Impact of PCSK9 inhibitors in glycaemic control and new-onset diabetes.

BACKGROUND: The diabetogenic effect of statins has been well established by clinical trials, Mendelian randomisation studies and meta-analyses. According to large clinical trials, PCSK9 inhibitors (PCSK9i) have no deleterious impact on glucose metabolism. However, few real-life studies have yet evaluated the long-term effects of these drugs on glucose homeostasis and their impact on new-onset diabetes (NODM). METHODS: We studied 218 patients treated with either alirocumab or evolocumab (70% with familial hypercholesterolemia) for at least three years (PCSK9iG). We studied the NODM rate in the nondiabetic group at baseline (168) and overall glucose metabolism control in the whole group. Incidental DM was compared with two groups. The first was a propensity score matching (PSM)-selected group (n = 168) from the database of patients attending the Reus lipid unit (Metbank, n = 745) who were not on PCSK9i (PSMG). The second was a subgroup with a similar age range (n = 563) of the Di@bet.es study (Spanish prospective study on diabetes development n = 5072) (D@G). The incidence was reported as the percentage of NODM cases per year. RESULTS: The fasting glucose (FG) level of the subjects with normoglycaemia at baseline increased from 91 (86-95.5) to 93 (87-101) mg/dL (p = 0.014). There were 14 NODM cases in the PCSK9i group (2.6%/y), all among people with prediabetes at baseline. The incidence of NODM in PSMG and D@G was 1.8%/y (p = 0.69 compared with the PCSK9iG). The incidence among the subjects with prediabetes was 5.1%/y in the PCSK9iG, 4.8%/y in the PSMG and 3.9%/y in the D@G (p = 0.922 and p = 0.682, respectively). In the multivariate analysis, only the FG level was associated with the development of NODM in the PCSK9iG (OR 1.1; 95% CI: 1.0-1.3; p = 0.027). Neither FG nor A1c levels changed significantly in patients with DM at baseline. CONCLUSION: A nonsignificant increase in NODM occurred in the PCSK9iG, particularly in patients with prediabetes, compared with the PSMG and D@G groups. Baseline FG levels were the main variable associated with the development of DM. In the subjects who had DM at baseline, glucose control did not change. The impact of PCSK9i on glucose metabolism should not be of concern when prescribing these therapies.

Maternal age, obesity and hyperglycaemia are associated with a delay in preimplantation embryo development in mouse.

In brief: Fertility has decreased due to advanced maternal age and the rising prevalence of the metabolic syndrome. Using quantitative image analysis methods, we show that these factors are associated with delayed preimplantation embryo development in a mouse model. Abstract: Delayed maternal age, obesity and diabetes are associated with reduced fertility. We investigated how age and obesity/metabolic syndrome impact fertility and hypothesized that its decrease is due to defects in preimplantation embryo development. Three groups of female C57Bl6 mice (12 weeks, 9 months and 1 year old) were fed either a high-fat diet for 8 weeks, to induce obesity and the metabolic syndrome, or a control chow diet. Body weight and composition, glucose tolerance and insulin resistance were assessed. Fecundity was evaluated by mating and pregnancy rates, as well as by the number of embryos. Embryo quality was assessed morphologically, and cell fate composition was analysed in preimplantation embryos by state-of-the-art single-cell quantitative confocal image analysis. The high-fat diet was associated with increased adiposity, glucose intolerance and insulin resistance, especially in the older mice. Fecundity was affected by age more than by the diet. Both age and high-fat diet were associated with reduced cell fate allocation, indicating a delay in the preimplantation embryo development, and with increased expression of GATA3, an inhibitor of placentation. These results support that age and the metabolic syndrome reduce fertility through mechanisms which are present at conception or very early in pregnancy.

Quality, Usability, and Effectiveness of mHealth Apps and the Role of Artificial Intelligence: Current Scenario and Challenges.

