Glucose uptake and binding of digoxin to skeletal muscle

Physical exercise induces increased uptake of both digoxin and glucose in exercising skeletal muscle. Glucose uptake could be a regulatory factor for the digoxin binding to skeletal muscle, since in dogs, insulin and glucose infusion have been reported to increase the uptake of digoxin in muscle. In the present study on eight healthy digitalized subjects (0.5 mg digoxin daily) the uptake of glucose in skeletal muscle was achieved by infusion of 6 mg/kg body weight/min glucose, 0.004 IE/kg body weight/min insulin and 300 micrograms/h somatostatin. Serum and skeletal muscle digoxin levels were analysed before and during the infusion. We found no changes in the digoxin levels in serum and skeletal muscle in spite of an increased uptake of glucose in the muscle. Thus, glucose uptake in skeletal muscle is probably not an important regulatory factor for the change in muscle digoxin binding induced by exercise.     

Two generations of insulinotropic imidazoline compounds

The imidazoline RX871024 increased basal- and glucose-stimulated insulin release in vitro and in vivo. The compound inhibited activity of ATP-sensitive K(+) channels as well as voltage-gated K(+) channels, which led to membrane depolarization, an increase in the cytosolic Ca(2+) concentration ([Ca(2+)](i)), and insulin release. Importantly, RX871024 also enhanced the insulinotropic effect of glucose in cells with clamped [Ca(2+)](i) but in the presence of high ATP and Ca(2+)concentration inside the cell. We believe that the latter effect on insulin exocytosis was at least in part mediated by a rise in diacylglycerol, which then activated protein kinase C (PKC) and increased the generation of arachidonic acid (AA) metabolites. Activation of both the PKC and AA pathways resulted in potentiation of glucose effects on insulin secretion. Unlike RX871024, the novel imidazoline BL11282 did not block ATP-dependent K(+) channels, but similarly to RX871024, it stimulated insulin secretion in depolarized or permeabilized islets. Accordingly, BL11282 did not influence glucose and insulin levels under basal conditions either in vitro or in vivo, but it markedly enhanced the insulinotropic effects of glucose. BL11282 restored the impaired insulin response to glucose in islets from spontaneously diabetic GK rats. We conclude that BL11282 belongs to a new class of insulinotropic compounds that demonstrate a strong glucose-dependent effect on insulin exocytosis.     

Accumulation of Nav1 mRNAs at differentiating postsynaptic sites in rat soleus muscles

Acetylcholine receptors (AChRs) and voltage-gated sodium channels (Na(V)1s) accumulate at different times in the development of the murine neuromuscular junction (NMJ). We used in situ hybridization to study the relationship of Na(V)1 mRNA accumulation to this difference. mRNAs encoding both muscle Na(V)1 isoforms, Na(v)1.4 and Na(v)1.5, were first concentrated at NMJs at birth, when the proteins start to accumulate. Within 4 weeks, Na(v)1.4 mRNA increased 5-fold at the NMJ while Na(v)1.5 mRNA became undetectable. Na(V)1 mRNA accumulation occurred even if the nerve was cut at birth. Like AChR mRNA, Na(V)1 mRNA accumulated at denervated synaptic sites on regenerating muscles and in response to ectopically expressed neural agrin. Clustering of Na(V)1 at the NMJ follows that of its mRNA while AChR clustering precedes its mRNA clustering by several days. This suggests that factors other than local mRNA upregulation determine the timing of clustering of these two important postsynaptic ion channels.     

