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1.
A. Haupt H. Staiger S. A. Schäfer K. Kirchhoff M. Guthoff F. Machicao B. Gallwitz N. Stefan H.-U. Häring A. Fritsche 《Diabetologia》2009,52(3):457-462
Aims/hypothesis Among the novel type 2 diabetes risk loci identified by genome-wide association studies, TCF7L2, HHEX, SLC30A8 and CDKAL1 appear to affect beta cell function. In the present study we examined the effect of these genes’ risk alleles on the age-dependent
decline in insulin secretion.
Methods The SNPs rs7903146 (TCF7L2), rs7754840(CDKAL1), rs7923837 (HHEX) and rs13266634 (SLC30A8) were genotyped in 1,412 non-diabetic patients, who were subsequently grouped according to their number of risk alleles.
All participants underwent an OGTT. Insulin secretion was assessed by validated indices and proinsulin conversion by calculating
AUCproinsulin/AUCinsulin.
Results The number of risk alleles revealed a Gaussian distribution, with most participants carrying four risk alleles. Stratification
into groups with low (LAL, up to three alleles), median (MAL, four alleles) and high (HAL, five to eight alleles) allele load
resulted in MAL and HAL participants displaying significantly lower insulin secretion and proinsulin conversion than LAL participants
(p ≤ 0.0014 and p = 0.0185, respectively). In the overall cohort, age was negatively associated with insulin secretion and proinsulin conversion
(both p < 0.0001). MAL and HAL participants showed a significantly more pronounced decline in insulin secretion with increasing age
than LAL participants (p ≤ 0.0325; analysis of covariance), and after stratification for BMI this relationship was maintained in obese, but not non-obese,
participants. Proinsulin conversion decreased with increasing age in MAL and HAL, but not LAL, participants (p ≤ 0.0003 vs p = 0.2).
Conclusions/interpretation The risk allele load significantly accelerates the age-dependent decline in beta cell function, and this might be of particular
importance in obese people.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
A. Haupt and H. Staiger contributed equally to this study. 相似文献
2.
E. Reiling E. van ’t Riet M. J. Groenewoud L. M. C. Welschen E. C. van Hove G. Nijpels J. A. Maassen J. M. Dekker L. M. ’t Hart 《Diabetologia》2009,52(9):1866-1870
Aims/hypothesis Variation in fasting plasma glucose (FPG) within the normal range is a known risk factor for the development of type 2 diabetes.
Several reports have shown that genetic variation in the genes for glucokinase (GCK), glucokinase regulatory protein (GCKR), islet-specific glucose 6 phosphatase catalytic subunit-related protein (G6PC2) and melatonin receptor type 1B (MTNR1B) is associated with FPG. In this study we examined whether these loci also contribute to type 2 diabetes susceptibility.
Methods A random selection from the Dutch New Hoorn Study was used for replication of the association with FGP (2,361 non-diabetic
participants). For the genetic association study we extended the study sample with 2,628 participants with type 2 diabetes.
Risk allele counting was used to calculate a four-gene risk allele score for each individual.
Results Variants of the GCK, G6PC2 and MTNR1B genes but not GCKR were associated with FPG (all, p ≤ 0.001; GCKR, p = 0.23). Combining these four genes in a risk allele score resulted in an increase of 0.05 mmol/l (0.04–0.07) per additional
risk allele (p = 2 × 10−13). Furthermore, participants with less than three or more than five risk alleles showed significantly different type 2 diabetes
susceptibility compared with the most common group with four risk alleles (OR 0.77 [0.65–0.93], p = 0.005 and OR 2.05 [1.50–2.80], p = 4 × 10−6 respectively). The age at diagnosis was also significantly associated with the number of risk alleles (p = 0.009).
Conclusions A combined risk allele score for single-nucleotide polymorphisms in four known FPG loci is significantly associated with FPG
and HbA1c in a Dutch population-based sample of non-diabetic participants. Carriers of low or high numbers of risk alleles show significantly
different risks for type 2 diabetes compared with the reference group.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
3.
C. Langenberg L. Pascoe A. Mari A. Tura M. Laakso T. M. Frayling I. Barroso R. J. F. Loos N. J. Wareham M. Walker 《Diabetologia》2009,52(8):1537-1542
Aims/hypothesis We investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals,
is associated with measures of beta cell function and whole-body insulin sensitivity.
Methods We studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and
Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic–hyperinsulinaemic clamp and
indices of beta cell function were derived from a 75 g oral glucose tolerance test (including 30 min insulin response and
glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre.
Results The minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d’Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU];
0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085,
0.25] per G allele, p = 5.8 × 10−5), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response
(−0.19 [−0.28, −0.10], p = 1.7 × 10−5), as well as with decreased beta cell glucose sensitivity (−0.11 [−0.20, −0.027], p = 0.010). No associations were observed with clamp-assessed insulin sensitivity (p = 0.15) or different measures of body size (p > 0.7 for all).
