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1.
Aims/hypothesis This study was designed to investigate the effect of short-term ACE inhibitor treatment on insulin sensitivity and to examine possible underlying metabolic and haemodynamic effects in obese insulin-resistant subjects.Methods A randomised, double-blind placebo-controlled trial was performed in 18 obese insulin-resistant men (age, 53 ± 2 years; BMI, 32.6 ± 0.8 kg/m2; homeostasis model assessment of insulin resistance, 5.6 ± 0.5; systolic blood pressure [SBP], 140.8 ± 3.2; diastolic blood pressure [DBP], 88.8 ± 1.6 mmHg), who were free of any medication. The aim was to examine the effects of 2 weeks of ACE inhibitor treatment (ramipril, 5 mg/day) on insulin sensitivity, forearm blood flow, substrate fluxes across the forearm, whole-body substrate oxidation and intramuscular triacylglycerol (IMTG) content.Results Ramipril treatment decreased ACE activity compared with placebo (−22.0 ± 1.7 vs 0.2 ± 1.1 U/l, respectively, p < 0.001), resulting in a significantly reduced blood pressure (SBP, −10.8 ± 2.1 vs −2.7 ± 2.0 mmHg, respectively, p = 0.01; DBP, −10.1 ± 1.3 vs −4.2 ± 2.1 mmHg, respectively, p = 0.03). Ramipril treatment had no effect on whole-body insulin-mediated glucose disposal (before: 17.9 ± 2.0, after: 19.1 ± 2.4 μmol kg body weight−1 min−1, p = 0.44), insulin-mediated glucose uptake across the forearm (before: 1.82 ± 0.39, after: 1.92 ± 0.29 μmol 100 ml forearm tissue−1 min−1, p = 0.81) and IMTG content (before: 45.4 ± 18.8, after: 48.8 ± 27.5 μmol/mg dry muscle, p = 0.92). Furthermore, the increase in carbohydrate oxidation (p < 0.001) and forearm blood flow (p < 0.01), and the decrease in fat oxidation (p < 0.001) during insulin stimulation were not significantly different between treatments.Conclusions/interpretation Short-term ramipril treatment adequately reduced ACE activity and blood pressure, but had no significant effects on insulin sensitivity, forearm blood flow, substrate fluxes across the forearm, whole-body substrate oxidation and IMTG content in obese insulin-resistant subjects. 相似文献
2.
G. Kacerovsky-Bielesz S. Lienhardt M. Hagenhofer M. Kacerovsky E. Forster R. Roth M. Roden 《Diabetologia》2009,52(5):781-788
Aims/hypothesis Women are at higher risk of diabetes-related cardiovascular complications than men. We tested the hypothesis that there are
sex-specific differences in glucometabolic control, and in social and psychological factors. We also examined the influence
of these factors on glucometabolic control.
Methods We examined 257 (126 men/131 women) consecutive patients (64 ± 9 years, means ± SD) of a metropolitan diabetes outpatient
service employing clinical testing and standardised psychological questionnaires.
Results Mean HbA1c (7.6 ± 1.2%) was not different between women and men. Women patients on oral hypoglycaemic agents were better informed about
diabetes (p = 0.012). They employed more strategies for coping with diabetes, including religion (p = 0.0001), active coping (p = 0.048) and distraction (p = 0.007). Women reported lower satisfaction with social support (p = 0.034), but not more depression than men. Although no differences were observed in compliance, insulin-treated patients
were more satisfied with their therapy (p = 0.007). Variables predicting poor metabolic control were different in men (R
2 = 0.737, p = 0.012) and women (R
2 = 0.597, p = 0.019). Major predictors of high HbA1c included depressive coping, lower sexual desire, quality of life and internal locus of control, but high external doctor-related
locus of control in women and frequent emotional experiences of hyperglycaemia in men.
Conclusions/interpretation Lower quality of life, internal control and socioeconomic status, and higher prevalence of negative emotions probably prevented
woman patients from achieving improved glucose control despite their better knowledge of and greater efforts to cope with
diabetes. We suggest that women patients would benefit from individualised diabetes care offering social support, whereas
men would benefit from knowledge-based diabetes management giving them more informational and instrumental support. 相似文献
3.
Teran-Garcia M Rankinen T Rice T Leon AS Rao DC Skinner JS Bouchard C 《Diabetologia》2007,50(9):1858-1866
Aims/hypothesis The expression of the four and a half LIM domains 1 gene (FHL1) is increased in the muscle of individuals who show an improvement in insulin sensitivity index (S
I) after 20 weeks of exercise training. The aim of the present study was to investigate associations between three FHL1 single nucleotide polymorphisms (SNPs) and variables derived from an IVGTT, both in the sedentary state and in response to
exercise training, in participants in the HERITAGE Family Study.
