| 1. |
- Korhonen, Laura, et al.
(författare)
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Expression of c-Met in developing rat hippocampus : evidence for HGF as a neurotrophic factor for calbindin D-expressing neurons
- 2000
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Ingår i: European Journal of Neuroscience. - Uppsala Univ, Dept Neurosci Neurobiol, S-75123 Uppsala, Sweden. Univ Kuopio, AI Virtanen Inst, FIN-70211 Kuopio, Finland. Univ Cologne, Inst Pathol, D-50924 Cologne, Germany. : Wiley-Blackwell Publishing Inc.. - 0953-816X .- 1460-9568. ; 12:10, s. 3453-3461
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocyte growth factor-scatter factor (HGF) is expressed in different parts of the nervous system, and has been shown to exhibit neurotrophic activity. Here we show that c-Met, the receptor for HGF, is expressed in developing rat hippocampus, with the highest levels during the first postnatal weeks. To study the function of HGF, hippocampal neurons were prepared from embryonic rats and treated with different HGF concentrations. In these cultures, HGF increased the number of neurons expressing the 28-kDa calcium-binding protein (calbindin D) in a dose-dependent manner. The effect of HGF was larger than that observed with either brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3), and cotreatment of the cultures with HGF and the neurotrophins was additive with respect to calbindin D neurons. Besides affecting the number of neurons, HGF significantly increased the degree of sprouting of calbindin D-positive neurons, suggesting an influence on neuronal maturation. BDNF and NT-3 stimulated neurite outgrowth of calbindin D neurons to a much smaller degree. In contrast to calbindin D neurons, HGF did not significantly increase the number of neurons immunoreactive with the neurotransmitter gamma-aminobutyric acid (GABA) in the hippocampal cultures. Immunohistochemical studies showed that c-Met-, calbindin D- and HGF-immunoreactive cells are all present in the dentate gyrus and partly colocalize within neurons. These results show that HGF acts on calbindin D-containing hippocampal neurons and increases their neurite outgrowth, suggesting that HGF plays an important role for the maturation and function of these neurons in the hippocampus.
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| 2. |
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| 3. |
- Li, Haiyan, et al.
(författare)
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Possible human leukocyte antigen-mediated genetic interaction between type 1 and type 2 Diabetes
- 2001
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - 1945-7197. ; 86:2, s. 574-582
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Tidskriftsartikel (refereegranskat)abstract
- We assessed the prevalence of families with both type 1 and type 2 diabetes in Finland; and we studied, in patients with type 2 diabetes, the association between a family history of type 1 diabetes, glutamic acid decarboxylase (GAD) antibodies (GADab), and type 1 diabetes-associated human leukocyte antigen (HLA) DQB1-genotypes. Further, in mixed type 1/type 2 diabetes families, we investigated whether sharing an HLA haplotype with a family member with type 1 diabetes influenced the manifestation of type 2 diabetes. Among 695 families ascertained through the presence of more than 1 patient with type 2 diabetes, 100 (14%) also had members with type 1 diabetes. Type 2 diabetic patients from the mixed families had, more often, GADab (18% vs. 8%, P < 0.0001) and DQB1*0302/X genotype (25% vs. 12%, P = 0.005) than patients from families with only type 2 diabetes; but they had a lower frequency of DQB1*02/0302 genotype, compared with adult-onset type 1 patients (4% vs. 27%, P < 0.0001). In the mixed families, the insulin response to oral glucose load was impaired in patients who had HLA class II risk haplotypes, either DR3(17)-DQA1*0501-DQB1*02 or DR4*0401/4-DQA1*0301-DQB1*0302, compared with patients without such haplotypes (P = 0.016). This finding was independent of the presence of GADab. We conclude that type 1 and type 2 diabetes cluster in the same families. A shared genetic background with a patient with type 1 diabetes predisposes type 2 diabetic patients both to autoantibody positivity and, irrespective of antibody positivity, to impaired insulin secretion. The findings support a possible genetic interaction between type 1 and type 2 diabetes mediated by the HLA locus.
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| 4. |
- Lindholm, Eero, et al.
(författare)
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Classifying diabetes according to the new WHO clinical stages.
