Latent Autoimmune Diabetes in Adults: Background, Safety and Feasibility of an Ongoing Pilot Study With Intra-Lymphatic Injections of GAD-Alum and Oral Vitamin D

BackgroundLatent Autoimmune Diabetes in Adults (LADA) constitutes around 10% of all diabetes. Many LADA patients gradually lose their insulin secretion and progress to insulin dependency. In a recent trial BALAD (Behandling Av LADa) early insulin treatment compared with sitagliptin failed to preserve insulin secretion, which deteriorated in individuals displaying high levels of antibodies to GAD (GADA). These findings prompted us to evaluate a treatment that directly affects autoimmunity. Intra-lymphatic GAD-alum treatment has shown encouraging results in Type 1 diabetes patients. We therefore tested the feasibility of such therapy in LADA-patients (the GADinLADA pilot study).Material and MethodsFourteen GADA-positive (>190 RU/ml), insulin-independent patients 30-70 years old, with LADA diagnosed within < 36 months were included in an open-label feasibility trial. They received an intra-nodal injection of 4 μg GAD-alum at Day 1, 30 and 60 plus oral Vitamin D 2000 U/d from screening 30 days before (Day -30) for 4 months if the vitamin D serum levels were below 100 nmol/L (40 ng/ml). Primary objective is to evaluate safety and feasibility. Mixed Meal Tolerance Test and i.v. Glucagon Stimulation Test at baseline and after 5 and 12 months are used for estimation of beta cell function. Results will be compared with those of the recent BALAD study with comparable patient population. Immunological response is followed.ResultsPreliminary results show feasibility and safety, with almost stable beta cell function and metabolic control during follow-up so far (5 months).ConclusionsIntra-lymphatic GAD-alum treatment is an option to preserve beta cell function in LADA-patients. An ongoing trial in 14 LADA-patients show feasibility and safety. Clinical and immunological responses will determine how to proceed with future trials

Demonstration: Reminiscence using mandala – Workshop for those who may have memories

Based on workshop the article introduces Mandala-method in reminiscence and as a pretext for drama. Artbased-methods and drama are used to discover memories. In the process participants of certain age group go together in groups to discuss various things that occurred during their youth and their childhood. Are memories alike everywhere? What similarities and di erences could be found?

Evidence for Presence and Functional Effects of Kv1.1 Channels in β-Cells: General Survey and Results from mceph/mceph Mice

BACKGROUND:Voltage-dependent K(+) channels (Kv) mediate repolarisation of β-cell action potentials, and thereby abrogate insulin secretion. The role of the Kv1.1 K(+) channel in this process is however unclear. We tested for presence of Kv1.1 in different species and tested for a functional role of Kv1.1 by assessing pancreatic islet function in BALB/cByJ (wild-type) and megencephaly (mceph/mceph) mice, the latter having a deletion in the Kv1.1 gene. METHODOLOGY/PRINCIPAL FINDINGS:Kv1.1 expression was detected in islets from wild-type mice, SD rats and humans, and expression of truncated Kv1.1 was detected in mceph/mceph islets. Full-length Kv1.1 protein was present in islets from wild-type mice, but, as expected, not in those from mceph/mceph mice. Kv1.1 expression was localized to the β-cell population and also to α- and δ-cells, with evidence of over-expression of truncated Kv1.1 in mceph/mceph islets. Blood glucose, insulin content, and islet morphology were normal in mceph/mceph mice, but glucose-induced insulin release from batch-incubated islets was (moderately) higher than that from wild-type islets. Reciprocal blocking of Kv1.1 by dendrotoxin-K increased insulin secretion from wild-type but not mceph/mceph islets. Glucose-induced action potential duration, as well as firing frequency, was increased in mceph/mceph mouse β-cells. This duration effect on action potential in β-cells from mceph/mceph mice was mimicked by dendrotoxin-K in β-cells from wild-type mice. Observations concerning the effects of both the mceph mutation, and of dendrotoxin-K, on glucose-induced insulin release were confirmed in pancreatic islets from Kv1.1 null mice. CONCLUSION/SIGNIFICANCE:Kv1.1 channels are expressed in the β-cells of several species, and these channels can influence glucose-stimulated insulin release