Conclusions/interpretation Genetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to
the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B.
Electronic supplementary material The online version of this article (doi:) contains a list of the members of the RISC Consortium, which is available to authorised users. 相似文献
4.
Y. M. Cho T. H. Kim S. Lim S. H. Choi H. D. Shin H. K. Lee K. S. Park H. C. Jang 《Diabetologia》2009,52(2):253-261
Aims/hypothesis New genetic variants associated with susceptibility to type 2 diabetes mellitus have been discovered in recent genome-wide
association (GWA) studies. The aim of the present study was to examine the association between these diabetogenic variants
and gestational diabetes mellitus (GDM).
Methods The study included 869 Korean women with GDM and 345 female and 287 male Korean non-diabetic controls. We genotyped the single
nucleotide polymorphisms (SNPs) rs7756992 and rs7754840 in CDKAL1; rs564398, rs1333040, rs10757278 and rs10811661 in the CDKN2A−CDKN2B region; rs8050136 in FTO; rs1111875, rs5015480 and rs7923837 in HHEX; rs4402960 in IGF2BP2; and rs13266634 in SLC30A8. In addition, rs7903146 and rs12255372 in TCF7L2; rs5215 and rs5219 in KCNJ11; and rs3856806 and rs1801282 in PPARG were genotyped. The genotype frequencies in the GDM patients were compared with those in the non-diabetic controls.
Results Compared with controls (men and women combined), GDM was associated with rs7756992 and rs7754840 (OR 1.55, 95% CI 1.34–1.79,
p = 4.17 × 10−9) in CDKAL1; rs10811661 (OR 1.49, 95% CI 1.29–1.72, p = 1.05 × 10−7) in the CDKN2A−CDKN2B region; rs1111875 (OR 1.27, 95% CI 1.09–1.49, p = 0.003), rs5015480, and rs7923837 in HHEX; rs4402960 (OR 1.18, 95% CI 1.01–1.38, p = 0.03) in IGF2BP2; rs13266634 (OR 1.24, 95% CI 1.07–1.43, p = 0.005) in SLC30A8; and rs7903146 (OR 1.58, 95% CI 1.03–2.43, p = 0.038) in TCF7L2. The risk alleles of the SNPs rs7756992 and rs7754840 in CDKAL1; rs10811661 in the CDKN2A–CDKN2B region; and rs1111875, rs5015480 and rs7923837 in HHEX were associated with significant decreases in the insulin AUC during a 100 g OGTT performed at the time of diagnosis of GDM.
Conclusions/interpretation Some of the type 2 diabetes-associated genetic variants that were discovered in the recent GWA studies are also associated
with GDM in Koreans.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
Y. M. Cho and T. H. Kim contributed equally to this study. 相似文献
5.
Q. Qi Y. Wu H. Li R. J. F. Loos F. B. Hu L. Sun L. Lu A. Pan C. Liu H. Wu L. Chen Z. Yu X. Lin 《Diabetologia》2009,52(5):834-843
Aims/hypothesis The GCKR rs780094 and GCK rs1799884 polymorphisms have been reported to be associated with dyslipidaemia and type 2 diabetes in white Europeans. The
aim of this study was to replicate these associations in Han Chinese individuals and to identify the potential mechanisms
underlying these associations.
Methods The single nucleotide polymorphisms rs780094 and rs1799884 were genotyped in a population-based sample of Han Chinese individuals
(n = 3,210) and tested for association with risk of type 2 diabetes and related phenotypes.
Results The GCKR rs780094 A allele was marginally associated with reduced risk of type 2 diabetes (OR 0.85, 95% CI 0.73–1.00, p value under an additive model [p
(add)] = 0.05) and significantly associated with reduced risk of impaired fasting glucose (IFG) or type 2 diabetes (OR 0.86, 95%
CI 0.77–0.96, p
[add] = 0.0032). It was also significantly associated with decreased fasting glucose and increased HOMA of beta cell function (HOMA-B)
and fasting triacylglycerol levels (p
[add] = 0.0169–5.3 × 10−6), but not with HOMA of insulin sensitivity (HOMA-S). The associations with type 2 diabetes and IFG remained significant after
adjustment for BMI, while adjustment for HOMA-B abolished the associations. The GCKR rs780094 was also associated with obesity and BMI, independently of its association with type 2 diabetes. The GCK rs1799884 A allele was significantly associated with decreased HOMA-B (p
[add] = 0.0005), but not with type 2 diabetes or IFG. Individuals with increasing numbers of risk alleles for both variants had
significantly lower HOMA-B (p
[add] = 5.8 × 10−5) in the combined analysis.