The use of artificial intelligence (AI) and big data in medicine has increased in recent years. Indeed, the use of AI in mobile health (mHealth) apps could considerably assist both individuals and health care professionals in the prevention and management of chronic diseases, in a person-centered manner. Nonetheless, there are several challenges that must be overcome to provide high-quality, usable, and effective mHealth apps. Here, we review the rationale and guidelines for the implementation of mHealth apps and the challenges regarding quality, usability, and user engagement and behavior change, with a special focus on the prevention and management of noncommunicable diseases. We suggest that a cocreation-based framework is the best method to address these challenges. Finally, we describe the current and future roles of AI in improving personalized medicine and provide recommendations for developing AI-based mHealth apps. We conclude that the implementation of AI and mHealth apps for routine clinical practice and remote health care will not be feasible until we overcome the main challenges regarding data privacy and security, quality assessment, and the reproducibility and uncertainty of AI results. Moreover, there is a lack of both standardized methods to measure the clinical outcomes of mHealth apps and techniques to encourage user engagement and behavior changes in the long term. We expect that in the near future, these obstacles will be overcome and that the ongoing European project, Watching the risk factors (WARIFA), will provide considerable advances in the implementation of AI-based mHealth apps for disease prevention and health promotion.

Age, Origin and Functional Study of the Prevalent LDLR Mutation Causing Familial Hypercholesterolaemia in Gran Canaria.

The p.(Tyr400_Phe402del) mutation in the LDL receptor (LDLR) gene is the most frequent cause of familial hypercholesterolaemia (FH) in Gran Canaria. The aim of this study was to determine the age and origin of this prevalent founder mutation and to explore its functional consequences. For this purpose, we obtained the haplotypic information of 14 microsatellite loci surrounding the mutation in one homozygous individual and 11 unrelated heterozygous family trios. Eight different mutation carrier haplotypes were identified, which were estimated to originate from a common ancestral haplotype 387 (110-1572) years ago. This estimation suggests that this mutation happened after the Spanish colonisation of the Canary Islands, which took place during the fifteenth century. Comprehensive functional studies of this mutation showed that the expressed LDL receptor was retained in the endoplasmic reticulum, preventing its migration to the cell surface, thus allowing us to classify this LDLR mutation as a class 2a, defective, pathogenic variant.

Ex vivo evaluation of adhesive strength and barrier effect of a novel treatment for esophagitis.

AIM: To investigate the mucoadhesive strength and barrier effect of Esophacare® (Atika Pharma SL, Las Palmas de Gran Canaria) in an ex vivo model of gastro-oesophageal reflux. METHODS: An ex vivo evaluation through the Falling Liquide Film Technique with porcine esophagi was performed, compared to a positive control (Ziverel®; Norgine, Amsterdam), after different washing periods with saline, acidified saline (pH 1.2) and acidified saline with pepsin (2000U/mL). RESULTS: The adhesive mean strength on the oesophageal mucosa of Esophacare was 94.7 (6.0)%, compared to 27.6 (19.1)% of the positive control (p<0.05). These results were homogeneous across the different washes and throughout the tissue. The area covered by 1mL of Esophacare, and its respective persistence after washing was also assessed, yielding a mean global persistence of 74.29 (19.7)% vs. 18.9 (12.3)% for the control (p<0.05). In addition, after 30min exposure to acidified saline with pepsin, Esophacare shows a protective effect on the oesophageal mucosa, detectable histologically: preserved integrity and structure of the apical layers was observed, as well as reduced permeability to the washing solution. CONCLUSIONS: Esophacare shows an adhesive strength close to 100%, irrespective of the washing solution applied or the oesophageal region studied. Histologically, it reduces the abrasive effects of the acidic solution on the oesophageal epithelium, reducing permeability to the washing solution. The results in this ex vivo model of gastro-oesophageal reflux disease (GERD) support its therapeutic potential.

Impact of anxiety, depression and disease-related distress on long-term glycaemic variability among subjects with Type 1 diabetes mellitus.

BACKGROUND: Anxiety, depression, and disease-related distress are linked to worse overall glycaemic control, in terms of HbA1c. This study was aimed to evaluate whether traits of these emotional disorders are associated with long-term glycaemic variability in subjects with Type 1 diabetes. METHODS: Longitudinal retrospective study. Six-year HbA1c data (2014-2019) from 411 subjects with Type 1 diabetes who had participated in a previous study to design a diabetes-specific quality of life questionnaire in the year 2014 were included. Scores for Spanish versions of the Hospital Anxiety and Depression Scale (HADS) and Problem Areas in Diabetes (PAID) scale were obtained at baseline, along with sociodemographic and clinical data. Long-term glycaemic variability was measured as the coefficient of variation of HbA1c (HbA1c-CV). The association between HADS and PAID scores and HbA1c-CV was analysed with Spearman correlations and multiple regression models, both linear and additive, including other covariates (age, sex, diabetes duration time, type of treatment, baseline HbA1c, use of anxiolytic or antidepressant drugs, education level and employment status). RESULTS: Scores of depression, anxiety and distress were positively and significantly correlated to HbA1c-CV in univariate analyses. Multiple regression study demonstrated an independent association only for diabetes distress score (p < 0.001). Age, diabetes duration time, baseline HbA1c, education level and employment status were also significantly associated with HbA1c-CV. However, when subjects were analyzed separately in two age groups, distress scores were associated with HbA1c-CV only among those aged 25 years or older, while anxiety scores, but not distress, were associated with HbA1c-CV among those younger than 25 years. CONCLUSIONS: Psychological factors, particularly disease-related distress and anxiety, are associated with long-term glycaemic variability in subjects with Type 1 diabetes.

