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G. Bryzgalova,
H. Gao,
B. Ahren,
J.R. Zierath,
D. Galuska,
T.L. Steiler,
K. Dahlman-Wright,
S. Nilsson,
J.-Å. Gustafsson, S. Efendic,
A. Khan
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ABSTRACT: Aims/hypothesisWe used oestrogen receptor-α (ERα) knockout (ERKO) and receptor-β (ERβ) knockout (BERKO) mice to investigate the mechanism(s)
behind the effects of oestrogens on glucose homeostasis.
MethodsEndogenous glucose production (EGP) was measured in ERKO mice using a euglycaemic–hyperinsulinaemic clamp. Insulin secretion
was determined from isolated islets. In isolated muscles, glucose uptake was assayed by using radiolabelled isotopes. Genome-wide
expression profiles were analysed by high-density oligonucleotide microarray assay, and the expression of the genes encoding
steroyl-CoA desaturase and the Leptin receptor (Scd1 and Lepr, respectively) was confirmed by RT-PCR.
ResultsERKO mice had higher fasting blood glucose, plasma insulin levels and IGT. The plasma leptin level was increased, while the
adiponectin concentration was decreased in ERKO mice. Levels of both glucose- and arginine-induced insulin secretion from
isolated islets were similar in ERKO and wild-type mice. The euglycaemic–hyperinsulinaemic clamp revealed that suppression
of EGP by increased insulin levels was blunted in ERKO mice, which suggests a pronounced hepatic insulin resistance. Microarray
analysis revealed that in ERKO mice, the genes involved in hepatic lipid biosynthesis were upregulated, while genes involved
in lipid transport were downregulated. Notably, hepatic Lepr expression was decreased in ERKO mice. In vitro studies showed a modest decrease in insulin-mediated glucose uptake in soleus
and extensor digitorum longus (EDL) muscles of ERKO mice. BERKO mice demonstrated normal glucose tolerance and insulin release.
Conclusions/interpretationWe conclude that oestrogens, acting via ERα, regulate glucose homeostasis mainly by modulating hepatic insulin sensitivity,
which can be due to the upregulation of lipogenic genes via the suppression of Lepr expression.
Diabetologia 04/2012; 49(3):588-597. · 6.81 Impact Factor
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ABSTRACT: Vitamin D deficiency may increase the risk of type 2 diabetes. We therefore investigated whether serum concentrations of 25-hydroxyvitamin D [25(OH)D] would predict the development of prediabetes (impaired fasting glucose, impaired glucose tolerance or the two combined) and type 2 diabetes, either on their own or when combined with serum concentrations of IGF-1 or IGF-binding protein-1 (IGFBP-1), which may interact with 25(OH)D.
At baseline, participants aged 35-56 years without known type 2 diabetes were examined using OGTTs, 25(OH)D and IGF peptide measurements, and anthropometric and lifestyle data. Participants who had prediabetes or type 2 diabetes at follow-up 8-10 years later were selected as cases; these were then age- and sex-matched to controls with normal glucose tolerance (NGT) at both baseline and follow-up, giving a total of 980 women and 1,398 men.
Men but not women in the highest quartile of 25(OH)D level had a decreased OR for developing type 2 diabetes after adjustment for confounders (OR 0.52, 95% CI 0.30, 0.90), an effect accounted for by individuals with prediabetes, but not with NGT, at baseline. In both sexes, progression from prediabetes to type 2 diabetes was reduced by about 25% per 10 nmol/l increase in 25(OH)D. A high IGFBP-1 value was a better predictor of a reduced risk of type 2 diabetes than high 25(OH)D for both sexes, whereas high IGF-1 concentrations predicted a decreased risk only in men.
High serum 25(OH)D concentrations predict a reduced risk of type 2 diabetes in individuals with prediabetes, but not NGT. There were no significant interactions between 25(OH)D and IGFBP-1 or IGF-1 in terms of risk of diabetes. Our data suggest that vitamin D supplementation should be evaluated for the prevention of type 2 diabetes in prediabetic individuals.
Diabetologia 03/2012; 55(6):1668-78. · 6.81 Impact Factor
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ABSTRACT: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are major incretins with important effects on glucoregulatory functions. The aim of this study was to investigate effects of GIP and GLP-1 on gastric emptying and appetite after a mixed meal, and effects on insulin secretion and glucose disposal in humans.