Conclusions/interpretation Consistent with observations in white Europeans, the GCKR rs780094 polymorphism contributes to the risk of type 2 diabetes and dyslipidaemia in Han Chinese individuals. In addition,
we showed that the effect on type 2 diabetes is probably mediated through impaired beta cell function rather than through
obesity.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
Q. Qi and Y. Wu contributed equally to this study. 相似文献
6.
Kirchhoff K Machicao F Haupt A Schäfer SA Tschritter O Staiger H Stefan N Häring HU Fritsche A 《Diabetologia》2008,51(4):597-601
Aims/hypothesis Variation within six novel genetic loci has been reported to confer risk of type 2 diabetes and may be associated with beta
cell dysfunction. We investigated whether these polymorphisms are also associated with impaired proinsulin to insulin conversion.
Methods We genotyped 1,065 German participants for single nucleotide polymorphisms rs7903146 in TCF7L2, rs7754840 in CDKAL1, rs7923837 and rs1111875 in HHEX, rs13266634 in SLC30A8, rs10811661 in CDKN2A/B and rs4402960 in IGF2BP2. All participants underwent an OGTT. Insulin, proinsulin and C-peptide concentrations were measured at 0, 30, 60, 90 and
120 min during the OGTT. Insulin secretion was estimated from C-peptide or insulin levels during the OGTT using validated
indices. We used the ratio proinsulin/insulin during the OGTT as indicator of proinsulin conversion.
Results In our cohort, we confirmed the significant association of variants in TCF7L2, CDKAL1 and HHEX with reduced insulin secretion during the OGTT (p < 0.05 for all). Variation in SLC30A8, CDKN2A/B and IGF2BP2 was not associated with insulin secretion. The risk alleles of the variants in TCF7L2, CDKAL1 and SLC30A8 reduced proinsulin to insulin conversion (p < 0.05 for all), whereas the risk alleles in HHEX, CDKN2A/B and IGF2BP2 were not associated with reduced proinsulin to insulin conversion (p > 0.6).
Conclusions/interpretation Diabetes-associated variants in TCF7L2 and CDKAL1 impair insulin secretion and conversion of proinsulin to insulin. However, both aspects of beta cell function are not necessarily
linked, as impaired insulin secretion is specifically present in variants of HHEX and impaired proinsulin conversion is specifically present in a variant of SLC30A8.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
7.
Stephanie-May Ruchat Cathy E. Elks Ruth J. F. Loos Marie-Claude Vohl S. John Weisnagel Tuomo Rankinen Claude Bouchard Louis Pérusse 《Acta diabetologica》2009,46(3):217-226
Several single nucleotide polymorphisms (SNPs) for type 2 diabetes mellitus (T2DM) risk have been identified by genome wide
association studies (GWAS). The objective of the present study was to investigate the impact of these SNPs on T2DM intermediate
phenotypes in order to clarify the physiological mechanisms through which they exert their effects on disease etiology. We
analysed 23 SNPs in 9 T2DM genes (CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8, TCF2, TCF7L2 and WFS1) in a maximum of 712 men and women from the Quebec Family Study. The participants underwent a 75 g oral glucose tolerance
test (OGTT) and were measured for glucose, insulin and C-peptide levels. Indices of insulin sensitivity and insulin secretion
were derived from fasting and OGTT measurements. We confirmed the significant associations of variants in CDKAL1, CDKN2B, HHEX/IDE, KCNJ11 and TCF7L2 with insulin secretion and also found associations of some of these variants with insulin sensitivity and glucose tolerance.
IGF2BP2 and SLC30A8 SNPs were not associated with insulin secretion but were with insulin sensitivity and glucose tolerance (0.002 ≤ P ≤ 0.02). To examine the joint effects of these variants and their contribution to T2DM endophenotypes variance, stepwise
regression models were used and the model R
2 was computed. The variance in the phenotypes explained by combinations of variants ranged from 2.0 to 8.5%. Diabetes-associated
variants in CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8 and TCF7L2 are associated with physiological alterations leading to T2DM, such as glucose intolerance, impaired insulin secretion or
insulin resistance, supporting their role in the disease aetiology. These variants were found to account for 2.0–8.5% of the
variance of T2DM-related traits. 相似文献
8.
Variations in the <Emphasis Type="Italic">HHEX</Emphasis> gene are associated with increased risk of type 2 diabetes in the Japanese population 总被引:1,自引:0,他引:1
Horikoshi M Hara K Ito C Shojima N Nagai R Ueki K Froguel P Kadowaki T 《Diabetologia》2007,50(12):2461-2466
Aims/hypothesis Recently, several groups have carried out whole-genome association studies in European and European-origin populations and
found novel type 2 diabetes-susceptibility genes, fat mass and obesity associated (FTO), solute carrier family 30 (zinc transporter), member 8 (SLC30A8), haematopoietically expressed homeobox (HHEX), exostoses (multiple) 2 (EXT2), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) (CDKN2B) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), which had not been in the list of functional candidates. The aim of this study was to determine the association between
single nucleotide polymorphisms (SNPs) in these genes and type 2 diabetes in participants from the Japanese population.
