Urine glucose concentration: A useful parameter as a surrogate for glycaemia on the first day of life in canine neonates.

INTRODUCTION: Hypoglycaemia is a well-known risk factor in neonatal puppies and kittens; glycaemia control is crucial during the first days of life. Kidneys immaturity provokes the presence of physiological glycosuria during the first 2-3 weeks of life in small animals. OBJECTIVES: The aim of this study was to evaluate the potential of glycosuria as a predictor of glycaemia in neonatal puppies during the first two weeks of life. METHODS: Prospective study. Thirty-three client-owned healthy neonatal puppies admitted to the Veterinary Teaching Hospital, Autonomous University of Barcelona, were included in the study and divided into four different groups according to the day of sampling (1, 4, 7, and 11 days post-delivery). Glucose levels in blood and urine samples were evaluated and compared between groups. Correlation between glucose levels in blood and urine was also determined. RESULTS: Hypoglycaemia was diagnosed in 17.14% of the puppies and only on day 1 after delivery. A positive and significant correlation between blood and urine glucose concentration on day 1 after delivery was observed. No significant correlation between blood and urine glucose was observed on days 4, 7 and 11 after delivery. CONCLUSIONS: Urine concentration of glucose is a useful parameter to establish glycaemic status on the first day of life in canine puppies.

Selective SGLT2 inhibition by tofogliflozin reduces renal glucose reabsorption under hyperglycemic but not under hypo- or euglycemic conditions in rats.

To understand the risk of hypoglycemia associated with urinary glucose excretion (UGE) induced by sodium-glucose cotransporter (SGLT) inhibitors, it is necessary to know the relationship between the ratio of contribution of SGLT2 vs. SGLT1 to renal glucose reabsorption (RGR) and the glycemic levels in vivo. To examine the contributions of SGLT2 and SGLT1 in normal rats, we compared the RGR inhibition by tofogliflozin, a highly specific SGLT2 inhibitor, and phlorizin, an SGLT1 and SGLT2 (SGLT1/2) inhibitor, at plasma concentrations sufficient to completely inhibit rat SGLT2 (rSGLT2) while inhibiting rSGLT1 to different degrees. Under hyperglycemic conditions by glucose titration, tofogliflozin and phlorizin achieved ≥50% inhibition of RGR. Under hypoglycemic conditions by hyperinsulinemic clamp, RGR was reduced by 20-50% with phlorizin and by 1-5% with tofogliflozin, suggesting the smaller contribution of rSGLT2 to RGR under hypoglycemic conditions than under hyperglycemic conditions. Next, to evaluate the hypoglycemic potentials of SGLT1/2 inhibition, we measured the plasma glucose (PG) and endogenous glucose production (EGP) simultaneously after UGE induction by SGLT inhibitors. Tofogliflozin (400 ng/ml) induced UGE of about 2 mg·kg⁻¹·min⁻¹ and increased EGP by 1-2 mg·kg⁻¹·min⁻¹, resulting in PG in the normal range. Phlorizin (1,333 ng/ml) induced UGE of about 6 mg·kg⁻¹·min⁻¹ and increased EGP by about 4 mg·kg⁻¹·min⁻¹; this was more than with tofogliflozin, but the minimum PG was lower. These results suggest that the contribution of SGLT1 to RGR is greater under lower glycemic conditions than under hyperglycemic conditions and that SGLT2-selective inhibitors pose a lower risk of hypoglycemia than SGLT1/2 inhibitors.

Multifactorial intervention in individuals with type 2 diabetes and microalbuminuria: the Microalbuminuria Education and Medication Optimisation (MEMO) study.

AIMS: To determine whether tighter cardiovascular risk factor control with structured education in individuals with type 2 diabetes (T2DM) and microalbuminuria benefits cardiovascular risk factors. METHODS: Participants from a multiethnic population, recruited from primary care and specialist clinics were randomised to intensive intervention with structured patient (DESMOND model) education (n=94) or usual care by own health professional (n=95). PRIMARY OUTCOME: change in HbA1c at 18months. SECONDARY OUTCOMES: changes in blood pressure (BP), cholesterol, albuminuria, proportion reaching risk factor targets, modelled cardiovascular risk scores. RESULTS: Mean (SD) age and diabetes duration of participants were 61.5 (10.5) and 11.5 (9.3) years, respectively. At 18months, intensive intervention showed significant improvements in HbA1c (7.1(1.0) vs. 7.8(1.4)%, p<0.0001), systolic BP (129(16) vs. 139(17) mmHg, p<0.0001), diastolic BP (70(11) vs. 76(12) mmHg, p<0.001), total cholesterol (3.7(0.8) vs. 4.1(0.9) mmol/l, p=0.001). Moderate and severe hypoglycaemia was 11.2 vs. 29.0%; p=0.001 and 0 vs. 6.3%; p=0.07, respectively. More intensive participants achieved ≥3 risk factor targets with greater reductions in cardiovascular risk scores. CONCLUSIONS: Intensive intervention showed greater improvements in metabolic control and cardiovascular risk profile with lower rates of moderate and severe hypoglycaemia. Intensive glycaemic interventions should be underpinned by structured education promoting self-management in T2DM.

