Effects of liraglutide versus sitagliptin on circulating cardiovascular biomarkers, including circulating progenitor cells, in individuals with type 2 diabetes and obesity: Analyses from the LYDIA trial.

The mechanisms behind the beneficial cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) compared with dipeptidyl peptidase-4 inhibitors (DPP4is) remain largely unknown, despite both targeting the incretin pathway to improve glycaemic control. In these prespecified secondary analyses of the LYDIA trial, we examined the impact of the GLP-1RA liraglutide (1.8 mg once-daily) and the DPP4i sitagliptin (100 mg once-daily) on circulating cardiovascular biomarkers associated with atherosclerotic risk, including circulating progenitor cells (CPCs). LYDIA was a 26-week, randomized, active-comparator trial in 61 adults with type 2 diabetes and obesity (mean ± SD: age 43.8 ± 6.5 years, body mass index 35.3 ± 6.4 kg/m2 , HbA1c 7.5% ± 0.83% [58.5 ± 9.1 mmol/mol]). Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1-alpha (SDF-1ɑ), both of which are implicated in endothelial function, were higher at 26 weeks with liraglutide therapy compared with sitagliptin (mean between-group difference [95% CI]: 77.03 [18.29, 135.77] pg/mL, p = .010; and 996.25 [818.85, 1173.64] pg/mL, p < .001, respectively). There were no between-group differences in CPCs, nitric oxide, C-reactive protein, interleukin-6, tumour necrosis factor alpha and advanced glycation end-products. These analyses suggest a favourable impact of liraglutide on VEGF and SDF-1ɑ levels compared with sitagliptin. These factors may therefore be implicated in the differential cardiovascular effects observed between these agents in large cardiovascular outcome trials. However, these are secondary analyses from a previous trial and thus hypothesis-generating. Purposive trials are required to examine these findings further.

A randomized, open-label, active comparator trial assessing the effects of 26 weeks of liraglutide or sitagliptin on cardiovascular function in young obese adults with type 2 diabetes.

AIM: To compare the effects of a glucagon-like peptide-1 receptor agonist and a dipeptidyl peptidase-4 inhibitor on magnetic resonance imaging-derived measures of cardiovascular function. MATERIALS AND METHODS: In a prospective, randomized, open-label, blinded endpoint trial liraglutide (1.8 mg) and sitagliptin (100 mg) were compared in asymptomatic, non-insulin treated young (aged 18-50 years) adults with obesity and type 2 diabetes. The primary outcome was difference in circumferential peak early diastolic strain rate change (PEDSR), a biomarker of cardiac diastolic dysfunction 26 weeks after randomization. Secondary outcomes included other indices of cardiac structure and function, HbA1c and body weight. RESULTS: Seventy-six participants were randomized (54% female, mean ± SD age 44 ± 6 years, diabetes duration 4.4 years, body mass index 35.3 ± 6.1 kg m-2 ), of whom 65% had ≥1 cardiovascular risk factor. Sixty-one participants had primary outcome data available. There were no statistically significant between-group differences (intention-to-treat; mean [95% confidence interval]) in PEDSR change (-0.01 [-0.07, +0.06] s-1 ), left ventricular ejection fraction (-1.98 [-4.90, +0.94]%), left ventricular mass (+1.14 [-5.23, +7.50] g) or aortic distensibility (-0.35 [-0.98, +0.28] mmHg-1 × 10-3 ) after 26 weeks. Reductions in HbA1c (-4.57 [-9.10, -0.37] mmol mol-1 ) and body weight (-3.88 [-5.74, -2.01] kg) were greater with liraglutide. CONCLUSION: There were no differences in cardiovascular structure or function after short-term use of liraglutide and sitagliptin in younger adults with obesity and type 2 diabetes. Longer studies in patients with more severe cardiac dysfunction may be necessary before definitive conclusions can be made about putative pleiotropic properties of incretin-based therapies.

Elevated Levels of Alpha Cells Emanating from the Pancreatic Ducts of a Patient with a Low BMI and Chronic Pancreatitis.

