[Lixisenatide in patients with type 2 diabetes and obesity: Beyond glycaemic control]. / Lixisenatida en pacientes con diabetes tipo 2 y obesidad: más allá del control glucémico.

AIM: To evaluate tolerance to lixisenatide and its effects on weight and metabolic control in type2 diabetes and obese patients. DESIGN: Prospective study. SETTING: Endocrinology clinics in Almeria, Granada and Malaga. PARTICIPANTS: Patients with type2 diabetes and obesity. INTERVENTIONS: Response and tolerance to lixisenatide treatment. MAIN MEASUREMENTS: Clinical and analytical data of the subjects were evaluated at baseline and after treatment. RESULTS: The study included 104 patients (51% women) with type2 diabetes and obesity (Almeria 18.3%; Granada 40.4%; Malaga 41.3%). The mean age was 58.4±10.5years, and the mean duration of diabetes was 11.2±6.7years. The patients were re-evaluated at 3.8±1.6months after treatment with lixisenatide. Significant improvements were found in weight (P<.001), body mass index (P<.001), waist circumference (P=.002), systolic blood pressure (P<.001), diastolic blood pressure (P=.001), fasting glucose (P<.001), HbA1c (P=.022), Total cholesterol (P<.001), LDL-cholesterol (P=.046), triglycerides (P=.020), hypertension drugs (P<.001), and lipids drugs (P<.001). No changes were observed in levels of amylase related to lixisenatide treatment, and 7.9% of patients did not tolerate it. CONCLUSIONS: Lixisenatide achieved significant improvements in anthropometric parameters, glycaemic control (fasting glucose and HbA1c), blood pressure and lipids. It was safe and well tolerated in most patients. In addition, there was a significant increase in the use of antihypertensive and lipid-lowering therapy.

Recurrent renal colic - A case study.

A previously well woman, 44 years of age, presented with 3 years of recurrent bilateral renal colic. Despite an increase in fluid intake and a low calcium diet, the intermittent episodes of renal colic continued and had become more frequent in the last year. An abdominal X-ray was performed, which showed some radio-opaque areas on both renal silhouettes (see Figure 1). Two stones in the right pelvic ureter were also seen following administration of contrast. No obstruction of the urinary tract was evident. Urinalysis revealed leukocyturia, a pH of 6.5 and specific gravity of 1.015. Blood testing showed hypercalcaemia of 2.96 mmol/L and hypophosphataemia of 0.71 mmol/L.

T1DiabetesGranada: a longitudinal multi-modal dataset of type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1D) patients face daily difficulties in keeping their blood glucose levels within appropriate ranges. Several techniques and devices, such as flash glucose meters, have been developed to help T1D patients improve their quality of life. Most recently, the data collected via these devices is being used to train advanced artificial intelligence models to characterize the evolution of the disease and support its management. Data scarcity is the main challenge for generating these models, as most works use private or artificially generated datasets. For this reason, this work presents T1DiabetesGranada, an open under specific permission longitudinal dataset that not only provides continuous glucose levels, but also patient demographic and clinical information. The dataset includes 257 780 days of measurements spanning four years from 736 T1D patients from the province of Granada, Spain. This dataset advances beyond the state of the art as one the longest and largest open datasets of continuous glucose measurements, thus boosting the development of new artificial intelligence models for glucose level characterization and prediction.

Factors Predicting the Response to a Vitamin D-Fortified Milk in Healthy Postmenopausal Women.

BACKGROUND: Milk products fortified with vitamin D may constitute an alternative to pharmacological supplements for reaching the optimal levels of serum 25-hydroxyvitamin D [25(OH)D]. Our aim was to analyze the response of serum 25(OH)D and its predictive factors in postmenopausal healthy women after a dietary intervention with a milk fortified with vitamin D and calcium. METHODS: We designed a prospective study including 305 healthy postmenopausal women who consumed a fortified milk with calcium (900 mg/500 mL) and vitamin D3 (600 IU/500 mL) daily for 24 months. RESULTS: The 25(OH)D concentrations at 24 months were correlated to weight, to body mass index, to the percentage of fat, triglycerides and to baseline 25(OH)D levels. We found significant differences in the levels of 25(OH)D at 24 months according to baseline 25(OH)D levels (p < 0.001) and body mass index (p = 0.019) expressed at quartiles. Multivariate analysis showed an association between levels of 25(OH)D after the intervention and at baseline 25(OH)D (Beta = 0.47, p < 0.001) and percentage of body fat (Beta = -0.227, p = 0.049), regardless of the body mass index. CONCLUSIONS: In healthy postmenopausal women, the improvement in 25(OH)D after an intervention with a fortified milk for 24 months depends mainly on the baseline levels of serum 25(OH)D and on the percentage of body fat.