[Prevalence of ketotic hypoglycaemia among schoolchildren in the village of Ahoué in Côte-d'Ivoire]. / Prévalence de l'hypoglycémie cétosique chez les enfants d'âge scolaire dans le village d'Ahoué en Côte-d'Ivoire.

To determine the prevalence of ketotic hypoglycemia among schoolchildren, a descriptive cross-sectional study was conducted in preschools and schools in rural areas that involved 102 schoolchildren, from 4 to 7 years old, comprised 51 girls and 51 boys. Index WHZ was used to evaluate the children's nutritional status. The sampling was obtained by a drop of capillary blood in the pulp of the finger. The determination of glucose was realized by glucose oxidase method using an ultra sensitive and fast (One Touch Ultra) glucometer, and ketonuria was detected by dipstick "Ketodiastix." The clinical results revealed that most of children had a normal birth weight with an average of 2.885 g, a good Apgar's score superior to 7, and then the nutritional index WHZ revealed 3% of severe malnutrition and 34% of moderate malnutrition. Ten children (9.8%) had a hypoglycemia with a median of 0.51 g/l and extreme values going from 0.42 to 0.59 g/l. Seven children had a hypoglycemia associated with ketonuria. The prevalence of ketotic hypoglycemia was 7% in this study, and more frequent in the children between 4 and 5 years with 57% of cases in this age group. Thus, this condition, found in Western countries is a reality in Côte d'Ivoire, where the diathesis of malnutrition (37% of the population of the study) is a favorable factor. Therefore, it is useful to prevent protein-energy malnutrition by a balanced food by avoiding fasting before school by diet management.

[Late onset 3-HMG-CoA lyase deficiency: a rare but treatable disorder]. / Déficit en 3-HMG-CoA lyase à révélation tardive : savoir reconnaître une maladie rare mais traitable.

3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive genetic disorder due to a deficiency of the 3-hydroxy-3-methylglutarylCoA lyase (HMG-CoA lyase), a mitochondrial enzyme involved in ketogenesis and in the final step of l-leucine catabolism. HMG-CoA lyase deficiency can lead, in particular circumstances, such as fever, prolonged fasting or digestive disorders, to brutal and severe hypoglycemia with metabolic acidosis and sometimes fatal coma. We report on a new case of 3-hydroxy-3-methylglutaric aciduria particular by its late onset in a 3-year-old patient. Molecular investigation identified two new sequence modifications in the HMGCL gene: c.494G>A (p.Arg165Gln) and c.820G>A (p.Gly274Arg). We remind about this case report that the therapeutical is mainly preventive and allows a very good prognosis for this disease. Long-term treatment consists in limited fasting time, continuous low protein diet and l-carnitine supplementation. Preventive measures are essential: prevention of fasting and emergency treatment during intercurrent infections.

Developmental pattern of urinary bile acid profile in preterm infants.

BACKGROUND: Bile acid metabolism in preterm infants is yet to be fully characterized. We compared the developmental pattern of urinary bile acid profiles in ten infants born at gestational ages from 25 to 33 weeks with previous data from full-term infants from birth to about 7 months of age. METHODS: Gas chromatography-mass spectrometry was performed on serial samples. RESULTS: Total urinary bile acid concentrations gradually increased until 1 to 2 months of age. After this peak of excretion (30 to 60 micromol/mmol creatinine), total urinary bile acid concentrations gradually decreased to less than 20 micromol/mmol creatinine. The percentage of usual bile acids (mainly cholic acid) relative to total urinary total bile acids gradually deceased from approximately 30% at birth to less than 15% at 7 months of age. On the other hand, 1beta-hydroxylated bile acids (mainly 1beta,3alpha,7alpha,12alpha-tetrahydroxy-5beta-cholan-24-oic acid) relative to total urinary bile acids were increased gradually from 60% at birth to reach 70% to 80% at 1 month of age. The percentage of 1beta-hydroxylated bile acids relative to total urinary bile acids then remained stable at a high percentage (70% to 90%) until the age of 7 months. CONCLUSION: Physiological cholestasis in preterm infants persists longer than in full-term infants. Moreover, as large amounts of cholic and 1beta,3alpha,7alpha,12alpha-tetrahydroxy-5beta-cholan-24-oic acids were detected in urine from preterm infants during this study, the 25-hydroxylation pathway may be particularly important for bile acid synthesis in early preterm infants.

