[Polyendocrine syndromes in dogs]. / Polyendokrine Syndrome beim Hund.

The autoimmune polyendocrine syndrome (APS) refers to a combination of autoimmune endocrine disorders. It is rarely described in dogs. The most common combinations are hypoadrenocorticism and hypothyroidism, followed by diabetes mellitus, and less often hypoparathyroidism and orchitis. The diagnosis of the APS is based on the diagnosis of each endocrinopathy, as is the therapy, which involves the substitution of deficient hormones. If a patient was previously stable under treatment and is showing further signs (e.g. polyuria, polydipsia, or weight loss), the development of additional endocrinopathies like hypoadrenocorticism or diabetes mellitus should be considered. The diagnosis of the initially diagnosed endocrinopathy should also be critically questioned. This article summarizes some cases of our own animal hospital and selected cases published in the available literature.

Assessment of the FreeStyle Libre 2 interstitial glucose monitor in hypo- and euglycemic cats.

BACKGROUND: Continuous glucose monitoring systems have been validated for eu- and hyperglycemic cats. The FreeStyle Libre 2 (FSL2) is sufficiently accurate in people during hypoglycemia to guide critical treatment decisions without confirmation of blood glucose concentration (BG). OBJECTIVES: Assess FSL2 accuracy in cats with hypoglycemia. ANIMALS: Nine healthy, purpose-bred cats. METHODS: Hyperinsulinemic-hypoglycemic clamps were performed by IV infusion of regular insulin (constant rate) and glucose (variable rate). Interstitial glucose concentration (IG), measured by FSL2, was compared to BG measured by AlphaTrak2. Data were analyzed for all paired measurements (n = 364) and separately during stable BG (≤1 mg/dL/min change over 10 minutes). Pearson's r test, Bland-Altman test, and Parkes Error Grid analysis respectively were used to determine correlation, bias, and clinical accuracy (P < .05 considered significant). RESULTS: Overall, BG and IG correlated strongly (r = 0.83, P < .0001) in stable glycemia and moderately at all rates of change (r = 0.69, P < .0001). Interstitial glucose concentration underestimated BG in euglycemia, but the BG-IG difference was progressively smaller as BG decreased (12.9 ± 12.2, 8.8 ± 11.2, -3.2 ± 7.4, and -7.8 ± 5.2 mg/dL in the ranges of 80-120 [n = 64], 60-79 [n = 29], 50-59 [n = 71], and 29-49 mg/dL [n = 53], respectively). CONCLUSIONS: Although IG underestimates BG throughout most of the hypo-euglycemic range, IG generally overestimates BG in marked hypoglycemia (<60 mg/dL). It is therefore imperative to evaluate FSL2 results in this critical range with caution.

Toceranib phosphate (Palladia) reverses type 1 diabetes by preserving islet function in mice.

In recent years, strategies targeting ß-cell protection via autoimmune regulation have been suggested as novel and potent immunotherapeutic interventions against type 1 diabetes mellitus (T1D). Here, we investigated the potential of toceranib (TOC), a receptor-type tyrosine kinase (RTK) inhibitor used in veterinary practice, to ameliorate T1D. TOC reversed streptozotocin-induced T1D and improved the abnormalities in muscle and bone metabolism characteristic of T1D. Histopathological examination revealed that TOC significantly suppressed ß-cell depletion and improved glycemic control with restoration of serum insulin levels. However, the effect of TOC on blood glucose levels and insulin secretion capacity is attenuated in chronic T1D, a more ß-cell depleted state. These findings suggest that TOC improves glycemic control by ameliorating the streptozotocin-induced decrease in insulin secretory capacity. Finally, we examined the role of platelet-derived growth factor receptor (PDGFR) inhibition, a target of TOC, and found that inhibition of PDGFR reverses established T1D in mice. Our results show that TOC reverses T1D by preserving islet function via inhibition of RTK. The previously unrecognized pharmacological properties of TOC have been revealed, and these properties could lead to its application in the treatment of T1D in the veterinary field.

