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PubMed2006

The central issue? Visceral fat mass is a good marker of insulin resistance and metabolic disturbance in women with polycystic ovary syndrome.

OBJECTIVE: To establish whether visceral fat mass is the most significant variable correlating with insulin resistance and other metabolic parameters in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective cross-sectional trial. SETTING: Reproductive medicine clinic. POPULATION: Forty women with anovulatory PCOS. METHODS: Measurements were taken at recruitment, and analysis was performed to define correlations between the outcome measures and the explanatory variables. MAIN OUTCOME MEASURES: Visceral and subcutaneous fat by computed tomography scan, insulin resistance, anthropometric measures, markers of the metabolic syndrome and androgens. RESULTS: Strong linear correlation of visceral fat to insulin resistance (r = 0.68, P < 0.001) was observed. There were also statistically significant correlations with fasting insulin (r = 0.73, P < 0.001), homeostasis model assessment beta-cell function (r = 0.50, P = 0.007), triglycerides (r = 0.45, P = 0.003), high-density lipoprotein cholesterol (r = -0.42, P = 0.007), urate (r = 0.47, P = 0.002), Sex hormone binding globulin (r = -0.39, P = 0.01) and luteinising hormone (r = -0.32, P = 0.02). There were no significant correlations of testosterone with fat distribution or metabolic parameters. Insulin resistance showed closest correlation to visceral fat mass (r = 0.68, P < 0.001), then to waist circumference (r = 0.62, P < 0.001), with the weakest correlation being waist:hip ratio (r = 0.36, P = 0.01). The best regression model for predicting insulin resistance is with visceral fat mass and triglycerides as the explanatory variables (r = 0.72, P < 0.001). CONCLUSIONS: Visceral fat is the most significant variable correlating with metabolic dysfunction in women with PCOS. Our data support the hypothesis that visceral fat either causes insulin resistance or is a very early effect of it. It also implies that reducing visceral fat should reduce insulin resistance which may account for the observations that exercise and weight loss appear to be more effective interventions than pharmacological treatments. The best anthropometric measure of insulin resistance is waist circumference.

Adult↗

PubMed1999

Magnetic resonance spectroscopy in focal epilepsy: 31P and 1H spectroscopy.

Magnetic resonance spectroscopy (MRS) is rapidly becoming a clinical and research tool in epilepsy. Animal studies have demonstrated metabolic abnormalities in the interictal and ictal state showing energy depletion and changes in neuronal compounds. Similarly, clinical studies have demonstrated consistent abnormalities involving energy (31P) and cellular dependent (1H) compounds. Phosphorus MRS (31P) shows lateralizing metabolic dysfunction in approximately 65-75 p. 100 of patients with temporal lobe epilepsy (PCr/Pi). Proton MRS (1H) using single-voxel or chemical shift imaging has demonstrated a high sensitivity in lateralizing temporal lobe epilepsy (65-96 p. 100) with bilateral changes seen in 35-45 p. 100 of patients. The role of MRS in extra-temporal lobe epilepsy is less accurate because of the spatial limitations of current techniques. Further advances in this field promise to improve the clinical utility of MRS in epilepsy.

Animals↗

PubMed2006

Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy.

Heritable mutations, known as inborn errors of metabolism, cause numerous devastating human diseases, typically as a result of a deficiency in essential metabolic products or the accumulation of toxic intermediates. We have isolated a missense mutation in the Drosophila sugarkill (sgk) gene that causes phenotypes analogous to symptoms of triosephosphate isomerase (TPI) deficiency, a human familial disease, characterized by anaerobic metabolic dysfunction resulting from pathological missense mutations affecting the encoded TPI protein. In Drosophila, the sgk gene encodes the glycolytic enzyme TPI. Our analysis of sgk mutants revealed TPI impairment associated with reduced longevity, progressive locomotor deficiency, and neural degeneration. Biochemical studies demonstrate that mutation of this glycolytic enzyme gene does not result in a bioenergetic deficit, suggesting an alternate cause of enzymopathy associated with TPI impairment.