3-hydroxy-3-methylglutaryl-CoA lyase deficiency in an adult with leukoencephalopathy.

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is a disorder of leucine metabolism that usually presents with recurrent episodes of life-threatening hypoglycemia during early childhood. We report on a 36-year-old woman with seizures, recurrent metabolic disturbances, and severe leukoencephalopathy. The diagnosis was made by analysis of amino acids in urine and serum and was confirmed by demonstration of the deficient enzyme in cultured skin fibroblasts. The patient improved clinically on oral L-carnitine substitution. This treatable condition can remain unrecognized in adults and should be considered a potential cause of leukoencephalopathy.

Hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia.

UNLABELLED: Two cases of hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia in unrelated infants of 7 days and 4 months of age are reported. Blood ammonia levels were 100-300 micromol/l (normal values <40 micromol/l). The hyperammonaemia was asymptomatic and not associated with any of the abnormalities of amino acids or organic acids observed in urea cycle enzyme defects. Orotic aciduria was normal. The hyperammonaemia was not influenced by the levels of blood glucose nor by subtotal pancreatectomy. On admission blood glucose was ca. 1.2 mmol/l (21.6 mg/dl) corresponding to blood insulin levels of 35 and 22 mU/l respectively in both infants. Continuous intravenous glucose perfusion was necessary to prevent hypoglycaemia. Furthermore 2-oxoglutaric acid in urine was increased in the second infant to 3.15 mg/mg creatinine (normal 0.41+/-0.12). This may point to mutations in the glutamate dehydrogenase gene. CONCLUSION: 2-Oxoglutaric aciduria may be an important clue to the diagnose in this syndrome.

Prolonged elimination of tolbutamide in a premature newborn with hyperinsulinaemic hypoglycaemia.

So far, gestational diabetes treated with tolbutamide has never been associated with severe hypoglycaemia in the newborn when the mother's diabetes was well controlled. We report a case of a premature neonate, gestational age 34 weeks, with severe and long-standing hypoglycaemia from birth. The mother had well-controlled gestational diabetes, treated with tolbutamide from the 24th week of gestation until delivery. The neonate had inappropriately high levels of serum proinsulin, insulin and C-peptide relative to blood glucose concentrations. From day 19 after birth, the levels were normalized. Serum tolbutamide was 140.6 micromol/l (38 microg/ml) at 3 h after birth. Zero-order kinetics were seen during the first 90 postnatal hours. The half-life of serum tolbutamide decreased from 46 to 6 h. It is suggested that tolbutamide, when given to the mother until delivery, may cause severe and prolonged hyperinsulinaemic hypoglycaemia in premature neonates. The initially prolonged tolbutamide half-lives and zero-order kinetics suggest immaturity of hepatic elimination during the first 2 days of postnatal life.

Urinary excretion of adrenaline and noradrenaline during hypoglycaemic clamp in diabetic and non-diabetic adolescents.

The urinary excretion of non-conjugated adrenaline and noradrenaline during hypoglycaemic clamp was investigated in 16 diabetic and 15 non-diabetic adolescents. In the diabetic adolescents, the mean excretion of adrenaline was approximately nine times higher in clamp urine than in morning urine (p < 0.0001). In the non-diabetic adolescents, the mean excretion of adrenaline was 20-30 times higher in clamp urine than in morning urine (p < 0.0001). Plasma catecholamines were measured, and the area under the plasma concentration-time curve (AUC) and renal clearance of catecholamines were calculated. There was a linear correlation between the AUC and the urinary excretion of adrenaline (r = 0.57, p = 0.001) and noradrenaline (r = 0.49, p = 0.006) during the hypoglycaemic clamp. The renal clearance of adrenaline and noradrenaline did not differ between the diabetic and non-diabetic subjects. In the diabetic group, there was a positive correlation between HbA1c and the adrenaline excretion in clamp urine (r = 0.60, p = 0.015). The eight diabetic subjects with HbA1c < 10% had lower adrenaline excretion in clamp urine than the subjects with HbA1c > 10% and the non-diabetic subjects (all p values < 0.05). We conclude that there is a marked increase in urinary adrenaline excretion during hypoglycaemia in diabetic and non-diabetic adolescents. The increase in adrenaline excretion during hypoglycaemia was attenuated in the better-controlled diabetic adolescents in our study.

