8 5 MONDAY their last infusion. Key changes from baseline to one year after last infusion were: HbA1c declined from 7.7+1.3% (mean+SD) to 6.2+0.9; C-peptide increased from 0.1+0.2 ng/mL to 1.3+1.1; and the proportion experiencing severe hypoglycemia events (80% pre-transplant) declined to 10%. About one-third of the recipients experienced one or more serious adverse events that were deemed related to either procedural or immunosuppression factors. In all but 14 patients, these events resolved without complications. One of the fi ve reported deaths was due to viral meningitis. Ten cases of neoplasm were reported. Conclusions: Islet transplantation in 1999-2007 represents a promising procedure for vastly improving glycemic control and nearly eliminating severe hypoglycemia. Procedural complications have been virtually eliminated. Undesirable effects of immunosuppression need to be balanced against the benefi ts of the procedure. The registry is growing large enough to begin identifying factors that affect success and identify the patients best suited for islet transplantation. The British Columbia Islet Transplant Program is conducting a prospective, crossover, cohort study comparing intensive medical therapy and islet cell transplantation (ICT) on the progression of diabetic retinopathy, nephropathy and neuropathy. A cohort of 44 patients was enrolled between January 2002 -January 2005. All patients began intensive medical therapy upon enrollment and then crossed-over to transplantation when an appropriate donor became available. Patients received immunosuppression with ATG induction, followed by tacrolimus and mycophenylate together with > 12,000 islet equivalents (IE) /kg from 1 -4 donors. 31 patients received 64 islet infusions. They were followed for an average duration of 39 months post-ICT and 37 months for medical treatment. Analysis was by intention to treat and endpoints were prespecifi ed before the study began. We present an interim analysis of outcomes. Comparison of median HbA1c (%) for all subjects showed 7.5±1.2 for medical versus 6.7±0.9 for ICT (p<0.01). Retinopathy was assessed using 7-fi eld stereo fundus photography and graded using the international scale. Progression was defi ned as nonproliferative retinopathy advancing by 1 or more levels or proliferative retinopathy reaching a severity that qualifi ed for laser treatment. Progression occurred signifi cantly more often in subjects on medical therapy (10/82 eyes) than after ICT (0/51 eyes) (p < .01). Considering only ICT subjects, progression occurred in 6/51 eyes while on medical treatment than post ICT (0/51) (p < .02). The primary endpoint for nephropathy was rate of change in GFR measured by blood clearance of 99mTc-DPTA measured every 6 months. GFR values were analysed by linear regression to calculate the rate of change for each subject. Individual patient results were combined to determine the mean intrapatient rate of change in GFR. Change in GFR did not differ for ICT (-3.8 ± 12.7 ml/ min/yr) compared with medical (-5.1 ± 8.4). Both...
Proinsulin (PI) is processed to mature insulin by prohormone convertases 1/3 (Pcsk1) and 2 (Pcsk2). In individuals with T1D and T2D, there is an increase in the circulating PI:insulin ratio. We hypothesized that beta-cell Pcsk1 deletion would result in beta-cell dysfunction and hyperglycemia. Male and female Pcsk1flox/flox Ins1cre/+ (Pcsk1beta-KO) and Pcsk1+/+ Ins1cre/+ (Pcsk1beta-WT) mice were fed either a chow or a high fat diet (HFD; 45% fat) and monitored until 30 weeks of age. Despite an approximately 150-fold increase in fasting plasma PI (p < 0.001) and only immature insulin granules detectable by electron microscopy, chow-fed Pcsk1beta-KO male mice had normal glucose tolerance early in life and only developed glucose intolerance by 26 weeks of age (AUC: 934±294 vs. 597±223; p = 0.008). Histological analysis showed that male Pcsk1beta-KO mice displayed a trend toward increased beta-cell area (1.3±0.6 vs. 0.8±0.4%; p = 0.08). The unexpectedly mild hyperglycemia in Pcsk1beta-KO mice is likely due to incomplete disruption of proinsulin processing, as mass spectrometry and western blot analysis of Pcsk1beta-KO islets confirmed markedly elevated proinsulin, but detectable mature insulin. In HFD-fed cohorts, 3/10 Pcsk1beta-KO male mice developed sustained fasting hyperglycemia (>16 mM) after 19 weeks of diet. Chow and HFD-fed female Pcsk1beta-KO mice displayed no differences in glycemia or body weight from Pcsk1beta-WT controls. Deletion of both Pcsk1 and Pcsk2 in beta cells (Pcsk1flox/flox Pcsk2flox/flox Ins1cre/+) resulted in undetectable mature insulin in islets (western blot), and impaired glucose tolerance at 10 weeks of age in both chow-fed male and female mice. Our results suggest that beta-cell Pcsk1 deficiency is not sufficient to drive diabetes development, but increases diabetes susceptibility in conditions of increased insulin secretory demand. Our data in mice support the idea that beta-cell prohormone processing errors likely contribute to pathogenesis of diabetes but not obesity. Disclosure A. Taylor: None. Y. Chen: None. B. Verchere: Advisory Panel; Self; Integrated Nanotherapeutics Inc., Sirona Biochem. Stock/Shareholder; Self; Integrated Nanotherapeutics Inc. Funding Canadian Institutes of Health Research (PJT153156)
The interactions of glucose, acetylcholine and gastric inhibitory polypeptide in the regulation of insulin secretion were examined using the in situ perfused rat pancreas. Acetylcholine (1 × 10–6M) had no effect on the release of immunoreactive insulin in the presence of 2.2 × 10–3M glucose. However, in the presence of 4.4, 6.6 or 8.9 × 10–3M glucose, the same concentration of acetylcholine stimulated insulin secretion approximately fourfold. At the highest glucose concentration tested (17.8 × 10–3M), the stimulatory effect of acetylcholine on insulin release was less pronounced. The insulin response to acetylcholine was potentiated by the presence of gastric inhibitory polypeptide. This potentiation was most marked when the peptide was present at a concentration of 1 × 10–9M, whereas the effect of concomitant infusion of acetylcholine and 2 × 10–10M gastric inhibitory polypeptide was only slightly greater than additive. Both atropine (1 × 10–6M) and hexamethonium (1 × 10–4M) inhibited the insulin response to acetylcholine. However, neither of these cholinergic antagonists had a significant effect on glucose- or gastric inhibitory polypeptide-stimulated insulin secretion. These results demonstrate that the insulinotropic action of acetylcholine is glucose-dependent. A synergistic interaction may exist between acetylcholine and gastric inhibitory polypeptide at the β-cell which does not involve glucose or gastric inhibitory polypeptide acting on cholinergic receptors in the pancreas. Cholinergic stimulation of insulin secretion in the perfused rat pancreas appears to be mediated by both muscarinic receptors on the β-cell and nicotinic receptors, presumably on intrapancreatic ganglia.
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