Duration of the diabetic state altered platelet indices from baseline values in a streptozotocin-induced rat model for type 1 diabetes mellitus.

BACKGROUND: Changes in platelet indices in naturally occurring type I diabetes mellitus (T1DM) have been described in several studies. In this study, platelet indices such as platelet count (PLT), plateletcrit (PCT), mean platelet volume (MPV), platelet distribution width (PDW), and MPV to PLT ratio were investigated according to diabetic duration after streptozotocin (STZ)-induced T1DM, as well as for their correlation with glucose. METHODS: Forty healthy adult Wistar rats were randomly assigned to four experimental groups of ten (5 rats of each sex), including the control group, the 7, 14, and 28 days diabetic groups (D7, D14, and D28, respectively). RESULTS: In diabetic groups, plasma glucose was significantly higher than in control (P < 0.01). D7, D14, and D28 groups presented significantly lower PLT than the control (P < 0. 01). A significant decrease in PCT was observed in D14 and D28 females (P < 0.05). Mean platelet volume was significantly higher in the D28 group than in to control. D28 females also showed a significant difference in PLT, MPV, and the MPV-to-PLT ratio compared with D7 females (P < 0.05). A comparison between D28 females and males showed a significant difference in PDW (P < 0.05). Both females and males showed a significant correlation between glucose and PLT, PCT, MPV, and the MPV-to-PLT ratio. CONCLUSIONS: Platelet indices change significantly with the duration of diabetes compared with the baseline values, and female and male rats did not have significant differences in platelet indices in any period except the 28 days.

Effects of gradient high-field static magnetic fields on diabetic mice.

Although 9.4 T magnetic resonance imaging (MRI) has been tested in healthy volunteers, its safety in diabetic patients is unclear. Furthermore, the effects of high static magnetic fields (SMFs), especially gradient vs. uniform fields, have not been investigated in diabetics. Here, we investigated the consequences of exposure to 1.0-9.4 T high SMFs of different gradients (>10 T/m vs. 0-10 T/m) on type 1 diabetic (T1D) and type 2 diabetic (T2D) mice. We found that 14 h of prolonged treatment of gradient (as high as 55.5 T/m) high SMFs (1.0-8.6 T) had negative effects on T1D and T2D mice, including spleen, hepatic, and renal tissue impairment and elevated glycosylated serum protein, blood glucose, inflammation, and anxiety, while 9.4 T quasi-uniform SMFs at 0-10 T/m did not induce the same effects. In regular T1D mice (blood glucose ≥16.7 mmol/L), the >10 T/m gradient high SMFs increased malondialdehyde ( P<0.01) and decreased superoxide dismutase ( P<0.05). However, in the severe T1D mice (blood glucose ≥30.0 mmol/L), the >10 T/m gradient high SMFs significantly increased tissue damage and reduced survival rate. In vitro cellular studies showed that gradient high SMFs increased cellular reactive oxygen species and apoptosis and reduced MS-1 cell number and proliferation. Therefore, this study showed that prolonged exposure to high-field (1.0-8.6 T) >10 T/m gradient SMFs (35-1 380 times higher than that of current clinical MRI) can have negative effects on diabetic mice, especially mice with severe T1D, whereas 9.4 T high SMFs at 0-10 T/m did not produce the same effects, providing important information for the future development and clinical application of SMFs, especially high-field MRI.

Exploration of autoantibody responses in canine diabetes using protein arrays.

Canine diabetes has been considered a potential model of human type 1 diabetes (T1D), however the detection of autoantibodies common in humans with T1D in affected dogs is inconsistent. The aim of this study was to compare autoantibody responses in diabetic and healthy control dogs using a novel nucleic acid programmable protein array (NAPPA) platform. We performed a cross-sectional study of autoantibody profiles of 30 diabetic and 30 healthy control dogs of various breeds. Seventeen hundred human proteins related to the pancreas or diabetes were displayed on NAPPA arrays and interrogated with canine sera. The median normalized intensity (MNI) for each protein was calculated, and results were compared between groups to identify candidate autoantibodies. At a specificity of 90%, six autoantibodies had sensitivity greater than 10% (range 13-20%) for distinguishing diabetic and control groups. A combination of three antibodies (anti-KANK2, anti-GLI1, anti-SUMO2) resulted in a sensitivity of 37% (95% confidence interval (CI) 0.17-0.67%) at 90% specificity and an area under the receiver operating characteristics curve of 0.66 (95% CI 0.52-0.80). While this study does not provide conclusive support for autoimmunity as an underlying cause of diabetes in dogs, future studies should consider the use of canine specific proteins in larger numbers of dogs of breeds at high risk for diabetes.

