Effects of diabetes mellitus on patients with acute intermittent porphyria

Andersson, Carina; Bylesjö, Ingemar; Lithner, Folke

doi:10.1046/j.1365-2796.1999.0448e.x

Cited by 21 publications

(25 citation statements)

References 20 publications

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“…We have previously suggested that diabetes mellitus may benefit patients with AIP, as acute attacks of AIP became significantly more rare after the onset of diabetes mellitus [24, 25]. In line with this finding, acute attacks of AIP may be successfully treated with glucose.…”

Section: Discussionmentioning

confidence: 57%

“…Three subjects with high levels of HbA1c were 58–60 years of age (2 without previous episodes of porphyria and 1 with previous attacks of porphyria), while 4 AIP gene carriers were 35–42 years of age, 3 of them were brothers. In previous studies [24, 25], we found a prevalence of 2.2–4.9% of diabetes mellitus in AIP gene carriers. It is surprising to find such a high frequency of AIP gene carriers with increased HbA1c levels, as the AIP gene carriers included in this study have the same gene mutation (W198X) as the Swedish AIP gene carriers studied earlier [24, 25].…”

Section: Discussionmentioning

confidence: 64%

“…In previous studies [24, 25], we found a prevalence of 2.2–4.9% of diabetes mellitus in AIP gene carriers. It is surprising to find such a high frequency of AIP gene carriers with increased HbA1c levels, as the AIP gene carriers included in this study have the same gene mutation (W198X) as the Swedish AIP gene carriers studied earlier [24, 25]. …”

Section: Discussionmentioning

confidence: 64%

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Brain Magnetic Resonance Imaging White-Matter Lesions and Cerebrospinal Fluid Findings in Patients with Acute Intermittent Porphyria

Bylesjö¹,

Brekke

Prytz³

et al. 2004

Eur Neurol

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Background: Case reports display similaritiesbetween multiple sclerosis and acute intermittent porphyria (AIP). This study examines whether patients with AIP in general demonstrate white-matter lesions on brain magnetic resonance imaging (MRI) and/or abnormalities in plasma and/or cerebrospinal fluid (CSF) when examined outside attacks. We looked particularly for the presence of oligoclonal bands (OB) of immunoglobulin (Ig) in liquor. Methods:Eight AIP gene carriers without previous episodes of porphyria, mean age 42.8 years (range 30–60), and 8 AIP gene carriers with previous episodes of porphyria, mean age 42.8 years (range 33–62), were examined with brain MRI, venous blood samples and lumbar punctures. Results: Two male AIP gene carriers with previous episodes of porphyria, 58 and 35 years of age, had multiple white-matter, high-signal lesions on T₂- weighted MRI sequences. Two AIP gene carriers without previous episodes of porphyria, 1 male and 1 female, had less than 5 such lesions. No OB were seen in the CSF in any patient, but 1 carrier had an increased level of protein in the CSF. Seven of 16 subjects (44%) had increased levels of HbA1c (>6.0), suggesting protracted hyperglycemia, and 3 further subjects had borderline levels (5.9). Conclusion: T₂-weighted MRI sequences demonstrated multiple white-matter, high-signal lesions in 4 out of 16 AIP gene carriers (25%). No carrier demonstrated OB of Ig in CSF, making it unlikely that demyelinating lesions play a pivotal role in the pathogenesis of CNS symptoms in AIP. Only 1 AIP gene carrier had an increased level of protein in CSF; this contrasts with studies during acute attacks of porphyria. Seven subjects (44%) had abnormally high levels of HbA1c, in spite of the fact that no patient had a previous diagnosis of diabetes mellitus.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 64%

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Brain Magnetic Resonance Imaging White-Matter Lesions and Cerebrospinal Fluid Findings in Patients with Acute Intermittent Porphyria

Bylesjö¹,

Brekke

Prytz³

et al. 2004

Eur Neurol

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“…This in turn leads to an accumulation of porphyrin precursors prior to porphobilinogen deaminase. The pathogenesis of AIP is not known, but it is suggested that the lack of heme, or an accumulation of porphyrin precursors affecting the nervous system, is chiefly responsible for the clinical expression of AIP (12,56). In many patients, the onset of acute AIP attacks can be aborted by adequate nutritional intake (12).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Nuclear Factor 3 and Nuclear Factor 1 Regulate 5-Aminolevulinate Synthase Gene Expression and Are Involved in Insulin Repression