In Vivo and In Vitro Models of Diabetes: A Focus on Pregnancy.

Diabetes in pregnancy is associated with an increased risk of poor outcomes, both for the mother and her offspring. Although clinical and epidemiological studies are invaluable to assess these outcomes and the effectiveness of potential treatments, there are certain ethical and practical limitations to what can be assessed in human studies.Thus, both in vivo and in vitro models can aid us in the understanding of the mechanisms behind these complications and, in the long run, towards their prevention and treatment. This review summarizes the existing animal and cell models used to mimic diabetes, with a specific focus on the intrauterine environment. Summary of this review.

Animal Models and Renal Biomarkers of Diabetic Nephropathy.

Diabetes mellitus (DM) is the first cause of end stage chronic kidney disease (CKD). Animal models of the disease can shed light on the pathogenesis of the diabetic nephropathy (DN) and novel and earlier biomarkers of the condition may help to improve diagnosis and prognosis. This review summarizes the most important features of animal models used in the study of DN and updates the most recent progress in biomarker research.

Fertility is reduced in women and in men with type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium (T1DGC).

AIMS/HYPOTHESIS: A recent Finnish study described reduced fertility in patients with childhood-onset type 1 diabetes. The Type 1 Diabetes Genetics Consortium (T1DGC) is an international programme studying the genetics and pathogenesis of type 1 diabetes that includes families with the disease. Our aim was to assess fertility, defined as number of offspring, in the affected and unaffected siblings included in the T1DGC. METHODS: Clinical information from participants aged ≥18 years at the time of examination was included in the present analysis. The number of offspring of affected and unaffected siblings was compared (in families including both) and the influence of birth year, disease duration and age of onset was assessed, the last in affected siblings only, using Poisson regression models. RESULTS: A total of 3010 affected and 801 unaffected adult siblings that belonged to 1761 families were assessed. The mean number of offspring was higher in the unaffected than in the affected individuals, and the difference between the two groups was more pronounced in women than men. Poisson regression analysis showed that both sex and birth cohort significantly affected the differences between groups. In the affected siblings, adult onset (≥18 years), female sex and older birth cohort were associated with higher fertility. CONCLUSIONS/INTERPRETATION: Patients with type 1 diabetes have fewer children than their unaffected siblings. This effect is more evident in women and in older birth cohorts. Onset of type 1 diabetes as an adult rather than a child is associated with a higher number of offspring, even after accounting for birth cohort and disease duration.

Real-World Evidence of Off-Label Use of Commercially Automated Insulin Delivery Systems Compared to Multiple Daily Insulin Injections in Pregnancies Complicated by Type 1 Diabetes.

Aims: To compare glycemic control and maternal-fetal outcomes of women with type 1 diabetes (T1D) using hybrid closed loop (HCL) versus multiple daily insulin injections (MDI) plus continuous glucose monitoring. Methods: Multicenter prospective cohort study of pregnant women with T1D in Spain. We evaluated HbA1c and time spent within (TIR), below (TBR), and above (TAR) the pregnancy-specific glucose range of 3.5-7.8 mmol/L. Adjusted models were performed for adverse pregnancy outcomes, including baseline maternal characteristics and center. Results: One hundred twelve women were included (HCL n = 59). Women in the HCL group had a longer duration of diabetes and higher rates of prepregnancy care. There was no between-group difference in HbA1c in any trimester. However, in the second trimester, MDI users had a greater decrease in HbA1c (-6.12 ± 9.06 vs. -2.16 ± 7.42 mmol/mol, P = 0.031). No difference in TIR (3.5-7.8 mmol/L) and TAR was observed between HCL and MDI users, but with a higher total insulin dose in the second trimester [+0.13 IU/kg·day)]. HCL therapy was associated with increased maternal weight gain during pregnancy (ßadjusted = 3.20 kg, 95% confidence interval [CI] 0.90-5.50). Regarding neonatal outcomes, newborns of HCL users were more likely to have higher birthweight (ßadjusted = 279.0 g, 95% CI 39.5-518.5) and macrosomia (ORadjusted = 3.18, 95% CI 1.05-9.67) compared to MDI users. These associations disappeared when maternal weight gain or third trimester HbA1c was included in the models. Conclusions: In a real-world setting, HCL users gained more weight during pregnancy and had larger newborns than MDI users, while achieving similar glycemic control in terms of HbA1c and TIR.