Amino Acid Sequence↗

PubMed2026

Circadian reprogramming of inflammation and metabolism in chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is driven by inflammation, fibrosis, and metabolic dysfunction. While circadian rhythm dysregulation is well documented in chronic disorders, its specific impact on CKD pathogenesis remains elusive. METHODS: We performed four-hour interval time-series RNA sequencing on renal tissues from control and CKD mice. We used the JTK_CYCLE algorithm to identify rhythmic genes and categorize them as lost, acquired, or sustained in CKD; we subsequently performed focused bioinformatic analyses. RESULTS: The renal circadian profile was substantially altered; acquired rhythmicity emerged as the dominant pattern, and core clock gene expression was disrupted. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that upregulated acquired-rhythmic genes in CKD were enriched in immune-inflammatory pathways; the expression of these genes peaked at Zeitgeber time (ZT) 12-16, consistent with a higher level of renal macrophage infiltration at ZT16 than at ZT0. Conversely, genes associated with nutrient and energy metabolism pathways were downregulated but acquired rhythmicity in CKD. Dapagliflozin improved renal function and restored the circadian expression rhythms of NR1D1 and p-BMAL1. CONCLUSIONS: CKD profoundly remodels the renal circadian transcriptome, driving immune-inflammatory and metabolic pathways into maladaptive rhythmicity. Furthermore, dapagliflozin can partially restore the expression of renal core clock genes.

Animals↗

PubMed2026

Exogenous lactate ameliorates Aβ-induced energy deficit and neurotoxicity with increased mitochondrial TCA cycle carbon flux in SH-SY5Y cells.

A growing body of evidence has demonstrated the existence of metabolic dysfunction in neurodegenerative diseases, including Alzheimer's disease (AD), suggesting that deprivation of energy substrates impairs cellular dynamics. As glucose utilization declines in patients with AD, the need for alternative energy sources becomes crucial to sustain neuronal activities and prevent cell death induced by neurotoxic proteins, such as amyloid beta (Aβ) aggregates. In this context, lactate has been investigated as a potential alternative brain energy substrate in several studies, yet its impact on neuronal cells under Aβ-induced toxicity remains unclear. We confirmed significant suppression of energy production-related biological pathways by analyzing brain transcriptomic data of patients with AD. In subsequent in vitro studies, exogenous lactate treatment ameliorated neuron-like cell death caused by Aβ aggregates. Using a 13C stable isotope tracer, we verified cellular lactate uptake and its incorporation into tricarboxylic acid (TCA) cycle in neurons under the neurotoxic condition. 13C metabolic flux analysis further supported these findings by revealing that lactate treatment restored Aβ-suppressed mitochondrial TCA cycle fluxes. These metabolic improvements were accompanied by increased expression of mitochondrial proteins. These findings support lactate shuttling as a mechanism for supplying lactate-derived carbon to mitochondrial energy metabolism, which may improve neuronal resilience under Aβ-induced metabolic stress.NEW & NOTEWORTHY This study shows that lactate treatment attenuates Aβ-induced cell death in neuron-like cells and supports mitochondrial carbon metabolism. Glycolytic hypometabolism was observed in human AD brain transcriptome and Aβ-treated neuron-like cells. We confirmed that lactate replenished mitochondrial energetics, making neurons more resilient to neurotoxicity. Using 13C tracing and metabolic flux analysis, we found that lactate-derived carbon was incorporated into the TCA cycle and that lactate treatment was associated with restoration of Aβ-suppressed mitochondrial fluxes.

Humans↗

PubMed2002

Effects of chronic epilepsy on intellectual functions.

Intractable epilepsy is related to various transient and chronic brain electric and neurochemical disturbances. There is increasing evidence that long-lasting chronic epilepsy may induce secondary neuronal loss and metabolic dysfunctions. Still a matter of controversy is, however, whether cognitive abilities of patients deteriorate with increasing duration of intractable epilepsy. We present results from two independent cross-sectional studies dealing with measures of global cognitive performance in two different ways. The first study investigated in 78 patients with refractory temporal lobe epilepsy (TLE) the influence of duration of epilepsy on the difference between an estimated measure of former or pre-morbid intelligence and the current performance in an intelligence test. The second study aimed at duration of epilepsy-dependent effects on current IQ measures of 209 patients with refractory TLE. Both studies showed that the duration of epilepsy contributes to the explanation of interindividual variability in IQ measures of adult TLE patients to a higher degree than age and age of epilepsy onset. Similar to several studies on hippocampal neuronal density, hippocampal volume, and glucose metabolism, the presented cross-sectional data demonstrate that a duration of chronic epilepsy exceeding two decades is associated with worse cognitive abilities. Consequently, refractory TLE seems to induce a very slow but ongoing cognitive deterioration. It is assumed that epilepsy-related noxious events and agents exhaust the compensatory capacity of brain functions. A high cognitive reserve capacity, however, might delay the onset of deterioration.