Effects of Daily Intake of Calcium and Vitamin D-Enriched Milk in Healthy Postmenopausal Women: A Randomized, Controlled, Double-Blind Nutritional Study.

OBJECTIVE: To determine the effect of the daily intake of calcium and vitamin D-enriched milk (with or without fructooligosaccharides [FOS]) on vitamin D, bone metabolism, and cardiovascular risk factors. MATERIALS AND METHODS: Two-year randomized controlled study, including 500 healthy postmenopausal women, assigned to 500 mL/day of skimmed milk to one of three groups: Low-dose (L): (120 mg/100 mL calcium, vitamin D3 30 UI/100 mL), group A: calcium and vitamin D (180 mg/100 mL and 120 UI/100 mL), and group B: calcium and vitamin D (180 mg/100 mL and 120 UI/100 mL) and FOS (5 g/L). We evaluated serum 25(OH)D, bone mineral density (BMD) by Dual Energy X-ray Absorptiometry, and biochemical data of glucose and lipid metabolism. RESULTS: After 24 months, vitamin D concentrations did not change in the control group, but increased in group A and group B, p < 0.001. We observed an increase in femoral neck BMD and an improvement in fasting plasma glucose, HbA1c, total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B 100. CONCLUSIONS: Daily intake of milk enriched with calcium and vitamin D in postmenopausal healthy women induces a significant improvement in vitamin D status, a significant increase in BMD at femoral neck, and also favorable effects on glucose and lipid profile.

Bone remodeling markers as lithogenic risk factors in patients with osteopenia-osteoporosis.

PURPOSE: To analyze the presence of phosphocalcic metabolism disorders in patients with osteopenia-osteoporosis without nephrolithiasis with respect to a control group. METHODS: A cross-sectional study was conducted in patients with osteopenia-osteoporosis without nephrolithiasis (n = 67) in lumbar spine or femur and in a control group (n = 61) with no lithiasis or bone disorders. Blood bone markers, phosphocalcic metabolism, fasting urine, 24-h urine lithogenic risk factors, and densitometry were recorded in both groups. SPSS 20.0 was used for statistical analysis. RESULTS: In comparison with the controls, significantly higher blood calcium (9.27 ± 0.36 vs. 9.57 ± 0.38, p = 0.0001), intact parathormone (45.6 ± 14.9 vs. 53.8 ± 18.9, p = 0.008), and alkaline phosphatase (61.9 ± 20.9 vs. 70.74 ± 18.9, p = 0.014) levels were found in patients with osteopenia-osteoporosis. In the 24-h urine test, citrate (1010.7 ± 647.8 vs. 617.6 ± 315.8, p = 0.0001) and oxalate (28.21 ± 17.65 vs. 22.11 ± 16.49, p = 0.045) levels were significantly lower in osteopenia-osteoporosis patients than in controls, with no significant difference in calcium (187.3 ± 106.9 vs. 207.06 ± 98.12, p = 0.27) or uric acid (540.7 ± 186.2 vs. 511.9 ± 167.06, p = 0.35) levels. Patients with osteopenia-osteoporosis had significantly higher levels of lithogenic risk factors associated with bone remodeling, including significantly increased ß-crosslaps and osteocalcin values and higher ß-crosslaps/osteocalcin ratios. CONCLUSION: Patients with osteopenia-osteoporosis without nephrolithiasis showed phosphocalcic metabolism disorders as well as lower urinary citrate and higher ß-crosslaps/osteocalcin and fasting calcium/creatinine ratios, which would increase the risk of nephrolithiasis. Hence, prospective studies are warranted to evaluate the long-term risks.

Analysis of vitamin D deficiency in calcium stone-forming patients.