Materials and methods SNPs were typed using fluorescence polarisation methodology. Analyses were performed separately by sex and in black and white
individuals.
Results In black participants, no associations were found with any of the SNPs. In white women (n = 207), SNP rs9018 was associated with the disposition index (D
I), which is calculated as S
I generated from the MINMOD program (×10−4 min−1[μU/ml]−1) multiplied by acute insulin response to glucose (AIRg; pmol/l × 10 min), and the glucose disappearance index (K
g) training responses (p = 0.016 and p = 0.008, respectively). In white men (n = 222), all SNPs were associated with fasting glucose levels (p ≤ 0.05) and SNP rs2180062 with the insulin sensitivity index (S
I) (p = 0.04) in the sedentary state. Two SNPs were associated with fasting insulin training response. Fasting insulin decreased
to a greater extent in carriers of the rs2180062 C allele (p = 0.01) and rs9018 T allele (p = 0.04). With exercise training, S
I (×10−4 min−1[μU/ml]−1: 0.68 ± 0.20 vs −0.77 ± 0.44, p = 0.046), D
I (319 ± 123 vs –528 ± 260, p = 0.006) and K
g (per 100 min: 0.09 ± 0.04 vs −0.14 ± 0.8, p = 0.03) improved more in the C allele carriers at rs2180062 than in the T allele carriers.
Conclusions/interpretation Fasting insulin and S
I responses to exercise training were associated with DNA sequence variation in FHL1 in white men. Whether these associations exist only in white men remains to be investigated.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
4.
Bakhtadze E Cervin C Lindholm E Borg H Nilsson P Arnqvist HJ Bolinder J Eriksson JW Gudbjörnsdottir S Nyström L Agardh CD Landin-Olsson M Sundkvist G Groop LC 《Diabetologia》2008,51(12):2224-2232
Aims/hypothesis Type 1 diabetes in children is characterised by autoimmune destruction of pancreatic beta cells and the presence of certain
risk genotypes. In adults the same situation is often referred to as latent autoimmune diabetes in adults (LADA). We tested
whether genetic markers associated with type 1 or type 2 diabetes could help to discriminate between autoimmune and non-autoimmune
diabetes in young (15–34 years) and middle-aged (40–59 years) diabetic patients.
Methods In 1,642 young and 1,619 middle-aged patients we determined: (1) HLA-DQB1 genotypes; (2) PTPN22 and INS variable-number tandem repeat (VNTR) polymorphisms; (3) two single nucleotide polymorphisms (rs7903146 and rs10885406) in
the TCF7L2 gene; (4) glutamic acid decarboxylase (GAD) and IA-2-protein tyrosine phosphatase-like protein (IA-2) antibodies; and (5)
fasting plasma C-peptide.
Results Frequency of risk genotypes HLA-DQB1 (60% vs 25%, p
= 9.4×10−34; 45% vs 18%, p
= 1.4 × 10−16), PTPN22 CT/TT (34% vs 26%, p
= 0.0023; 31% vs 23%, p
= 0.034), INS VNTR class I/I (69% vs 53%, p
= 1.3 × 10−8; 69% vs 51%, p
= 8.5 × 10−5) and INS VNTR class IIIA/IIIA (75% vs 63%, p
= 4.3 × 10−6; 73% vs 60%, p
= 0.008) was increased in young and middle-aged GAD antibodies (GADA)-positive compared with GADA-negative patients. The type
2 diabetes-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly more common in young GADA-negative than in GADA-positive patients (53% vs 43%; p
= 0.0004). No such difference was seen in middle-aged patients, in whom the frequency of the CT/TT genotypes of TCF7L2 was similarly increased in GADA-negative and GADA-positive groups (55% vs 56%).
Conclusions/interpretation Common variants in the TCF7L2 gene help to differentiate young but not middle-aged GADA-positive and GADA-negative diabetic patients, suggesting that young
GADA-negative patients have type 2 diabetes and that middle-aged GADA-positive patients are different from their young GADA-positive
counterparts and share genetic features with type 2 diabetes.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
G. Sundkvist died in September 2006. 相似文献
5.
J. Koska E. Ortega J. C. Bunt A. Gasser J. Impson R. L. Hanson J. Forbes B. de Courten J. Krakoff 《Diabetologia》2009,52(3):385-393
Aim/hypothesis Low-grade inflammation may contribute to obesity-related insulin resistance and has been associated with increased risk of
type 2 diabetes mellitus. The present study evaluated whether treatment with salsalate, a traditional anti-inflammatory medication,
would improve insulin action in obese non-diabetic individuals.