Scassa

Guberman

Ceruti

et al. 2004

Journal of Biological Chemistry

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Although the negative regulation of gene expression by insulin has been widely studied, the transcription factors responsible for the insulin effect are still unknown. The purpose of this work was to explore the molecular mechanisms involved in the insulin repression of the 5-aminolevulinate synthase (ALAS) gene. Deletion analysis of the 5 -regulatory region allowed us to identify an insulin-responsive region located at ؊459 to ؊354 bp. This fragment contains a highly homologous insulin-responsive (IRE) sequence. By transient transfection assays, we determined that hepatic nuclear factor 3 (HNF3) and nuclear factor 1 (NF1) are necessary for an appropriate expression of the ALAS gene. Insulin overrides the HNF3␤ or HNF3␤ plus NF1-mediated stimulation of ALAS transcriptional activity. Electrophoretic mobility shift assay and Southwestern blotting indicate that HNF3 binds to the ALAS promoter. Mutational analysis of this region revealed that IRE disruption abrogates insulin action, whereas mutation of the HNF3 element maintains hormone responsiveness. This dissociation between HNF3 binding and insulin action suggests that HNF3␤ is not the sole physiologic mediator of insulin-induced transcriptional repression. Furthermore, Southwestern blotting assay shows that at least two polypeptides other than HNF3␤ can bind to ALAS promoter and that this binding is dependent on the integrity of the IRE. We propose a model in which insulin exerts its negative effect through the disturbance of HNF3␤ binding or transactivation potential, probably due to specific phosphorylation of this transcription factor by Akt. In this regard, results obtained from transfection experiments using kinase inhibitors support this hypothesis. Due to this event, NF1 would lose accessibility to the promoter. The posttranslational modification of HNF3 would allow the binding of a protein complex that recognizes the core IRE. These results provide a potential mechanism for the insulin-mediated repression of IRE-containing promoters.

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“…49 Induction of ALA-S1 Via Metabolic Signaling Some nuclear signaling, such as peroxisome proliferatoractivated receptor-gamma coactivator 1α (PGC-1α), which is involved in a different manner in the endogenous regulation of many metabolic pathways, can take part in the global inductive process of the ALA-S1 activation, which explains why the ALA-S1 transcription is also controlled by some endocrine-metabolic circuits (starvation, gonadal activity, activity of the hypothalamic-hypophysis-adrenal axis, hormone signaling, etc), whose interference may have porphyrogenic effects. 34,40,[50][51][52][53][54] Induction of ALA-S1 Via the Induction of Heme-Oxygenase Expression Agents or conditions that upregulate heme oxygenase, the main enzyme of heme catabolism, may be considered as porphyrogenic; they cause an increase in heme catabolism, thus reducing free heme pool concentrations and activating ALA-S1 transcription. Well-known inducers of HO-1 are stress, fasting, endotoxins, heavy metals, and organic solvents.…”

Section: Mechanisms Of Drug Porphyrogenicitymentioning

confidence: 99%

Drugs and Acute Porphyrias: Reasons for a Hazardous Relationship

Roveri

Nascimbeni

Rocchi

et al. 2014

Postgraduate Medicine

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The porphyrias are a group of metabolic diseases caused by inherited or acquired enzymatic deficiency in the metabolic pathway of heme biosynthesis. Simplistically, they can be considered as storage diseases, because the partial enzymatic defect gives rise to a metabolic "bottleneck" in the biosynthetic pathway and hence to an accumulation of different metabolic intermediates, potentially toxic and responsible for the various (cutaneous or neurovisceral) clinical manifestations observed in these diseases. In the acute porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and the very rare delta-aminolevulinic acid dehydratase ALAD-d porphyria), the characteristic severe neurovisceral involvement is mainly ascribed to a tissue accumulation of delta-aminolevulinic acid, a neurotoxic nonporphyrin precursor. Many different factors, both endogenous and exogenous, may favor the accumulation of this precursor in patients who are carriers of an enzymatic defect consistent with an acute porphyria, thus contributing to trigger the serious (and potentially fatal) clinical manifestations of the disease (acute porphyric attacks). To date, many different drugs are known to be able to precipitate an acute porphyric attack, so that the acute porphyrias are also considered as pharmacogenetic or toxygenetic diseases. This article reviews the different biochemical mechanisms underlying the capacity of many drugs to precipitate a porphyric acute attack (drug porphyrogenicity) in carriers of genetic mutations responsible for acute porphyrias, and addresses the issue of prescribing drugs for patients affected by these rare, but extremely complex, diseases.

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Effects of diabetes mellitus on patients with acute intermittent porphyria

Abstract: This study raises the possibility that diabetes mellitus may be beneficial for patients with severe AIP.

Cited by 21 publications

References 20 publications

Brain Magnetic Resonance Imaging White-Matter Lesions and Cerebrospinal Fluid Findings in Patients with Acute Intermittent Porphyria

Brain Magnetic Resonance Imaging White-Matter Lesions and Cerebrospinal Fluid Findings in Patients with Acute Intermittent Porphyria

Hepatic Nuclear Factor 3 and Nuclear Factor 1 Regulate 5-Aminolevulinate Synthase Gene Expression and Are Involved in Insulin Repression

Drugs and Acute Porphyrias: Reasons for a Hazardous Relationship

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