Short-term evaluation of renal markers in overweight adult cats.

BACKGROUND: Obesity has been proposed as an independently risk factor for chronic kidney disease (CKD) in people, but its role in feline kidney function is unknown. OBJECTIVE: Obesity has been proposed as an independent risk factor for chronic kidney disease (CKD) in people, but its role in feline kidney function is unknown. This study prospectively evaluated the effect of overweight on the concentration of symmetric dimethylarginine (SDMA) and creatinine in a cohort of healthy cats. METHODS: Forty healthy adult cats were included, 14 with a body condition score (BCS) = 5 and 26 with a BCS > 5. Cats were examined every 6 months, for up to 12 months. SDMA and creatinine were measured at baseline and follow-up. RESULTS: No effect was found for time of follow-up (p = 0.072), overweight (p = 0.9442) or their interaction (p = 0.902) on SDMA, though a significant effect was found for age (p < 0.001) [older cats showing higher SDMA] and sex (p = 0.007) [male cats showing higher SDMA]. Regarding creatinine, no effect for time (p = 0.671), age (p = 0.061), overweight (p = 0.319) or the latter's interaction (p = 0.386) were found. CONCLUSIONS: In the short term, markers of renal function did not show an association with overweight. The role of obesity in feline kidney function still warrants further evaluation.

Age and Red Blood Cell Parameters Mainly Explain the Differences Between HbA1c and Glycemic Management Indicator Among Patients With Type 1 Diabetes Using Intermittent Continuous Glucose Monitoring.

BACKGROUND: Glycated hemoglobin (HbA1c) is the gold standard to assess glycemic control in patients with diabetes. Glucose management indicator (GMI), a metric generated by continuous glucose monitoring (CGM), has been proposed as an alternative to HbA1c, but the two values may differ, complicating clinical decision-making. This study aimed to identify the factors that may explain the discrepancy between them. METHODS: Subjects were patients with type 1 diabetes, with one or more HbA1c measurements after starting the use of the Freestyle Libre 2 intermittent CGM, who shared their data with the center on the Libreview platform. The 14-day glucometric reports were retrieved, with the end date coinciding with the date of each HbA1c measurement, and those with sensor use ≥70% were selected. Clinical data prior to the start of CGM use, glucometric data from each report, and other simultaneous laboratory measurements with HbA1c were collected. RESULTS: A total of 646 HbA1c values and their corresponding glucometric reports were obtained from 339 patients. The absolute difference between HbA1c and GMI was <0.3% in only 38.7% of cases. Univariate analysis showed that the HbA1c-GMI value was associated with age, diabetes duration, estimated glomerular filtration rate, mean corpuscular volume (MCV), red cell distribution width (RDW), and time with glucose between 180 and 250 mg/dL. In a multilevel model, only age and RDW, positively, and MCV, negatively, were correlated to HbA1c-GMI. CONCLUSION: The difference between HbA1c and GMI is clinically relevant in a high percentage of cases. Age and easily accessible hematological parameters (MCV and RDW) can help to interpret these differences.

25OHVitamin D Levels in a Canarian Pediatric Population with and without Type 1 Diabetes: The Role of Acidosis.

