Intermittent Hypoglycemia Research Articles

Index of Suspicion * Case 1: Leg Cramps, Hand Spasms, Diarrhea, and Substantial Weight Loss in a 12 Year Old * Case 2: Hypothermia, Hypoglycemia, and Hyperbilirubinemia in a Neonate * Case 3: Recurrent Fevers, Abdominal Pain, and Cervical Lymphadenopathy in a 7 Year Old

A 12-year-old previously healthy boy presents with leg cramps for 2 weeks and spasms of his hands since yesterday. He also complains of nausea, bloating, epigastric pain, and recurrent watery and loose stools for 1 month. Currently, he is taking lansoprazole for epigastric pain without any relief. He also has a history of involuntary weight loss of 10 lb over 2 months. The family history contains no findings of note. On physical examination, the boy's weight is 36 kg (25th percentile) and height is 140 cm (10th percentile) and he exhibits a positive Trousseau sign and negative Chvostek sign. Remaining physical signs, including on abdominal examination, are normal. Laboratory evaluation shows hypocalcemia (total calcium of 5.3 mg/dL [1.3 mmol/L], ionized calcium of 2 mg/dL [0.5 mmol/L], and corrected calcium of 6.1 mg/dL [1.5 mmol/L]) as well as hypoalbuminemia (3 g/dL [30 g/L]). Serum magnesium measures 1.6 g/dL. CBC shows Hgb of 9.3 g/dL (93 g/L), Hct of 29% (0.29), WBC count of 9.9×103/μL (9.9×109/L), platelet count of 471×103/μL (471×109/L), mean corpuscular volume of 67 fL, and reticulocyte count of 1% (0.01). Results of the iron studies are consistent with iron deficiency anemia, with a serum iron concentration of 6 μg/dL (1.07 μmol/L) (31 to 144 μg/dL [5.5 to 25.8 μmol/L]), transferrin saturation of 3% (0.3), and serum ferritin less than 5 ng/mL (11.23 pmol/L) (21 to 275 ng/mL [47.2 to 617.9 pmol/L]). ESR is 46 mm/h and CRP is 9.5 mg/dL (normal <0.05 mg/dL). His serum 25-hydroxyvitamin D concentration is low at 5.7 ng/mL (14.2 nmol/L) (normal, 32 to 100 ng/mL [79.9 to 249.6 nmol/L]) and serum parathyroid hormone, urine calcium, and creatinine values are within normal limits. His tetany and hypocalcemia resolve with calcium replacement. Additional evaluation leads to the diagnosis. …

Molecular confirmation of VLCAD deficiencies in newborns

MOLECULAR CONFIRMATION OF VLCAD DEFICIENCIES IN NEWBORNS Megan L Landsverk, Fernando Scaglia, Lee-Jun Wong Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States Oxidation of fatty acids in the mitochondria provides the main source of energy in the brain, as well as skeletal and cardiac muscle. Acyl-CoA dehydrogenases are a group of enzymes that catalyze the initial step in the β-oxidation of fatty acids in the mitochondrial matrix. Deficiencies in acyl-CoA dehydrogenases are autosomal recessive disorders that result in a decreased ability to oxidize fatty acids, thereby leading to metabolic dysfunction. Very-long chain acyl-CoA dehydrogenase (VLCAD) targets long-chain fatty acids with a chain length of 14 to 20 carbons. VLCAD deficiency (VLCADD) can generally be group into three phenotypes: a severe, early-onset, form with a high incidence of cardiac and multiorgan failure, intermittent hypoglycemia, hepatomegaly and hypotonia; a milder childhood form usually presenting with hypoketotic hypoglycemia; and an adult myopathic form with intermittent rhabdomyolysis, muscle cramps and exercise intolerance. Early detection through newborn screening (NBS) by measuring acylcarnitines using tandem mass spectrometry has increased the number of patients identified with VLCADD, and has allowed for the identification of milder clinical phenotypes. Although, acylcarnitine profiles alone cannot confirm a diagnosis. An increase in acylcarnitine C14:1 is suggestive for VLCADD. However, normal biochemical testing on follow-up of abnormal NBS for VLCADD does not rule out the disorder since C14:1 levels tend to normalize over time. Conversely, initial elevations of C14:1 on NBS may reflect neonatal stress. Molecular identification of deleterious mutations in the ACADVL gene is necessary to confirm the diagnosis. From January 2007 to October 2009 we analyzed 175 individuals, ages 6 months and younger, presenting with abnormal NBS or clinical indications suggestive of VLCADD for mutations in ACADVL. We identified previously reported mutations as single heterozygotes in 36 (21%) individuals, double heterozygotes in nine (5%), and homozygotes in five (3%). An additional 13 (6%) individuals harbored known mutations as double heterozygotes with unclassified variants. We also identified 6 novel frameshift mutations leading to premature stop codons, 1 novel indel, 1 novel in-frame deletion, and 4 novel splice-site mutations, all heterozygous. Unclassified variants were found as single and double heterozygous in 21 (12%) and 8 (5%) individuals respectively. However, we found no known mutations or unclassified variants in the coding exons of ACADVL in 66 (38%) individuals tested for VLCADD. These results underscore the necessity of mutation analysis of the ACADVL gene when VLCADD is suspected in children under the age of 6 months based on suggestive clinical indication or positive NBS results. Poster Presentations