Methods Sixteen previously reported SNPs were genotyped in 864 Japanese type 2 diabetes individuals (535 men and 329 women; age 63.1 ± 9.5 years
(mean±SD), BMI 24.3 ± 3.9 kg/m2) and 864 Japanese control individuals (386 men and 478 women; age 69.5 ± 6.8 years, BMI 23.8 ± 3.7 kg/m2).
Results The SNPs rs5015480 [odds ratio (OR) = 1.46 (95% CI 1.20–1.77), p = 2.0 × 10−4], rs7923837 [OR = 1.40 (95% CI 1.17–1.68), p = 2.0 × 10−4] and rs1111875 [OR = 1.30 (95% CI 1.11–1.52), p = 0.0013] in HHEX were significantly associated with type 2 diabetes with the same direction as previously reported. SNP rs8050136 in FTO was nominally associated with type 2 diabetes [OR = 1.22 (95% CI 1.03–1.46), p = 0.025]. SNPs in other genes such as rs7756992 in CDKAL1, rs10811661 in CDKN2B and rs13266634 in SLC30A8 showed nominal association with type 2 diabetes. rs7756992 in CDKAL1 and rs10811661 in CDKN2B were correlated with impaired pancreatic beta cell function as estimated by the homeostasis model assessment beta index (p = 0.023, p = 0.0083, respectively).
Conclusions/interpretation
HHEX is a common type 2 diabetes-susceptibility gene across different ethnic groups.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
M. Horikoshi and K. Hara contributed equally to this study. 相似文献
9.
Hertel JK Johansson S Raeder H Midthjell K Lyssenko V Groop L Molven A Njølstad PR 《Diabetologia》2008,51(6):971-977
Aims/hypothesis Recent genome-wide association studies performed in selected patients and control participants have provided strong support
for several new type 2 diabetes susceptibility loci. To get a better estimation of the true risk conferred by these novel
loci, we tested a completely unselected population of type 2 diabetes patients from a Norwegian health survey (the HUNT study).
Methods We genotyped single nucleotide polymorphisms (SNPs) in PKN2, IGFBP2, FLJ39370 (also known as C4ORF32), CDKAL1, SLC30A8, CDKN2B, HHEX and FTO using a Norwegian population-based sample of 1,638 patients with type 2 diabetes and 1,858 non-diabetic control participants
(the HUNT Study), for all of whom data on BMI, WHR, cholesterol and triacylglycerol levels were available. We used diabetes,
measures of obesity and lipid values as phenotypes in case-control and quantitative association study designs.
Results We replicated the association with type 2 diabetes for rs10811661 in the vicinity of CDKN2B (OR 1.20, 95% CI: 1.06–1.37, p = 0.004), rs9939609 in FTO (OR 1.14, 95% CI: 1.04–1.25, p = 0.006) and rs13266634 in SLC30A8 (OR 1.20, 95% CI: 1.09–1.33, p = 3.9 × 10−4). We found borderline significant association for the IGFBP2 SNP rs4402960 (OR 1.10, 95% CI: 0.99–1.22). Results for the HHEX SNP (rs1111875) and the CDKAL1 SNP (rs7756992) were non-significant, but the magnitude of effect was similar to previous estimates. We found no support
for an association with the less consistently replicated FLJ39370 or PKN2 SNPs. In agreement with previous studies, FTO was most strongly associated with BMI (p = 8.4 × 10−4).
Conclusions/interpretation Our data show that SNPs near IGFBP2, CDKAL1, SLC30A8, CDKN2B, HHEX and FTO are also associated with diabetes in non-selected patients with type 2 diabetes.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
10.
Aims/hypothesis The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic peptide (GIP) are released from
intestinal endocrine cells in response to luminal glucose. Glucokinase is present in these cells and has been proposed as
a glucose sensor. The physiological role of glucokinase can be tested using individuals with heterozygous glucokinase gene
(GCK) mutations. If glucokinase is the gut glucose sensor, GLP-1 and GIP secretion during a 75 g OGTT would be lower in GCK mutation carriers compared with controls.
Methods We compared GLP-1 and GIP concentrations measured at five time-points during a 75 g OGTT in 49 participants having GCK mutations with those of 28 familial controls. Mathematical modelling of glucose, insulin and C-peptide was used to estimate
basal insulin secretion rate (BSR), total insulin secretion (TIS), beta cell glucose sensitivity, potentiation factor and
insulin secretion rate (ISR).