Methods The study was a randomised, double-blind, placebo-controlled, parallel trial conducted at the inpatient clinical research
unit of the NIDKK (Phoenix, AZ, USA). Participants were 54 adults (18 to 45 years of age) with BMI ≥ 30 kg/m2. The intervention was salsalate (3 g/day, n = 28) or identical placebo (n = 26) for 7 days. The allocation was kept concealed by giving the investigator only a number corresponding to a vial of placebo
or salsalate sequentially randomised in blocks by sex. Main outcomes were changes in insulin action assessed as rate of glucose
disposal (R
d) by euglycaemic–hyperinsulinaemic clamp (insulin infusion rate 40 mU m−2 min−1) and glucose tolerance by 75 g OGTT.
Results The study was completed by 47 participants, of which 40 were analysed (salsalate n = 22, placebo n = 18). Salsalate treatment resulted in decreased fasting plasma glucose concentration (mean [SD]; 4.83 [0.28] vs 5.11 [0.33]
mmol/l, p = 0.001) and glucose AUC during the OGTT (p = 0.01), and in increased R
d (20 [8] vs 18 [6] μmol [kg estimated metabolic body size]−1 min−1, p = 0.002), while there was no significant change in these variables with placebo (p > 0.3 for all). The effect of salsalate on R
d disappeared (p = 0.9) after normalising to increased insulin concentrations (701 [285] vs 535 [201] pmol/l, p < 0.0001) measured during the clamp. No side effects of salsalate were observed during the study.
Conclusions/interpretation The glucose-lowering potential of salicylates appears to be due to effects on insulin concentration rather than improved insulin
action. Salicylate-based compounds may be useful for the treatment and prevention of type 2 diabetes.
Trial registration: ClinicalTrials.gov NCT 00339833.
Funding: Intramural research programme of the NIDDK/NIH/DHHS.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.
J. Koska and E. Ortega contributed equally to this work. 相似文献
6.
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
7.
Di Marzo V Côté M Matias I Lemieux I Arsenault BJ Cartier A Piscitelli F Petrosino S Alméras N Després JP 《Diabetologia》2009,52(2):213-217
Aims/hypothesis We previously reported that the plasma levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), in a cohort of viscerally
obese men are directly correlated with visceral adipose tissue (VAT) accumulation and metabolic risk factors including low
HDL-cholesterol and high triacylglycerol. It is not known, however, if such correlations persist after vigorous lifestyle
interventions that reduce metabolic risk factors. We analysed the changes in endocannabinoid levels in a subsample from the
same cohort following a 1 year lifestyle modification programme, and correlated them with changes in VAT and metabolic risk
factors.
Methods Forty-nine viscerally obese men (average age 49 years, BMI 30.9 kg/m2, waist 107.3 cm) underwent a 1 year lifestyle modification programme including healthy eating and physical activity. Plasma
levels of 2-AG and the other most studied endocannabinoid, anandamide, were measured by liquid chromatography–mass spectrometry.
Anthropometric and metabolic risk factors, including VAT, insulin resistance and glucose intolerance, HDL-cholesterol and
triacylglycerol, were measured.
Results Most risk factors were improved by the intervention, which led to a significant decrease in body weight (−6.4 kg, p < 0.0001), waist circumference (−8.0 cm, p < 0.0001) and VAT (−30%, p < 0.0001), and in plasma 2-AG (−62.3%, p < 0.0001) and anandamide (−7.1%, p = 0.005) levels. The decrease in levels of 2-AG but not those of anandamide correlated with decreases in VAT and triacylglycerol
levels, and with the increase in HDL3-cholesterol levels. Multivariate analyses suggested that decreases in 2-AG and VAT were both independently associated with
decreases in triacylglycerol.
Conclusions/interpretation This study shows that a strong correlation exists between 2-AG levels and high plasma triacylglycerol and low HDL3-cholesterol in viscerally obese men.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
8.
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
9.
Selvarajah D Wilkinson ID Emery CJ Shaw PJ Griffiths PD Gandhi R Tesfaye S 《Diabetologia》2008,51(11):2088-2092
Aims/hypothesis Although clear peripheral nerve pathological abnormalities have been demonstrated in diabetic peripheral neuropathy (DPN),
there is little information with regard to brain involvement. Our aim was to use in vivo proton magnetic resonance specroscopy
(H-MRS) in patients with DPN in order to assess the neuro-chemical status of the thalamus, which acts as the gateway to the
brain for somatosensory information.