Randomized crossover single-blind study in 17 healthy volunteers receiving GIP (2 or 5 pmol kg(-1) min(-1), n = 8), GLP-1 (0.75 pmol kg(-1) min(-1), n = 9) or NaCl for 180 min with a radionuclide-labeled omelette and fruit punch (370 kcal). Outcome measures were gastric emptying rate, insulinogenic index, hunger, satiety, desire to eat, and prospective food consumption. Blood was analyzed for GIP, GLP-1, glucagon, C-peptide, peptide YY (PYY) and ghrelin.
Glucose-dependent insulinotropic polypeptide 2 and 5 pmol kg(-1) min(-1) decreased gastric half-emptying time from 128.5 ± 34.0 min in controls to 93.3 ± 6.3 and 85.2 ± 11.0 min (P < 0.05). Glucose-dependent insulinotropic polypeptide 5 pmol kg(-1) min(-1) decreased postprandial glucose (P < 0.001) and insulin (P < 0.05) with increased insulinogenic index. Glucose-dependent insulinotropic polypeptide had no effects on hunger, desire to eat, satiety or prospective consumption. Glucagon-like peptide-1 0.75 pmol kg(-1) min(-1) increased half-emptying time from 76.6 ± 7.6 min to 329.4 ± 71.6 (P < 0.01). Glucagon-like peptide-1 decreased plasma glucose and insulin (both P < 0.05-0.001), and increased insulinogenic index markedly. Hunger, desire to eat and prospective consumption were decreased (P < 0.05), and satiety borderline increased (P < 0.06).
The incretin effect of GIP and GLP-1 differs as GLP-1 exerts a strong glucoregulatory incretin through inhibition of gastric emptying, which GIP does not. Thus, GLP-1 as incretin mimetic may offer unique benefits in terms of weight loss in treatment of type 2 diabetes.
Neurogastroenterology and Motility 11/2010; 22(11):1191-200, e315. · 3.41 Impact Factor
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ABSTRACT: TCF7L2, HHEX and IDE on chromosome 10q23-25 reside within the linkage region for type 2 diabetes (T2D). Previous studies including ours have demonstrated that genetic polymorphisms in these three loci are associated with T2D, respectively. But, it is unclear whether TCF7L2, independently or interactively with HHEX and IDE, confer the susceptibility to T2D. In the present study, we first replicated genetic association study of the TCF7L2 gene in a Swedish cohort including 528 non-diabetic healthy controls and 243 T2D patients and then evaluated combining effect from common risk polymorphisms in TCF7L2-HHEX-IDE loci. T2D patients were diagnosed in the intermediate study time. To avoid influence from anti-diabetic treatment, baseline data in all T2D patients were used for analysis. We found that SNPs rs7901695, rs4506565, rs7903146 and rs12255372 in the TCF7L2 gene were strongly associated with T2D (p<0.004). In rs7903146, T2D patients carrying genotypes CT or TT had higher fasting plasma glucose (FPG) levels (p=0.042) and lower HOMA-beta index (p=0.015) and BMI (p=0.015) compared to the patients carrying CC genotype. Furthermore, the risk alleles from TCF7L2 rs7903146 polymorphism either with IDE rs2251101 polymorphism (p=0.0257, OR=1.398) or with HHEX rs1544210 polymorphism (p=0.0024, OR=1.514) were significantly associated with T2D. When risk alleles from three loci were combined, the association with T2D remained significant (p=0.0018, OR=1.506). The present study thus provides evidence that TCF7L2, as the main gene, together with HHEX and IDE loci have combining effects on genetic predisposition to T2D.
