Roser Casamitjana

Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association

The association of high levels of autoantibodies to glutamic acid decarboxylase (GAD-ab) and stiff-person syndrome (SPS) is well known. However, the full spectrum of neurological syndromes associated with GAD-ab is not well established. In addition, these patients usually present type 1 diabetes mellitus (DM1) that could justify the presence of high GAD-ab levels. To clarify these issues, we reviewed the clinical and immunological features of patients in whom high GAD-ab levels were detected in a reference centre for DM1 and for the detection of antineuronal antibodies in suspected paraneoplastic neurological syndromes (PNS). High GAD-ab levels were defined as values > or =2000 U/ml by radioimmunoassay. Intrathecal synthesis (IS) of GAD-ab was calculated in paired serum/CSF samples. Values higher than the IgG index were considered indicators for positive GAD-ab-specific IS. High GAD-ab levels were identified in 61 patients, 22 (36%) had SPS, 17 (28%) cerebellar ataxia, 11 (18%) other neurological disorders (epilepsy -- four, PNS -- four; idiopathic limbic encephalitis -- two; myasthenia gravis -- one), and 11 (18%) isolated DM1. Patients with SPS and cerebellar ataxia had the same frequency of female gender (86% vs 94%), DM1 (59% vs 53%), CSF oligoclonal bands (35% vs 69%). Three of the four PNS patients, with paraneoplastic encephalomyelitis, a predominant gait cerebellar ataxia, and limbic encephalitis, had neuroendocrine carcinomas. GAD expression was confirmed in the two tumours in which the study was done. The fourth patient presented with paraneoplastic cerebellar degeneration antedating a lung adenocarcinoma. The frequency of increased IS of GAD-ab was 85% in SPS, 100% in cerebellar ataxia, and 86% in other neurological disorders. In conclusion, our study emphasizes that high GAD-ab levels associate with other neurological disorders besides SPS. Cerebellar ataxia, the second most common syndrome associated with high GAD-ab levels, shares with SPS the same demographic, clinical and immunological features. The demonstration of an increased IS of GAD-ab is important to confirm that the GAD autoimmunity is related to the neurological syndrome particularly when there is a concomitant DM1 that could justify the presence of high GAD-ab levels. Lastly, in patients who develop neurological syndromes that suggest a PNS, the finding of GAD-ab does not rule out this possibility and appropriate studies should be done to confirm an underlying cancer.

Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine

OBJECTIVES To assess the effects of switching from HIV-1 protease inhibitors (PI) to nevirapine on metabolic abnormalities in patients with fat redistribution and on CD4 T lymphocytes and plasma HIV-1 RNA. DESIGN Longitudinal data analysis of 23 consecutive patients treated with two nucleoside reverse transcriptase inhibitors and at least one PI who decided to stop PI despite sustained virological suppression (< 200 copies/ml) because of psychological repercussions caused by body changes. PI were replaced by nevirapine in all patients. METHODS Physical examination [including measurements of body mass index (BMI) and waist: hip ratio (WHR)], fasting cholesterol, triglycerides, glucose, insulin, CD4 T lymphocytes and plasma HIV-1 RNA were performed at baseline and every 3 months. RESULTS Awareness of body changes occurred after a median of 12 months (range, 6-26 months) from the commencement of PI. Seventeen patients complained of increased abdominal girth (in 15 also of peripheral fat wasting) and six of peripheral fat wasting only. Hypertriglyceridemia (> or = 200 mg/dl) was present in 23 (100%), hypercholesterolemia (> or = 200 mg/dl) in 18 (78%), and impaired fasting glucose (> or = 110 mg/dl) in seven (30%) patients. Baseline CD4 T lymphocytes were 514 x 10(6)/l (range, 83-994 x 10(6)/l). HIV-1 RNA had been < 200 copies/ml a median of 9 months (range, 3-14 months) prior to withdrawal of PI. Median follow-up from the replacement of PI by nevirapine was 8 months (range, 7-11 months). Six months after PI withdrawal there was a significant improvement in cholesterol (decrease of 22%; P = 0.0005), triglycerides (decrease of 57%; P = 0.0001), glucose (decrease of 15%; P = 0.008), and fasting insulin resistance index (decrease of 45%; P = 0.0001). CD4 T-lymphocyte counts remained unchanged (401 x 10(6)/l; range, 57-941 x 10(6)/l; P = 0.13) and in only one patient did the viral load become detectable at a low count (546 copies/ml; P = 0.32). BMI did not vary (23.30 versus 23.56 kg/m2; P = 0.73), but WHR decreased significantly from 0.91 to 0.85 (P = 0.048). Twenty-one patients (91%) subjectively reported a partial improvement in their body shape (particularly in peripheral fat wasting), although none admitted to have their body shaped as prior to body changes. CONCLUSIONS Metabolic abnormalities associated with potent antiretroviral regimens including PI may revert at least partially, whereas the suppression achieved may be preserved at least at mid-term after replacing PI by nevirapine.

