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.

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.

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.

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.

Recovery of hypothalamic-pituitary-gonadal function with low dose testosterone treatment in a male with congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare disease caused by deficiency or action of gonadotropin-releasing hormone. While generally considered a long-life condition, CHH can be reversible in about 5%-20% of cases, but mechanisms of reversibility are unknown. We report the case of a male with CHH who began treatment with low dose (20 mg/day) transdermal testosterone to induce pubertal development at age 17. Following the start of treatment, he experienced testicular growth and his serum testosterone concentrations increased beyond the expectations in relation to the dose. Treatment was withdrawn, but this led to the reappearance of symptoms of hypogonadism and a drop in testosterone levels. Testosterone was again prescribed at the same dose and, for the subsequent years, he completed full puberty, including attainment of 20 cc testicular volume, mature secondary sexual characteristics, normal levels of testosterone and only partially arrested germinal function, as demonstrated by inhibin B levels and spermogram. Testosterone treatment was withdrawn three more times, but hypogonadism resumed on each occasion. This case suggests that low-dose testosterone treatment can induce reversal of CHH through the activation, albeit non-permanent, of the hypothalamic-pituitary-gonadal axis, indicating that testosterone administration might be a reliable therapeutic option for reverting GnRH deficiency.

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.

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.

Familial hypercholesterolemia in Gran Canaria: Founder mutation effect and high frequency of diabetes. / Hipercolesterolemia familiar en Gran Canaria: mutación con efecto fundador y alta frecuencia de diabetes.

INTRODUCTION: Gran Canaria is a region of genetic isolation of familial hypercholesterolemia due to a founder mutation, p. [Tyr400_Phe402del], in the LDL receptor (LDLR) gene. Initial data suggest that its carriers could have a high prevalence of diabetes. MATERIAL AND METHODS: Patients over 30 years of age with familial hypercholesterolemia and a confirmed mutation in LDLR were recruited from a tertiary hospital in Gran Canaria. The prevalence of diabetes and other clinical data were compared among carriers of p. [Tyr400_Phe402del] and those with other LDLR mutations. RESULTS: 76.4% of the 89 participants were carriers of p.[Tyr400_Phe402del]. The prevalence of diabetes in this group was significantly higher (25 vs. 4%, P=.045). These cases also had a higher prevalence of cardiovascular disease and higher levels of LDL cholesterol and triglycerides. There were no differences in age, weight, body mass index, waist, age of onset, and time of statin treatment. However, they required PCSK9 inhibitors more often (51.5 vs 24%, P=.027). CONCLUSIONS: The mutation p.[Tyr400_Phe402del] is associated with a high prevalence of diabetes, not explained by classic risk factors, such as age, obesity, or long-term use of statins.

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.

Correlation between TSH levels and quality of life among subjects with well-controlled primary hypothyroidism.

PURPOSE: It has been suggested that increasing levothyroxine dose to lower TSH levels within the normal laboratory range might be a therapeutic option for patients with apparently well-controlled primary hypothyroidism who are dissatisfied with their treatment and complain of physical or psychological symptoms. This study assessed whether there is a relationship between TSH levels and health-related quality of life (HRQoL) among subjects with adequately treated hypothyroidism. METHODS: HRQoL was measured with the specific thyroid disease ThyPRO-39 questionnaire in 218 consecutive patients with primary hypothyroidism of any cause attending an Endocrinology Department in a single center. Patients had TSH values within the normal laboratory range on a blood test performed not before than 6 weeks prior to study participation, but they were not aware of their lab results. The association between TSH values and the different ThyPRO-39 scales was analyzed by means of multiple regression models, both linear and additive, in which, in addition to TSH, a wide set of clinical and sociodemographic variables potentially related to HRQoL were also considered. RESULTS: TSH levels and the use of anxiolytic and antidepressant drugs were the only variables that showed a positive linear correlation with the ThyPRO-39 composite scale in the multivariate regression analysis, indicating greater impairment in HRQoL with increasing TSH values. TSH was also independently correlated to scores of scales dealing on tiredness and emotional susceptibility. CONCLUSIONS: In patients with primary hypothyroidism, higher TSH values, even within the normal reference range, are associated with greater deterioration of HRQoL.