Experimental and Clinical Endocrinology & Diabetes 01/2009; 117(4):186-90. · 1.69 Impact Factor
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ABSTRACT: Incretin hormones often display inhibitory actions on gut motility. The aim of this study was to investigate if altered responsiveness to glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) as regards insulin release and small bowel motility could bring further clarity to the pathophysiology of diabetes in the Goto-Kakizaki (GK) rat. The isolated perfused pancreas was studied in male GK and Wistar rats (controls) under euglycemic and hyperglycemic conditions. Glucose-dependent insulinotropic peptide (10 nmol L(-1)) or GLP-1 (10 nmol L(-1)) were added to the medium and perfusate was collected and analysed for insulin. Moreover, GK and Wistar rats were supplied with bipolar electrodes in the small bowel and myoelectric activity was recorded during intravenous administration of GIP (1-400 pmol kg(-1) min(-1)) or GLP-1 (0.1-20 pmol kg(-1) min(-1)). Finally, tissue was collected from GK and Wistar rats for RNA extraction. Under euglycemia, GIP and GLP-1 stimulated the initial insulin response by 10-fold in GK rats (P < 0.05). At later hyperglycemia, the insulin response to GIP and GLP-1 was blunted to about one-third compared with controls (P < 0.05). In the bowel GLP-1 was about 2.6-16.7 times more potent than GIP in abolishing the migrating myoelectric complex in the GK and control rats. Polymerase chain reaction (PCR) showed GIP and GLP-1 receptor gene expression in pancreatic islets and in small bowel. The initially high, but later low insulin responsiveness to stimulation with GIP and GLP-1 along with inhibition of small bowel motility in the GK rat indicates a preserved incretin response on motility in diabetes type 2.
Neurogastroenterology and Motility 12/2008; 21(3):313-21. · 3.41 Impact Factor
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Diabetologia 10/2008; 51(12):2333-4. · 6.81 Impact Factor
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ABSTRACT: Glucagon-like peptide-1 (GLP-1) is released after food intake to act as an incretin. GLP-1 also inhibits gastric emptying and increases satiety. In rats, GLP-1 inhibits small bowel motility. Our aim was to study the effects of GLP-1 on gastrointestinal motility in healthy subjects and patients with irritable bowel syndrome (IBS). Antro-duodeno-jejunal manometry was carried out during a 4-h control period with saline, followed by a 4-h period with intravenous GLP-1 (healthy: 0.7 and 1.2 pmol kg(-1) min(-1) (n = 16); IBS, 1.2 and 2.5 pmol kg(-1) min(-1) (n = 14). Plasma was analysed for GLP-1 and gut hormones, and gut tissue expression of GLP-1 receptor was studied. In healthy subjects, GLP-1 0.7 pmol kg(-1) min(-1) reduced the migrating motor complexes (MMCs) from a median of 2 (range 2-3) to 0.5 (0-2), and motility index from 4.9 +/- 0.1 to 4.3 +/- 0.3 ln Sigma(mmHg*s min(-1)) in jejunum, while GLP-1 1.2 pmol kg(-1) min(-1) diminished MMCs from 2 (2-3) to 1.5 (1-2.5), and motility index from 5.2 +/- 0.2 to 4.4 +/- 0.2. In IBS patients, GLP-1 1.2 pmol kg(-1) min(-1) reduced the MMCs from 2.5 (2-3.5) to 1 (0-1.5) without affecting motility index. At 2.5 pmol kg(-1) min(-1) GLP-1 decreased MMCs from 2 (1.5-3) to 1 (0.5-1.5), and motility index from 5.2 +/- 0.2 to 4.0 +/- 0.5. Motility responses to GLP-1 were similar in antrum and duodenum. Presence of the GLP-1 receptor in the gut was verified by reverse transcriptase PCR. In conclusion, the gut peptide GLP-1 decreases motility in the antro-duodeno-jejunal region and inhibits the MMC in healthy subjects and IBS patients.
Neurogastroenterology and Motility 07/2008; 20(6):649-59. · 3.41 Impact Factor
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ABSTRACT: The diabetogenic effect of excess growth hormone (GH) such as that in acromegaly is well known. However, the contribution of the various components to hepatic glucose production (HGP) is not completely understood. In this study we evaluated insulin resistance, HGP, gluconeogenesis (GNG), and glycogenolysis (GLY) in five patients with acromegaly before and after pituitary microsurgery. Insulin resistance was estimated by the HOMA index. HGP was measured using a primed continuous (6,6- 2H2) glucose infusion, and GNG was measured from 2 H enrichment at carbons 2 and 5 of blood glucose on ingestion of 2H2O. The ratio of these enrichments equals the fractional contribution of GNG to HGP, and GLY was calculated as the difference between HGP and GNG. All measurements were performed after 12 hours of fasting. Levels of GH and IGF-I decreased, as did the HOMA index (p<0.05). HGP was reduced from 11.4 micromol/kg/min to 9.7 micromol/kg/min (p=0.032). GNG contributed most to HGP. GNG was unchanged, whereas GLY's fraction decreased 29% (p=0.056) postoperatively. This pilot study indicates that GNG is the main contributor to HGP and that GLY is more sensitive than is GNG to the insulin resistance existing in acromegaly.