Effects of dapagliflozin in combination with insulin on cytochrome P450 activities in a diabetes type 1 rat model.

Previous studies reported that diabetes alters the activities of hepatic cytochrome P450 (CYP) enzymes, which, in turn, affects the disposition of some drugs. We herein examined and compared the effects of the combination of dapagliflozin with a low insulin dose, a full dose of insulin alone, and dapagliflozin alone for 3 and 8 weeks on CYP activities in a diabetes type 1 rat model. We induced type 1 diabetes in rats using a single intraperitoneal injection of 60 mg/kg streptozotocin (STZ). Daily treatment with the full dose of insulin alone, dapagliflozin alone, or dapagliflozin in combination with a low dose of insulin was then initiated. STZ-induced rats developed marked hyperglycemia and altered CYP2E activities. Dapagliflozin in combination with a low dose of insulin stabilized hyperglycemia and CYP1A, 2D, 2E and 3A activities. However, dapagliflozin alone did not improve blood glucose levels or CYP activities. These results suggest that the effects of dapagliflozin in combination with a low dose of insulin are similar to those of a full dose of insulin, and stabilize CYP activities in type 1 diabetes.

Autoimmune polyendocrine syndrome with hypoadrenocorticism and diabetes mellitus in a dog: A rare case.

BACKGROUND: Autoimmune polyendocrine syndrome, also called polyglandular autoimmune syndrome, is a rare immune-mediated disorder that involves various endocrine glands. PURPOSE: To report autoimmune polyendocrine syndrome in a dog. METHODS: A 9-year-old spayed female miniature poodle diagnosed with insulin-dependent diabetes mellitus emergently visited our clinic for anorexia, severe depression, and vomiting. Hyponatremia, hypochloridemia, and recurrent hypoglycaemia were found. Hypoadrenocorticism was diagnosed based on consistent clinical signs and repeated adrenocorticotropic hormone stimulation tests. RESULTS: After injecting deoxycorticosterone pivalate and increasing the oral prednisolone dose, the patient's systemic condition improved. CONCLUSIONS: To the best of our knowledge, this is the first case report of hypoadrenocorticism concurrent with diabetes mellitus in a dog. Furthermore, we would like to present the probability of an immune-mediated disorder with multiple organs involved, like type IV autoimmune polyendocrine syndrome in humans.

Sex difference feeding behaviour of NOD SCID mice in a pharmacological model of type 1 diabetes.

This study aimed to assess the sex differences in the feeding behaviour of non-obese diabetic severe combined immunodeficient (NOD SCID) mice in a pharmacological model of type 1 diabetes mellitus (T1Dm). In our study, we chose NOD SCID mice of both sexes and assessed their feeding behaviour, body weight, body fat and water content under identical experimental conditions and diets. After 1 month of diabetes mellitus in mice in the experimental group, males and females did not show any increase in body weight, and they weighed significantly less than the control group. However, compared with the control group, in females with a background of T1Dm, there was a significant decrease in body fat. The amount of water consumed in the experimental groups was higher than that in the control groups. The amount of food consumed by males increased when they increased their water consumption, whereas food consumption in females decreased significantly with an increase in water consumption. Thus, we discovered sex differences in the feeding behaviour, body weight and body fat and water content in the pharmacological model of T1Dm after 1 month in NOD SCID mice.

Efficacy and safety of allogenic canine adipose tissue-derived mesenchymal stem cell therapy for insulin-dependent diabetes mellitus in four dogs: A pilot study.