PURPOSE: The aim of this study is to analyse the percentage of hypovitaminosis D, as well as its relationship with the various parameters of calcium-phosphate metabolism. METHODS: A case control study was conducted on 366 patients, divided into two groups: Group 1: 127 non-stone-forming patients, and Group 2: 239 calcium stone forming. A study was performed on calcium-phosphate metabolism and urinary lithogenic factors. The percentage of vitamin D deficiency (25-OH-vitamin D levels <20 ng/ml) between the groups was analysed and compared. The SPSS 20.0 statistics program was used for the analysis, with a p ≤ .05 being considered significant. RESULTS: The mean age of Group 1 was 52.1 years compared to 49.6 years in Group 2, with no significant differences (p = .07). Vitamin D levels were lower in Group 2 compared to Group 1 (25.7 vs. 28.4 ng/ml, p = .02). A vitamin D deficiency was observed in 28 % of the Group 2 stone-forming patients versus 15.7 % in Group 1 (p = .009), with an odds ratio (OR) of 2.09 (95 % CI; 1.19-3.63). In the stone-forming patients with a vitamin D deficiency, the only difference observed was the higher levels of iPTH compared to those stone-formers with a normal vitamin D (56.9 vs. 45.5 pg/ml, respectively; p = .0001). CONCLUSION: Calcium stone-forming patients have lower mean levels of vitamin D and a higher percentage of hypovitaminosis D than in non-stone-forming patients. This was only related to increased iPTH levels, with urine calcium and other lithogenic parameters having no obvious effect.

Retrospective review of serum and urinary lithogenic risk factors in patients with osteoporosis and osteopenia.

OBJECTIVE: To analyze differences in bone remodeling markers, lithogenic factors and bone densitometry among the 3 groups of patients (controls, patients with relapsing calcium renal lithiasis, and patients with loss of bone mineral density without lithiasis). MATERIAL AND METHODS: This is a cross-sectional study including 203 patients who were divided in 3 groups: group 1 (controls), group 2 (patients with relapsing calcium renal lithiasis), and group 3 (patients with osteopenia and/or osteoporosis in the lumbar spine or hip). Bone densitometry, calcium-phosphorous and bone metabolism analysis, and analysis of lithogenic risk factors in fasting urine samples and 24-hour urine samples were performed. Statistical analysis was performed with SPSS 17.0. A P ≤.05 was considered statistically significant. RESULTS: Patients in group 2 presented greater calcium excretion and a lower citrate excretion in 24-hour urine samples as compared with the other 2 groups. The proportion of hypercalciuria and hypocitraturia was higher in group 2. In addition, patients in group 2 presented a lower loss of bone mineral density as well as altered bone remodeling markers as compared with those in group 1. Patients in group 3 also presented alterations in urine calcium and citrate excretion with respect to the control group, with elevated fasting calcium and citrate levels and calcium-to-citrateratio. CONCLUSION: Lithogenic risk factors are altered in patients with osteopenia and/or osteoporosis without renal lithiasis although to a lesser extent than patients with calcium renal lithiasis.

The importance of calciuria as lithogenic factors in patients with osteopenia/osteoporosis.

PURPOSE: Recurrent kidney stones are associated with bone mineral density loss, altered bone remodeling markers, hypercalciuria and increased in fasting calcium/creatinine ratio. The objective was to determine biochemical alterations in urine in patients with osteopenia/osteoporosis without calcium kidney stones compared with patients with calcium kidney stones. METHODS: This is a cross-sectional study including 142 patients who were divided in two groups: Group 1 (patients with recurrent calcium kidney stones) and Group 2 (patients with osteopenia/osteoporosis in the lumbar spine or hip). Analyses of bone mineral density, calcium-phosphorous and bone metabolism and lithogenic risk factors in fasting urine samples and 24-h urine samples were performed. Statistical analysis was carried out with SPSS 17.0. A p ≤ 0.05 was considered statistically significant. RESULTS: Patients in Group 2 presented greater loss of bone mineral density and more elevated alkaline phosphatase, iPTH, phosphorous and ß-crosslaps levels, as compared to patients in Group 1. However, Group 1 presented greater urine calcium, oxalate and uric acid and a higher proportion of hypocitraturia, hypercalciuria and hyperoxaluria, as compared to Group 2. Multivariate analysis revealed that advanced age and ß-crosslaps levels are risk factors for bone mineral density loss, while low urinary calcium excretion was protective against bone demineralization. CONCLUSION: Patients with osteopenia/osteoporosis without lithiasis present some urinary biochemical alterations. This would explain the lack of lithogenic activity, although low calcium excretion in 24-h urine samples is a protective factor against the loss of bone mineral density.

Cardiovascular risk factors in patients with asymptomatic primary hyperparathyroidism.