Adult↗

PubMed1990

Hyperglycemia-induced B cell toxicity. The fate of pancreatic islets transplanted into diabetic mice is dependent on their genetic background.

The role of pancreatic B cell dysfunction in the phase preceding clinical onset of insulin-dependent and non-insulin-dependent diabetes mellitus has been much debated. In this investigation, the impact of a prolonged diabetic environment on pancreatic islet B cells transplanted syngeneically under the kidney capsule of C57BL/6 (B6) and C57BL/Ks (BKs) mice was studied. Alloxan-diabetic mice bearing a subcapsular islet graft insufficient to normalize the blood glucose level were rendered normoglycemic by a second intrasplenic islet graft after various period of hyperglycemia to examine the reversibility of hyperglycemia-induced B cell dysfunction. Using a perfusion technique of the graft-bearing, it was found that both strains of mice exhibited a diminished glucose-induced insulin secretion after 6 wk of hyperglycemia, when compared with normoglycemic mice carrying islet grafts. When normoglycemia was restituted by the splenic graft after 4 or 12 wk, there was a normalization of glucose-stimulated insulin secretion in the renal islet grafts in B6 mice, whereas insulin secretion from the grafted BKs islets remained impaired. Morphometric measurements of the islet grafts demonstrated a 50% reduction in the graft volume in diabetic BKs mice after 12 wk, compared with normoglycemic animals, whereas no such decrease was observed in B6 mice. Islet grafts removed from hyperglycemic mice of both strains exhibited diminished insulin mRNA contents, and in the BKs mice there was also a reduced glucose oxidation rate in the islet grafts in vitro. This metabolic dysfunction can only partly be explained by a reduced graft size. The present findings emphasize the genetic constitution as a decisive factor for the survival and function during a period of sustained stress on a limited B cell mass.

Animals↗

PubMed2006

Adverse hepatic and cardiac responses to rosiglitazone in a new mouse model of type 2 diabetes: relation to dysregulated phosphatidylcholine metabolism.

Given the heterogeneous nature of metabolic dysfunctions associated with insulin resistance and type 2 diabetes (T2D), a single pharmaceutical cannot be expected to provide complication-free therapy in all patients. Thiazolidinediones (TZD) increase insulin sensitivity, reduce blood glucose and improve cardiovascular parameters. However, in addition to increasing fat mass, TZD have the potential in certain individuals to exacerbate underlying hepatosteatosis and diabetic cardiomyopathy. Pharmacogenetics should allow patient selection to maximize therapy and minimize risk. To this end, we have combined two genetically diverse inbred strains, NON/Lt and NZO/Lt, to produce a "negative heterosis" increasing the frequency of T2D in F1 males. As in humans with T2D, treatment of diabetic and hyperlipemic F1 males with rosiglitazone (Rosi), an agonist of peroxisome proliferator-activated gamma receptor (PPARgamma), reverses these disease phenotypes. However, the hybrid genome perturbed both major pathways for phosphatidylcholine (PC) biosynthesis in the liver, and effected remarkable alterations in the composition of cardiolipin in heart mitochondria. These metabolic defects severely exacerbated an underlying hepatosteatosis and increased levels of the adipokine, plasminogen activator inhibitor-1 (PAI-1), a risk factor for cardiovascular events. This model system demonstrates how the power of mouse genetics can be used to identify the metabolic signatures of individuals who may be prone to drug side effects.

Animals↗

PubMed1991

Low level developmental lead exposure decreases the sensitivity, amplitude and temporal resolution of rods.