The TNF-alpha gene Nco I polymorphism influences the relationship among insulin resistance, percent body fat, and increased serum leptin levels.

Tumor necrosis factor-α (TNF-α), acting as a modulator of gene expression in adipocytes, is implicated in the development of insulin resistance and obesity. The aim of this study was to investigate whether the Nco I polymorphism of the TNF-a gene influences the relationship among insulin resistance, percent body fat, and serum leptin levels. A sample of 38 subjects (19 men, mean age 36.2 ± 1.9 years, BMI 28.8 ± 1.2 kg/m2, range 22.2–35.7; and 19 women, age 34.9 ± 1.4 years, BMI 28.1 ± 0.8 kg/m2, range 19–37.9) was divided into two groups on the basis of the Nco I genotype. Twenty-three subjects were (+/+) homozygotes for the presence of the Nco I restriction site that is associated with a guanine at position −308 of the TNF-a promoter. Of the other subjects, 12 were (+/−) heterozygotes and 3 (−/−) homozygotes for the absence of the restriction site, resulting from a guanine-to-adenine substitution at position −308 of the TNF-a promoter. This substitution (termed TNF-2) leads to higher rate of transcription of TNF-a than the wild-type allele TNF-1 in vitro. TNF-1 (+/+) and TNF-2 (+/− and −/−) groups of subjects were comparable in sex, age, BMI, waist-to-hip ratio, and several skinfold measurements. Basal serum insulin was greater (14.2 ± 2 vs. 9.2 ± 0.9 mlM, P = 0.041) in the TNF-2 group in the presence of comparable serum glucose concentration. The integrated area under the curve of serum insulin concentrations, measured in response to a 75-g oral glucose challenge, and the percent body fat, measured by bioelectric impedance, were significantly increased in TNF-2 subjects (226.8 ± 33 vs. 139.4 ± 17.8 mU/l, P = 0.032; 33.6 ± 2.8 vs. 24.9 ± 2%, P = 0.01). TNF-2 subjects also showed a decreased insulin sensitivity index, as determined by the frequently sampled intravenous glucose tolerance test with minimal model analysis (1.9 ± 0.4 vs. 3.05 ± 0.3 min−1 · mU−1 · 1−1 P = 0.03). These differences were more marked among women. Paralleling the known relationship between insulin and leptin levels, serum leptin concentration was clearly increased in the TNF-2 group (19.6 ± 3.4 vs. 11.1 ± 1.5 ng/ml, P = 0.03). Therefore, (+/−) heterozygotes and (−/−) homozygotes may be more susceptible to developing insulin resistance and increased percent body fat. Results of the present study suggest that TNF-αNco I polymorphism may exacerbate the alterations in leptin levels normally found among insulin-resistant subjects.

Serum Visfatin Increases With Progressive β-Cell Deterioration

Visfatin has shown to be increased in type 2 diabetes but to be unrelated to insulin sensitivity. We hypothesized that visfatin is associated with insulin secretion in humans. To this aim, a cross-sectional study was conducted in 118 nondiabetic men and 64 (35 men and 29 women) type 2 diabetic patients. Type 1 diabetic patients with long-standing disease (n = 58; 31 men and 27 women) were also studied. In nondiabetic subjects, circulating visfatin (enzyme immunoassay) was independently associated with insulin secretion (acute insulin response to glucose [AIRg] from intravenous glucose tolerance tests) but not with insulin sensitivity (Si) or other metabolic or anthropometric parameters, and AIRg alone explained 8% of visfatin variance (β = −0.29, P = 0.001). Circulating visfatin was increased in type 2 diabetes (mean 18 [95% CI 16–21] vs. 15 ng/ml [13–17] for type 2 diabetic and nondiabetic subjects, respectively; P = 0.017, adjusted for sex, age, and BMI), although this association was largely attenuated after accounting for HbA1c (A1C). Finally, circulating visfatin was found to be increased in patients with long-standing type 1 diabetes, even after adjusting for A1C values (37 ng/ml [34–40]; P < 0.0001, adjusted for sex, age, BMI, and A1C compared with either type 2 diabetic or nondiabetic subjects). In summary, circulating visfatin is increased with progressive β-cell deterioration. The study of the regulation and role of visfatin in diabetes merits further consideration.