Results GIP and GLP-1 profiles during the OGTT were similar in GCK mutation carriers and controls (p = 0.52 and p = 0.44, respectively). Modelled variables of beta cell function showed a reduction in beta cell glucose sensitivity (87 pmol
min−1 m−2 [mmol/l]−1 [95% CI 66–108] vs 183 pmol min−1 m−2 [mmol/l]−1 [95% CI 155–211], p < 0.001) and potentiation factor (1.5 min [95% CI 1.2–1.8] vs 2.2 min [95% CI 1.8–2.7], p = 0.007) but no change in BSR or TIS. The glucose/ISR curve was right-shifted in GCK mutation carriers.
Conclusions/interpretation Glucokinase, the major pancreatic glucose sensor, is not the main gut glucose sensor. By modelling OGTT data in GCK mutation carriers we were able to distinguish a specific beta cell glucose-sensing defect. Our data suggest a reduction in
potentiation of insulin secretion by glucose that is independent of differences in incretin hormone release. 相似文献
11.
Sparsø T Andersen G Albrechtsen A Jørgensen T Borch-Johnsen K Sandbaek A Lauritzen T Wasson J Permutt MA Glaser B Madsbad S Pedersen O Hansen T 《Diabetologia》2008,51(9):1646-1652
Aim/hypothesis Recently, variants in WFS1 have been shown to be associated with type 2 diabetes. We aimed to examine metabolic risk phenotypes of WFS1 variants in glucose-tolerant people and in individuals with abnormal glucose regulation.
Methods The type 2 diabetes-associated WFS1 variant rs734312 (His611Arg) was studied in the population-based Inter99 cohort involving 4,568 glucose-tolerant individuals
and 1,471 individuals with treatment-naive abnormal glucose regulation, and in an additional 3,733 treated type 2 diabetes
patients.
Results The WFS1 rs734312 showed a borderline significant association with type 2 diabetes with directions and relative risks consistent with
previous reports. In individuals with abnormal glucose regulation, the diabetogenic risk A allele of rs734312 was associated
in an allele-dependent manner with a decrease in insulinogenic index (p = 0.025) and decreased 30-min serum insulin levels (p = 0.047) after an oral glucose load. In glucose-tolerant individuals the same allele was associated with increased fasting
serum insulin concentration (p = 0.019) and homeostasis model assessment of insulin resistance (HOMA-IR; p = 0.026). To study the complex interaction of WFS1 rs734312 on insulin release and insulin resistance we introduced Hotelling’s T
2 test. Assuming bivariate normal distribution, we constructed standard error ellipses of the insulinogenic index and HOMA-IR
when stratified according to glucose tolerance status around the means of each WFS1 rs734312 genotype level. The interaction term between individuals with normal glucose tolerance and abnormal glucose regulation
on the insulinogenic index and HOMA-IR was significantly associated with the traits (p = 0.0017).
Conclusions/interpretation Type 2 diabetes-associated risk alleles of WFS1 are associated with estimates of a decreased pancreatic beta cell function among middle-aged individuals with abnormal glucose
regulation.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
12.
Seghieri G Tesi F Anichini R De Bellis A Barsotti E Mari A Ferrannini E 《Diabetologia》2007,50(11):2234-2238
Aims/hypothesis Gestational diabetes (GDM) carries a high risk of subsequent diabetes. We asked what impact prior GDM has on beta cell function
and insulin action in women who maintain normal glucose tolerance (NGT) for a long time.
Methods Ninety-one women with NGT (aged 41 ± 8 years, mean±SD) were studied (by mathematical modelling of the C-peptide response to
an OGTT) 7 [6] years (median [interquartile range]) after the index pregnancy, during which 52 had GDM (pGDM) and 39 had NGT
(pNGT). In all women an OGTT had also been performed at 29 ± 3 weeks of the index pregnancy.
Results Women with pGDM were matched with women with pNGT for age, familial diabetes, time and weight gain since index pregnancy,
parity, BMI (25.4 ± 3.9 vs 26.8 ± 6.4 kg/m2), and fasting (4.64 ± 0.56 vs 4.97 ± 0.46 mmol/l) and 2 h plasma glucose levels (5.91 ± 1.14 vs 5.91 ± 1.21 mmol/l). Nonetheless,
fasting (49 [29] vs 70 [45] pmol min−1 m−2, p < 0.001) and total insulin secretion (32 [17] vs 48 [21] nmol m−2, p < 0.0001) and beta cell glucose sensitivity (slope of the insulin secretion/plasma glucose concentration–response function)
(95 [71] vs 115 [79] pmol min−1 m−2 (mmol/l)−1, p = 0.025) were reduced in the pGDM group compared with the pNGT group, while insulin sensitivity was preserved (424 [98] vs
398 [77] ml min−1 m−2). At index pregnancy, women with pGDM and those with pNGT had similar age and BMI. However, both insulin sensitivity (359
[93] vs 417 [92] ml min−1 m−2, p = 0.0012) and the insulin/glucose incremental area ratio (an empirical index of beta cell function; 98 [74] vs 138 [122]
pmol/mmol, p = 0.028) were reduced in women with pGDM.