Motivational Interviewing and Self-Care in Type 1 Diabetes: A Randomized Controlled Clinical Trial Study Protocol.

Background: Type 1 diabetes is a disease with complex therapeutic recommendations that require day-to-day lifestyle changes. Motivational Interviewing is a communication tool that has proved effective in changing behaviors in people with addictions, obesity and type 2 diabetes. Our objective is to evaluate the effects of a Motivational Interviewing intervention in people with type 1 diabetes. Methods: Sixty-six patients with type 1 diabetes and hemoglobin A1c >= 8% have been included and randomly assigned (computer-generated sequence, sealed envelopes, ratio 1:1) either to the intervention or to the control group. In the intervention group, appointments every 4 months with the endocrinologist include Motivational Interviewing; in the control group, the appointments proceed as usual. Patients will be followed for 16 months. The primary outcome will be self-care behaviors, assessed by a validated questionnaire, the Diabetes Self-Care Inventory-Revised Version. Secondary outcomes include: HbA1c, motivation for self-care, self-efficacy, health-related quality of life, satisfaction with professional-patient relationship, and fulfillment of patients' own objectives. The practitioners receive training in Motivational Interviewing in order to help them promote adherence to self-care, encourage patient motivation and improve the doctor-patient relationship. The Motivational Interviewing intervention will be evaluated by two psychologists, blinded to the assigned treatment, through video recordings of the sessions and the administration of a purpose-built questionnaire, the EVEM 2.0 scale. Discussion: There is evidence that MI can improve self-care in type 2 diabetes. In this study, we aim to evaluate the effect of MI on self-care and HbA1c in people with type 1 diabetes. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03906786, identifier NCT03906786.

Effectiveness of Internet-Based Multicomponent Interventions for Patients and Health Care Professionals to Improve Clinical Outcomes in Type 2 Diabetes Evaluated Through the INDICA Study: Multiarm Cluster Randomized Controlled Trial.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic disease in which health outcomes are related to decision making by patients and health care professionals. OBJECTIVE: This study aims to assess the effectiveness of internet-based multicomponent interventions to support decision making of all actors involved in the care of patients with T2DM in primary care. METHODS: The INDICA study is an open, community-based, multicenter trial with random allocation to usual care or the intervention for patients, the intervention for health care professionals in primary care, or the combined intervention for both. In the intervention for patients, participants received an educational group program and were monitored and supported by logs, a web-based platform, and automated SMS. Those in the intervention for professionals also received an educational program, a decision support tool embedded in the electronic clinical record, and periodic feedback about patients' results. A total of 2334 people with T2DM, regardless of glycated hemoglobin (HbA1c) levels and without diabetes-related complications, were included. The primary end point was change in HbA1c level. The main analysis was performed using multilevel mixed models. RESULTS: For the overall sample, the intervention for patients attained a significant mean reduction in HbA1c levels of ‒0.27 (95% CI ‒0.45 to ‒0.10) at month 3 and ‒0.26 (95% CI ‒0.44 to ‒0.08) at month 6 compared with usual care, which remained marginally significant at month 12. A clinically relevant reduction in HbA1c level was observed in 35.6% (191/537) of patients in the intervention for patients and 26.0% (152/586) of those in usual care at month 12 (P=.006). In the combined intervention, HbA1c reduction was significant until month 18 (181/557, 32.6% vs 140/586, 23.9%; P=.009). Considering the subgroup of patients uncontrolled at baseline, all interventions produced significant reductions in HbA1c levels across the entire study period: ‒0.49 (95% CI ‒0.70 to ‒0.27) for the intervention for patients, ‒0.35 (95% CI ‒0.59 to ‒0.14) for the intervention for professionals, and ‒0.35 (95% CI ‒0.57 to ‒0.13) for the combined intervention. Differences in HbA1c for the area under the curve considering the entire period were significant for the intervention for patients and the combined intervention compared with usual care (P=.03 for both). Compared with usual care, the intervention for professionals and the combined intervention had significant longer-term reductions in systolic and diastolic blood pressure. CONCLUSIONS: In uncontrolled patients, the intervention for patients at baseline provided clinically relevant and significant longer-term reductions of HbA1c levels. The intervention for professionals and combined intervention also improved the cardiovascular risk profile of patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01657227; https://clinicaltrials.gov/ct2/show/NCT01657227.