Hormone and Metabolic Research 07/2008; 40(7):498-501. · 2.19 Impact Factor
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ABSTRACT: Insulin-like growth factor-binding protein-1 (IGFBP-1) production in the liver is inhibited by insulin, and low circulating levels are associated with the metabolic syndrome. The aim of this study was to evaluate the predictive role and change in IGFBP-1 concentrations during development of abnormal glucose regulation.
IGFBP-1 levels were determined at baseline and at 10 years in an incident case-control prospective study of Swedish white men aged 35-56 years. Individuals with normal glucose tolerance at baseline who developed abnormal glucose tolerance during a 10 year period (n = 355) according to WHO criteria were pair-matched to controls for age and family history of diabetes.
Fasting IGFBP-1 concentrations were lower in individuals who later developed abnormal glucose regulation and correlated inversely with fasting proinsulin values (r = -0.48; p < 0.0001), and both were significant predictors. Individuals in the highest quartile at baseline for an algorithm incorporating fasting IGFBP-1, blood glucose, proinsulin and waist and height had a 40-fold increased risk of developing type 2 diabetes compared with the lowest quartile (95% CI 7.7-214). IGFBP-1 increased 32% (95% CI 17-49%) during the 10 years in those developing diabetes and was increased in relation to insulin levels, suggesting the emergence of hepatic insulin resistance. Moreover, elevated IGFBP-1 levels at follow-up were associated with higher 2 h glucose values during an OGTT.
Low IGFBP-1 predicts the development of abnormal glucose regulation and, as an inhibitor of the insulin-like actions of insulin-like growth factors, elevated levels of IGFBP-1 after the development of diabetes may also play a pathophysiological role.
Diabetologia 07/2008; 51(7):1135-45. · 6.81 Impact Factor
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ABSTRACT: To determine the role of psychological distress as a predictor of pre-diabetes and Type 2 diabetes.
This cohort study comprised 2127 Swedish middle-aged men and 3100 women with baseline normal glucose tolerance measured by oral glucose tolerance test. At follow-up 8-10 years later, 245 men and 177 women had pre-diabetes [impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and IFG + IGT] and Type 2 diabetes was detected in 103 men and 57 women. Baseline psychological distress was measured by an index of five questions concerning anxiety, apathy, depression, fatigue and insomnia. Odds ratios (ORs) were estimated for pre-diabetes and Type 2 diabetes in association with total psychological distress. In addition, ORs of the single-item questions were calculated.
In men, adjusted ORs (95% confidence interval) in the highest index group of psychological distress compared with the lowest group were 1.9 (1.2-2.8) and 2.2 (1.2-4.1) for pre-diabetes and Type 2 diabetes, respectively. Corresponding estimates in women were 1.2 (0.7-2.1) and 0.5 (0.2-1.2). In the middle symptoms groups, adjusted ORs in men were 1.1 (0.8-1.4) for pre-diabetes and 1.2 (0.7-2.0) for Type 2 diabetes and in women 1.8 (1.1-3.0) and 0.7 (0.3-1.4). When analysed separately, the associations with each of the five single factors were similar.
The results indicate that psychological distress, including symptoms of anxiety, apathy, depression, fatigue and insomnia, increases the risk of pre-diabetes and Type 2 diabetes in Swedish middle-aged men. Increased risks were not present in women, except for pre-diabetes in the middle index group.
Diabetic Medicine 06/2008; 25(7):834-42. · 2.90 Impact Factor
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ABSTRACT: Our previous study using the Goto-Kakizaki rat implicates that the adenylyl cyclase 3 (AC3) is a candidate gene for genetic study of metabolic disorders. The present study aimed to investigate the susceptibility of genetic variation of the AC3 gene in type 2 diabetes (T2D) patients and obese subjects.
Variation screening in the putative promoter and validation of single nucleotide polymorphisms (SNPs) covering the AC3 gene were performed. In total, 630 Swedish men, including 243 T2D patients (BMI from 18.4 to 45.6 kg m(-2)), 199 obese subjects with normal glucose tolerance (NGT, BMI> or =30 kg m(-2)) and 188 control subjects (NGT, BMI< or =26 kg m(-2)), were genotyped.