OBJECTIVES: Patients with primary hyperparathyroidism (PHP), even asymptomatic, have an increased cardiovascular risk. However, data on reversibility or improvement of cardiovascular disorders with surgery are controversial. Our aims were to assess the prevalence of classic cardiovascular risk factors in patients with asymptomatic PHP, to explore their relationship with calcium and PTH levels, and analyze the effect of parathyroidectomy on those cardiovascular risk factors. PATIENTS AND METHODS: A retrospective, observational study of two groups of patients with asymptomatic PHP: 40 patients on observation and 33 patients who underwent surgery. Clinical and biochemical data related to PHP and various cardiovascular risk factors were collected from all patients at baseline and one year after surgery in the operated patients. RESULTS: A high prevalence of obesity (59.9%), type 2 diabetes mellitus (25%), high blood pressure (47.2%), and dyslipidemia (44.4%) was found in the total sample, with no difference between the study groups. Serum calcium and PTH levels positively correlated with BMI (r=.568, P=.011, and r=.509, P=.026 respectively) in non-operated patients. One year after parathyroidectomy, no improvement occurred in the cardiovascular risk factors considered. CONCLUSIONS: Our results confirm the high prevalence of obesity, type 2 diabetes mellitus, high blood pressure, and dyslipidemia in patients with asymptomatic PHP. However, parathyroidectomy did not improve these cardiovascular risk factors.

Association of severe calcium lithogenic activity and bone remodeling markers.

OBJECTIVE: To establish cutoff points for markers of bone remodeling that allow for screening of patients at risk for serious lithogenic activity. MATERIALS AND METHODS: We conducted a cross-sectional study with 182 patients (aged between 25 and 60 years) divided into 3 groups: group 1, 56 patients without lithiasis; group 2, 67 patients with light calcium lithiasis; and group 3, 59 patients with severe calcium lithiasis. The criteria for inclusion in and exclusion from the study were established, and light and severe lithogenic activity were defined. Metabolic variables in blood and urine, along with bone densitometry, were studied for the groups. Statistical analysis of the results and preparation of receiver operating characteristic curves to establish optimal cutoff points were performed. RESULTS: The patients in group 3 showed the greatest bone mineral density loss and the highest values for markers of bone remodeling, together with increased 24-hour calciuria. Using the receiver operating characteristic curves developed and based on statistical significance (P = .0001), the following cutoff points for severe lithogenic activity, with a sensitivity between 75% and 85%, were established: ß-crosslaps >0.331 ng/mL; osteocalcin >13.2 ng/mL; ß-crosslaps/osteocalcin >0.024; 24-hour calciuria >306.6 mg; and fasting urine calcium/creatinine >0.105. CONCLUSION: Patients with calcium lithiasis and elevated values for osteocalcin, ß-crosslaps, ß-crosslaps/osteocalcin, 24-hour calciuria, and fasting urine calcium/creatinine may present a high risk of severe lithogenic activity.

[Effect of milk product with soy isoflavones on quality of life and bone metabolism in postmenopausal Spanish women: randomized trial]. / Efecto de un preparado lácteo con isoflavonas de la soja sobre la calidad de vida y el metabolismo óseo en mujeres posmenopáusicas: estudio aleatorizado.

BACKGROUND AND OBJECTIVE: To analyze the effects of nutritional intervention with a milk product enriched with soy isoflavones on quality of life and bone metabolism in postmenopausal Spanish women. PATIENTS AND METHOD: We performed a double-blind controlled randomized trial in ninety-nine postmenopausal women. Group S women (n=48) were randomized to consume milk product enriched with soy isoflavone (50 mg/day) while group C (n=51) consumed product control for 12 months. Parameters of quality of life (Cervantes scale), markers of bone metabolism and bone mass estimated by ultrasound of the calcaneus (QUS) were evaluated. RESULTS: Overall, there was an improvement in the domains menopause (P=.015) and vasomotor symptoms (P<.001). S group emphasized the assessment of vasomotor symptoms (P=.001) and differed positively from group C in health (P=.019), sex (P=.021) and partner (P=.002). Serum levels TRAP (P<.001) and OPG (P=.007) decreased and concentrations of 25-OH-vitamin D increased (P<.001) without differences between groups. In the assessment of QUS, there was an increase in estimated bone mineral density in group S (P=.040), whereas in group C there were no significant differences. CONCLUSIONS: Daily consumption of these milk products increases levels of 25-OH-vitamin D and decreases bone metabolism markers. Additional supplementation with soy isoflavones seems to improve quality of life and bone mass in Spanish postmenopausal women.

MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma.

PURPOSE: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. DESIGN: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. RESULTS: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. CONCLUSIONS: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients.

Osteocalcin as a marker of metabolic risk in healthy postmenopausal women.

OBJECTIVE: Several studies have reported the role of osteocalcin on glucose and fat metabolism. In this study, we analyzed the relationship between the concentration of osteocalcin and metabolic risk factors in healthy postmenopausal women. METHODS: Cross-sectional analyses of 54 postmenopausal women aged 56 ± 3.5 years were conducted. We recorded clinical and biochemical data of metabolic risk including fasting plasma glucose (FPG) level and evaluated the relationship between serum osteocalcin and bone formation markers. RESULTS: Serum osteocalcin concentration was negatively correlated with FPG (ß = -0.328, P = 0.035). When osteocalcin levels were divided into tertiles, we found significant differences in FPG between the highest and the lowest tertiles (84 ± 11 vs 98 ± 30 mg/dL, respectively; P = 0.029). We found significantly lower osteocalcin levels in women with impaired fasting glucose levels than in those with normoglycemia (10.7 ± 6.1 vs 17.1 ± 7.4 ng/mL, respectively; P = 0.006). We also found lower concentrations of osteocalcin in obese women versus nonobese women (14.4 ± 8.8 vs 17.3 ± 6.2 ng/mL; P = 0.034) and women with increased low-density lipoprotein cholesterol levels versus those with low LDL-c levels (14.1 ± 5.4 vs 18.9 ± 9.1 ng/mL; P = 0.045). A concentration of 13.5 ng/ mL or lower showed a sensitivity of 85.7% and a specificity of 63.8% to detect increased risk for diabetes (FPG ≥100 mg/dL). In contrast, serum levels of bone alkaline phosphatase did not correlate with any variable. CONCLUSIONS: In this population, there is a consistent association between osteocalcin and markers of metabolic syndrome. We suggest potential usefulness of serum osteocalcin as a predictor for increased risk of diabetes in postmenopausal women.

[Primary hyperparathyroidism in special situations: multiple endocrine neoplasia syndromes and parathyroid cancer]. / Hiperparatiroidismo primario en situaciones especiales: síndromes de neoplasia endocrina múltiple y cáncer de paratiroides.

Primary hyperparathyroidism (PHP) is a known endocrine disorder. Many years ago, the most frequent forms of clinical presentation were symptomatic renal or skeletal disease with moderate or severe hypercalcemia; however, currently, most patients have few symptoms and mild hypercalcemia. The last NIH Workshop on Asymptomatic PHP developed criteria for the management of this disease. Multiple endocrine neoplasia (MEN) types 1 and 2 are two genetic syndromes caused by different types of molecular abnormalities. PHP is the most common manifestation of MEN-1 and is the last feature to appear in MEN 2A. Parathyroid carcinoma (PC) is a rare neoplasm and an uncommon cause of parathyroid hormone (PTH)-dependent hypercalcemia. In this report, the treatment of PHP in MEN syndrome and PC are reviewed. Special attention is paid to a new class of drugs called "calcimimetics", which are powerful compounds that may be highly useful in the treatment of both conditions.

Dramatic response to cholestyramine in a patient with Graves' disease resistant to conventional therapy.

BACKGROUND: Resistance to the conventional treatment of hyperthyroidism with antithyroid drugs is not commonly found in clinical practice, and only few other treatment options have been reported on in detail. For example, surgery or radioiodine ablation are well-accepted interventions that must be always considered. The euthyroid state is strongly recommended before both of these as this might reduce complications. There are few studies indicating that bile acid sequestrants, when added to antithyroid drugs, produce a more rapid decline in serum thyroid hormone levels and that this effect is maintained for at least 4 weeks. Complete normalization of serum thyroid hormone levels is generally not expected, however. SUMMARY: We report a patient whose thyrotoxicosis failed to respond to conventional treatment. The patient remained persistently hyperthyroid, both clinically and biochemically, despite several months of methimazole and propranolol and the addition of iodine. Cholestyramine, a bile acid sequestrant, was then added, and a dramatic improvement was observed. CONCLUSION: We report a patient who was resistant to conventional antithyroid drugs in whom thyroid hormone levels completely normalized after 1 week of additional treatment with cholestyramine.