A Case of Gastrointestinal Stromal Tumor with Recurrent Hypoglycemia

Non-islet cell tumor induced hypoglycemia (NICTH) is attributable to overproduction of insulin-like growth factor-II (IGF-II) by solid tumors, and these tumors usually originate from mesenchymal or epithelial cells. Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor and most commonly find in the gastrointestinal tract. It is usually expresses the CD117 (stem cell factor receptor, c-kit) detected by immunohistochemistry. Hypoglycemia associated with GIST is very rare and this has not yet been reported in Korea. A 72-year-old man was hospitalized due to frequent episodes of confusion. It was observed that non-hyperinsulinemic hypoglycemia, an elevated serum IGF-II level and a huge liver mass. The histology of liver mass showed c-kit (CD117) positivity, which was consistent with GIST, but it was surgically unresectable. He was treated with imatinib mesylate. Although he recieved palliative treatment, he still experienced intermittent fasting hypoglycemia. After 2 months, the serum IGF-II level was even higher than before. We changed imatinib mesylate to sunitinib malate and performed radiotherapy on the liver mass. Although the change of the liver mass was not significant, he did not suffer from hypoglycemia for three months afterwards.

Hyperinsulinaemic hypoglycaemia associated with a heterozygous missense mutation of R1174W in the insulin receptor (IR) gene

Mutations in the insulin receptor (IR) gene are known to cause severe insulin resistance. Although clinical features due to a mutation can be diverse, hypoglycaemia is found in some cases. A family with a female proband diagnosed with type A insulin resistance syndrome was studied. Clinical characteristics were compared with the Arginine1174Glutamine (R1174N) mutation reported in the literature. The proband was a 16-year-old girl who was presented with intermittent hypoglycaemia, hirsutism, darkened skin, acne and oligomenorrhoea. A 5-h oral glucose tolerance test (OGTT), intravenous glucose tolerance test and continuous glucose monitoring system were performed for evaluation of glucose metabolism and insulin secretion. Results from a hyperinsulinaemic euglycaemic clamp on the proband were compared to nine normal glucose tolerance (NGT) controls. The IR gene of the proband, along with her parents and two dizygotic twin brothers were scanned for mutations by direct sequencing. Elevated serum insulin and insulin : C-peptide ratios were found in the proband, the father and one of the twin brothers, carried a heterozygous missense mutation of Arginine1174Tryptophan (R1174W) in exon20 of the IR gene. The clamp study showed that the nonoxidative glucose disposal rates of the proband were near zero, and that the metabolic clearance rate for insulin was markedly reduced. R1174 of the IR gene may be a candidate locus for hyperinsulinaemic hypoglycaemia. Clinical heterogeneity is not uncommon within families as well as among mutation carriers with different amino acid replacements. More pedigrees and long-term follow-up data are needed to document the evolution of beta-cell function and clarify the role of R1174 on insulin resistance and hyperinsulinaemic hypoglycaemia.