Conclusions Even in women who maintain normal insulin sensitivity, impaired beta cell function is carried over into the NGT status several
years after a GDM pregnancy. 相似文献
13.
Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes 总被引:3,自引:0,他引:3
Zheng L Du Y Miller C Gubitosi-Klug RA Ball S Berkowitz BA Kern TS 《Diabetologia》2007,50(9):1987-1996
Aims/hypothesis Diabetes results in the upregulation of the production of several components of the inflammatory response in the retina, including
inducible nitric oxide synthase (iNOS). The aim of this study was to investigate the role of iNOS in the pathogenesis of the
early stages of diabetic retinopathy using iNOS-deficient mice (iNos
−/−).
Materials and methods
iNos
−/− mice and wild-type (WT; C57BL/6J) mice were made diabetic with streptozotocin or kept as non-diabetic controls. Mice were
killed at different time points after the induction of diabetes for assessment of vascular histopathology, cell loss in the
ganglion cell layer (GCL), retinal thickness, and biochemical and physiological abnormalities.
Results The concentrations of nitric oxide, nitration of proteins, poly(ADP-ribose) (PAR)-modified proteins, endothelial nitric oxide
synthase, prostaglandin E2, superoxide and leucostasis were significantly (p < 0.05) increased in retinas of WT mice diabetic for 2 months compared with non-diabetic WT mice. All of these abnormalities
except PAR-modified proteins in retinas were inhibited (p < 0.05) in diabetic iNos
−/− mice. The number of acellular capillaries and pericyte ghosts was significantly increased in retinas from WT mice diabetic
for 9 months compared with non-diabetic WT controls, these increases being significantly inhibited in diabetic iNos
−/− mice (p < 0.05 for all). Retinas from WT diabetic mice were significantly thinner than those from their non-diabetic controls, whereas
diabetic iNos
−/− mice were protected from this abnormality. We found no evidence of cell loss in the GCL of diabetic WT or iNos
−/− mice. Deletion of iNos had no beneficial effect on diabetes-induced abnormalities on the electroretinogram.
Conclusions/interpretation We demonstrate that the inflammatory enzyme iNOS plays an important role in the pathogenesis of vascular lesions characteristic
of the early stages of diabetic retinopathy in mice.
An erratum to this article can be found at 相似文献
14.
Ferrannini E Muscelli E Natali A Gabriel R Mitrakou A Flyvbjerg A Golay A Hojlund K;Relationship between Insulin Sensitivity Cardiovascular Disease Risk 《Diabetologia》2007,50(11):2342-2347
Aims/hypothesis Hyperproinsulinaemia and relative hyperglucagonaemia are features of type 2 diabetes. We hypothesised that raised fasting
glucagon and proinsulin concentrations may be associated with insulin resistance (IR) in non-diabetic individuals.
Methods We measured IR [by a euglycaemic–hyperinsulinaemic (240 pmol min−1 m−2) clamp technique] in 1,296 non-diabetic (on a 75 g OGTT) individuals [716 women and 579 men, mean age 44 years, BMI 26 kg/m2 (range 18–44 kg/m2)] recruited at 19 centres in 14 European countries. IR was related to fasting proinsulin or pancreatic glucagon concentrations
in univariate and multivariate analyses. Given its known relationship to IR, serum adiponectin was used as a positive control.
Results In either sex, both glucagon and proinsulin were directly related to IR, while adiponectin was negatively associated with
it (all p < 0.0001). In multivariate models, controlling for known determinants of insulin sensitivity (i.e. sex, age, BMI and glucose tolerance) as well as factors potentially affecting glucagon and proinsulin (i.e. fasting plasma
glucose and C-peptide concentrations), glucagon and proinsulin were still positively associated, and adiponectin was negatively
associated, with IR. Finally, when these associations were tested as the probability that individuals in the top IR quartile
would have hormone levels in the top quartile of their distribution independently of covariates, the odds ratio was ∼2 for
both glucagon (p = 0.05) and proinsulin (p = 0.02) and 0.36 for adiponectin (p < 0.0001).
Conclusions/interpretation Whole-body IR is independently associated with raised fasting plasma glucagon and proinsulin concentrations, possibly as a
result of IR at the level of alpha cells and beta cells in pancreatic islets.
Electronic supplementary material The online version of this article (doi:) contains a list of the European Group for the Study of Insulin Resistance RISC investigators, which is available to authorised
users. 相似文献
15.