Methods Participants included 18 type 1 diabetic men (eight without DPN, ten with DPN) and six non-diabetic healthy volunteers, who
all underwent detailed clinical and neurophysiological assessments yielding a Neuropathy Composite Score (NCS) derived from
Neuropathy Impairment Score of the Lower Limbs plus seven tests of nerve function prior to investigation via a single-voxel
H-MRS technique, which was used to sample ventral posterior thalamic parenchyma. Spectroscopic resonances including those
due to N-acetyl aspartate (NAA) were assessed at both short and long echo-time, providing putative indicators of neuronal function
and integrity, respectively.
Results At long echo-time we observed significantly lower NAA:creatine (p = 0.04) and NAA:choline (p = 0.02) ratios in DPN patients than in the other groups. No group differences were detected at short echo-time. We found
a significant positive association between both sural amplitude (ρ = 0.61, p = 0.004) and nerve conduction velocity (r = 0.58, p = 0.006) and NAA:creatine signal among participants with diabetes. Vibration detection threshold (ρ = −0.70, p = 0.004) was significantly related to NAA:choline ratio. Heart rate variability with deep breathing (ρ = −0.46, p = 0.05) and NCS (ρ = −0.53, p = 0.03) were significantly related to NAA:creatine ratio.
Conclusions/interpretation The significantly lower NAA:creatine ratio in DPN is suggestive of thalamic neuronal dysfunction, while the lack of difference
in short echo-time between the groups does not suggest neuronal loss. Taken together with the observed correlations between
NAA and neurophysiological assessments, these findings provide evidence for thalamic neuronal involvement in DPN. 相似文献
10.
R. A. Chudleigh R. L. Ollerton G. Dunseath R. Peter J. N. Harvey S. Luzio D. R. Owens 《Diabetologia》2009,52(7):1274-1278
Aims/hypothesis The Modification of Diet in Renal Disease (MDRD) equation has recognised limitations when using estimated GFR in persons at
risk of chronic kidney disease. Equations based on cystatin C provide an alternative method. We compared performance of the
MDRD equation with a selection of cystatin C-based formulae for estimation of GFR in normoalbuminuric patients with type 2
diabetes.
Methods Estimated GFR was calculated using the MDRD equation and the cystatin C formulae proposed by several investigator teams. Isotopic
GFR was measured using plasma clearance of 51Cr-EDTA.
Results We studied 106 participants, of whom 83 (78%) were men with the following characteristics, mean (SD): age 61 (9) years, HbA1c 7.10 (1.27)%, creatinine 89.0 (12.7) μmol/l, cystatin C 0.859 (0.234) mg/l and isotopic GFR 104.5 (20.1) ml min−1 1.73 m−2. MDRD estimated GFR was 77.4 (13.6) ml min−1 1.73 m−2 (p < 0.05 for difference from isotopic GFR). Cystatin C-based calculations of estimated GFR were: Perkins 124.5 (31.8), Rule
90.0 (30.0), Stevens (age) 96.0 (30.4) and Stevens (creatinine) 85.6 (19.0) ml min−1 1.73 m−2 (p < 0.05 for difference with isotopic GFR). For Arnal’s, MacIsaac’s and Tan’s formulae cystatin-C estimated GFR were 101.7
(34.8), 102.1 (27.0) and 101.6 (27.8) ml min−1 1.73 m−2, respectively (p = NS for difference with isotopic GFR). Cystatin C-based formulae were less biased and, with the exception of Perkins’ formula,
more accurate to within 10% of isotopic GFR than MDRD.
Conclusions/interpretation Performance of cystatin C equations was superior to MDRD in normoalbuminuric patients with type 2 diabetes. These results
support further evaluation of cystatin C for estimation of GFR in persons at risk of chronic kidney disease. 相似文献
11.
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
12.
Circadian rhythms of GIP and GLP1 in glucose-tolerant and in type 2 diabetic patients after biliopancreatic diversion 总被引:1,自引:1,他引:0
G. Mingrone G. Nolfe G. Castagneto Gissey A. Iaconelli L. Leccesi C. Guidone G. Nanni J. J. Holst 《Diabetologia》2009,52(5):873-881
Aims/hypothesis We tested the hypothesis that the reversibility of insulin resistance and diabetes observed after biliopancreatic diversion
(BPD) is related to changes in circadian rhythms of gastrointestinal hormones.
Methods Ten morbidly obese participants, five with normal glucose tolerance (NGT) and five with type 2 diabetes, were studied before
and within 2 weeks after BPD. Within-day variations in glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like
peptide 1 (GLP1) levels were assessed using a single cosinor model. Insulin sensitivity was assessed by euglycaemic–hyperinsulinaemic
clamp.