Mesenchymal stem cells (MSCs) possess regenerative and immunomodulatory properties and can control the immune dysregulation that leads to ß-cell destruction. Stem-cell transplantation could thus manage insulin-dependent diabetes mellitus (IDDM) in dogs. In this pilot study, we aimed to assess canine adipose tissue-derived MSCs (cAT-MSCs) transplantation as a treatment for canine diabetes mellitus. This study included four dogs with over a year of insulin treatment for IDDM, following diagnosis at the Veterinary Medicine Teaching Hospital of Seoul National University. Allogenic cAT-MSCs were infused intravenously three or five times monthly to dogs with IDDM. Blood and urine samples were obtained monthly. General clinical symptoms, including changes in body weight, vitality, appetite, and water intake were assessed. Three of the four owners observed improvement of vitality after stem cell treatment. Two of the four dogs showed improvement in appetite and body weight, polyuria, and polydipsia. C-peptide has increased by about 5-15% in three of the cases, and fructosamine and HbA1c levels have improved in two of the cases. Hyperlipidemia was resolved in two of the dogs, and there was no concurrent bacterial cystitis in any of the dogs. C-peptide secretion and lipid metabolism are associated with diabetic complications. Improvement in these parameters following the treatment suggests that cAT-MSC transplantation in dogs with IDDM might help to improve their insulin secretory capacity and prevent diabetic complications.

Co-impairment of autonomic and glucagon responses to insulin-induced hypoglycemia in dogs with naturally occurring insulin-dependent diabetes mellitus.

This study aimed to investigate the contributions of two factors potentially impairing glucagon response to insulin-induced hypoglycemia (IIH) in insulin-deficient diabetes: 1) loss of paracrine disinhibition by intra-islet insulin and 2) defects in the activation of the autonomic inputs to the islet. Plasma glucagon responses during hyperinsulinemic-hypoglycemic clamps ([Formula: see text]40 mg/dL) were assessed in dogs with spontaneous diabetes (n = 13) and in healthy nondiabetic dogs (n = 6). Plasma C-peptide responses to intravenous glucagon were measured to assess endogenous insulin secretion. Plasma pancreatic polypeptide, epinephrine, and norepinephrine were measured as indices of parasympathetic and sympathoadrenal autonomic responses to IIH. In 8 of the 13 diabetic dogs, glucagon did not increase during IIH (diabetic nonresponder [DMN]; ∆ = -6 ± 12 pg/mL). In five other diabetic dogs (diabetic responder [DMR]), glucagon responses (∆ = +26 ± 12) were within the range of nondiabetic control dogs (∆ = +27 ± 16 pg/mL). C-peptide responses to intravenous glucagon were absent in diabetic dogs. Activation of all three autonomic responses were impaired in DMN dogs but remained intact in DMR dogs. Each of the three autonomic responses to IIH was positively correlated with glucagon responses across the three groups. The study conclusions are as follows: 1) Impairment of glucagon responses in DMN dogs is not due to generalized impairment of α-cell function. 2) Loss of tonic inhibition of glucagon secretion by insulin is not sufficient to produce loss of the glucagon response; impairment of autonomic activation is also required. 3) In dogs with major ß-cell function loss, activation of the autonomic inputs is sufficient to mediate an intact glucagon response to IIH.NEW & NOTEWORTHY In dogs with naturally occurring, insulin-dependent (C-peptide negative) diabetes mellitus, impairment of glucagon responses is not due to generalized impairment of α-cell function. Loss of tonic inhibition of glucagon secretion by insulin is not sufficient, by itself, to produce loss of the glucagon response. Rather, impaired activation of the parasympathetic and sympathoadrenal autonomic inputs to the pancreas is also required. Activation of the autonomic inputs to the pancreas is sufficient to mediate an intact glucagon response to insulin-induced hypoglycemia in dogs with naturally occurring diabetes mellitus. These results have important implications that include leading to a greater understanding and insight into the pathophysiology, prevention, and treatment of hypoglycemia during insulin treatment of diabetes in companion dogs and in human patients.