Central hypothyroidism or subclinical hyperthyroidism: can they be confused with each other?

SUMMARY: Isolated, adult-onset central hypothyroidism is very rare, and its diagnosis can be challenging. A 42-year-old patient was referred for evaluation of a 2.8 cm thyroid nodule. She referred symptoms that could be attributed to hypothyroidism and thyroid tests showed low TSH and normal-low levels of free T4. However, evaluation of the remaining pituitary hormones and pituitary MRI were normal, yet a radionuclide scanning revealed that the thyroid nodule was 'hot' and the tracer uptake in the remaining thyroid tissue was suppressed. Interpretation of these studies led to a misdiagnosis of subclinical hyperthyroidism and the patient was treated with radioiodine. Soon after treatment, she developed a frank hypothyroidism without appropriate elevation of TSH and the diagnosis of central hypothyroidism was made a posteriori. Long term follow-up revealed a progressive pituitary failure, with subsequent deficiency of ACTH and GH. This case should alert to the possibility of overlooking central hypothyroidism in patients simultaneously bearing primary thyroid diseases able to cause subclinical hyperthyroidism. LEARNING POINTS: Although rarely, acquired central hypothyroidism can occur in the absence of other pituitary hormone deficiencies. In these cases, diagnosis is challenging, as symptoms are unspecific and usually mild, and laboratory findings are variable, including low, normal or even slightly elevated TSH levels, along with low or low-normal concentrations of free T4. In cases with low TSH levels, the coexistence of otherwise common disorders able to cause primary thyroid hyperfunction, such as autonomous nodular disease, may lead to a misdiagnosis of subclinical hyperthyroidism.

TSH Level and Risk of Malignancy in Patients with Bethesda Category IV Thyroid Nodules.

Fine needle aspiration biopsy does not permit to distinguish between benign and malignant follicular thyroid lesions (category IV in the Bethesda Cytopathology System). Some reports have suggested an association between increased serum TSH levels and thyroid cancer, so the aim of this study was to investigate the association between TSH levels and malignancy in patients with follicular thyroid nodules. Therefore, we conducted a retrospective study of all subjects who underwent surgical treatment for Bethesda IV thyroid nodules in a single center (years 2012-2017). A total of 127 patients were analyzed, and malignancy was present in 38.6% of the patients. Using ROC analysis, the best TSH cut-off point to differentiate benign from malignant disease was 2.1 mU/l and the age cut-off with better sensitivity and specificity was 47 years. The proportion of subjects with TSH ≥ 2.1 mU/l was greater among subjects with cancer than in those with benign diseases (65.3 vs 44.9%, P = 0.029). The concurrence of both cut-off points (TSH ≥ 2.1 mU/l and age ≥ 47 years) showed a higher diagnostic accuracy than either of the two variables separately. Therefore, the present study supports an association between serum concentrations of TSH and risk of malignancy among subjects with Bethesda IV thyroid nodules. TSH levels could modify the diagnostic and therapeutic approach of patients with Bethesda IV nodules.

Identification of Psychological Factors Associated with Adherence to Self-Care Behaviors amongst Patients with Type 1 Diabetes.