Capillary electrophoretic detection of metabolites in the urine of patients receiving hypoglycemic drug therapy.

Micellar electrokinetic chromatography (MEKC) in tandem with diode array detection (DAD) has been exploited as an analytical method for the separation and detection of sulfonylurea drugs. The ultimate goal is the development of an assay to detect these drugs or their metabolites in urine as a means of diagnosing sulfonylurea drug abuse. Using a separation buffer consisting of 5 mM borate/5 mM phosphate/75 mM sodium cholate, separation of both the second and third generation sulfonylurea drugs can be achieved. The characteristic absorbance spectra associated with each of the third generation drugs, glipizide and glyburide, allow for their identification in mixtures. Coinjection of glyburide, its primary metabolite, hydroxy glyburide, and glipizide demonstrated that the metabolite was resolved from the parent drug but shared its absorbance spectral properties. MEKC analysis of a series of solid phase-extracted urine samples from patients prescribed glipizide or glyburide, as well as from control patients not ingesting the drug, showed that the parent compounds were difficult to detect in the urine. However, the use of DAD allowed for detection of metabolites in the urine of these patients. With glyburide patients, only primary metabolites were detected, while urine from patients on glipizide showed a series of peaks whose absorbance spectra was consistent with the presence of both primary and secondary metabolites. In addition, the intensity of the metabolite peaks corresponded reasonably well with the respective dose and in vivo time interval associated with the urine collection. This study shows that MEKC with DAD has potential for further exploration as a clinical assay for detecting surreptitious abuse of sulfonylurea drugs.

Hyperprolactinaemia is associated with a higher prevalence of pituitary-adrenal dysfunction in non-functioning pituitary macroadenoma.

In non-functioning pituitary macroadenoma (NFMA), hyperprolactinaemia (hyperPRL) is considered to be a sign of hypothalamic-pituitary dysregulation, but it is unknown whether hyperPRL is associated with an increased frequency of pituitary hormone deficiencies. Forty consecutive patients with histology-proven NFMA were studied and hyperPRL was defined as serum prolactin (PRL) > 200 mIU/l in men and > 600 mIU/l in women. The pituitary-adrenal axis was evaluated by measurement of urinary free cortisol (N = 38), peak cortisol to insulin-induced hypoglycaemia (IIH, N = 36) and to human corticotrophin-releasing hormone (hCRF, N = 40) and by urinary tetrahydrol 11-deoxycortisol (H4S, N = 39), plasma androstenedione increment (N = 39) and serum 11-deoxycortisol (N = 1) after metyrapone. Central hypothyroidism, gonadotrophin deficiency and growth hormone (GH) reserve were also assessed. Twenty patients had hyperPRL (serum PRL 331 (223-1120) mIU/l (median, range) in men and 932 (660-3927) mIU/l in women): urinary free cortisol excretion (p < 0.03) and peak serum cortisol in response to IIH (p < 0.02) were lower in hyperPRL than in normoPRL patients; peak serum cortisol after hCRF was not different between groups but occurred later in hyperPRL patients (at 60vs 30 min, p < 0.03); urinary H4S excretion and androstenedione response after metyrapone were lower in hyperPRL than in normoPRL patients (p < 0.05 for both): 60% of hyperPRL patients and 15% of normoPRL patients had an abnormal H4S response (p < 0.025): central hypothyroidism (overt + subclinical) was present in 74% of hyperPRL and in 60% of normoPRL patients (NS); 78% of hyperPRL and 55% of normoPRL patients had gonadotrophin deficiency (NS): growth hormone (GH) deficiency was present in 83% of hyperPRL and in 89% of normoPRL patients (NS); 73.3% of 75 evaluable pituitary hormone axes were abnormal in hyperPRL patients compared to 53.8% of 78 hormone axes in normoPRL patients (by metyrapone test to examine adrenal function, p < 0.025); and no significant differences in tumour grade and stage distribution were found between hyperPRL and normoPRL patients. It is concluded that hyper-prolactinaemia in NFMA is associated with a higher prevalence of pituitary-adrenal dysfunction, which is likely to be explained at least in part by functional hypothalamic-pituitary interruption.

The investigation of beta-hydroxybutyrate as a marker for sudden death due to hypoglycemia in alcoholics.