Engineered PD-L1-Expressing Platelets Reverse New-Onset Type 1 Diabetes.

The pathogenesis of Type 1 diabetes (T1D) arises from the destruction of insulin-producing ß-cells by islet-specific autoreactive T cells. Inhibition of islet-specific autoreactive T cells to rescue ß-cells is a promising approach to treat new-onset T1D. The immune checkpoint signal axis programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) can effectively regulate the activity of T cells and prevent autoimmune attack. Here, megakaryocyte progenitor cells are genetically engineered to overexpress PD-L1 to produce immunosuppressive platelets. The PD-L1-overexpressing platelets (designated PD-L1 platelets) accumulate in the inflamed pancreas and may suppress the activity of pancreas autoreactive T cells in newly hyperglycemic non-obese diabetic (NOD) mice, protecting the insulin-producing ß-cells from destruction. Moreover, PD-L1 platelet treatment also increases the percentage of the regulatory T cells (Tregs) and maintains immune tolerance in the pancreas. It is demonstrated that the rescue of ß-cells by PD-L1 platelets can effectively maintain normoglycemia and reverse diabetes in newly hyperglycemic NOD mice.

Diabetic remission in a cat treated with an implantable pump to deliver insulin.

A diabetic cat was referred because of poor metabolic control and difficulties the owner experienced injecting insulin. A pump, telemetrically controlled with a smartphone, was implanted subcutaneously to deliver insulin. Before implantation, the pump reservoir was filled with a rapid-acting human recombinant insulin. The insulin was administered through continuous infusion or periodic boluses over 2 weeks while the cat was hospitalized and over another 2 weeks after discharge from the hospital. Adjustments of insulin dosage were performed based on blood glucose concentrations measured with a continuous blood monitoring system (CGMS). The cat achieved diabetic remission that is still lasting after 1 year. The treatment protocol adopted in this cat contributed to achieving remission. The owner's unwillingness to inject insulin into an uncooperative cat was circumvented with the implantable pump. Key clinical message: The implantable subcutaneous pump, telemetrically controlled by a smartphone, easily allowed the clinician to modify the type of administration and the amount of insulin delivered; the concurrent use of a CGMS allowed detection of sudden changes in blood glucose while limiting stress to the cat.

Rémission du diabète chez un chat traité avec une pompe implantable pour administrer l'insuline.Un chat diabétique fut référé pour cause de pauvre contrôle métabolique et des difficultés rencontrées par le propriétaire pour injecter l'insuline. Une pompe, contrôlée par télémétrie avec un téléphone intelligent, fut implantée sous-cutané afin d'injecter l'insuline. Avant l'implantation, le réservoir de la pompe fut rempli avec une insuline humaine recombinante à action rapide. L'insuline était administrée par infusion continue ou des bolus périodiques pendant une période de 2 semaines alors que le chat était hospitalisé et pendant un 2 semaines supplémentaires après avoir obtenu son congé de l'hôpital. Des ajustements du dosage de l'insuline furent effectués sur la base des concentrations de glucose sanguin mesurées par un système continu de surveillance du sang (CGMS). Une rémission du diabète fut possible pour ce chat et persiste toujours après 1 an. Le protocole de traitement adopté chez ce chat a contribué à atteindre cette rémission. La réticence du propriétaire à injecter l'insuline chez un chat non-collaborateur fut contournée par une pompe implantable.Message clinique important :La pompe implantable sous-cutanée, contrôlée par télémétrie avec un téléphone intelligent, a facilement permis au clinicien de modifier le type d'administration et la quantité d'insuline donnée; l'utilisation concomitante d'un CGMS a permis la détection de changements soudains dans la glycémie tout en limitant le stress au chat.(Traduit par Dr Serge Messier).

Interim report on the effective intraperitoneal therapy of insulin-dependent diabetes mellitus in pet dogs using "Neo-Islets," aggregates of adipose stem and pancreatic islet cells (INAD 012-776).

