and reduced β-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased β-cell mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased β-cell area quantified on histological sections is correlated with increased β-cell apoptosis. Formalin-fixed, paraffin-embedded human pancreas sections from subjects with (n = 29) and without (n = 39) diabetes were obtained at autopsy (64 ± 2 and 70 ± 4 islets/subject, respectively). Amyloid and β cells were visualized by thioflavin S and insulin immunolabeling. Apoptotic β cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased -cell area, and increased β-cell βapoptosis, as expected. There was a strong inverse correlation between β-cell area and amyloid deposition (r=0.42, P < 0.001). β-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had β-cell area equivalent to islets from control subjects. Increased amyloid deposition was associated with β-cell apoptosis (r= 0.56, P < 0.01). Thus, islet amyloid is associated with decreased β-cell area and increased β-cell apoptosis, suggesting that islet myloid deposition contributes to the decreased β-cell mass that characterizes type 2 diabetes.

Neprilysin impedes islet amyloid formation by inhibition of fibril formation rather than peptide degradation

Deposition of islet amyloid polypeptide (IAPP) as islet amyloid in type 2 diabetes contributes to loss of β-cell function and mass, yet the mechanism for its occurrence is unclear. Neprilysin is a metallopeptidase known to degrade amyloid in Alzheimer disease. We previously demonstrated neprilysin to be present in pancreatic islets and now sought to determine whether it plays a role in degrading islet amyloid. We used an in vitro model where cultured human IAPP (hIAPP) transgenic mouse islets develop amyloid and thereby have increased β-cell apoptosis. Islet neprilysin activity was inhibited or up-regulated using a specific inhibitor or adenovirus encoding neprilysin, respectively. Following neprilysin inhibition, islet amyloid deposition and β-cell apoptosis increased by 54 and 75%, respectively, whereas when neprilysin was up-regulated islet amyloid deposition and β-cell apoptosis both decreased by 79%. To determine if neprilysin modulated amyloid deposition by cleaving hIAPP, analysis of hIAPP incubated with neprilysin was performed by mass spectrometry, which failed to demonstrate neprilysin-induced cleavage. Rather, neprilysin may act by reducing hIAPP fibrillogenesis, which we showed to be the case by fluorescence-based thioflavin T binding studies and electron microscopy. In summary, neprilysin decreases islet amyloid deposition by inhibiting hIAPP fibril formation, rather than degrading hIAPP. These findings suggest that targeting the role of neprilysin in IAPP fibril assembly, in addition to IAPP cleavage by other peptidases, may provide a novel approach to reduce and/or prevent islet amyloid deposition in type 2 diabetes.

Capecitabine and oral cyclophosphamide : a novel oral treatment combination for advanced cancer

Background: This dose escalation study assessed feasibility of a totally oral chemotherapy regimen using cyclophosphamide and capecitabine. The rationale for this combination was based on the observation that preclinical models of cyclophosphamide up-regulated tumor thymidine phosphorylase and increased the activation of capecitabine. Methods: Eligible patients with advanced cancer were treated with oral cyclophosphamide and capecitabine on a 28-day cycle. If no dose limiting toxicities (DLT) were encountered during the first two treatment cycles, the next patient group was assigned to the next highest dose level until the maximum tolerable dose (MTD) was determined. Results: Twenty-seven patients entered treatment. The majority of non-DLT were grades 1 and 2. DLT experienced in the first 8-week observation period were grade 3 diarrhea (one patient, level III) and grade 3 emesis (two patients, level V). MTD was observed at level 5, 1331 mg/m2/day capecitabine days 1–28 with 125 mg/m2/day cyclophosphamide days 1–14 of the 28-day cycle. The recommended phase II dose is therefore 1331 mg/m2/day capecitabine with 100 mg/m2/day cyclophosphamide. The best response evaluation showed four partial responses (breast, colon, ovary and pancreas). Conclusion: Cyclophosphamide and capecitabine can be combined at their full oral single agent dose with promising tolerability and activity.

Effect of pregnancy for females born small on later life metabolic disease risk

There is a strong inverse relationship between a females own birth weight and her subsequent risk for gestational diabetes with increased risk of developing diabetes later in life. We have shown that growth restricted females develop loss of glucose tolerance during late pregnancy with normal pancreatic function. 

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.

Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation

 OBJECTIVE: Evidence indicates an increased risk of certain cancers among people with type 2 diabetes. Evidence for rarer cancers and for type 1 diabetes is limited. We explored the excess risk of site-specific cancer incidence and mortality among people with type 1 and type 2 diabetes, compared with the general Australian population. RESEARCH DESIGN AND METHODS: Registrants of a national diabetes registry (953,382) between 1997 and 2008 were linked to national death and cancer registries. Standardized incidence and mortality ratios (SIRs/SMRs) are reported. RESULTS: For type 1 diabetes, significant elevated SIRs were observed for pancreas, liver, esophagus, colon and rectum (females only [F]), stomach (F), thyroid (F), brain (F), lung (F), endometrium, and ovary, and decreased SIRs were observed for prostate in males. Significantly increased SMRs were observed for pancreas, liver, and kidney (males only), non-Hodgkin's lymphoma, brain (F), and endometrium. For type 2 diabetes, significant SIRs were observed for almost all site-specific cancers, with highest SIRs observed for liver and pancreas, and decreased risks for prostate and melanoma. Significant SMRs were observed for liver, pancreas, kidney, Hodgkin's lymphoma, gallbladder (F), stomach (F), and non-Hodgkin's lymphoma (F). Cancer risk was significantly elevated throughout follow-up time but was higher in the first 3 months postregistration, suggesting the presence of detection bias and/or reverse causation. CONCLUSIONS: Type 1 and type 2 diabetes are associated with an excess risk of incidence and mortality for overall and a number of site-specific cancers, and this is only partially explained by bias. We suggest that screening for cancers in diabetic patients is important.

Privacy-enabled mobile-health (mhealth)-based diabetic solution

Diabetes is one of the leading chronic diseases affecting the lives of millions globally and early detection and treatment of this disease can serve to improve the quality of life for patients as well as suspend further health complications arising from diabetes. Continuous Glucose Monitors (CGM) and Insulin Pumps (IP) have been widely deployed to monitor the sugar levels in the blood stream and inject appropriate amounts of insulin to compensate for the underperforming pancreas functions of the patients’ bodies and thereby may provide appropriate treatment solutions for many diabetic sufferers. With the invention and deployment of Smartphones, the quality and performance associated with treating diabetes has reached new heights, however the privacy and security of mobilebased diabetic systems remain in ongoing challenges. This paper aims to focus on the privacy and security challenges of Mobile-Health (mHealth)-based Diabetic solutions.