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Lars Hansen

Publications and source records attributed to Lars Hansen.

34 records · Page 2Linked to original sources
PubMed2005

Genetics of type 2 diabetes mellitus: status and perspectives.

Throughout the last decade, molecular genetic studies of non-autoimmune diabetes mellitus have contributed significantly to our present understanding of this disease's complex aetiopathogenesis. Monogenic forms of diabetes (maturity-onset diabetes of the young, MODY) have been identified and classified into MODY1-6 according to the mutated genes that by being expressed in the pancreatic beta-cells confirm at the molecular level the clinical presentation of MODY as a predominantly insulin secretory deficient form of diabetes mellitus. Genomewide linkage studies of presumed polygenic type 2 diabetic populations indicate that loci on chromosomes 1q, 5q, 8p, 10q, 12q and 20q contain susceptibility genes. Yet, so far, the only susceptibility gene, calpain-10 (CAPN10), which has been identified using genomewide linkage studies, is located on chromosome 2q37. Mutation analyses of selected 'candidate' susceptibility genes in various populations have also identified the widespread Pro12Ala variant of the peroxisome proliferator-activated receptor-gamma and the common Glu23Lys variant of the ATP-sensitive potassium channel, Kir6.2 (KCNJ11). These variants may contribute significantly to the risk type 2 diabetes conferring insulin resistance of liver, muscle and fat (Pro12Ala) and a relative insulin secretory deficiency (Glu23Lys). It is likely that, in the near future, the recent more detailed knowledge of the human genome and insights into its haploblocks together with the developments of high-throughput and cheap genotyping will facilitate the discovery of many more type 2 diabetes gene variants in study materials, which are statistically powered and phenotypically well characterized. The results of these efforts are likely to be the platform for major progress in the development of personalized antidiabetic drugs with higher efficacy and few side effects.

Age of Onset↗
PubMed2004

Expression profiling of insulin action in human myotubes: induction of inflammatory and pro-angiogenic pathways in relationship with glycogen synthesis and type 2 diabetes.

Myotube cultures from patients with type 2 diabetes mellitus (T2DM) represent an experimental in vitro model of T2DM that offers a possibility to perform gene expression studies under standardized conditions. During a time-course of insulin stimulation (1 microM) at 5.5 mM glucose for 0 (no insulin), 0.5, 1, 2, 4, 8, and 24 h, mRNA contents were analyzed in human myotubes for each time point using Affymetrix DNA chip technology. Insulin treatment induced an inflammatory and pro-angiogenic response in the myotubes, with expression of early response factors followed by inflammatory chemokines, metabolic enzymes, and finally cell cycle regulating genes. One-hundred-forty-four genes were differentially expressed in myotubes from donors with type 2 diabetes compared with control subjects, including HSP70, apolipoprotein D/E, tropomyosin, myosin, and actin previously reported from in vivo studies of diabetic skeletal muscle. We conclude, (i) that insulin induces a time-dependent inflammatory and pro-angiogenic transcriptional response in cultured human myotubes, (ii) that myotubes in vitro retain a gene expression pattern specific for type 2 diabetes and sharing five genes with that of type 2 diabetic skeletal muscle in vivo, and (iii) that insulin, despite similar metabolic effects of glucose uptake and glycogen synthesis, regulates different pools of genes in skeletal muscle during in vivo and in vitro conditions.

Adult↗
PubMed2004

Mutation analysis of the Sonic hedgehog promoter and putative enhancer elements in Parkinson's disease patients.

Sonic hedgehog (SHH) is involved in the induction and differentiation of nigrostriatale dopaminergic neurons. We have investigated the promoter, two putative enhancer elements and the coding region of SHH for mutations in patients with Parkinson's disease (PD). None of the identified sequence variations were present at a significantly different frequency in PD patients compared to healthy individuals, suggesting that they are not involved in the pathogenesis of PD.

DNA Mutational Analysis↗
PubMed2004

Novel Connexin 43 (GJA1) mutation causes oculo-dento-digital dysplasia with curly hair.

Oculo-dento-digital dysplasia (ODDD) [OMIM 164200] is a rare autosomal dominant pleiotropic disorder comprising ocular, craniofacial, and digital anomalies, caused by mutations in the gap junction alpha-1 gene (GJA1 or Connexin 43 (CX43)) [Paznekas et al., 2003]. In a Danish family affected over five generations, we found a novel mutation, 286G --> A, resulting in Val96Met. We provide an easy method for mutation detection by use of the restriction enzyme Nde1 and discuss possible pathogenetic mechanisms, arguing that loss of function cannot be excluded. This is the second article reporting ODDD mutations.