Chronic pancreatitis (CP) is an inflammatory disease that causes progressive damage to the pancreatic parenchyma with irreversible morphological changes and fibrotic replacement of the gland. The risk factors associated with developing CP have been described as toxic (e.g., alcohol and tobacco); idiopathic (e.g., unknown); genetic, autoimmune, recurrent acute pancreatitis, and obstructive (the TIGAR-O system). Upon histological screening of the pancreata from a cohort of CP patients who had undergone pancreatectomy for the treatment of intractable pain in Leicester, UK, one sample showed a striking change in the morphological balance toward an endocrine phenotype, most notably there was evidence of substantial α cell genesis enveloping entire cross sections of ductal epithelium and the presence of α cells within the ductal lumens. This patient had previously undergone a partial pancreatectomy, had severe sclerosing CP, an exceptionally low body mass index (15.2), and diabetes at the time the pancreas was removed, and although these factors have been shown to induce tissue remodeling, such high levels of α cells was an unusual finding within our series of patients. Due to the fact that α cells have been shown to be the first endocrine cell type that emerges during islet neogenesis, future research profiling the factors that caused such marked α cell genesis may prove useful in the field of islet transplantation.

The socio-economic impact of chronic pancreatitis: a systematic review.

RATIONALE, AIMS AND OBJECTIVES: Chronic pancreatitis (CP) is a progressive inflammatory disorder with pain being the most frequent symptom. It is associated with loss of function, pancreatogenic diabetes and digestive enzyme deficiency. The impact of local complications and loss of pancreatic function results in unknown and unreported costs. This study attempts to identify both the direct and indirect costs associated with CP. METHODS: A MEDLINE literature review was performed for all relevant articles relating to any aspect of direct and indirect costs as a result of CP. RESULTS: In the UK, there are 12,000 admissions per annum of patients with CP at an estimated cost of £55.8 million. The costs for loss of pancreatic function are estimated at £45-90 million and $75.1 million for endocrine and exocrine function, respectively. Chronic pain contributes $638 million per year in costs. The protracted course of CP and paucity of monetary data make quantifying direct and indirect costs difficult. An estimate of direct and indirect costs is at £285.3 million per year. This equates to £79,000 per person per year. CONCLUSIONS: Patients with CP consume a disproportionately high volume of resources.

The potential benefit of non-purified islets preparations for islet transplantation.

Since the advent of islet transplantation, there has been a significant emphasis on the importance of islet purity despite an inevitable associated loss of islet mass during the purification process. One of the key elements of the 'Edmonton Protocol' for islet transplantation published in 2000 was an emphasis on the need for sequential transplants of highly purified islets (averaging 24% beta cell purity) and the close correlation between the numbers of islets transplanted and the success of the procedure. However, the emphasis on islet purity may warrant further consideration as auto transplantation of non-purified islets currently provides the most successful insulin independence rates within the field of islet transplantation. While the role of auto and allo immunity could contribute to the differences in the success rates it is clear that within the clinical setting, significant acinar and ductal contamination is well tolerated. However, one could go further and hypothesize that extra-insular tissue including acinar tissue, ductal tissue, peri-pancreatic lymph nodes and vascular tissue actually confer an advantage to islet survival/function and may even contribute to the insulin secreting capacity of the graft post transplant. As such this review will assess the influence of extra-insular pancreatic tissue on the results of islet transplantation based on published evidence and will also explore the possibility that non-islet pancreatic cells are capable of differentiating into a beta cell phenotype in vivo contributing to an ongoing regeneration of endocrine mass during the period following transplantation.

Total pancreatectomy with and without islet cell transplantation for chronic pancreatitis: a series of 85 consecutive patients.