Permanent Neonatal Diabetes in a Patient with a KCNJ11/Q52R Mutation Accompanied by Intermittent Hypoglycemia and Liver Failure

Permanent Neonatal Diabetes in a Patient with a KCNJ11/Q52R Mutation Accompanied by Intermittent Hypoglycemia and Liver Failure

Permanent Neonatal Diabetes in a Patient with a KCNJ11/Q52R Mutation Accompanied by Intermittent Hypoglycemia and Liver Failure

The most common monogenic cause of neonatal diabetes is mutation in KCNJ11, which encodes a potassium channel in pancreatic beta cells. Some mutations in this gene, including Q52R, have been described in association with neurological deficits, but never with hepatic involvement. We report the second case of neonatal diabetes in a patient with a KCNJ11/Q52R mutation. This patient's clinical course did not include obvious neurological deficits despite the presence of prematurity, but did include transient hyperbilirubinemia, and recurrent hypoglycemia. The phenotypic spectrum of KCNJ11 mutations is variable and is likely influenced by additional genetic and environmental factors.

Hyperglycemia not hypoglycemia alters neuronal dendrites and impairs spatial memory

We previously reported that chronic hyperglycemia, but not hypoglycemia, was associated with the reduction of neuronal size in the rat brain. We hypothesized that hyperglycemia-induced changes in neuronal structure would have negative consequences, such as impaired learning and memory. We therefore assessed the effects of hyperglycemia and hypoglycemia on neuronal dendritic structure and cognitive functioning in young rats. Experimental manipulations were conducted on male Wistar rats for 8 wk, beginning at 4 wk of age. At the completion of the treatments, all rats were trained in the radial-arm water maze, a spatial (hippocampus-dependent) learning and memory task. Three groups of rats were tested: an untreated control group, a streptozotocin-induced diabetic (STZ-D) group, and an intermittent hypoglycemic group. Following behavioral training, the brains of all animals were examined with histologic and biochemical measurements. Peripheral hyperglycemia was associated with significant increases in brain sorbitol (7.5 +/- 1.6 vs. 5.84 +/- 1.0 microM/mg) and inositol (9.6 +/- 1.4 vs. 7.1 +/- 1.1 microM/mg) and reduced taurine (0.65 +/- 0.1 vs. 1.3 +/- 0.1 mg/mg). Histologic evaluation revealed neurons with reduced dendritic branching and spine density in STZ-D rats but not in control or hypoglycemic animals. In addition, the STZ-D group exhibited impaired performance on the water maze memory test. Hyperglycemia, but not hypoglycemia, was associated with adverse effects on the brain polyol pathway activity, neuronal structural changes, and impaired long-term spatial memory. This finding suggests that the hyperglycemic component of diabetes mellitus has a greater adverse effect on brain functioning than does intermittent hypoglycemia.

Genotyping Has a Minor Role in Selecting Therapy for Congenital Long-QT Syndromes at Present

Genotyping has led to enormous advances in understanding the phenotype and clinical course of the congenital long-QT syndromes (LQTS). In the most common LQTS forms, LQT1, LQT2, and LQT3, genotyping a clearly affected person in each family provides the ability to easily identify family members with reduced penetrance of the QTc and symptoms phenotypes, thus, providing also the opportunity to prevent sudden death and cardiac arrest by administering presymptomatic therapy. Response by Moss and Goldberg see p 227 The role of genotyping in selecting the therapy for LQTS is, on the other hand, unclear. Data from the literature and from the Salt Lake City LQTS database will be presented to show that genotyping has only a minor role in selecting therapy for LQTS. The discussion will primarily address the LQT1, LQT2, and LQT3 forms (caused by mutations of the LQT1, 2, 3, 5, and 6 genes)1 and the rare LQT4, LQT7, and LQT8 forms will be discussed briefly, and because so little is known about the new LQT9-11 forms they are not ready for a discussion of genotyping for therapy decisions. The pleural term “Long-QT syndromes” is indeed now very appropriate because of the diversity (both molecular and phenotype) of the conditions caused by the 11 accepted or proposed LQTS genes. The idea of genotype-based therapy has been discussed for some time, being encouraged by the experimental findings with mexiletine and flecainide in LQT3 and potassium supplementation in LQT2, plus other laboratory findings.2–8 The concept has received additional attention recently as some details outlining the complexity of the molecular substrate of LQTS are being reported.9–18 There are several concepts that are important for the discussion of this controversy. First, what we really want to accomplish by treatment is to prevent sudden death and aborted cardiac arrest. Most …