Abnormalities, Multiple↗
PubMed2004

A common polymorphism in the promoter of the IGF-I gene associates with increased fasting serum triglyceride levels in glucose-tolerant subjects.

OBJECTIVE: The aim of the present study was to examine if absence of a common allele in a microsatellite polymorphism in the insulin-like growth factor I (IGF-I) promoter was associated with type 2 diabetes and alterations in quantitative traits in glucose-tolerant subjects. METHODS: The IGF-I promoter polymorphism was investigated in a case-control study comprising 694 type 2 diabetic patients and 218 glucose-tolerant control subjects, and in two genotype-quantitative trait studies involving 208 glucose-tolerant first-degree offspring of type 2 diabetic patients and 218 unrelated middle-aged subjects with normal glucose tolerance. RESULTS: No associations were found between the lack of the common promoter allele and type 2 diabetes (P = 0.25) or estimates of glucose metabolism in glucose-tolerant subjects. Presence of the wild-type allele was associated with an increase in fasting serum triglyceride levels in the group of 208 glucose-tolerant first-degree offspring of type 2 diabetic patients (P = 0.002). This finding was replicated in an independent sample of 218 unrelated middle-aged subjects with normal glucose tolerance (P = 0.007). CONCLUSION: The present study provides evidence that the common wild-type allele of the IGF-I promoter polymorphism is associated with increased levels of fasting serum triglyceride in glucose-tolerant whites.

Aged↗
PubMed2004

Correspondence analysis of microarray time-course data in case-control design.

Although different statistical approaches have been proposed for analyzing microarray time-course data, method for analyzing such data collected using the popular case-control design in clinical investigations has not been proposed perhaps due to the increased complexity for the existing parametric or non-parametric approaches. In this paper, we introduce a new multivariate data analyzing technique, the correspondence analysis, to analyze the high dimensional microarray time-course data in case-control design. We show, through an example on type 2 diabetes, how the nice features of the correspondence analysis can be use to explore the various time-course gene expression profiles that exist in the data. By coordinating and examining the projections on the reduced dimensions by both the genes and the time-course experiments, we are able to identify important genes and time-course patterns and make inferences on their biological relevance. Using the sample replicates, we propose a bootstrap procedure for inferring the significance of contributions on the leading dimensions by both the time-course experiments and the genes. Striking differences in the time-course patterns in the normal controls and diabetes patients have been revealed. In addition, the method also identifies genes that display similar or comparable time-course expression patterns shared by both the cases and the controls. We conclude that our correspondence analysis based approach can be a useful tool for analyzing high dimensional microarray data collected in clinical investigations.

Algorithms↗
PubMed2004

No association between akathisia or Parkinsonism and suicidality in treatment-resistant Schizophrenia.

Akathisia and drug-induced Parkinsonism have traditionally been associated with depression and suicidality based on case study evidence. In this subanalysis, patients with treatment resistant schizophrenia were rated on the Comprehensive Psychopathological Rating Scale, Barnes Akathisia Scale and Simpson-Angus extrapyramidal side-effect scale at two time points (n=86 at first assessment; n=67 at second assessment). At no time point was there any significant relationship between akathisia and depression/suicidality or distress associated with akathisia and Parkinsonism with suicidality. These preliminary findings warrant further investigation.

Adult↗
PubMed2003

Evidence for an association between the Leu162Val polymorphism of the PPARalpha gene and decreased fasting serum triglyceride levels in glucose tolerant subjects.

The aim of the study was to investigate whether genetic variation in the peroxisome proliferator-activated receptor-alpha (PPARalpha) is associated with type 2 diabetes and altered lipid or carbohydrate metabolism in glucose tolerant subjects. Mutation analyses of PPARalpha were performed in 56 type 2 diabetic patients. Six variants were identified: IVS3 + 76T>C, IVS3-19C>T, IVS4 + 35C>T, Leu162Val, Arg178Gly and Ala268Val. In a case-control study comprising 738 type 2 diabetic patients and 524 glucose tolerant subjects, the three exon variants did not show any significant differences in allele frequencies between type 2 diabetic patients and control subjects. The functional Leu162Val polymorphism was further investigated in genotype-phenotype studies involving 340 young, healthy subjects and 502 middle-aged glucose tolerant subjects. The young, healthy subjects who were heterozygous for the Leu162Val variant had, on average, a 20% decrease in fasting serum triglyceride levels (P=0.014). This finding was replicated in middle-aged subjects (P=0.023). The Leu162Val polymorphism was not related to alterations in insulin sensitivity, insulin release or level of glycaemia. In conclusion, the Leu162Val polymorphism of PPARalpha is associated with a decreased level of fasting serum triglyceride in glucose tolerant white subjects.