Elina Sakellaridou Heike Wersching Julia Reinholz Hubertus Lohmann Stefan Knecht 《Age (Dordrecht, Netherlands)》2011,33(1):101-106
Verbal comprehension is critical to the success of medical counseling. Here, we tested how age and vascular risk factors affect
the ability to understand complex instructions. Verbal comprehension, cognitive functions, and vascular risk factors were
assessed in 39 mid- and 38 late-life community-dwelling individuals (48 to 59 years and >59 years of age, respectively). To
test for verbal comprehension, we used a modified version of the Token Test (TT). In midlife individuals, education (β = 0.572, p < 0.05) was the only predictor for extended-TT performance. In late-life individuals, age (β = −1.015, p < 0.001) and body mass index (β = −0.651, p = 0.003) were significantly correlated with extended-TT performance and explained 50% of the variance in extended-TT performance
(adjusted R
2 = 0.503). This relation is only partly explained by conventional neuropsychological measures as the ones used in our test
battery. These results indicate that aging and overweight impair comprehension of complex instructions. Therefore, medical
counseling appropriate for midlife individuals may be less successful in elderly people and particularly in those with metabolic
disturbances. 相似文献
16.
C. Hu C. Wang R. Zhang X. Ma J. Wang J. Lu W. Qin Y. Bao K. Xiang W. Jia 《Diabetologia》2009,52(7):1322-1325
Aims/hypothesis Recent genome-wide association studies in East Asian populations reported that single nucleotide polymorphisms (SNPs) in KCNQ1 are associated with type 2 diabetes. The aim of this study was to validate this finding in a Chinese population.
Methods We genotyped four SNPs, rs2074196, rs2237892, rs2237895 and rs2237897, in a group of 3,503 Shanghai Chinese individuals, comprising
1,769 type 2 diabetic patients and 1,734 normoglycaemic controls. Both the cases and the controls were extensively phenotyped
for anthropometric and biochemical traits related to glucose metabolism. Arginine stimulation tests under fasting conditions
were performed in a subgroup of 466 cases.
Results All four of the SNPs were associated with type 2 diabetes, with rs2237892 showing strongest evidence for association (OR 1.532,
95% CI 1.381–1.698, p = 5.0 × 10−16). The SNP rs2237897 was associated with both acute insulin and C-peptide response after arginine stimulation in a subgroup
of cases (p = 0.0471 and p = 0.0156, respectively). The SNP rs2237895 was associated with both first- and second-phase insulin secretion in the controls
(p = 0.0334 and p = 0.0002, respectively).
Conclusions/interpretation In this study we found that KCNQ1 was associated with type 2 diabetes susceptibility in a Chinese population, possibly through its effect on beta cell function.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
17.
Aims/hypothesis In addition to the improvement in insulin sensitivity, it has been shown that thiazolidinediones modulate beta cell function
and insulin clearance in type 2 diabetic subjects. However, interactions between all these actions, and confounding factors
due to co-morbidities and co-treatments in diabetic individuals, complicate the identification of specific effects. The aim
of this pilot study was to investigate the potential acute effects of rosiglitazone on beta cell function and insulin sensitivity
by the hyperglycaemic clamp technique in healthy volunteers.
Subjects and methods Twelve healthy men were included in a randomised, double-blind crossover study. Rosiglitazone (8 mg) or placebo was given
orally 45 min before the hyperglycaemic clamp (10 mmol/l for 2 h).
Results The second phase of the insulin response was significantly decreased by rosiglitazone: 13,066 ± 1,531 vs 16,316 ± 2,813 pmol
l−1 110 min in controls (p < 0.05), without change in the first phase. Serum C-peptide was not modified. Rosiglitazone treatment significantly increased
insulin clearance (molar ratio of the C-peptide to insulin AUCs: 12.80 ± 1.34 vs 11.38 ± .33, p < 0.05) and the insulin sensitivity index (12.0 ± 1.5 vs 8.5 ± 1.1 μmol m−2 min−1 pmol−1l, p < 0.01).
Conclusions/interpretation The present results show that a single dose of rosiglitazone rapidly increases insulin clearance and insulin sensitivity index
in healthy volunteers, with no direct effect on insulin secretion. The precise mechanisms mediating these actions remain to
be determined. ClinicalTrials.gov ID no.: NCT00285142 相似文献
18.
Y. Liu D. Z. Zhou D. Zhang Z. Chen T. Zhao Z. Zhang M Ning X. Hu Y. F. Yang Z. F. Zhang L. Yu L. He H. Xu 《Diabetologia》2009,52(7):1315-1321
Aims/hypothesis Two recent genome-wide association studies have identified several novel type 2 diabetes susceptibility variants in intron
15 of the KCNQ1 gene. We aimed to evaluate the effects of the variants in KCNQ1 on type 2 diabetes and metabolic traits in the population of mainland China.
Methods Three candidate single nucleotide polymorphisms were genotyped in 1,912 individuals with type 2 diabetes and 2,041 normal
controls using the ligase detection reaction method.