Expanding spectrum of congenital disorder of glycosylation Ig (CDG‐Ig): Sibs with a unique skeletal dysplasia, hypogammaglobulinemia, cardiomyopathy, genital malformations, and early lethality

In this report, we describe a brother and sister who presented at birth with short-limb skeletal dysplasia, polyhydramnios, prematurity, and generalized edema. Dysmorphic features included broad nose, thick ears, thin lips, micrognathia, inverted nipples, ulnar deviation at the wrists, spatulate fingers, fifth finger camptodactyly, nail hypoplasia, and talipes equinovarus. Other features included short stature, microcephaly, psychomotor retardation, B-cell lymphopenic hypogammaglobulinemia, sensorineural deafness, retinal detachment and blindness, intestinal malrotation with poor gastrointestinal motility, persistent hyponatremia, intermittent hypoglycemia, and thrombocytopenia. Cardiac anomalies included PDA, VSD, hypertrophic cardiomyopathy, and arrhythmias. The brother had a small penis with hypospadias, hypoplastic scrotum, and non-palpable testes. Skeletal findings included absent ossification of cervical vertebral bodies, pubic bones, knee epiphyses, and tali. Both sibs died before age 2 years, one of overwhelming sepsis and the other of cardiorespiratory failure associated with her cardiomyopathy. Metabolic studies showed a type 1 pattern of abnormal serum transferrin glycosylation. Fibroblasts synthesized truncated LLOs, primarily Man(7)GlcNAc(2), suggestive of CDG-Ig. Both sibs were compound heterozygotes for a novel 301 G > A (G101R) mutation and a previously described 437 G > A (R146Q) mutation in ALG12. Congenital disorders of glycosylation should be considered for children with undiagnosed multi-system disease including neurodevelopmental delay, skeletal dysplasia, immune deficiency, male genital hypoplasia, and cardiomyopathy.

Hyperglycemic brain injury in the rat

Children with diabetes onset before 5 years of age have reduced neurocognitive function. This problem has been attributed to hypoglycemia, a complication of insulin therapy. The eye, kidney, and nerve complications of diabetes (hyperglycemia) have been reduced by intensified insulin therapy which is associated with a 3-fold increase in severe hypoglycemia and therefore is not recommended for children less than 13 years of age. Since hyperglycemia is much more common than intermittent hypoglycemia during early childhood diabetes, it is important to determine if hyperglycemia affects brain growth and development. Rats were exposed to 4 weeks of either continuous hyperglycemia (diabetes) or intermittent (3 h, 3 times/week) hypoglycemia from 4 to 8 weeks of age. The brains of these animals were compared to those of similarly aged normal control animals. The cell number was increased, and the cell size reduced in the cortex of diabetic animals as assessed by DNA/wet weight of brain and protein/DNA content. Reduced amounts of protein, fatty acids, and cholesterol/μgram DNA also indicate smaller cells with reduced myelin content in the cortex of the diabetic animals. Histologic evaluation of these brains confirmed the biochemical findings. These observations require further confirmation and evaluation but indicate that continuous hyperglycemia may be more damaging than intermittent hypoglycemia to the developing brain. This is an important consideration for the management of diabetes mellitus in young children.