Electroretinographic (ERG), morphometric and biochemical studies on retinas from monkeys or rats reveal that moderate level developmental lead (Pb) exposure produces long-term selective rod deficits and degeneration. The present studies determined whether similar alterations occur following low level developmental Pb exposure. Long-Evans rats, exposed to Pb only via dam's milk from parturition to weaning, had mean blood Pb of 18.8 micrograms/dl at weaning and 6.6 micrograms/dl at 90 days of age. Morphometric and ultrastructural studies revealed no signs of rod loss or degeneration although the presence of glycogen in some rod mitochondria suggests the occurrence of a metabolic dysfunction. Retinal sensitivity and rhodopsin content per eye were decreased in a manner such that, they followed the established log-linear relationship. A- and b-wave voltage- and latency-log intensity functions, generated from single-flash ERGs in fully dark-adapted rats, revealed that low level Pb exposure caused a 25% and 15% decrease in mean amplitude, a 0.5 and a 0.5 log unit decrease in absolute sensitivity, and a 23% and 16% increase in mean latency, respectively. Scotopic (rod-mediated) and photopic (cone-mediated) flicker fusion frequency measures revealed selective rod deficits. Adult rats had a 15% inhibition of retinal cGMP-phosphodiesterase resulting in a 19% and 12% increase in cGMP in dark- and light-adapted states, respectively. The above data confirm and extend our previous studies conducted in rats with blood lead levels of 59 micrograms/dl during development. The rhodopsin and cyclic nucleotide metabolism data, as well as our recent data showing an inhibition of retinal Na+, K(+)-ATPase, are entirely consistent with the observed ERG changes. The fact that rat rods are similar to monkey and human rods suggests the relevance and applicability of these data to low level pediatric Pb poisoning. Thus, these data suggest that alterations in rod sensitivity and temporal processing may occur in children exposed to low levels of lead during perinatal development.

Animals↗

PubMed2003

Lower concentration of hippocampal N-acetylaspartate in familial bipolar I disorder.

OBJECTIVE: Previous studies attempting to identify neuropathological alterations in the hippocampus in bipolar disorder have been inconclusive. The objective of this study was to determine if the concentration of N-acetylaspartate, a neuronal and axonal marker, was lower in subjects with familial bipolar I disorder than in healthy comparison subjects, suggesting possible neuronal loss, neuronal dysfunction, or neuropil reduction in bipolar I disorder. METHOD: N-acetylaspartate, choline, and creatine in the right and left hippocampus were measured in 15 euthymic male patients with familial bipolar I disorder and 20 healthy male comparison subjects by using proton magnetic resonance spectroscopy ((1)H-MRS). RESULTS: Relative to the comparison group, the patients with bipolar I disorder demonstrated significantly lower concentrations of N-acetylaspartate and creatine but normal choline concentration in both the right and left hippocampus. There were no group or lateralized differences in the percentages of different tissue types within the MRS voxels, suggesting that the hippocampal N-acetylaspartate and creatine alterations were not an artifact of variations in tissue types represented in the voxels. There was also a significant negative correlation between N-acetylaspartate concentration in the right hippocampus and illness duration, after adjustment for the effects of age. CONCLUSIONS: This preliminary study provides support for the existence of neuronal loss, neuronal metabolic dysfunction, or interneuronal neuropil reduction in the hippocampal region in male patients with familial bipolar I disorder. The finding of normal hippocampal choline levels in these patients does not provide support for ongoing myelin breakdown or glial cell proliferation in this brain region in familial bipolar I disorder. The significant association between illness duration and N-acetylaspartate concentration in the right hippocampus supports the idea that neuronal pathology may increase with disease progression and that this effect may be lateralized, involving the right but not the left hippocampus.

Adult↗

PubMed2000

Alleviation of brain injury-induced cerebral metabolic depression by amphetamine: a cytochrome oxidase histochemistry study.

Measurements of oxidative metabolic capacity following the ablation of rat sensorimotor cortex and the administration of amphetamine were examined to determine their effects on the metabolic dysfunction that follows brain injury. Twenty-four hours after surgery, rats sustaining either sham operations or unilateral cortical ablation were administered a single injection of D-amphetamine (2 mg/kg; i.p.) or saline and then sacrificed 24 h later. Brain tissue was processed for cytochrome oxidase histochemistry, and 12 bilateral cerebral areas were measured, using optical density as an index of the relative amounts of the enzyme. Compared with that of the control groups, cytochrome oxidase in the injured animals was significantly reduced throughout the cerebral cortex and in 5 of 11 subcortical structures. This injury-induced depression of oxidative capacity was most pronounced in regions of the hemisphere ipsilateral to the ablation. Animals given D-amphetamine had less depression of oxidative capacity, which was most pronounced bilaterally in the cerebral cortex, red nucleus, and superior colliculus; and in the nucleus accumbens, caudateputamen, and globus pallidus ipsilateral to the ablation. The ability of D-amphetamine to alleviate depressed cerebral oxidative metabolism following cortical injury may be one mechanism by which drugs increasing noradrenaline release accelerate functional recovery in both animals and humans.