The purpose of this study was to determine if the ketone body beta-hydroxybutyrate (beta-HBA) is a useful positive marker for sudden deaths in chronic alcoholics, thought to be due to hypoglycemia. Beta-HBA can be reliably measured in postmortem samples of vitreous humour and urine. In fatalities where there is a history of chronic alcoholism and routine investigations, including autopsy and routine toxicology, yield only a fatty liver as positive findings, a raised level of beta-HBA can be used as an indicator for alcoholic ketosis. Alcoholic ketosis is often associated with antemortem hypoglycemia. Caution should be observed in attributing the significance of ketosis exclusively to alcohol in those conditions where it would otherwise be expected (i.e. diabetic ketoacidosis and chronic starvation). A measurement of this marker of alcoholic ketosis may also help in the investigation of cases where hypothermia or alcohol withdrawal fits are suspected.

Oral cornstarch therapy: is persorption harmless?

Sediments prepared from freshly voided urine of four patients with glycogenosis Ia, or leucine-sensitive hypoglycaemia, on oral cornstarch therapy contained starch granules, evidence for persorption i.e. the incorporation of undissolved starch particles. In these patients, amyluria was more marked than in untreated controls. While cornstarch therapy is successful and causes few side-effects, the possibility of late adverse reactions to persorbed starch should not be disregarded.

Chronic effects of methylmercury on the urinary excretion of catecholamines and their responses to hypoglycemic stress.

Five male Wistar rats were treated with methylmercury chloride (MMC) and compared with five age-matched control rats. A dose of 10 mg/kg was given three times. The chronic effects of the MMC administration on the urinary output of catecholamines [norepinephrine (NE), epinephrine (E) and dopamine (DA)] were measured for 50 days. On the 69th day after MMC administration, the rats were examined for insulin-induced hypoglycemic stress. On the 90th day, the animals were decapitated and various organs were weighed and serum thyroid hormones [thyroid stimulating hormone (TSH) and total and free thyroxine (T4)] were measured. Decreases in DA excretion and DA response to stress were observed in the MMC-treated group. Inflammation of the kidney was also found, suggesting MMC-induced damage to the renal tubular region, the apparent site of renal DA synthesis. The MMC group and the control group showed differential NE and E response patterns. The lowered baseline excretion of NE appeared to continue even 70 days after MMC administration, while the difference in E excretion between the two groups disappeared 1 month after MMC administration. Both NE and E showed normal responsiveness to hypoglycemic stress induced by insulin. All serum TSH and total and free T4 baseline levels showed slight increases, and the thyroid gland weights in the MMC group were slightly heavier. These findings suggest a rather hyperthyroid state after the initial acute phase suppression, as suggested by the previous examinations. Thus, these findings suggest long-lasting effects of methylmercury administration, especially on renal DA synthesis. Baseline urinary excretion of NE and thyroid function could also be affected for a long time.

[Catecholamine excretion in insulin-treated diabetic patients]. / Katecholaminausscheidung bei insulinbehandelten Diabetikern.

The urine excretion of the catecholamines adrenalin, noradrenalin and dopamine as well as the serum levels of cortisol and STH were determined with the aim to establish objective criteria for a "latent" hypoglycaemia in diabetics. The altogether 45 insulin-requiring diabetics had no hypoglycaemia (n = 28) and the decrease of blood sugar, respectively, occurred during the daytime (n = 6) or at night (n = 11). From the results no significance for the catecholamines as parameters of a hypoglycaemia that happened long ago can be derived. Deviation in the circadian rhythms of the cortisol levels in diabetics with hypoglycaemias need the securing by further investigations.

[Catecholamine excretion in diabetics on insulin treatment]. / Katekholaminova ekskretsiia pri diabetno bolni na insulinolechenie.

In order to find out objective indices for "hidden" hypoglycemia in diabetic patients the urine excretion of the catecholamines adrenaline, noradrenaline, dopamine and the serum levels of cortisol and somatotrophic hormone (STH) were followed up. 45 diabetics on insulin treatment were included in the study: 32 patients with type I diabetes mellitus and 13 patients with diabetes mellitus type II with secondary resistance to sulfanilurea drugs and insulin. The patients were classified into the following groups: I. without hypoglycemia--28 patients; 2. with diurnal hypoglycemia--6 patients and 3. with nocturnal hypoglycemia--II patients. In the patients with hypoglycemia the 24 h adrenaline urine excretion was higher than in the patients without hypoglycemia. No such differences were found for noradrenaline and dopamine. The separate examination of the diurnal and nocturnal catecholamines excretion showed in all groups that they cannot serve as an objective index for determination of hypoglycemia. The STH showed no differences in all groups of diabetics. Disturbances in the circadian rhythm of cortisol secretion in diabetics were found. This could be a good and available marker for detecting "hidden" hypoglycemia in diabetics.