Prolonged hypoglycaemia after insulin lispro overdose

Insulin lispro has a more rapid onset and a shorter duration of hypoglycaemic action than regular insulin. We report a 39-year-old woman, with no previous medical history, who injected 300 U of the insulin lispro (Humalog) in an attempted suicide. Half an hour later, she was found comatose and brought to our emergency department. On arrival, she was comatose, with capillary glucose of 0.4 mmol/L. She awoke after a 50 ml intravenous bolus of 50% glucose. A continuous infusion of 10% glucose was started. Intermittent hypoglycaemia with neurological signs requiring treatment with 50% glucose was recorded three times during subsequent hospitalization, the last episode being 11 h after insulin injection. The plasma insulin level 4 h after injection was 1465 mU/L, and 18 h after injection was 11 mU/L. Hypoglycaemia after an insulin lispro overdose may last for more than 11 h. Repeated hypoglycaemia after an insulin overdose could be avoided with a glucose infusion rate equivalent to the maximal glucose disposal rate.

Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations

Timothy syndrome (TS) is a multisystem disorder that causes syncope and sudden death from cardiac arrhythmias. Prominent features include congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. All TS individuals have syndactyly (webbing of fingers and toes). We discovered that TS resulted from a recurrent, de novo cardiac L-type calcium channel (CaV1.2) mutation, G406R. G406 is located in alternatively spliced exon 8A, encoding transmembrane segment S6 of domain I. Here, we describe two individuals with a severe variant of TS (TS2). Neither child had syndactyly. Both individuals had extreme prolongation of the QT interval on electrocardiogram, with a QT interval corrected for heart rate ranging from 620 to 730 ms, causing multiple arrhythmias and sudden death. One individual had severe mental retardation and nemaline rod skeletal myopathy. We identified de novo missense mutations in exon 8 of CaV1.2 in both individuals. One was an analogous mutation to that found in exon 8A in classic TS, G406R. The other mutation was G402S. Exon 8 encodes the same region as exon 8A, and the two are mutually exclusive. The spliced form of CaV1.2 containing exon 8 is highly expressed in heart and brain, accounting for approximately 80% of CaV1.2 mRNAs. G406R and G402S cause reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase risk of arrhythmia. These data indicate that gain-of-function mutations of CaV1.2 exons 8 and 8A cause distinct forms of TS.

Ca V1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism

Ca V1.2, the cardiac L-type calcium channel, is important for excitation and contraction of the heart. Its role in other tissues is unclear. Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. In every case, Timothy syndrome results from the identical, de novo Ca V1.2 missense mutation G406R. Ca V1.2 is expressed in all affected tissues. Functional expression reveals that G406R produces maintained inward Ca 2+ currents by causing nearly complete loss of voltage-dependent channel inactivation. This likely induces intracellular Ca 2+ overload in multiple cell types. In the heart, prolonged Ca 2+ current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in this disorder. These discoveries establish the importance of Ca V1.2 in human physiology and development and implicate Ca 2+ signaling in autism.

Glycogen Branching Enzyme Deficiency in Quarter Horse Foals

Seven related Quarter Horse foals that died by 7 weeks of age were examined for glycogen branching enzyme (GBE) deficiency. Clinical signs varied from stillbirth, transient flexural limb deformities, seizures, and respiratory or cardiac failure to persistent recumbency. Leukopenia (5 of 5 foals) as well as high serum creatine kinase (CK; 5 of 5), aspartate transaminase (AST; 4 of 4), and gamma glutamyl transferase (GGT; 5 of 5) activities were present in most foals, and intermittent hypoglycemia was present in 2 foals. Gross postmortem lesions were minor, except for pulmonary edema in 2 foals. Muscle, heart, or liver samples from the foals contained abnormal periodic acid Schiff's (PAS)‐positive globular or crystalline intracellular inclusions in amounts proportional to the foal's age at death. Accumulation of an unbranched polysaccharide in tissues was suggested by a shift in the iodine absorption spectra of polysaccharide isolated from the liver and muscle of affected foals. Skeletal muscle total polysaccharide concentrations were reduced by 30%, but liver and cardiac muscle glycogen concentrations were normal. Several glycolytic enzyme activities were normal, whereas GBE activity was virtually absent in cardiac and skeletal muscle, as well as in liver and peripheral blood cells of affected foals. GBE activities in peripheral blood cells of dams of affected foals and several of their half‐siblings or full siblings were ∼50% of controls. GBE protein in liver determined by Western blot was markedly reduced to absent in affected foals, and in a half‐sibling of an affected foal, it was approximately one‐half the amount of normal controls. Pedigree analysis also supported an autosomal recessive mode of inheritance. The affected foals have at least 2,600 half‐siblings. Consequently, GBE deficiency may be a common cause of neonatal mortality in Quarter Horses that is obscured by the variety of clinical signs that resemble other equine neonatal diseases.

