Long-term effects of intracranial islet grafting on cognitive functioning in a rat metabolic model of sporadic Alzheimer's disease-like dementia.

Accumulating evidence suggests that Alzheimer's disease is associated with brain insulin resistance, as are some other types of dementia. Intranasal insulin administration has been suggested as a potential approach to overcoming brain insulin resistance and improving cognitive functions. Islet transplantation into the cranial subarachnoid cavity was used as an alternative route for insulin delivery into the brain.

Intracranial Transplantation of Pancreatic Islets Attenuates Cognitive and Peripheral Metabolic Dysfunctions in a Rat Model of Sporadic Alzheimer's Disease.

Background: Alzheimer's disease (AD) is often associated with brain insulin resistance and peripheral metabolic dysfunctions. Recently, we developed a model of sporadic AD associated with obesity-related peripheral metabolic abnormalities in Lewis rats using intracerebroventricular administration of streptozotocin (icv-STZ).

Objective: We aimed to assess the effect of intracranially grafted pancreatic islets on cognitive and peripheral metabolic dysfunctions in the icv-STZ Lewis rats.

Intracerebroventricular Streptozotocin Induces Obesity and Dementia in Lewis Rats.

Background: Animal models of dementia associated with metabolic abnormalities play an important role in understanding the bidirectional relationships between these pathologies. Rodent strains develop cognitive dysfunctions without alteration of peripheral metabolism following intracerebroventricular administration of streptozotocin (icv-STZ).

Objective: We aimed to estimate the effect of icv-STZ on cognitive functions and peripheral metabolism in Lewis rats, which are rarely used for the induction of cognitive abnormalities.

Insulin delivery to the brain using intracranial implantation of alginate-encapsulated pancreatic islets.

There is increasing evidence supporting a link between cognitive dysfunctions and impaired brain insulin signalling. Insulin therapy has previously been tested as an approach to ameliorate brain insulin resistance and deficiency in patients with various brain disorders. However, current strategies for insulin delivery to the brain may induce severe hypoglycaemia when injected peripherally or show poor uptake when delivered intranasally.

Intracranial pancreatic islet transplantation increases islet hormone expression in the rat brain and attenuates behavioral dysfunctions induced by MK-801 (dizocilpine).

The treatment of rodents with non-competitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor, MK-801 (dizocilpine), induces symptoms of psychosis, deficits in spatial memory and impairment of synaptic plasticity. Recent studies have suggested that insulin administration might attenuate the cognitive dysfunctions through the modulatory effect on the expression of NMDA receptors and on the brain insulin signaling. Intrahepatic pancreatic islet transplantation is known as an efficient tool for correcting impaired insulin signaling.

Anti-diabetic and neuroprotective effects of pancreatic islet transplantation into the central nervous system.

During the last decades, the central nervous system (CNS) was intensively tested as a site for islet transplantation in different animal models of diabetes. Immunoprivilege properties of intracranial and intrathecal sites were found to delay and reduce rejection of transplanted allo-islets and xeno-islets, especially in the form of dispersed single cells. Insulin released from islets grafted in CNS was shown to cross the blood-brain barrier and to act as a regulator of peripheral glucose metabolism.

The efficacy of an immunoisolating membrane system for islet xenotransplantation in minipigs.

Developing a device that protects xenogeneic islets to allow treatment and potentially cure of diabetes in large mammals has been a major challenge in the past decade. Using xenogeneic islets for transplantation is required in light of donor shortage and the large number of diabetic patients that qualify for islet transplantation. Until now, however, host immunoreactivity against the xenogeneic graft has been a major drawback for the use of porcine islets.

Enhanced oxygen supply improves islet viability in a new bioartificial pancreas.

The current epidemic of diabetes with its overwhelming burden on our healthcare system requires better therapeutic strategies. Here we present a promising novel approach for a curative strategy that may be accessible for all insulin-dependent diabetes patients. We designed a subcutaneous implantable bioartificial pancreas (BAP)-the "β-Air"-that is able to overcome critical challenges in current clinical islet transplantation protocols: adequate oxygen supply to the graft and protection of donor islets against the host immune system.

Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist.

Islet transplantation is a feasible therapeutic alternative for metabolically labile patients with type 1 diabetes. The primary therapeutic target is stable glycemic control and prevention of complications associated with diabetes by reconstitution of endogenous insulin secretion. However, critical shortage of donor organs, gradual loss in graft function over time, and chronic need for immunosuppression limit the indication for islet transplantation to a small group of patients.

Induction of beta-cell resistance to hypoxia and technologies for oxygen delivery to transplanted pancreatic islets.

Hypoxia is believed to be a crucial factor involved in cell adaptation to environmental stress. Islet transplantation, especially with immunoisolated islets, interrupts vascular connections, resulting in the substantially decreased delivery of oxygen and nutrients to islet cells. Insulin-producing pancreatic beta cells are known to be highly susceptible to oxygen deficiency.

Different susceptibility of rat pancreatic alpha and beta cells to hypoxia.

Insulin-producing beta cells are known to be highly susceptible to hypoxia, which is a major factor in their destruction after pancreatic islet transplantation. However, whether the glucagon-producing pancreatic islet alpha cells are sensitive to hypoxia is not known. Our objective was to compare the sensitivity of alpha and beta cells to hypoxia.