Impact of Switching from Human Immunodeficiency Virus Type 1 Protease Inhibitors to Efavirenz in Successfully Treated Adults with Lipodystrophy

We prospectively followed 20 consecutive patients with human immunodeficiency virus type 1 (HIV-1) with viral loads of <200 RNA copies/mL. These patients had been treated with 2 nucleoside reverse transcriptase inhibitors and > or =1 HIV-1 protease inhibitor for > or =3 months; they developed body changes consistent with lipodystrophy and requested they be switched from protease inhibitor to efavirenz. At baseline and every 3 months, we assessed the following: body mass index, waist-to-hip ratio, regional fat thickness (assessed by sonography), fasting total and high-density lipoprotein cholesterol, triglycerides, glucose, insulin, CD4(+) cells, and viral load. At baseline, hypertriglyceridemia (> or =200 mg/dL) was present in 17 (85%) patients, hypercholesterolemia (> or =200 mg/dL) in 14 (70%), and impaired fasting glucose (> or =110 mg/dL) in 8 (40%); CD4(+) T cells were 280x10(6) cells/L (range, 64-942x10(6) cells/L). HIV-1 RNA had been at <200 copies/mL for a median of 14 months (range, 3-24 months). Six months after switching to efavirenz, there was a reduction in triglyceride levels (a decrease of 31%; P=.03) and fasting insulin resistance index (a decrease of 28%; P=.03), but total and high-density lipoprotein cholesterol and glucose did not change. Waist-to-hip ratio decreased from 0.92 to 0.87 (P=.06). Subcutaneous fat thickness did not change. CD4(+) cells remained stable (363x10(6) cells/L; range, 102-741x10(6) cells/L; P=.65). Nineteen patients (95%) had HIV-1 RNA levels that remained at <200 copies/mL. Although CD4(+) response and viral suppression remained preserved after 6 months of switching from protease inhibitor to efavirenz, the benefits of this approach on the evolution of lipodystrophy were limited, and our findings do not support its routine recommendation to treat lipodystrophy.

Hepatic Nuclear Factor 1-α Directs Nucleosomal Hyperacetylation to Its Tissue-Specific Transcriptional Targets

ABSTRACT Mutations in the gene encoding hepatic nuclear factor 1-α (HNF1-α) cause a subtype of human diabetes resulting from selective pancreatic β-cell dysfunction. We have analyzed mice lacking HNF1-α to study how this protein controls β-cell-specific transcription in vivo. We show that HNF1-α is essential for the expression ofglut2 glucose transporter and L-type pyruvate kinase (pklr) genes in pancreatic insulin-producing cells, whereas in liver, kidney, or duodenum tissue, glut2 andpklr expression is maintained in the absence of HNF1-α. HNF1-α nevertheless occupies the endogenous glut2 andpklr promoters in both pancreatic islet and liver cells. However, it is indispensable for hyperacetylation of histones inglut2 and pklr promoter nucleosomes in pancreatic islets but not in liver cells, where glut2 andpklr chromatin remains hyperacetylated in the absence of HNF1-α. In contrast, the phenylalanine hydroxylase promoter requires HNF1-α for transcriptional activity and localized histone hyperacetylation only in liver tissue. Thus, different HNF1-α target genes have distinct requirements for HNF1-α in either pancreatic β-cells or liver cells. The results indicate that HNF1-α occupies target gene promoters in diverse tissues but plays an obligate role in transcriptional activation only in cellular- and promoter-specific contexts in which it is required to recruit histone acetylase activity. These findings provide genetic evidence based on a live mammalian system to establish that a single activator can be essential to direct nucleosomal hyperacetylation to transcriptional targets.

Interactions between serum leptin, the insulin-like growth factor-I system, and sex, age, anthropometric and body composition variables in a healthy population randomly selected.

objective Leptin secretion is influenced by many factors and the GH/IGF axis plays an important role in the regulation of body composition, but the physiological interactions between leptin and the IGF‐I system remain unknown. In this study we investigated the relationship between leptin, the IGF‐I system, and sex, age, anthropometric and body composition variables in a group of healthy adults randomly selected.

Cerebrospinal hypocretin, daytime sleepiness and sleep architecture in Parkinson's disease dementia