Intermittent hypoglycemia in a horse with anaplastic carcinoma of the kidney

Clinically apparent hypoglycemia is rare in adult horses. Hypoglycemia is a well-recognized paraneoplastic syndrome in humans and dogs with non-insulin-secreting tumors and may occur in horses as well. Hypoglycemia associated with non-insulin-secreting tumors is believed to result from production of an abnormal form of insulin-like growth factor II. Neoplasia should be considered in the differential diagnosis for adult horses with hypoglycemia.

Alteration in brain glucose metabolism induced by hypoglycaemia in man.

Glucose is the usual fuel of brain tissue. As hypoglycaemia develops, a level of glycaemia is reached where glucose transport from the circulation is no longer sufficient to meet metabolic demands, and the brain signals for peripheral counter-regulatory responses and symptoms of hypoglycaemia ensue. The glycaemic threshold for these events can be shifted to lower glucose concentrations following a single episode of hypoglycaemia, and compensating central nervous system adaptations have been postulated in man. In nondiabetic subjects, rates of brain glucose uptake are initially impaired at a systemic glucose concentration of 3.6 mmol/l; whereas after 56 h of intermittent hypoglycaemia (3.0 mmol/l) brain uptake is preserved at normal rates even at 2.5 mmol/l. Increments in counter-regulatory hormones and symptoms are also triggered at lower glucose concentrations following recurrent hypoglycaemia. In 24 patients with insulin-dependent diabetes stratified into three equal groups by HbA1c value, those in the lowest third of HbA1c range had rates of brain glucose uptake at 3.0 mmol/l that were equivalent to rates measured at 5.3 mmol/l. Patients in the other HbA1c groups had rates of brain glucose uptake during hypoglycaemia that were reduced by 30% relative to normoglycaemia-comparable to reductions seen in non-diabetic subjects. Thus, alterations in glucose uptake occur in the brain in order to maintain normal brain metabolism following experimental and clinical hypoglycaemia. Because of this enhanced glucose uptake, the brain has no need to signal for counter-regulatory responses and hypoglycaemia unawareness occurs.

Impaired hormonal responses to hypoglycemia in spontaneously diabetic and recurrently hypoglycemic rats. Reversibility and stimulus specificity of the deficits.

To evaluate the roles of iatrogenic hypoglycemia and diabetes per se in the pathogenesis of defective hormonal counterregulation against hypoglycemia in insulin-dependent diabetes mellitus (IDDM), nondiabetic, and spontaneously diabetic BB/Wor rats were studied using a euglycemic/hypoglycemic clamp. In nondiabetic rats, recurrent (4 wk) insulin-induced hypoglycemia (mean daily glucose, MDG, 59 mg/dl) dramatically reduced glucagon and epinephrine responses by 84 and 94%, respectively, to a standardized glucose fall from 110 to 50 mg/dl. These deficits persisted for > 4 d after restoring normoglycemia, and were specific for hypoglycemia, with normal glucagon and epinephrine responses to arginine and hypovolemia, respectively. After 4 wk of normoglycemia, hormonal counterregulation increased, with the epinephrine, but not the glucagon response reaching control values. In diabetic BB rats (MDG 245 mg/dl with intermittent hypoglycemia), glucagon and epinephrine counterregulation were reduced by 86 and 90%, respectively. Chronic iatrogenic hypoglycemia (MDG 52 mg/dl) further suppressed counterregulation. Prospective elimination of hypoglycemia (MDG 432 mg/dl) improved, but did not normalize hormonal counterregulation. In diabetic rats, the glucagon defect appeared to be specific for hypoglycemia, whereas deficient epinephrine secretion also occurred during hypovolemia. We concluded that both recurrent hypoglycemia and the diabetic state independently lead to defective hormonal counterregulation. These data suggest that in IDDM iatrogenic hypoglycemia magnifies preexisting counterregulatory defects, thereby increasing the risk of severe hypoglycemia.