PURPOSE: To explore the factors involved in adherence to self-care behaviors in patients with type 1 diabetes. MATERIALS AND METHODS: Patients with type 1 diabetes (age range: 14-71 years) were invited to participate at seven Spanish hospitals. They completed a dossier which recorded sociodemographic and clinical variables and also measured personality variables, emotional state, beliefs, and concerns regarding the illness, by means of questionnaires. RESULTS: A total of 428 patients with type 1 diabetes were included (58% women, age 36 (11.8) years, diabetes duration 18.3 (10.2) years, HbA1c 7.9 +/-1.3%). A total of 60.1% of patients found it difficult to follow the treatment recommendations for the care of their disease. The reasons given were mood (25.2%), lack of motivation (13.4%), work (12%), and economic difficulties (3.8%). Other personal reasons were reported by 5.7%. Motivation, training in diabetes management, importance the patient attributed to the disease, and self-efficacy were the variables that predicted adherence to self-care behaviors, together accounting for 32% of its variance. Anxiety and depression were highly prevalent in this study population (57.1% and 23.1%, respectively) and were associated with lower adherence. CONCLUSION: In the present study assessing patients with type 1 diabetes, motivation, training in diabetes management, beliefs regarding the disease, and self-efficacy were the main contributors to adherence to self-care behaviors. On the other hand, anxiety and depression were highly prevalent and associated with lower adherence. Thus, supplementing therapeutic education with strategies designed to raise levels of motivation, discussion of beliefs about the disease, and encouragement of self-efficacy might be a useful way to increase patient involvement in self-care.

The Arg499His gain-of-function mutation in the C-terminal domain of PCSK9.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a monogenic disease characterized by high levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease. FH is caused by loss of function mutations in genes encoding LDL receptor (LDLR), and Apolipoprotein B (APOB) or gain of function (GOF) mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, we identified a novel variant in PCSK9, p.(Arg499His), located in the C-terminal domain, in two unrelated FH patients from Spain and Italy. METHODS: We studied familial segregation and determined variant activity in vitro. RESULTS: We determined PCSK9 expression, secretion and activity of the variant in transfected HEK293 cells; extracellular activity of the recombinant p.(Arg499His) PCSK9 variant in HEK 293 and HepG2 cells; PCSK9 affinity to the LDL receptor at neutral and acidic pH; the mechanism of action of the p.(Arg499His) PCSK9 variant by co-transfection with a soluble construct of the LDL receptor and by determining total PCSK9 intracellular accumulation when endosomal acidification is impaired and when an excess of soluble LDLr is present in the culture medium. Our results show high LDL-C concentrations and FH phenotype in p.(Arg499His) carriers. In vitro functional characterization shows that p.(Arg499His) PCSK9 variant causes a reduction in LDLr expression and LDL uptake. An intracellular activity for this variant is also shown when blocking the activity of secreted PCSK9 and by inhibiting endosomal acidification. CONCLUSIONS: We demonstrated that p.(Arg499His) PCSK9 variant causes a direct intracellular degradation of LDLr therefore causing FH by reducing LDLr availability.

Assessment of the association between diabetes mellitus and chronic kidney disease in adult cats.

BACKGROUND: Diabetes mellitus is the main cause of chronic kidney disease (CKD) in humans. The relationship between the 2 diseases in cats is unclear. OBJECTIVE: To assess the association between diabetes and CKD in a population of adult cats. ANIMALS: Five hundred sixty-one cats that attended 2 veterinary centers in Gran Canaria, Spain, between 2014 and 2016. METHODS: Medical records were retrospectively reviewed. Cats aged 3 years or older, with sufficient data to define whether or not they had diabetes and CKD, were selected. Cats in critical condition, with dehydration or potential causes of prerenal azotemia and those treated with nephrotoxic drugs were excluded. Diagnosis of CKD was established when creatinine concentrations were >2 mg/dL, or serum creatinine 1.6-2 mg/dL and urine specific gravity <1.035, or serum creatinine 1.6-2 mg/dL and urine protein/creatinine ratio >0.4. Factors associated with CKD were identified through multivariate logistic regression analyses. RESULTS: Sixty-seven (11.9%) cats had CKD and 16 (2.9%) cats had diabetes. Sixty cats without diabetes (11%) and 7 with diabetes (44%) had CKD. Among the latter, both conditions were diagnosed simultaneously in 6 cases, whereas diabetes preceded CKD in the other. Multivariate analysis showed that diabetes was significantly associated with CKD (odds ratio = 4.47; 95% confidence interval, 1.51-13.28; P = .007). Other variables associated with CKD were age and mixed breed. CONCLUSIONS AND CLINICAL IMPORTANCE: After adjusting for age, this study showed an association between diabetes and CKD in adult cats.