Amphetamine↗

PubMedDate not supplied

Tc-99m tetrofosmin tomography after nitrate administration in patients with ischemic left ventricular dysfunction: relation to metabolic imaging by PET.

BACKGROUND: In patients with ischemic left ventricular (LV) dysfunction, myocardial perfusion imaging after nitrate administration may improve the identification of dysfunctional but viable myocardium. This study was designed to assess the relationship between tetrofosmin uptake after nitrate administration and metabolic activity as assessed by positron emission tomography (PET) in patients with ischemic LV dysfunction. METHODS AND RESULTS: Thirty-six patients with chronic myocardial infarction and LV dysfunction (ejection fraction, 35% +/- 6%) underwent resting technetium 99m tetrofosmin single photon emission computed tomography (SPECT) imaging under control conditions (baseline) and after sublingual administration of 10 mg isosorbide dinitrate. Within 1 week, all patients underwent metabolic PET imaging with fluorine 18-fluorodeoxyglucose. Tetrofosmin uptake and metabolic activity were measured in 13 segments/patient. Regional LV function was assessed in corresponding segments by echocardiography. On baseline tetrofosmin imaging, 53 (40%) of the 131 akinetic or dyskinetic segments had reduced (<55% of peak activity) tracer uptake. Of these segments, 14 (26%) showed enhanced tetrofosmin uptake after nitrate administration (>/=10% vs baseline) and the remaining 38 (74%) did not change. The sensitivity and specificity of baseline tetrofosmin SPECT for detecting preserved metabolic activity were 69% and 86%, respectively. After nitrate administration, the sensitivity was higher (81%, P <.05 vs baseline) whereas the specificity was not different (86%, P = not significant). Concordance between tetrofosmin SPECT and PET in differentiating viable and necrotic myocardium was observed in 94 (72%) of the 131 akinetic or dyskinetic segments at baseline (kappa = 0.35) and in 108 segments (82%) after nitrate administration (kappa = 0.53). CONCLUSIONS: After nitrate administration, tetrofosmin uptake in dysfunctional segments correlated with metabolic activity as assessed by fluorodeoxyglucose PET imaging better than baseline. Thus tetrofosmin SPECT after nitrate administration may improve the identification of ischemic but still viable myocardium in patients with chronic ischemic LV dysfunction.

Adult↗

PubMed1994

A single amino acid substitution in the exoplasmic domain of the human growth hormone (GH) receptor confers familial GH resistance (Laron syndrome) with positive GH-binding activity by abolishing receptor homodimerization.

Growth hormone (GH) elicits a variety of biological activities mainly mediated by the GH receptor (GHR), a transmembrane protein that, based on in vitro studies, seemed to function as a homodimer. To test this hypothesis directly, we investigated patients displaying the classic features of Laron syndrome (familial GH resistance characterized by severe dwarfism and metabolic dysfunction), except for the presence of normal binding activity of the plasma GH-binding protein, a molecule that derives from the exoplasmic-coding domain of the GHR gene. In two unrelated families, the same GHR mutation was identified, resulting in the substitution of a highly conserved aspartate residue by histidine at position 152 (D152H) of the exoplasmic domain, within the postulated interface sequence involved in homodimerization. The recombinant mutated receptor protein was correctly expressed at the plasma membrane. It displayed subnormal GH-binding activity, a finding in agreement with the X-ray crystal structure data inferring this aspartate residue outside the GH-binding domain. However, mAb-based studies suggested the critical role of aspartate 152 in the proper folding of the interface area. We show that a recombinant soluble form of the mutant receptor is unable to dimerize, the D152H substitution also preventing the formation of heterodimers of wild-type and mutant molecules. These results provide in vivo evidence that monomeric receptors are inactive and that receptor dimerization is involved in the primary signalling of the GH-associated growth-promoting and metabolic actions.