Late onset primary systemic carnitine deficiency exacerbated by carnitine-free parenteral nutrition

We describe a 21-year-old male with previously normal plasma total and free carnitine levels who developed a deficiency manifest by decreased plasma and muscle total and free carnitine, decreased urine carnitine, severe hepatic steatosis, mediastinal lipomatosis, progressively impaired triglyceride clearance, myopathy and intermittent hypoglycemia. This case demonstrates that systemic carnitine deficiency may occur in some patients receiving long term carnitine-free TPN. Carnitine may be an essential element of the diet in this patient population.

Intermittent hypoglycemia impairs glucose counterregulation.

IDDM patients who maintain strict glycemic control have impaired counterregulatory hormone and symptomatic responses to hypoglycemia. To test the hypothesis that intermittent exposure to hypoglycemia plays an etiological role in these defective responses, we produced 4 consecutive daily episodes of hypoglycemia in 10 healthy, nondiabetic volunteers by using the insulin clamp technique. Fasting (5.3 +/- 0.1 vs. 5.4 +/- 0.1 mM) and nadir (2.3 +/- 0.1 vs. 2.4 +/- 0.1 mM) glucose levels achieved during insulin infusion did not differ on study days 1 and 4. In contrast, the glucose levels required to stimulate an increase in EPI (2.8 vs. 3.1 mM), glucagon (2.8 vs. 3.2 mM), cortisol (2.4 vs. 2.9 mM), GH (2.6 vs. 3.0 mM), and autonomic hypoglycemic symptoms (2.2 vs. 2.5 mM) were all significantly lower on study day 4 versus study day 1 (P < 0.005-0.05). Basal levels of EPI and cortisol, but not glucagon, GH, or NE also were reduced on the final study day. We conclude that intermittent hypoglycemia can result in attenuation of the hormonal and symptomatic responses to insulin-induced hypoglycemia and may contribute to the defective counterregulatory responses in patients with well-controlled IDDM.

Chronic stress enhances vasopressin but not corticotropin-releasing factor secretion during hypoglycemia.

Quantitative immunocytochemistry was used to investigate the effect of chronic intermittent stress on the storage and release of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) in the zona externa of the median eminence (ZEME). Wistar rats were subjected to repeated once daily insulin stress and studied 24 h after the last episode of hypoglycemia. Chronic intermittent hypoglycemia differentially affected CRF immuno-staining (CRFi) and AVPi stores in the ZEME, characterized by a transitory fall in CRFi (7 days) and a gradual increase in AVPi (11 days). The acute hypothalamic response to stress was studied by measuring insulin-induced depletion of CRFi and AVPi in the ZEME after blockade of fast axonal transport with colchicine (5 micrograms/rat ic). Three hours after insulin, CRFi was reduced by 24 and 28% in naive and repeatedly (11 times) stressed animals, respectively. In contrast, insulin did not affect CRFi in rats exposed to hypoglycemia for 7 days. In addition, hypoglycemia reduced AVPi in the ZEME by 37, 42, and 54% in naive and repeatedly (7 and 11 times) stressed rats, respectively. We conclude that chronic intermittent hypoglycemia induces a shift in hypothalamic signals for adrenocorticotropic hormone release in favor of AVP. This may result in altered sensitivity of the corticotrophs for hypophysiotropic factors and corticosteroids that are of physiological importance for the pituitary response to subsequent stressors.