Neurological complications of kernicterus

OBJECTIVE AND BACKGROUND: Prevention of bilirubin encephalopathy relies on the detection of newborns who are at risk of developing serious hyperbilirubinemia. The objective of this study was to reassess the clinical syndrome of kernicterus as neurodiagnostic studies have become more readily available and can be used to evaluate these infants. METHODS: The study population was neonates born at term or near term admitted to The Hospital for Sick Children in Toronto, Ontario, Canada, between January 1990 and May 2000. During the study period, there were 9776 admissions (average number of admissions per year--888 infants). The inclusion criteria were that patients had total serum bilirubin levels of >400 micromol/L at the time of diagnosis and no evidence of hypoxic ischemic encephalopathy. Records were reviewed to establish neurodevelopment outcomes. RESULTS: Twelve neonates (nine males) were identified. Bilirubin levels at the time of diagnosis ranged from 405 to 825 micromol/L. Causes of these elevated levels included glucose-6-phosphate dehydrogenase deficiency (seven patients), dehydration (three patients), sepsis (one patient), and was undetermined in one patient. Abnormal visual evoked potentials were found in three of nine patients and abnormal brainstem auditory evoked potentials in seven of ten patients. Abnormal electroencephalograms were documented in five patients studied. Brain magnetic resonance imaging results were abnormal in three of four patients. CONCLUSIONS: Magnetic resonance imaging typically showed an increased signal in the posteromedial aspect of the globus pallidus and was, therefore, useful in the assessment of the structural changes of chronic bilirubin encephalopathy after kernicterus.     

Review of antipsychotics in children and adolescents

The use of antipsychotics in children and adolescents in the clinical setting is increasing. This article reviews 77 clinical trials published in the last 10 years, investigating their efficacy, effectiveness, safety and pharmacokinetic data in paediatric populations. The diagnostic categories in which the antipsychotics are commonly used (schizophrenia, pervasive developmental disorders, Tourette's disorder, mental retardation/subaverage intelligence, mood disorders and disruptive behaviour disorders) were used in order to review the evidence and effectiveness. All randomised, double-blind, placebo-controlled trials from the past decade are also summarised. This review refers to recent relevant practice parameters, guidelines and reviews throughout the text. Consistent with previous reviews, it is concluded that the recent trend of increased use of antipsychotics in children and adolescents is not adequately supported by evidence. Specific suggestions have been provided on how to incorporate the existing evidence base into clinical decision making. The review ends with the authors' opinion on the clinical and research implications for the field and future directions.     

Hyperproinsulinemia and proinsulin-to-insulin ratios in Swedish middle-aged men: association with glycemia and insulin resistance but not with family history of diabetes

Elevated proinsulin and proinsulin/insulin ratios are features of abnormal beta-cell function in type 2 diabetes. The participation of genetic factors is disputed. The authors wished to investigate relations between family history of diabetes on one hand and proinsulin as well as proinsulin/immunoreactive insulin ratios on the other. A large, population-based sample of Swedish men aged 35-54 years in 1992 was studied. Subjects without known diabetes were selected either to have a strong family history of diabetes (n = 1,619) or no history of the disease (n = 1,495). An oral glucose tolerance test detected 172 subjects with impaired glucose tolerance and 55 subjects with previously unknown diabetes according to World Health Organization 1985 criteria. In multiple regression analysis, fasting levels of proinsulin and proinsulin/insulin ratios were positively associated both with the 2-hour glucose level (as a continuous variable) and with obesity, whereas a negative association was found with birth weight. No association was found with family history of diabetes or with chronologic age. These findings indicate that elevated proinsulin and proinsulin/insulin ratios are secondary to increased demands on beta-cell secretion induced by hyperglycemia and insulin resistance with no discernible influence of family history of diabetes.     