Adult↗
PubMed2003

Fluoxetine dose-increment related akathisia in depression: implications for clinical care, recognition and management of selective serotonin reuptake inhibitor-induced akathisia.

We report the case of a 22-year-old woman presenting major depressive episode with severe akathisia after an increase in fluoxetine. The patient developed severe restlessness and de novo suicidal ideation approximately 1 week after the dosage of fluoxetine was doubled, 1 year on from when the drug was first introduced. This case illustrates the importance of being alert to movement disorders in patients treated with selective serotonin reuptake inhibitors. The clinical implications are discussed. A management strategy based on the evidence in the existing literature is suggested.

Adult↗
PubMed2003

The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes.

The E23K polymorphism of the pancreatic beta-cell ATP-sensitive K(+) (K(ATP)) channel subunit Kir6.2 (KCNJ11) is associated with type 2 diabetes in whites, and a recent in vitro study of the E23K variant suggests that the association to diabetes might be explained by a slight inhibition of serum insulin release. In a study comprising 519 unrelated glucose-tolerant subjects, we addressed the question as to whether the E23K variant was related to reduced serum insulin release during an oral glucose tolerance test (OGTT). Furthermore, the polymorphism was examined in a case-control study comprising 803 type 2 diabetic patients and 862 glucose-tolerant control subjects. The E23K variant was associated with significant reductions in the insulinogenic index (P = 0.022) and serum insulin levels under the response curve during an OGTT (0-120 min) (P = 0.014) as well as with an increase in BMI (P = 0.013). In the present study, the association of the E23K polymorphism with type 2 diabetes was not significant (P = 0.26). However, the K23K genotype significantly associated with type 2 diabetes in a meta-analysis of white case and control subjects (n = 2,824, odds ratio [OR] 1.49, P = 0.00022). In conclusion, the widespread E23K polymorphism may have a diabetogenic effect by impairing glucose-induced insulin release and increasing BMI.

Amino Acid Substitution↗
PubMed2003

Candidate genes and late-onset type 2 diabetes mellitus. Susceptibility genes or common polymorphisms?

Several lines of evidence suggest that the aetio-pathogenesis of the common form of type 2 diabetes mellitus and its intrinsically related features of impaired insulin secretion and decreased insulin sensitivity (insulin resistance) includes a strong genetic component. At present, however, little is known about the nature of this genetic component although familial clustering of the disease has been described for decades. Major break-throughs in the genetic sciences of type 2 diabetes have been identifications of insulin receptor gene mutations in syndromes of severe insulin resistance and mutations in pancreatic beta-cell genes in the monogenic sub-group of type 2 diabetes: maturity-onset-diabetes-of-the-young, MODY. Pathophysiological models of insulin resistance in skeletal muscles and impaired glucose-induced insulin secretion in the beta-cells have formed a basis for selecting candidate genes with potential influence on the development of type 2 diabetes ("diabetogenes"). This process of selecting and analyzing genes for mutations that potentially associate with either type 2 diabetes mellitus, insulin resistance or impaired insulin secretion is often described as the "candidate gene approach". The studies reported in this thesis are excerpts from an extensive strategy of genetically dissecting (mutation analysis) in: 1) patients with the common form of late-onset type 2 diabetes mellitus the pathways that transduce the insulin signals from the plasma membrane to the activation of glycogen synthesis in skeletal muscle, and in 2) patients with either late-onset type diabetes or MODY the pathways involved in normal beta-cell development and beta-cell function (insulin secretion). Twelve of the genes that encode proteins in the insulin-signalling pathway from the insulin receptor through the phosphatidylinositide-regulated kinases down to the complex of phosphatases that regulate glycogen synthesis in skeletal muscle were analyzed. We could not confirm that a Val985Met variant in the insulin receptor is associated with type 2 diabetes or that the Met326Val of the p85 alpha regulatory subunit of the phosphoinositide-3 kinase is associated with insulin resistance. We found no coding mutations (missense) in the insulin signalling protein kinases but we confirmed that the 5 bp deletion (PP1ARE) in the 3'-end of the PPP1R3 gene that encodes the glycogen-associated regulatory subunit of protein phosphatase-1 (PP1G) is associated with insulin resistance estimated as insulin mediated glucose uptake. In contrast to protein kinases in skeletal muscles the genes encoding beta-cell transcription factors (IPF-1, NeuroD1/BETA2, and Neurogenin 3) are polymorphic but we could not confirm that the Asp76Asn of IPF-1 is a susceptibility gene for late-onset type 2 diabetes. On the other hand we confirmed that the Ala45Thr variant in NeuroD1/BETA2 may represent a susceptibility gene for type 1 diabetes but none of these genes revealed any MODY-specific mutations. Also the gene encoding the ATP-regulatable potassium channels of the beta-cell (Kir6.2) is polymorphic but none of these polymorphisms associated with changes in glucose-induced insulin secretion. Reviewed in context of the existing data our studies support the candidate gene approach as a feasible method for directly either identifying or excluding any gene as a diabetes-susceptibility gene ("diabetogene").