The role of Vitamin D in the development of type 1 diabetes (T1D) is controversial. The Canary Islands have the highest incidence of childhood-onset T1D in Spain and one of the highest in Europe. We aimed to evaluate 25OHVitamin D concentrations in a Canarian pediatric population, to assess the existence of seasonal variation, to study their association with T1D, and to evaluate the role of acidosis in its levels. In a retrospective, case-control study, we obtained data from 146 T1D patients (<15 years of age) and 346 control children; 25OHVitamin D concentrations were assessed in serum by automatic ChemiLuminescence ImmunoAssay technology. We found significantly higher 25OHVitamin D levels in the summer and autumn months and an inverse correlation between T1D and age; 25OHVitamin D sufficiency was similar in both groups (44.5% vs. 45.1%), with significant differences in the percentage of patients presenting vitamin D deficiency (11.6% (T1D) vs. 16.4% (controls)). When stratified according to the presence of ketoacidosis at sampling, only patients with acidosis showed lower 25OHVitamin D concentrations than controls. Despite its subtropical geographic location, Vitamin D deficiency is frequent in children in Gran Canaria, and 25OHVitamin D concentrations show seasonal variation. After adjusting for acidosis, no differences were found between children with and without T1D.

Synthetic Patient Data Generation and Evaluation in Disease Prediction Using Small and Imbalanced Datasets.

The increasing prevalence of chronic non-communicable diseases makes it a priority to develop tools for enhancing their management. On this matter, Artificial Intelligence algorithms have proven to be successful in early diagnosis, prediction and analysis in the medical field. Nonetheless, two main issues arise when dealing with medical data: lack of high-fidelity datasets and maintenance of patient's privacy. To face these problems, different techniques of synthetic data generation have emerged as a possible solution. In this work, a framework based on synthetic data generation algorithms was developed. Eight medical datasets containing tabular data were used to test this framework. Three different statistical metrics were used to analyze the preservation of synthetic data integrity and six different synthetic data generation sizes were tested. Besides, the generated synthetic datasets were used to train four different supervised Machine Learning classifiers alone, and also combined with the real data. F1-score was used to evaluate classification performance. The main goal of this work is to assess the feasibility of the use of synthetic data generation in medical data in two ways: preservation of data integrity and maintenance of classification performance.

Impact of a Mediterranean diet, physical activity, body composition, and insulin delivery methods on metabolic control in children with type 1 diabetes.

Aims: To evaluate the synergistic impact of diet, lifestyle and technology on glycemic control in children with type 1 diabetes (T1D). Methods: This cross-sectional study included 112 randomly selected patients with T1D from Gran Canaria (median age 12 years; 51.8% female). The study collected data on height, weight, body composition (bioimpedance), age, disease duration, and method of insulin delivery. Physical activity was evaluated using the Krece questionnaire and an accelerometer (GENEActiv). Adherence to the Mediterranean diet was assessed using the KIDMED Quick Nutrition Test. Glycemic control was evaluated using HbA1c and the percentage of time in range. SPSS version 21 and RStudio were used for statistical analysis of the data. Stepwise linear regression analysis (backwards) was used to identify factors independently associated with metabolic control. Results: Insulin pump use, age and adherence to the Mediterranean diet were found to be significantly and independently associated with better glycemic control, whereas years with T1D was associated with worse HbA1c values. No relationship was found between body composition and physical activity measured by accelerometry or questionnaire. Conclusion: Adherence to the Mediterranean diet, insulin delivery methods, age, and number of years with T1D are important factors to consider in the management of T1D in children.

Diabetes and Familial Hypercholesterolemia: Interplay between Lipid and Glucose Metabolism.

Familial hypercholesterolemia (FH) is a genetic disease characterized by high low-density lipoprotein (LDL) cholesterol (LDL-c) concentrations that increase cardiovascular risk and cause premature death. The most frequent cause of the disease is a mutation in the LDL receptor (LDLR) gene. Diabetes is also associated with an increased risk of cardiovascular disease and mortality. People with FH seem to be protected from developing diabetes, whereas cholesterol-lowering treatments such as statins are associated with an increased risk of the disease. One of the hypotheses to explain this is based on the toxicity of LDL particles on insulin-secreting pancreatic ß-cells, and their uptake by the latter, mediated by the LDLR. A healthy lifestyle and a relatively low body mass index in people with FH have also been proposed as explanations. Its association with superimposed diabetes modifies the phenotype of FH, both regarding the lipid profile and cardiovascular risk. However, findings regarding the association and interplay between these two diseases are conflicting. The present review summarizes the existing evidence and discusses knowledge gaps on the matter.

Role of the SARS-CoV-2 virus in the appearance of new onset type 1 diabetes mellitus in children in Gran Canaria, Spain.