Excessive daytime sleepiness is common in Parkinsons disease and has been associated with Parkinsons disease-related dementia. Narcoleptic features have been observed in Parkinsons disease patients with excessive daytime sleepiness and hypocretin cell loss has been found in the hypothalamus of Parkinsons disease patients, in association with advanced disease. However, studies on cerebrospinal fluid levels of hypocretin-1 (orexin A) in Parkinsons disease have been inconclusive. Reports of sleep studies in Parkinsons disease patients with and without excessive daytime sleepiness have also been disparate, pointing towards a variety of causes underlying excessive daytime sleepiness. In this study, we aimed to measure cerebrospinal fluid hypocretin-1 levels in Parkinsons disease patients with and without dementia and to study their relationship to dementia and clinical excessive daytime sleepiness, as well as to describe potentially related sleep architecture changes. Twenty-one Parkinsons disease patients without dementia and 20 Parkinsons disease patients with dementia, along with 22 control subjects without sleep complaints, were included. Both Epworth sleepiness scale, obtained with the help of the caregivers, and mini-mental state examination were recorded. Lumbar cerebrospinal fluid hypocretin-1 levels were measured in all individuals using a radio-immunoassay technique. Additionally, eight Parkinsons disease patients without dementia and seven Parkinsons disease patients with dementia underwent video-polysomnogram and multiple sleep latencies test. Epworth sleepiness scale scores were higher in Parkinsons disease patients without dementia and Parkinsons disease patients with dementia than controls (P < 0.01) and scores >10 were more frequent in Parkinsons disease patients with dementia than in Parkinsons disease patients without dementia (P = 0.04). Cerebrospinal fluid hypocretin-1 levels were similar among groups (controls = 321.15 +/- 47.15 pg/ml; without dementia = 300.99 +/- 58.68 pg/ml; with dementia = 309.94 +/- 65.95 pg/ml; P = 0.67), and unrelated to either epworth sleepiness scale or mini-mental state examination. Dominant occipital frequency awake was slower in Parkinsons disease patients with dementia than Parkinsons disease patients without dementia (P = 0.05). Presence of slow dominant occipital frequency and/or loss of normal non-rapid eye movement sleep architecture was more frequent among Parkinsons disease patients with dementia (P = 0.029). Thus, excessive daytime sleepiness is more frequent in Parkinsons disease patients with dementia than Parkinsons disease patients without dementia, but lumbar cerebrospinal fluid hypocretin-1 levels are normal and unrelated to severity of sleepiness or the cognitive status. Lumbar cerebrospinal fluid does not accurately reflect the hypocretin cell loss known to occur in the hypothalamus of advanced Parkinsons disease. Alternatively, mechanisms other than hypocretin cells dysfunction may be responsible for excessive daytime sleepiness and the sleep architecture alterations seen in these patients.

Glucagon hinders the effects of somatostatin on portal hypertension: A study in rats with partial portal vein ligation

Whether the decrease of portal venous inflow and portal pressure induced by somatostatin is related to the effects of somatostatin in inhibiting the secretion of glucagon and other vasodilatory peptides that are increased in portal hypertension was investigated in the current study. Splanchnic vascular resistance and splanchnic blood flow were determined using radioactive microspheres in rats with portal hypertension caused by partial portal vein ligation. Somatostatin infusion significantly decreased portal pressure (from 13.1 +/- 1.9 to 12.1 +/- 2.2 mm Hg; P less than 0.05). This was associated with a significant decrease in portal venous inflow caused by splanchnic vasoconstriction, as evidenced by increased splanchnic vascular resistance, and with a marked suppression of glucagon secretion. The simultaneous infusion of somatostatin and glucagon (2.8 ng/min, a dose that prevented any decrease in circulating glucagon levels) abolished all the hemodynamic effects of somatostatin. This effect seems to be specific because no hemodynamic changes were noted in portal hypertensive rats receiving only the glucagon infusion.

GLP-1 Action and Glucose Tolerance in Subjects With Remission of Type 2 Diabetes After Gastric Bypass Surgery

OBJECTIVE Glucagon like peptide-1 (GLP-1) has been suggested as a major factor for the improved glucose tolerance ensuing after Roux-en-Y gastric bypass (RYGBP) surgery. We examined the effect of blocking endogenous GLP-1 action on glucose tolerance in subjects with sustained remission of type 2 diabetes mellitus (T2DM) present before RYGBP. RESEARCH DESIGN AND METHODS Blood glucose, insulin, C-peptide, glucagon, GLP-1, and glucose-dependent insulinotropic peptide levels were measured after a meal challenge with either exendin-(9–39) (a GLP-1r antagonist) or saline infusion in eight subjects with sustained remission of T2DM after RYGBP and seven healthy controls. RESULTS Infusion of exendin-(9–39) resulted in marginal deterioration of the 2-h plasma glucose after meal intake in RYGBP subjects [saline 78.4 ± 15.1 mg/dL compared with exendin-(9–39) 116.5 ± 22.3 mg/dL; P < 0.001]. Furthermore, glucose response to meal intake was similarly enlarged in the two study groups [percent change in the area under the curve of glucose exendin-(9–39) infusion versus saline infusion: controls 10.84 ± 8.8% versus RYGBP 9.94 ± 8.4%; P = 0.884]. In the RYGBP group, the blockade of the enlarged GLP-1 response to meal intake resulted in reduced insulin (P = 0.001) and C-peptide (P < 0.001), but no change in glucagon (P = 0.258) responses. CONCLUSIONS The limited deterioration of glucose tolerance on blockade of GLP-1 action in our study suggests the resolution of T2DM after RYGBP may be explained by mechanisms beyond enhancement of GLP-1 action.