Amino Acid Sequence↗

PubMed2001

Cardiac energetics are abnormal in Friedreich ataxia patients in the absence of cardiac dysfunction and hypertrophy: an in vivo 31P magnetic resonance spectroscopy study.

OBJECTIVE: Friedreich ataxia (FRDA), the commonest form of inherited ataxia, is often associated with cardiac hypertrophy and cardiac dysfunction is the most frequent cause of death. In 97%, FRDA is caused by a homoplasmic GAA triplet expansion in the FRDA gene on chromosome 9q13 that results in deficiency of frataxin, a mitochondrial protein of unknown function. There is evidence that frataxin deficiency leads to a severe defect of mitochondrial respiration associated with abnormal mitochondrial iron accumulation. To determine whether bioenergetics deficit underlies the cardiac involvement in Friedreich ataxia (FRDA) we measured cardiac phosphocreatine to ATP ratio non-invasively in FRDA patients. METHODS AND RESULTS: Eighteen FRDA patients and 18 sex- and age-matched controls were studied using phosphorus MR spectroscopy and echocardiography. Left ventricular hypertrophy was present in eight FRDA patients while fractional shortening was normal in all. Cardiac PCr/ATP in FRDA patients as a group was reduced to 60% of the normal mean (P<0.0001). In the sub-group of patients with no cardiac hypertrophy PCr/ATP was also significantly reduced (P<0.0001). CONCLUSION: Cardiac bioenergetics, measured in vivo, is abnormal in FRDA patients in the absence of any discernible deterioration in cardiac contractile performance. The altered bioenergetics found in FRDA patients without left ventricle hypertrophy implies that cardiac metabolic dysfunction in FRDA precedes hypertrophy and is likely to play a role in its development.

Adenosine Triphosphate↗

PubMed2004

Hypoxia decreases cellular ATP demand and inhibits mitochondrial respiration of a549 cells.

Hypoxia inhibits activity and expression of transporters involved in alveolar Na reabsorption and fluid clearance. We studied whether this represents a mechanism for reducing energy consumption or whether it is the consequence of metabolic dysfunction. Oxygen consumption (JO2) of A549 cells and primary rat alveolar type II cells was measured by microrespirometry during normoxia, hypoxia (1.5% O2), and reoxygenation. In both cell types, acute and 24-h hypoxia decreased total JO2 significantly and reoxygenation restored JO2 after 5 min but not after 24 h of hypoxia in A549 cells, whereas recovery was complete in type II cells. In A549 cells under normoxia Na/K-ATPase accounted for approximately 15% of JO2, whereas Na/K-ATPase-related JO2 was decreased by approximately 25% in hypoxia. Inhibition of other ion transporters did not affect JO2. Protein synthesis-related JO2 was not affected by acute hypoxia, but decreased by 30% after 24-h hypoxia. Acute and 24-h hypoxia decreased JO2 of A549 cell mitochondrial complexes I, II, and III by 30-40%. Reoxygenation restored complex I activity after acute hypoxia but not after 24-h hypoxia. ATP was decreased 30% after 24-h hypoxia, but lactate production rate was not affected. Reduced nicotinamine adenine dinucleotide was slightly elevated in acute hypoxia. Our findings indicate that inhibition of the Na/K-ATPase by hypoxia contributes little to energy preservation in hypoxia. It remains unclear to what extent hypoxic inhibition of mitochondrial metabolism affects ATP-consuming processes.

Adenosine Triphosphate↗

PubMed2006

Metformin for prevention of weight gain and insulin resistance with olanzapine: a double-blind placebo-controlled trial.