The island of Gran Canaria: A genetic isolate for familial hypercholesterolemia.

BACKGROUND: Genetic diagnosis of familial hypercholesterolemia (FH) has not been universally performed in the Canary Islands (Spain). OBJECTIVES: This study aimed to genetically characterize a cohort of patients with FH in the island of Gran Canaria. METHODS: Study subjects were 70 unrelated index cases attending a tertiary hospital in Gran Canaria, with a clinical diagnosis of FH, according to the criteria of the Dutch Lipid Clinic Network. Given that 7 of the first 10 cases with positive genetic study were carriers of a single mutation in the LDLR gene [p.(Tyr400_Phe402del)], a specific polymerase chain reaction-based assay was developed for the detection of this variant as a first screening step on the remaining subjects. In those without this mutation, molecular diagnosis was completed using a next-generation sequencing panel including LDLR, APOB, PCSK9, LDLRAP1, APOE, STAP1, and LIPA genes and incorporating copy number variation detection in LDLR. RESULTS: On the whole, 44 subjects (62%) had a positive genetic study, of whom 30 (68%) were heterozygous carriers of the p.(Tyr400_Phe402del) variant. Eleven subjects carried other mutations in LDLR, including the novel mutation NM_000527.4: c.877dupG; NP_000518.1: p.(Asp293Glyfs*8). An unclassified PCSK9 gene variant was found in one subject [(NM_174936.3:c.1496G>A; NP_777596.2: p.(Arg499His)]. Other single patients had mutations in APOB (heterozygous) and in LIPA (homozygous). All identified variants co-segregated with the disease phenotype. CONCLUSIONS: These findings suggest a founder effect for the p.(Tyr400_Phe402del) LDLR mutation in Gran Canaria. A cost-effective local screening strategy for genetic diagnosis of FH could be implemented in this region.

Association between polymorphism rs2032487 in the non-muscle myosin heavy chain IIA gene (MHY9) and chronic kidney disease secondary to type 2 diabetes mellitus in a population of the Canary Islands. / Asociación entre el polimorfismo rs2032487 del gen de la cadena pesada de la miosina no muscular tipo IIA (MHY9) y la enfermedad renal crónica secundaria a diabetes tipo 2 en población de las Islas Canarias.

INTRODUCTION: Certain polymorphisms in the non-muscle myosin IIA (MYH9) and apolipoprotein L1 (APOL1) genes have been associated to chronic kidney disease (CKD) in different populations. This study examined the association between the MHY9 rs2032487 and APOL1 rs73885319 polymorphisms and advanced CKD related to type 2 diabetes mellitus (T2DM) in a population of Gran Canaria (Canary Islands, Spain). PATIENTS AND METHODS: Polymorphisms were genotyped in 152 patients with advanced CKD (estimated glomerular filtration rate [eGFR]<30mL/min/1.73 m2) secondary to T2DM, 110 patients with T2DM onset ≥ 20 years before without advanced CKD (eGFR ≥ 45mL/min/1.73 m2 and no proteinuria), and 292 healthy blood donors over 50 years of age without CKD or diabetes. RESULTS: The frequency of the risk allele for rs2032487 was 10.7% in patients with diabetes and advanced CKD, 7.1% in those with diabetes but without advanced CKD, and 6.1% in healthy subjects, with significant differences between the first and third groups (P=.015). Among subjects with advanced CKD, 78.5% were homozygous for the protective allele, as compared to 87.9% in the other two groups (P=.015 and P=.016 respectively). The frequency of the risk allele for the rs73885319 polymorphism did not exceed 0.5% in any of the three groups. CONCLUSIONS: These data suggest that polymorphism rs2032487 is associated to advanced CKD related to T2DM in the population of Gran Canaria.