OBJECTIVES: This study examined 85 consecutive patients undergoing total pancreatectomy (+/-islet cell transplant), examining pain relief, insulin requirements, and glycemic control postoperatively. METHODS: A prospective database of all patients undergoing total pancreatectomy for chronic pancreatitis was used to record preoperative and postoperative details from 1996 to 2006. RESULTS: There were 3 postoperative deaths (1 islet recipient and 2 nonislet patients). The median number of acute admissions for pain fell from 5 to 2 after pancreatectomy, and the median length of stay from 6.2 days to 3.3 days. At 12 months postoperatively, the number of patients on regular opiate analgesia fell from 90.6% to 40.2% and by 5 years to 15.9%. There was a significant reduction in the patients' visual analogue pain score after surgery from 9.7 to 3.7 (P < 0.001). Five patients were insulin independent at 5 years. Median 24-hour insulin requirements were significantly lower in the islet group (15.5 vs 40 units at 5 years postoperatively; P < 0.001). CONCLUSIONS: Total pancreatectomy is effective in reducing pain and dependence on opioid analgesia in patients with chronic pancreatitis. The addition of an islet cell transplant results in a reduction in 24-hour insulin demands, as well as potentially achieving insulin independence.

Total pancreatectomy with islet autotransplantation: an overview.

Pain control is one of the most challenging aspects in the management of chronic pancreatitis. Total pancreatectomy can successfully relieve the intractable abdominal pain in these patients but will inevitably result in insulin-dependent diabetes. Islet autotransplantation aims to preserve, as far as possible, the insulin secretory function of the islet cell mass thereby reducing (or even removing) the requirement for exogenous insulin administration after a total pancreactomy. Despite the relatively small number of centres able to perform these procedures, there are important technical variations in the details of their approaches. The aim of this review is to provide details of the current surgical practice for total pancreatectomy combined with islet autotransplantation, and outline the potential advantages and disadvantages of the variations adopted in each centre.

Islet auto transplantation following total pancreatectomy: a long-term assessment of graft function.

UNLABELLED: Total pancreatectomy is considered the final resort in the treatment of chronic pancreatitis; however, here we show that simultaneous islet autotransplantation can abrogate the onset of diabetes. METHODS: : In Leicester, 46 patients have now undergone total pancreatectomy with immediate islet auto transplant, and they have received a median of 2246 islet equivalent (IEQ)/kg body weight (range, 405-20,385 IEQ/kg body weight). RESULTS: : Twelve patients have shown periods of insulin independence, for a median of 16.5 months (range, 2-63 months), and 5 remain insulin independent. Over the 10 years of follow-up, there has been a notable increase in insulin requirement per kilogram per day, and percentage of glycosylated hemoglobin levels have increased significantly (r = 0.66, P = 0.01). However, 100% of patients tested were C-peptide positive at their most recent assessment, and high fasting and stimulated C-peptide values recorded at 10 years after transplantation, 1.44 (range, 1.09-1.8 ng/mL) and 2.86 ng/mL (range, 1.19-4.53 ng/mL), respectively, suggest significant graft function in the long term. In addition, median serum creatinine has increased very little after the operation (71 nmol/L [range, 49-125 nmol/L] atpreoperation vs 76.5 nmol/L [range 72-81 nmol/L] at year 10), suggesting no diabetic nephropathy. CONCLUSIONS: : Although there is a notable decline in islet function after islet auto transplant, there is still evidence of significant long-term insulin secretion and possible protection against diabetic complications.

Immunohistochemical evidence that culture in the high aspect rotating vessel can up-regulate hormone expression in growth dedifferentiated PHHI-derived islet cells.

Islet cells derived from patients with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) have the ability to grow readily in simple culture media. However, as with primary islets and cell lines, they lose hormone expression upon growth. In this study, we have investigated the role of three-dimensional cell-to-cell contact in the reinitiation of hormone expression in growth dedifferentiated PHHI-derived cells. Two main methods of cell aggregation were studied; the promotion of pseudoislets through petri dish culture and the creation of cell aggregates in the microgravity environment of the high aspect ratio vessel (HARV). Immunohistochemical analysis and ELISA assay showed that petri dish culture did not re-establish endocrine expression in any of the five cultures tested. However, through HARV technology, we have demonstrated that it is possible to reactivate insulin, glucagon, somatostatin, and GAD expression in PHHI-derived cells that had previously stopped expressing these markers. These results indicate that the unique environment of the HARV can be conducive to the upregulation of endocrine expression of islet-derived cells and optimization of culture conditions may prove useful in the sphere of beta cell proliferation.