Selective effect of some somatostatin analogs on glucagon as opposed to insulin release in rats in vivo

Cyclic somatostatin, at a dose of 700 but not 70 ng/kg/min, inhibited arginine-induced insulin and glucagon release as well as glucose stimulated insulin release in rats in vivo. Three somatostatin (S-S) analogs (D-Cys14-S-S, D-Trp8-D-Cys14-S-S and Ala2-D-Trp8-D-Cys14-S-S), at a dose of 70 ng/kg/min, suppressed arginine-induced glucagon but not insulin release. At the same dose, the first two of these analogs had no effect on glucose-induced insulin release, while the third one. Ala2-D-Trp8-D-Cys14-somatostatin, enhanced insulin release induced by glucose. A fourth analog, D-Trp8-somatostatin, was more potent than somatostatin with regard to arginine stimulated insulin and glucagon release, and equipotent with somatostatin with respect to glucose stimulated insulin release. These studies show, firstly, that the inhibitory effect of somatostatin analogs on arginine induced insulin release may be different from that when glucose is used as a stimulant and, secondly, that Ala2-D-Trp8-D-Cys14-somatostatin inhibits arginine-induced glucagon release while enhancing insulin release on glucose stimulation.     

Effects of dexamethasone on glucose-induced insulin and proinsulin release in low and high insulin responders

We compared the effects of dexamethasone-induced insulin resistance on B-cell secretory performance in 12 low insulin responders (LIR) and in eight high insulin responders (HIR). A hyperglycemic clamp (120 minutes) was performed before and after the subjects had ingested dexamethasone 3 mg x 2 for 2 1/2 days. Fasting levels of blood glucose increased from 4.60 +/- 0.13 to 5.74 +/- 0.23 mmol/L after dexamethasone in LIR and from 4.37 +/- 0.18 to 5.26 +/- 0.13 mmol/L in HIR. Dexamethasone treatment increased fasting levels of total immunoreactive insulin (IRI), C-peptide, and proinsulin, as well as the proinsulin to IRI ratio to a similar degree in LIR and HIR. The amount of glucose infused to uphold hyperglycemia during the clamp decreased by 54% after dexamethasone in LIR and by 46% in HIR. Mean level of stimulated IRI during the clamp increased after dexamethasone by 43% in LIR and by 53% in HIR. Mean level of stimulated C-peptide increased by 11% (not significant) in LIR and by 24% in HIR. Mean level of stimulated proinsulin increased by 86% in LIR and by 93% in HIR. The effects of dexamethasone on insulin secretion varied among individuals, since steroid treatment failed to affect IRI responses to glucose in two LIR and two HIR. The magnitude of dexamethasone effects on secretion was not correlated to pre-dexamethasone insulin sensitivity as assessed by a somatostatin-insulin-glucose infusion test (SIGIT) or by M/I (glucose infused/insulin level) ratios of the control clamp.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term stability of low insulin responses to glucose in non-diabetic subjects.

We investigated the stability of the insulin response to glucose in healthy subjects by making retrospective comparisons of insulin responses after two 60 min glucose infusion tests performed many years apart. The subjects (N = 49) were divided into two lower and two higher quartiles as assessed by the incremental 0-10 min insulin area during the initial glucose infusion test. Ages were initially 32.3 +/- 2.8 years in lower quartiles and 26.6 +/- 1.1 in higher quartiles and body mass indexes 21.6 +/- 0.6 kg/m2 and 21.8 +/- 0.5, respectively. The interval between the first and second glucose infusion tests was 8.1 +/- 2.8 years for lower quartiles and 10.4 +/- 1.3 for higher quartiles. In lower quartiles, the 0-10 min insulin area at first testing was 157.1 +/- 15.9 mU/l x 10 min and at follow-up 202.2 +/- 26.6 (+29%, NS). In higher quartiles, the insulin area decreased from 654.8 +/- 70.6 mU/l x 10 min at first testing to 489.8 +/- 53.6 at follow-up (-25%, p less than 0.05). The 0-60 min glucose area did not change significantly between glucose infusion tests in lower quartiles (+5%), but did increase by 12% (p less than 0.005) in higher quartiles. Only one subject of the lowest quartile at first testing changed to higher quartiles at follow-up. Predictable "regression toward the mean" at follow-up was moderate, hence the individual insulin response to glucose was relatively stable with time. This finding is compatible with the hypothesis that genetic factors are of major importance for the insulin response to glucose.