Results We confirmed the association of KCNQ1 with type 2 diabetes in the population of mainland China. Allele frequency ORs of the three single nucleotide polymorphisms
(SNPs) were: rs2237892 (OR 1.19, 95% CI 1.08–1.31, p = 3.0 × 10−4); rs2237895 (OR 1.20, 95% CI 1.09–1.32, p = 1.9 × 10−4); and rs2237897 (OR 1.24, 95% CI 1.13–1.36, p = 3.9 × 10−5). We also found a significant difference in the distribution of the global haplotypes between the type 2 diabetes group and
the normal control group (p = 2.6 × 10−5). In addition, in the control group SNP rs2237892 was marginally associated with increasing fasting plasma glucose and SNPs
rs2237892 and rs2237897 were associated with HbA1c. Furthermore, for all three variants, homozygous carriers of the diabetes-associated allele had significantly decreased BMI
and waist circumferences.
Conclusions/interpretation Our investigation confirmed the effects of KCNQ1 variants on type 2 diabetes risk in the Chinese population.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
Y. Liu and D. Z. Zhou contributed equally to this study. 相似文献
19.
Højberg PV Zander M Vilsbøll T Knop FK Krarup T Vølund A Holst JJ Madsbad S 《Diabetologia》2008,51(4):632-640
Aims/hypothesis The ability of glucagon-like peptide-1 (GLP-1) to enhance beta cell responsiveness to i.v. glucose is impaired in patients
with type 2 diabetes mellitus compared with healthy individuals. We investigated whether 4 weeks of near normalisation of
blood glucose (BG) improves the potentiation of glucose-stimulated insulin secretion by GLP-1.
Methods Nine obese patients with type 2 diabetes and inadequate glycaemic control (HbA1c 8.0 ± 0.4%) were investigated before and after 4 weeks of near normalisation of BG using insulin treatment (mean diurnal
blood glucose 6.4 ± 0.3 mmol/l, HbA1c 6.6 ± 0.3%). Nine matched healthy participants were also studied. Beta cell function was investigated before and after insulin
treatment using stepwise glucose infusions and infusion of saline or GLP-1 (1.0 pmol kg−1 min−1), resulting in supraphysiological total GLP-1 concentrations of approximately 200 pmol/l. The responsiveness to glucose or
glucose+GLP-1 was expressed as the slope of the linear regression line relating insulin secretion rate (ISR) and plasma glucose
concentration (pmol kg−1 min−1 [mmol/l]−1).
Results In the diabetic participants, the slopes during glucose+saline infusion did not differ before and after insulin treatment
(0.33 ± 0.07 and 0.39 ± 0.04, respectively; p = NS). In contrast, near normalisation of blood glucose improved beta cell sensitivity to glucose during glucose+GLP-1 infusion
(1.27 ± 0.2 before vs 1.73 ± 0.31 after; p < 0.01). In the healthy participants, the slopes during the glucose+saline and glucose+GLP-1 infusions were 1.01 ± 0.14 and
4.79 ± 0.53, respectively.
Conclusions/interpretation A supraphysiological dose of GLP-1 enhances beta cell responses to glucose in patients with type 2 diabetes, and 4 weeks of
near normalisation of blood glucose further improves this effect.
ClinicalTrials.gov ID no.: NCT00612625 相似文献
20.
Varona-Santos JL Pileggi A Molano RD Sanabria NY Ijaz A Atsushi M Ichii H Pastori RL Inverardi L Ricordi C Fornoni A 《Diabetologia》2008,51(12):2271-2280
Aims/hypothesis Inhibition of c-jun N-terminal kinase (JNK) favours pancreatic islet function and survival. Since two JNK isoforms are present
in the pancreas (JNK1 and JNK2), we addressed their specific roles in experimental islet transplantation.
Methods C57BL/6J (wild-type [WT]), Jnk1 (also known as Mapk8)−/− and Jnk2 (also known as Mapk9)−/− mice were used as donor/recipients in a syngeneic islet transplantation model. Islet cell composition, function, viability,
production of cytokines and of vascular endothelial growth factor (VEGF) were also studied in vitro.
Results
Jnk1
−/−
islets secreted more insulin in response to glucose and were more resistant to cytokine-induced cell death compared with
WT and Jnk2
−/− islets (p < 0.01). Cytokines reduced VEGF production in WT and Jnk2
−/− but not Jnk1
−/−
islets; VEGF blockade restored Jnk1
−/−
islet susceptibility to cytokine-induced cell death. Transplantation of Jnk1
−/−
or WT islets into WT recipients made diabetic had similar outcomes. However, Jnk1
−/−
recipients of WT islets had shorter time to diabetes reversal (17 vs 55 days in WT, p = 0.033), while none of the Jnk2
−/− recipients had diabetes reversal (0% vs 71% in WT, p = 0.0003). Co-culture of WT islets with macrophages from each strain revealed a discordant cytokine production.
Conclusions/interpretation We have shown a deleterious effect of JNK2 deficiency on islet graft outcome, most likely related to JNK1 activation, suggesting
that specific JNK1 blockade may be superior to general JNK inhibition, particularly when administered to transplant recipients. 相似文献