We previously reported that allogeneic, intraperitoneally administered "Neo-Islets," composed of cultured pancreatic islet cells co-aggregated with high numbers of immunoprotective and cytoprotective Adipose-derived Stem Cells, reestablished, through omental engraftment, redifferentiation and splenic and omental up-regulation of regulatory T-cells, normoglycemia in autoimmune Type-1 Diabetic Non-Obese Diabetic (NOD) mice without the use of immunosuppressive agents or encapsulation devices. Based on these observations, we are currently testing this Neo-Islet technology in an FDA guided pilot study (INAD 012-776) in insulin-dependent, spontaneously diabetic pet dogs by ultrasound-guided, intraperitoneal administration of 2x10e5 Neo-Islets/kilogram body weight to metabolically controlled (blood glucose, triglycerides, thyroid and adrenal functions) and sedated animals. We report here interim observations on the first 4 canine Neo-Islet-treated, insulin-dependent pet dogs that are now in the early to intermediate-term follow-up phase of the planned 3 year study (> 6 months post treatment). Current results from this translational study indicate that in dogs, Neo-Islets appear to engraft, redifferentiate and physiologically produce insulin, and are rejected by neither auto- nor allo-immune responses, as evidenced by (a) an absent IgG response to the allogeneic cells contained in the administered Neo-Islets, and (b) progressively improved glycemic control that achieves up to a 50% reduction in daily insulin needs paralleled by a statistically significant decrease in serum glucose concentrations. This is accomplished without the use of anti-rejection drugs or encapsulation devices. No adverse or serious adverse events related to the Neo-Islet administration have been observed to date. We conclude that this minimally invasive therapy has significant translational relevance to veterinary and clinical Type 1 diabetes mellitus by achieving complete and at this point partial glycemic control in two species, i.e., diabetic mice and dogs, respectively.

Relative Quantification of Phosphatidylcholine sn-Isomers Using Positive Doubly Charged Lipid-Metal Ion Complexes.

Phosphatidylcholines are the major phospholipid component of most eukaryotic cell membranes. Phosphatidylcholines have been shown to actively participate in regulatory and metabolic processes. Dysfunctional metabolic processes have been linked to human disease and can result in altered phosphatidylcholine structural features, such as permutation of fatty acid connectivity. Assignment and relative quantitation of structural isomers that arise from fatty acid permutation on the phosphatidylcholine backbone, so-called sn-isomers, is difficult with routine tandem mass spectrometry or with liquid chromatography without authentic standards. In this work, we report on the observation that phosphatidylcholines form abundant doubly charged metal ion complexes during electrospray ionization (ESI) and show that these complexes can be used to assign fatty acid moieties, relatively quantify sn-isomers in MS2 experiments, and mass spectrometrically separate phosphatidylcholines from other phospholipid classes in positive ion mode. Addition of Fe2+ salts (20 mol %) to ESI spray solutions affords highly abundant doubly charged metal ion phosphatidylcholine complexes (∼110% of protonated compounds) and allows sensitive fragment ion detection (limit of detection = 100 pM). Higher energy collisional dissociation, collision-induced dissociation, and ultraviolet photodissociation of doubly charged complexes yield two fragment ions for every fatty acid moiety. The latter two tandem MS methods preferentially yield sn-2 associated product ions enabling relative sn-isomer quantification. The analytical utility of doubly charged phosphatidylcholine-metal ion complexes is demonstrated for polar lipid extracts, including extracts from diabetes type 1 and type 2 mouse models, and sn-isomer abundances are derived.

Evaluation of tissue Doppler ultrasonographic and strain imaging for assessment of myocardial dysfunction in dogs with type 1 diabetes mellitus.