A novel variant -17A/T in the promoter was identified, but no significant association of this polymorphism with T2D was found. SNPs rs2033655 C/T and rs1968482 A/G were found to be significantly associated with obesity when T2D patients had BMI> or =30 kg m(-2) (P=0.003 and 0.005). The significance was borderline in T2D patients with BMI<30 kg m(-2) (P=0.051 and 0.084) and disappeared in T2D patients with BMI< or =26 kg m(-2). Importantly, analysis in obese subjects with NGT demonstrated that these two polymorphisms were strongly associated with obesity per se (P=0.028 and 0.003). Furthermore, analyses for diplotypes (haplotypic genotypes) predicted an association with BMI in obese subjects.
The present study provides the first evidence that AC3 polymorphisms confer the risk susceptibility to obesity in Swedish men with and without type 2 diabetes.
International journal of obesity (2005) 03/2008; 32(3):407-12. · 4.34 Impact Factor
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ABSTRACT: It is generally accepted that a poor glycaemic control increases the risk for development of vascular complications in diabetic patients. This advocates for early introduction of insulin treatment in patients with type 2 diabetes exhibiting a secondary failure to oral treatment. This strategy is facilitated by introduction of long-acting insulin glargine and biphasic insulin aspart 70/30. The introduction of Glucagon-like peptide-1 (GLP-1) mimetics and dipeptidyl peptidase 4 (DPP-4) inhibitors in treatment of type 2 diabetes will however, to a large extent, influence therapeutic policy. Thus we suggest that DPP-4 inhibitors or long-acting GLP-1 mimetics will be used as either first-line therapy or as an early addition to metformin. The already generated results in animal and clinical studies suggest that these two classes of antidiabetic drugs may in addition to improving glycaemic control protect islet beta-cell mass and thereby postpone development of a secondary failure. When patients treated with metformin, sulfonylurea (SU), tiazolidinediones or a combination of these drugs fail, the GLP-1 mimectics may be preferred to insulin treatment. First, the risk of hypoglycaemia is less if not combined with SU. Secondly, the body weight is usually decreased while insulin treatment increases weight. Patients not responding to GLP-1 mimetics or experiencing significant side effects will be treated with insulin. Irrespective of the policy used for the drug treatment of type 2 diabetes, exercise and proper diet will remain important for optimization of metabolic control.
Acta Physiologica 02/2008; 192(1):117-25. · 3.09 Impact Factor
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Diabetic Medicine - DIABETIC MED. 01/2008; 25(7):834-842.
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ABSTRACT: Defective beta-cell function with resulting impairment of glucose-stimulated insulin release is a critical factor in the pathogenesis of type 2 diabetes. Accumulated studies in pancreatic islets of the spontaneously diabetic Goto-Kakizaki (GK) rat suggest that this is a useful animal model of type 2 diabetes. The GK rat is non-obese, and abnormal glucose regulation develops early in life in association with impaired insulin secretion. There are some differences in islet morphology and function reported between different GK rat colonies. In addition to reduction of beta-cell mass, a number of beta-cell defects have been described with possible relevance for the reduced insulin secretion. Interestingly, some of these defects have also been shown in isolated islets from type 2 diabetic humans. The polygenic nature of diabetes heredity in the GK rat may well resemble the genetic basis in the majority of patients with type 2 diabetes. Here, we review studies concerning beta-cell function and islet gene expression in the GK rat and compare it with the limited number of investigations on similar topics in isolated islets from patients with type 2 diabetes.