Effects of over-stimulation by glucose on pancreatic beta-cell functioning : studies in vitro with diazoxide

Long term hyperglycemia impairs pancreatic ß-cell function. In vivo studies in rats have shown a decreased glucose-induced insulin response in the perfused pancreas after high glucose infusions. If insulin secretion was blocked by diazoxide in the presence of high glucose, the subsequent insulin response to glucose was restituted, indicating that overstimulation was an important factor behind the impairment. Long term exposure of rat pancreatic islets to high glucose in vitro also resulted in a decreased glucose-induced insulin response, which could be prevented by previous exposure to diazoxide. The after-effect of diazoxide was not present after low glucose culture and not tightly coupled to its interaction with K+-ATP channels. Omitting Ca2+ during cooling completely mimicked the effect of diazoxide indicating that diazoxide acts on both the level of Ca2+ inflow and exocytosis. Also in human islets cultured at 27 mM glucose for 48 h previous diazoxide restituted a glucose-induced insulin response in final incubations. Diazoxide also protected against specific [Ca2+]i abnormalities seen after high glucose culture such as a rise in basal [Ca2+]i and a loss of slow oscillations. On the other hand, diazoxide did not restore a glucose-induced rise in [Ca2+ ]i. Diazoxide protected against over-stimulation also with regard to the adenylate cyclase-cAMP system. Exposing pancreatic islets from GK rats and GK hybrids to diazoxide increased intracellular insulin content. In contrast previous exposure to diazoxide failed to improve an impaired insulin response to glucose Culture of human pancreatic islets at high glucose increased intraislet PI/I (proinsulin/insulin) ratios and PI/I ratios of secretion. Co-culture with diazoxide normalized these parameters. The inclusion of palmitate enhanced PI/I ratios of secretion. This effect was additive to that of glucose. In conclusion, over-stimulation by long term elevated glucose induces several effects that may be harmful to the ß-cell, indicating that inducing "ß-cell rest" may offer a new approach in the treatment of type 2 diabetes

Vem är musikalisk? : en studie av musiklärares uppfattningar om musikalitet

Validerat; 20101217 (root

Vem är musikalisk? : en studie av musiklärares uppfattningar om musikalitet

Validerat; 20101217 (root

A TRPM4 Inhibitor 9-Phenanthrol Inhibits Glucose- and Glucagon-Like Peptide 1-Induced Insulin Secretion from Rat Islets of Langerhans

Pancreatic beta-cells express several ion channels of the transient receptor potential family, which play important roles in mediating the stimulus-secretion coupling. One of these channels, the TRPM4 is a Ca2+-activated monovalent cation channel. This channel is inhibited by 9-phenanthrol, which also inhibits the TMEM16a Cl- channel, and activates the Ca2+-activated K+ channel, K(ca)3.1. The net effects of ion-channel modulation by 9-phenantherol on the insulin secretion remain unclear. We tested the effects of 9-phenanthrol on glucose-and GLP-1-induced insulin secretion from isolated rat islets in static incubations. When applied to the islets in the presence of 3.3mM glucose, 9-phenanthrol caused a small increase in insulin secretion (similar to 7% of the insulin secretion stimulated by 10mM glucose). 10 mu M 9-phenanthrol did not inhibit glucose-or GLP-1-induced insulin secretion. 20 mu M and 30 mu M 9-phenanthrol inhibited glucose-induced insulin secretion by similar to 80% and similar to 85%, respectively. Inhibition of the GLP-1-induced insulin secretion by 20 mu M and 30 mu M 9-phenanthrol was 65% and 94%, respectively. Our study shows that the major effect of 9-phenanthrol on the islets is a strong inhibition of insulin secretion, and we speculate that compounds related to 9-phenanthrol may be potentially useful in treating the pancreatogenous hyperinsulinemic hypoglycemia syndromes