OBJECTIVES: It has been hypothesized that SARS-CoV-2 may play a role in the development of different forms of diabetes mellitus (DM). The Canary Islands have the highest incidence of type 1 DM (T1DM) reported in Spain (30-35/100,000 children under 14 years/year). In 2020-2021 we observed the highest incidence so far on the island of Gran Canaria, as a result of which we decided to evaluate the possible role of COVID-19 in the increased number of onsets. METHODS: We examined the presence of IgG antibodies against SARS-CoV-2 in children with new onset T1DM between October 2020 and August 2021. We compared recent T1DM incidence with that of the previous 10 years. RESULTS: Forty-two patients were diagnosed with T1DM (48.1/100,000 patients/year), representing a nonsignificant 25.7% increase from the expected incidence. Of the 33 patients who consented to the study, 32 presented negative IgG values, with only one patient reflecting undiagnosed past infection. Forty-four percent of patients presented with ketoacidosis at onset, which was similar to previous years. CONCLUSIONS: We conclude that there is no direct relationship between the increased incidence of T1DM and SARS-CoV-2 in the region. The COVID-19 pandemic did not result in an increased severity of T1DM presentation.

Predictors of associated autoimmune diseases in families with type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium.

BACKGROUND: Type 1 diabetes (T1D) is a clinically heterogeneous disease. The presence of associated autoimmune diseases (AAIDs) may represent a distinct form of autoimmune diabetes, with involvement of specific mechanisms. The aim of this study was to find predictors of AAIDs in the Type 1 Diabetes Genetics Consortium data set. METHODS: Three thousand two hundred and sixty-three families with at least two siblings with T1D were included. Clinical information was obtained using questionnaires, anti-GAD (glutamic acid decarboxylase) and anti-protein tyrosine phosphatase (IA-2) were measured and human leukocyte antigen (HLA) genotyping was performed. Siblings with T1D with and without AAIDs were compared and a multivariate regression analysis was performed to find predictors of AAIDs. T1D-associated HLA haplotypes were defined as the four most susceptible and protective, respectively. RESULTS: One or more AAIDs were present in 14.4% of the T1D affected siblings. Age of diabetes onset, current age and time since diagnosis were higher, there was a female predominance and more family history of AAIDs in the group with AAIDs, as well as more frequent anti-GAD and less frequent anti-IA-2 antibodies. Risk and protective HLA haplotype distributions were similar, though DRB1*0301-DQA1*0501-DQB1*0201 was more frequent in the group with AAIDs. In the multivariate analysis, female gender, age of onset, family history of AAID, time since diagnosis and anti-GAD positivity were significantly associated with AAIDs. CONCLUSIONS: In patients with T1D, the presence of AAIDs is associated with female predominance, more frequent family history of AAIDs, later onset of T1D and more anti-GAD antibodies, despite longer duration of the disease. The predominance of certain HLA haplotypes suggests that specific mechanisms of disease may be involved.

Studying the heterogeneous pathogenesis of canine diabetes: Observational characterization of an island population.

BACKGROUND: Canine diabetes mellitus has mostly been studied in northern European, Australian and American populations, whereas other regions have received less attention. OBJECTIVES: We evaluated the epidemiological, clinical and histopathological features of diabetic dogs in Gran Canaria, Spain. METHODS: Prevalence and incidence were estimated. Clinical features were analysed, and serum and genomic DNA were obtained. Dogs with presumed idiopathic or immune-mediated diabetes, were DLA-typed and antibodies against GAD65 and IA-2 were assessed. Pancreases from ten diabetic dogs were examined and compared with pancreases from non-diabetic dogs. RESULTS AND CONCLUSIONS: Twenty-nine diabetic dogs were identified in a population of 5,213 (prevalence: 0.56%; incidence: 0.37%). Most were female (79%) and sexually intact (87% of females, 83% of males). Diabetes secondary to dioestrus (55.2%) and insulin-deficient diabetes (20.7%) were the most frequent types. Antibodies against GAD65 and IA-2 were identified in two out of five cases and DLA-genotyping revealed novel haplotypes. Breed distribution differed between diabetic and non-diabetic dogs. Reduced number of pancreatic islets and ß-cell mass were observed, with vacuolation of islet cells and ductal epithelium. In this population, where neutering is not standard practice, diabetes secondary to dioestrus is the most frequent diabetes subtype. Genetic susceptibility also differed from previous studies. These results support the heterogeneous pathogenesis of canine diabetes.