Diabetes Obesity and Metabolism 12/2007; 9 Suppl 2:180-6. · 3.38 Impact Factor
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ABSTRACT: Growth hormone (GH) signaling via the growth hormone receptor (GHR) forms a major part of the GH-IGF-I axis, which is crucial for controlling metabolism and anabolism. Two common variants of the GHR differ by the presence (full length or GHR(fl)) or absence of exon 3 (exon 3 deleted or GHR(d3)), the function of which is unknown. However, differential response to GH treatment has been observed with carriers of the GHR(d3) variant conferring a greater growth rate. This study investigates these GHR variants in subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT), including Type 2 diabetes mellitus (T2DM). DNA was extracted from blood samples from subjects with NGT (n=158), IGT (n=116) and T2DM (n=194). The T2DM subjects in set 1 (n= 39) were newly diagnosed, whilst those in set 2 (n=155) had a mean duration of 7 years. Set 1 also included NGT and IGT subjects. Genotyping by standard PCR and gel electrophoresis were carried out. A significant difference was observed between T2DM and NGT (p<0.0001) with a significantly lower frequency of GHR(d3) in T2DM (3.6% compared to 17% in NGT). Both sets of T2DM subjects with at least one GHR(d3) allele had significantly higher BMI. In the larger subset of T2DM, GHR(d3) was associated with higher CRP levels as well as age adjusted IGF-I, with a trend of higher C-peptide secretion and impaired lipid levels, indicating a phenotype with metabolic disorder when compared to the GHR(fl/fl) T2DM subjects. In conclusion, homozygosity for the GHR(d3) allele appears to be preventive of T2DM. However, when other factors cause overt T2DM, the GHR(d3) allele confers a phenotype indicative of metabolic disorder. This study supports the hypothesis that the two GHR alleles by their inclusion or exclusion of exon 3 are functionally different.
Growth Hormone & IGF Research 10/2007; 17(5):392-8. · 2.16 Impact Factor
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ABSTRACT: The effects of an imidazoline compound (BL11282) on protein expression in rat pancreatic islets were investigated with a proteomic approach. The compound increases insulin release selectively at high glucose concentrations and is therefore of interest in type 2 diabetes. Whole cell extracts from isolated drug-treated and native pancreatic rat islets were compared after separation by 2-D gel electrophoresis. Differentially expressed proteins were identified by mass spectrometry; 15 proteins were selectively up-regulated and 7 selectively down-regulated in drug-treated islets. Of special interest among the differentially expressed proteins are those involved in protein folding (Hsp60, protein disulfide isomerase, calreticulin), Ca(2+) binding (calgizzarin, calcyclin and annexin I) and metabolism or signalling (pyruvate kinase, alpha enolase and protein kinase C inhibitor 1).
Cellular and Molecular Life Sciences CMLS 06/2007; 64(10):1310-6. · 6.57 Impact Factor
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ABSTRACT: It has been suggested that low socio-economic position (SEP) during childhood and adolescence predicts risk of adult type 2 diabetes. We investigated the associations between type 2 diabetes and childhood SEP (fathers' occupational position), participants' education and adult SEP (participants' occupational position). To determine possible independent associations between early SEP (fathers' occupational position and participants' education) and disease, we adjusted for adult SEP and factors present in adult life associated with type 2 diabetes.
This cross-sectional study comprised 3128 men and 4821 women aged 35-56 years. All subjects have gone through a health examination and answered a questionnaire on lifestyle factors. At the health centre, an oral glucose tolerance test was administered and identified 55 men and 52 women with previously undiagnosed type 2 diabetes. Relative risks (RRs) with 95% CIs were calculated in multiple logistic regression analyses.
The age-adjusted RRs of type 2 diabetes if having a father with middle occupational position were 2.3 [Confidence interval (CI:1.0-5.1) for women and, 2.0 (CI:0.7-5.6) for men]. Moreover, low education was associated with type 2 diabetes in women, RR = 2.5 (CI:1.2-4.9). Low occupational position in adulthood was associated with type 2 diabetes in women, RR = 2.7 (CI:1.3-5.9) and men, RR = 2.9 (CI:1.5-5.7). The associations between early SEP and type 2 diabetes disappeared after adjustment for adult SEP and factors associated with type 2 diabetes.
The association between type 2 diabetes and low SEP during childhood and adolescence in middle-aged Swedish subjects disappeared after adjustment for adult SEP and adult risk factors of diabetes.
International Journal of Epidemiology 03/2007; 36(1):84-92. · 6.41 Impact Factor
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ABSTRACT: We investigated associations between abnormal glucose regulation and family history of diabetes, separately and in combination with lifestyle risk factors.
This cross-sectional study comprised 3,128 men and 4,821 women, aged 35-56 years, half with a family history of diabetes. Oral glucose tolerance testing identified subjects with previously undiagnosed prediabetes (IFG, IGT) and type 2 diabetes. Information on lifestyle factors was obtained by questionnaire. Biological interaction was measured with the synergy index.