OBJECTIVE To investigate cardiac structural and functional changes by tissue Doppler imaging (TDI) and strain imaging in dogs with spontaneous type 1 diabetes mellitus. ANIMALS 30 client-owned dogs, of which 10 had normotensive type 1 diabetes mellitus and 20 were healthy. PROCEDURES All dogs underwent physical examination, laboratory analyses, standard echocardiography, and TDI. RESULTS On TDI and strain imaging, transmitral peak early diastolic velocity (E)-to-tissue Doppler-derived peak early diastolic velocity at basal segment (E') of septum ratio, E:lateral E' ratio, and septal tissue Doppler-derived peak late diastolic velocity at basal segment (A') were significantly higher and the septal E':A' ratio and lateral longitudinal strain were significantly lower for diabetic dogs than for control dogs. Furthermore, in diabetic dogs, serum glucose and fructosamine concentrations after a 12-hour period of food withholding were positively correlated with regional systolic functional variables (septal and lateral longitudinal strain) and left ventricular filling pressure indices (E:septal E' and E:lateral E' ratios) but were negatively correlated with diastolic functional variables (E:transmitral peak late diastolic velocity and septal and lateral E':A' ratios). CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that myocardial function in diabetic dogs may be altered before the development of clinical heart-associated signs and that the change may be more readily detected by TDI and strain imaging than by conventional echocardiography. In addition, findings indicated that hyperglycemia could have detrimental effects on myocardial function, independent of hypertension, other cardiac diseases, and left ventricular hypertrophy, in dogs with type 1 diabetes.

Carbamazepine, a beta-cell protecting drug, reduces type 1 diabetes incidence in NOD mice.

Pancreatic beta-cells are selectively destroyed by the host immune system in type 1 diabetes. Thus, drugs that preserve beta-cell mass and/or function have the potential to prevent or slow the progression of this disease. We recently reported that the use-dependent sodium channel blocker, carbamazepine, protects beta-cells from inflammatory cytokines in vitro. Here, we tested the effects of carbamazepine treatment in female non-obese diabetic (NOD) mice by supplementing LabDiet 5053 with 0.5% w/w carbamazepine to achieve serum carbamazepine levels of 14.98 ± 3.19 µM. Remarkably, diabetes incidence over 25 weeks, as determined by fasting blood glucose, was ~50% lower in carbamazepine treated animals. Partial protection from diabetes in carbamazepine-fed NOD mice was also associated with improved glucose tolerance at 6 weeks of age, prior to the onset of diabetes in our colony. Less insulitis was detected in carbamazepine treated NOD mice at 6 weeks of age, but we did not observe differences in CD4+ and CD8+ T cell composition in the pancreatic lymph node, as well as circulating markers of inflammation. Taken together, our results demonstrate that carbamazepine reduces the development of type 1 diabetes in NOD mice by maintaining functional beta-cell mass.

The Metabolic Responses to L-Glutamine of Livers from Rats with Diabetes Types 1 and 2.

There are several claims about the beneficial effects of supplementing L-glutamine to both type 1 and type 2 diabetes. The purpose of the present study was to provide detailed knowledge about the fate of this amino acid in the liver, the first organ that receives the compound when ingested orally. The study was done using the isolated perfused rat liver, an experimental system that preserves the microcirculation of the organ and that allows to measured several parameters during steady-state and pre steady-state conditions. L-Glutamine was infused in the portal vein (5 mM) and several parameters were monitored. Livers from type 1 diabetic rats showed an accelerated response to L-glutamine infusion. In consequence of this accelerated response livers from type 1 diabetic rats presented higher rates of ammonia, urea, glucose and lactate output during the first 25-30 minutes following L-glutamine infusion. As steady-state conditions approached, however, the difference between type 1 diabetes and control livers tended to disappear. Measurement of the glycogen content over a period of 100 minutes revealed that, excepting the initial phase of the L-glutamine infusion, the increased glucose output in livers from type 1 diabetic rats was mainly due to accelerated glycogenolysis. Livers from type 2 diabetic rats behaved similarly to control livers with no accelerated glucose output but with increased L-alanine production. L-Alanine is important for the pancreatic ß-cells and from this point of view the oral intake of L-glutamine can be regarded as beneficial. Furthermore, the lack of increased glucose output in livers from type 2 diabetic rats is consistent with observations that even daily L-glutamine doses of 30 g do not increase the glycemic levels in well controlled type 2 diabetes patients.