Tight junction proteins expression and modulation in immune cells and multiple sclerosis.

The tight junction proteins (TJPs) are major determinants of endothelial cells comprising physiological vascular barriers such as the blood-brain barrier, but little is known about their expression and role in immune cells. In this study we assessed TJP expression in human leukocyte subsets, their induction by immune activation and modulation associated with autoimmune disease states and therapies. A consistent expression of TJP complexes was detected in peripheral blood leukocytes (PBLs), predominantly in B and T lymphocytes and monocytes, whereas the in vitro application of various immune cell activators led to an increase of claudin 1 levels, yet not of claudin 5.

A strategy for the engineering of insulin producing cells with a broad spectrum of defense properties.

Insulin-producing pancreatic beta cells are known to be extremely susceptible to the oxidative stress and hypoxia generated following islet transplantation in diabetic patients. We hereby present a novel in vivo selection strategy based on the isolation of insulin-producing cells with enhanced protection after repeated rounds of encapsulation and xenotransplantation. Rat insulinoma INS-1 cells were encapsulated in alginate macrobeads and transplanted in the peritoneal cavity of mice.

The novel multifunctional, iron-chelating drugs M30 and HLA20 protect pancreatic beta-cell lines from oxidative stress damage.

Increasing evidence suggests that oxidative stress (OS)-induced pancreatic beta-cell impairments is involved in diabetes and diabetic complications. Our group has recently synthesized two multifunctional nontoxic, lipophilic, iron-chelating drugs, 5-{N-methyl-N-propargylaminomethyl}-8-hydroxyquinoline (M30) and 5-{4-propargylpiperazin-1-ylmethyl}-8-hydroxyquinoline (HLA20), for the treatment of various OS-mediated pathogeneses. These compounds contain the N-propargylamine cytoprotective moiety of the antiparkinsonian drug rasagiline (Azilect) and the iron-complexing component 8-hydroxyquinoline.

Celiac disease and HLA in a Bedouin kindred.

We report the prevalence of celiac disease (CD) and its relationship with other autoimmune diseases and HLA haplotypes in a Bedouin kindred. Of 175 individuals sampled and typed for autoantibodies and HLA class II genotypes, six (3.4%) members had CD, and an additional 10 (5.

Catalase expression in pancreatic alpha cells of diabetic and non-diabetic mice.

The pancreatic islet beta cells are very sensitive to oxidative stress, probably due to the extremely low level of anti-oxidant enzymes, particularly catalase. In contrast to beta cells, pancreatic alpha cells are significantly more resistant to diabetogenic toxins. However, whether alpha cells express a different level of catalase is not known.

Immobilized microalgal cells as an oxygen supply system for encapsulated pancreatic islets: a feasibility study.

Recently, a novel technique for oxygen supply to immunoisolated islets, which adopts the photosynthetic capacity of microalgae to generate oxygen, has been described. Illuminated alga cells, co-immobilized with islets in one compartment, were capable of restoring glucose-stimulated insulin secretion during perifusion with anoxic medium. In the present study, a new model system for photosynthetic oxygen supply to encapsulated islets, containing two separate compartments-one for oxygen-producing alga cells and the other for insulin-secreting pancreatic islets-is described.

Impact of gastric banding on plasma adiponectin levels.

Background: Several endocrine abnormalities are reported in obesity. In an earlier study, we found that the changes in BMI following laparoscopic adjustable gastric banding (LAGB) were associated with changes in hormone profiles such as insulin and proinsulin. In the current study, we explored the changes in plasma adiponectin levels in morbidly obese subjects who lost abundant weight following LAGB.

Increased prevalence of microvascular complications in type 2 diabetes patients with the metabolic syndrome.

Background: Microvascular complications of diabetes contribute significantly to the disease morbidity. The metabolic syndrome is common among subjects with diabetes and is a very important risk factor for macrovascular complications. However, its contribution to the microvascular complication has not been assessed.

Photosynthetic oxygen generator for bioartificial pancreas.

Immunoisolation of pancreatic islets interrupts their vascular connections and results in severe cell hypoxia and dysfunction. This process is believed to be the major obstacle to a successful cure of diabetes by implantation of bioartificial pancreas. Here we describe a new technology for microalga-based, photosynthetic oxygen supply to encapsulated islets, in which a thermophylic strain of the unicellular alga Chlorella was used as a natural photosynthetic oxygen generator.

The relationship between BMI, plasma leptin, insulin and proinsulin before and after laparoscopic adjustable gastric banding.

Background: Morbid obesity is associated with over-secretion of leptin and insulin, and predisposes to development of carbohydrate intolerance. In the current study, we explored the impact of BMI after laparoscopic adjustable gastric banding (LAGB) on leptin, insulin and proinsulin levels.

Methods: 23 obese patients (8 males, 15 females) were included in the study.

Impact of gastric banding on plasma ghrelin, growth hormone, cortisol, DHEA and DHEA-S levels.

Background: Several endocrine abnormalities are reported in obesity. Some are considered as causative factors, whereas others are considered to be secondary effects of obesity. In the current study, we explored the changes in cortisol, growth hormone (GH), DHEA, DHEA-S and GH releasing hormone (ghrelin) plasma levels in morbidly obese subjects who lost abundant weight following laparoscopic adjustable gastric banding (LAGB).