OBJECTIVE: To assess whether metformin prevents body weight gain (BWG) and metabolic dysfunction in patients with schizophrenia who are treated with olanzapine. METHOD: Forty patients taking olanzapine (10 mg daily) were randomly allocated to a metformin (n = 20; 850 to 1700 mg daily) or placebo (n = 20) group in a 14-week double-blind study. Waist circumference (WC), BWG, body mass index (BMI) fasting glucose, insulin, and lipids were evaluated at baseline and at Weeks 7 and 14 of treatment. RESULTS: At Week 14, BWG (kg) was similar in the metformin group (5.5 kg) and the placebo group (6.3 kg), P = 0.4. There were no differences between the changes in BMI, WC, glucose, insulin, insulin resistance index (HOMA-IR), and plasma lipid levels observed in the treatment group and the placebo group; however, glucose levels decreased significantly after metformin administration (P = 0.02). The HOMA-IR decreased significantly in both groups, but 3 subjects from the placebo group developed fasting glucose levels greater than 5 mmol/L. After taking metformin, triglyceride levels increased, but the cholesterol profile improved significantly. CONCLUSIONS: Metformin did not prevent olanzapine-induced BWG. While some lipid parameters worsened during placebo, the HOMA-IR improved in both the placebo and the metformin groups. Carbohydrate metabolism impairment was not systematically observed during short-term olanzapine administration.

Adult↗

PubMed2005

Hemiballismus.

Hemiballismus is the most dramatic movement disorder seen in clinical practice. Its emergence points to a structural lesion or metabolic dysfunction in the region of the subthalamic nucleus, its afferent or efferent pathways, or interconnected deep brain nuclei, usually on the side contralateral to the movements. Any focal process may be to blame, but elderly sufferers generally have had vascular events, whereas the etiology is infectious or inflammatory in younger patients. Severe nonketotic hyperglycemia is another important cause of hemiballismus in the elderly. Hemiballismus patients require treatment both for the underlying etiology of the movement and for the movements themselves. There are no large controlled clinical trials to guide anti-ballismus therapy. However, dopamine receptor blocking agents have an established track record in suppressing choreic and ballistic movements, and are first-line agents for acute treatment. Standard neuroleptics such as haloperidol and perphenazine are started at low doses and titrated as tolerated until the movements are controlled. Atypical antipsychotics such as risperidone and clozapine have been used in small series and may have a reduced risk of extrapyramidal side effects. Catecholamine-depleting agents such as reserpine and tetrabenazine may be considered when long-term therapy is required. Other pharmacologic agents have met with varying success. The course of hemiballismus may be complicated by exhaustion, injury, or metabolic disorders, but with good supportive care, acute survival is good, and long-term survival reflects the prognosis of the underlying etiology. In time, the ballistic movements themselves tend to subside allowing withdrawal of drugs in many cases. When movements persist, stereotactic functional neurosurgical procedures may be considered in good surgical candidates.

Journal Article↗

PubMed2000

Effect of nutrient ingestion on glucagon-like peptide 1 (7-36 amide) secretion in human type 1 and type 2 diabetes.

Exogenous glucagon-like peptide 1(GLP-1) bioactivity is preserved in type 2 diabetic patients, resulting the peptide administration in a near-normalization of plasma glucose mainly through its insulinotropic effect. GLP-1 also reduces meal-related insulin requirement in type 1 diabetic patients, suggesting an impairment of the entero-insular axis in both diabetic conditions. To investigate this metabolic dysfunction, we evaluated endogenous GLP-1 concentrations, both at fasting and in response to nutrient ingestion, in 16 type 1 diabetic patients (age = 40.5 +/- 14yr, HbA1C = 7.8 +/- 1.5%), 14 type 2 diabetics (age = 56.5 +/- 13yr, HbA1C = 8.1 +/- 1.8%), and 10 matched controls. In postabsorptive state, a mixed breakfast (230 KCal) was administered to all subjects and blood samples were collected for plasma glucose, insulin, C-peptide and GLP-1 determination during the following 3 hours. In normal subjects, the test meal induced a significant increase of GLP-1 (30', 60': p < 0.01), returning the peptide values towards basal concentrations. In type 2 diabetic patients, fasting plasma GLP-1 was similar to controls (102.1 +/- 1.9 vs. 97.3 +/- 4.01 pg/ml), but nutrient ingestion failed to increase plasma peptide levels, which even decreased during the test (p < 0.01). Similarly, no increase in postprandial GLP-1 occurred in type 1 diabetics, in spite of maintained basal peptide secretion (106.5 +/- 1.5 pg/ml). With respect to controls, the test meal induced in both diabetic groups a significant increase in plasma glucagon levels at 60' (p < 0.01). In conclusion, either in condition of insulin resistance or insulin deficiency chronic hyperglycemia, which is a common feature of both metabolic disorders, could induce a progressive desensitization of intestinal L-cells with consequent peptide failure response to specific stimulation.

Adult↗