A family history of diabetes conferred a higher odds ratio (OR) for type 2 diabetes in men (OR=3.1, 95% CI 1.7-5.6) than in women (OR=1.7, 95% CI 1.0-3.0), and the synergy index was 2.8 (95% CI 0.9-9.0), suggesting interaction between a family history of diabetes and sex. For prediabetes and diabetes combined, the synergy index was 1.7 (1.0-2.8). Exposure to only one lifestyle risk factor (obesity, physical inactivity, smoking or low sense of coherence [a psychosocial index]) increased the risk to a similar extent in men and women. Combined exposure to a family history of diabetes and lifestyle-related risk factors had a greater effect on type 2 diabetes than any of these factors alone, especially in men. However, analysis of interaction between a family history of diabetes and the lifestyle factors did not indicate any interaction for diabetes, but did indicate interaction for a family history of diabetes and obesity in women with prediabetes.
Our data suggest a more pronounced effect of a family history of diabetes on the risk of type 2 diabetes in men than in women. While both a family history of diabetes and lifestyle risk factors had effects on type 2 diabetes, irrespective of sex, these effects did not appear to interact.
Diabetologia 12/2006; 49(11):2589-98. · 6.81 Impact Factor
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ABSTRACT: The intercellular adhesion molecule-1 (ICAM-1) gene is located on chromosome 19p13, which is linked to Type 1 diabetes (T1D). ICAM-1 expression is related to development of T1D and diabetic nephropathy. The present study aims to evaluate the genetic influence of ICAM-1 gene polymorphisms on the development of T1D and diabetic nephropathy.
Five valid single nucleotide polymorphisms (SNPs) were genotyped in 432 T1D patients (196 patients had diabetic nephropathy) and 187 non-diabetic control subjects by using dynamic allele-specific hybridization (DASH) and pyrosequencing.
SNPs rs281432(C/G) and rs5498 E469K(A/G) had high heterozygous indexes. They were significantly associated with T1D [P = 0.026, OR = 1.644 (95% CI 1.138-2.376) and P < 0.001, OR = 2.456 (1.588-3.8)]. Frequencies of the C allele in SNP rs281432(C/G) and the A allele in SNP rs5498 E469K(A/G) increased stepwise from non-diabetic control subjects to T1D patients without diabetic nephropathy and T1D patients with diabetic nephropathy. Further analysis for these two SNPs indicated that T1D patients had increased frequency of the common haplotype C-A, in comparison with non-diabetic control subjects (38.1 vs. 32.1%, P = 0.035).
The present study provided evidence that SNPs rs281432(C/G) and rs5498 E469K(A/G) in the ICAM-1 gene confer susceptibility to the development of T1D and might also be associated with diabetic nephropathy in Swedish Caucasians.
Diabetic Medicine 11/2006; 23(10):1093-9. · 2.90 Impact Factor
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ABSTRACT: Early islet graft survival is crucial in determining the outcome after clinical islet transplantation. Exendin-4 has anti-apoptotic and beta cell proliferative properties, which could improve islet graft survival and function. The aim of these studies was to evaluate the effect of exendin-4 on graft function after islet transplantation.
Rat islets were transplanted under the kidney capsule of diabetic athymic mice. First, we performed a dose-finding study and found that 30 islets just failed to cure diabetic mice. In the following two studies, we transplanted 30 islets and treated the mice that had received these islets with exendin-4 i.p. (100 ng/mouse) once daily for 1 week. Blood glucose levels and body weights were used as evaluation criteria. In the short-term study evaluation was done at day 8. This study was followed by a long-term study that was evaluated at 4 weeks. In this study, islets were precultured with exendin-4 (0.1 nmol/l) in addition to the treatment given to mouse-recipients of transplanted islets. The cured mice underwent an intraperitoneal glucose tolerance test (IPGTT).
In the short-term study, 63% of exendin-4-treated mice achieved graft function compared with 21% of untreated mice (p = 0.033). In the long-term study, 88% of treated mice had functioning grafts compared with 22% of controls (p = 0.015). Cured mice showed a normal response in the IPGTT, comparable to that of healthy mice. Exendin-4-treated mice gained significantly more weight than their untreated counterparts.
Islet preculture and a short course of therapy with exendin-4 improves metabolic control after rat islet transplantation in athymic mice. The beneficial effect lasts beyond the treatment period.
Diabetologia 07/2006; 49(6):1247-53. · 6.81 Impact Factor