- 2001
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Ingår i: European Journal of Epidemiology. - 1573-7284. ; 17:11, s. 983-989
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Tidskriftsartikel (refereegranskat)abstract
- Aims/Hypothesis: To test the usefulness of the new WHO criteria for clinical staging of diabetes in the characterization of 1977 diabetic patients. Methods: The following clinical stages were used: patients on diet and/or oral antidiabetic agents 2 years after diagnosis were considered as non-insulin requiring (NIR; n = 711) and patients who required insulin therapy after 1 year as insulin requiring for control (IRC; n = 543). Patients who because of deteriorating hyperglycemia within 1 year required insulin therapy were considered as insulin requiring for survival (IRS; n = 743). Results: The NIR patients had the highest age at onset (52 ± 12 years; mean ± SD), BMI (29.3 ± 5.2 kg/m2) and C-peptide concentrations (median 0.98 nmol/l; interquartile range 0.72–1.31 nmol/l) but the lowest frequency of GAD antibodies (5.5%) compared to the IRC and IRS groups. The IRC group had a high age at onset (49 ± 13 years), BMI (28.0 ± 4.8 kg/m2), frequency of GAD antibodies (16.8%), intermediate C-peptide concentrations (0.56 nmol/l, interquartile range 0.28–0.94), and the highest prevalence of nephropathy (31.5%) and neuropathy (68.1%). The IRS group had the lowest age at onset (23 ± 15 years), BMI (24.2 ± 3.4 kg/m2), C-peptide concentrations (0.05 nmol/l, interquartile range below detection limit 0.01) and highest frequency of GAD antibodies (44.5%). Retinopathy was more common in IRS than in IRC patients (62.1 vs. 43.9%; p < 0.001). Conclusions: The new WHO criteria seem to discriminate three distinct subgroups and thus provide a useful tool for clinical staging. The IRC patients seem to have a more severe disease than the IRS patients, which has not been clearly acknowledged in the etiological classification. However, because of the cross-sectional nature of these data, they need to be confirmed in a prospective study with defined cut-off limits for when insulin should be initiated.
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| 5. |
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| 6. |
- Lindholm, Eero, et al.
(författare)
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Putative role of polymorphisms in UCP1-3 genes for diabetic nephropathy.
- 2004
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Ingår i: Journal of Diabetes and its Complications. - 1873-460X. ; 18:2, s. 103-107
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Tidskriftsartikel (refereegranskat)abstract
- Increased production of reactive oxygen species (ROS) has been suggested as a cause of diabetic complications. Uncoupling proteins (UCPs) have been ascribed a role in reducing the formation of ROS, and genetic variation in genes encoding for UCPs could thus be putative candidate genes for diabetic nephropathy. To test this hypothesis we searched for association between the A→G (−3862) variant in UCP1, the insertion/deletion (I/D) polymorphism in exon 8 in UCP2, and the C→T (−55) polymorphism in UCP3 and diabetic nephropathy in 218 diabetic patients with normal urinary albumin excretion rate (AER), 216 with micro- or macroalbuminuria, and in 106 control subjects without a family history of diabetes. We did not find any association between the different polymorphisms and diabetic nephropathy, nor did we observe any difference in AER among carriers of different UCP1–3 genotypes. We could, however, confirm the reported association between BMI and the UCP3 −55 C→T polymorphism; patients carrying the T allele had higher BMI than patients homozygous for the C allele (26.4±4.2 vs. 25.3±4.3 kg/m2; P=.01). We conclude that studied polymorphisms in the UCP1–3 genes do not play a major role in the development of micro- or macroalbuminuria in Scandinavian diabetic patients.
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| 7. |
- Tripathy, Devjit, et al.
(författare)
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Familiality of metabolic abnormalities is dependent upon age at onset and phenotype of the type 2 diabetic proband.
- 2003
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Ingår i: American Journal of Physiology: Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 285:6, s. 1297-1303
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Tidskriftsartikel (refereegranskat)abstract
- To determine the impact of a family history of the common form of type 2 diabetes and the phenotype of the proband on anthropometric and metabolic variables in normoglycemic first degree relatives, we studied 2100 first degree relatives of patients with the common form of type 2 diabetes (FH+) and 388 subjects without a family history of diabetes (FH-). All subjects participated in an oral glucose tolerance test to allow measurement of insulin secretion (30min incremental insulin /glucose, I/G 30), and insulin sensitivity (HOMA insulin resistance). A subset participated in a euglycemic clamp (n=75) and an intravenous glucose tolerance test (n=300). To study the effect of a particular phenotype of the proband, insulin secretion and sensitivity were also compared between first degree relatives of diabetic probands with high and low waist to hip ratio (WHR) and probands with early and late onset of diabetes. FH+ subjects were more insulin resistant as seen from higher HOMA-IR index (P=0.007) and lower rate of insulin-stimulated glucose uptake (P=0.001) and had more features of the metabolic syndrome (P=0.02, P=0.0002) compared with FH- subjects. Insulin secretion adjusted for insulin resistance (disposition index, DI) was also lower in the FH+ vs FH- subjects (P=0.04). Relatives of diabetic probands with a high WHR had reduced insulin mediated glucose uptake compared with relatives of probands with a low WHR (P = 0.04). Relatives of diabetic patients with age at onset < 44 years had higher HOMA IR (P < 0.005) and lower DI (P < 0.005) than relatives of patients with age at onset >65 yrs (highest quartile). We conclude that early age at onset of type 2 diabetes and abdominal obesity have a significant influence on the metabolic phenotype in the non-diabetic firstdegree relative
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