Age of Onset↗
PubMed2002

Variants within the calpain-10 gene on chromosome 2q37 (NIDDM1) and relationships to type 2 diabetes, insulin resistance, and impaired acute insulin secretion among Scandinavian Caucasians.

Variations in the calpain-10 gene (CAPN10) have been identified among Mexican-Americans, and an at-risk haplotype combination (112/121) defined by three polymorphisms, UCSNP-43, -19, and -63, confers increased risk of type 2 diabetes. Here we examine the three polymorphisms in 1,594 Scandinavian subjects, including 409 type 2 diabetic patients, 200 glucose-tolerant control subjects, 322 young healthy subjects, 206 glucose-tolerant offspring of diabetic patients, and 457 glucose-tolerant 70-year-old men. The frequency of the 112/121 combination was not significantly different in 409 type 2 diabetic subjects compared with 200 glucose-tolerant control subjects (0.06 vs. 0.05; odds ratio 1.32 [95% CI 0.58-3.30]). In glucose-tolerant subjects, neither the single-nucleotide polymorphisms individually nor the 112/121 combination were associated with alterations in plasma glucose, serum insulin, or serum C-peptide levels at fasting or during an oral glucose tolerance test, estimates of insulin sensitivity, or glucose-induced insulin secretion. In conclusion, the frequency of the 112/121 at-risk haplotype of CAPN10 is low among Scandinavians and we were unable to demonstrate significant associations between the CAPN10 variants and type 2 diabetes, insulin resistance, or impaired insulin secretion.

Adult↗
PubMed2001

A critical review of akathisia, and its possible association with suicidal behaviour.

The purpose of this paper was to make a critical review of akathisia, based on the principles of evidence-based medicine, and to explore a possible link between akathisia and suicidal behaviour (suicidal thinking, parasuicide and completed suicide). An extensive systematic search was carried out on three major databases, Embase, ClinPsych and Medline. Fifty-seven relevant references were found, and a further 26 references were reviewed after careful selection from the references of the original references. The Cochrane Library did not contain any systematic reviews on the subject. Akathisia can be caused by several different groups of drugs, but most frequently by antipsychotics and to a lesser extent antidepressants. Research into akathisia is made considerably more difficult by the lack of a universally agreed definition of the condition. The underlying pathophysiology is still far from clear, but the literature offers guidelines on less hazardous management regimes for patients. On the basis of the existing literature, akathisia cannot at this stage unequivocally be linked to suicidal behaviour. It is certain, however, that the condition of akathisia does cause considerable distress in an already vulnerable group of patients. Because it is largely avoidable, new, more rigorous strategies must be put in place to prevent it. Copyright 2001 John Wiley & Sons, Ltd.

Journal Article↗
PubMedDate not supplied

Child, adolescent and youth suicide and undetermined deaths in England and Wales compared with Australia, Canada, France, Germany, Italy, Japan and the USA for the 1974-1999 period.

Successive British Governments have aimed to reduce suicide, especially amongst younger people. Using WHO standardised data for the age bands "child" (5-14 years) and "adolescent and youth" (15-24 years) suicide rates for England and Wales were compared with the other major Western countries with end-points being average of 1974-1976 and average 1997-1999, by gender. "Undetermined deaths" were also analysed to consider any "hidden suicides". Over the period there was little change in child suicide for both genders in any country. Female "adolescent and youth" suicide rates fell in most countries, in contrast to male "adolescent and youth" rates, which rose substantially in six countries, including England & Wales. With the exception of Spain, there was little statistical significant difference between female Anglo-Welsh rates and the other countries. Apart from Spain and Australia, Anglo-Welsh youth rates were significantly worse than Canada, France, Germany and Japan. "Undetermined" deaths showed marked variation across many countries, but Anglo-Welsh rates were up substantially for both males and females [116% and 83%, respectively], whilst falling substantially in six countries. Child suicide continues to be a statistical rarity with little change in either suicide or "undetermined" deaths over the period. The dichotomy between male and female young people's suicide is a matter of concern, as the improvements in female rates are not matched in the male rates--the majority of which rose substantially. The "undetermined deaths" results continue to be problematic, especially regarding the substantial rises in England and Wales. Country-specific research is required to determine, why Anglo-Welsh adolescent and youth rates have deteriorated relative to other countries.

Adolescent↗