Results Basal GLP1 relative amplitude (amplitude/mesor × 100) was 25.82–4.06% in NGT; it increased to 41.38–4.32% after BPD but was
unchanged in diabetic patients. GLP1 and GIP mesor were shifted in time after surgery in diabetic patients but not in NGT
participants. After BPD, the GLP1 AUC significantly increased from 775 ± 94 to 846 ± 161 pmol l−1 min in NGT, whereas GIP AUC decreased significantly from 1,373 ± 565 to 513 ± 186 pmol l−1 min in diabetic patients. Two-way ANOVA showed a strong influence of BPD on both GIP (p = 0.010) and GLP1 AUCs (p = 0.033), which was potentiated by the presence of diabetes, particularly for GIP (BPD × diabetes, p = 0.003). Insulin sensitivity was markedly improved (p < 0.01) in NGT (from 9.14 ± 3.63 to 36.04 ± 8.55 μmol [kg fat-free mass]−1 min−1) and diabetic patients (from 9.49 ± 3.56 to 38.57 ± 4.62 μmol [kg fat-free mass]−1 min−1).
Conclusions/interpretation An incretin circadian rhythm was shown for the first time in morbid obesity. The effect of BPD on the 24 h pattern of incretin
differed between NGT and diabetic patients. GLP1 secretion impairment was reversed in NGT and could not be overcome by surgery
in diabetes. On the other hand, GIP secretion was blunted after the operation only in diabetic patients, suggesting a role
in insulin resistance and diabetes. 相似文献
13.
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
14.
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
15.
Aims/hypothesis The aim of this study was to ascertain whether treatment of GAD65 autoantibody (GADA)-positive diabetic patients with alum-formulated
recombinant GAD65 (GAD-alum) is safe and does not compromise beta cell function.
Methods This Phase 2, placebo-controlled, dose-escalation clinical trial, which was randomized through a central office, was performed
in 47 GADA-positive type 2 diabetic patients, who received subcutaneous injections of GAD-alum (4 [n = 9], 20 [n = 8], 100 [n = 9] or 500 [n = 8] μg) or placebo (n = 13) at weeks 1 and 4 of the trial. Participants and caregivers were blinded to group assignments. The primary outcome was
safety as assessed by neurological tests, medications and beta cell function evaluated over 5 years, representing the end
of the trial.
Results No severe study-related adverse events occurred during the 5 year follow-up. None of the dose groups was associated with an
increased risk of starting insulin treatment compared with the placebo group. The use of oral hypoglycaemic agents did not
differ between the dose groups. After 5 years, fasting C-peptide levels declined in the placebo group (−0.24; 95% CI −0.41
to −0.07 log10 nmol/l; p = 0.01) and the 500 μg dose group (−0.37; 95% CI −0.57 to −0.17 log10 nmol/l; p = 0.003), but not in the 4 μg (−0.10; 95% CI −0.28 to 0.07 log10 nmol/l; p = 0.20), 20 μg (0.04; 95% CI −0.12 to 0.19 log10 nmol/l; p = 0.58) and 100 μg (0.00; 95% CI −0.20 to −0.20 log10 nmol/l; p = 0.98) dose groups.
Conclusions/interpretation The primary outcome of safety was achieved, since no severe study-related adverse events occurred.
Trial registration Because the study was initiated before 1 July 2005, the protocol was not registered in a registry.
Funding This trial was funded by the National Institutes of Health (grant numbers DK26190 and DK53004), the Swedish Research Council
(grant number 72X-14064) and Diamyd Therapeutics (Stockholm, Sweden).
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
16.
Pascoe L Frayling TM Weedon MN Mari A Tura A Ferrannini E Walker M;RISC Consortium 《Diabetologia》2008,51(11):1989-1992
Aims/hypothesis Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased
diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk
alleles on measures of beta cell function in non-diabetic individuals.
Methods A total of 1,211 non-diabetic individuals underwent metabolic assessment including an OGTT, from which measures of beta cell
function were derived. Individuals were genotyped at each of the risk loci and then classified according to the total number
of risk alleles that they carried. Initial analysis focused on CDKAL1, HHEX/IDE and TCF7L2 loci, which were individually associated with a decrease in beta cell function in our cohort. Risk alleles for CDKN2A/B, SLC30A8, IGF2BP2 and KCNJ11 loci were subsequently included into the analysis.
Results The diabetes-risk alleles for CDKAL1, HHEX/IDE and TCF7L2 showed an additive model of association with measures of beta cell function. Beta cell glucose sensitivity was decreased
by 39% in those individuals with five or more risk alleles compared with those individuals with no risk alleles (geometric
mean [SEM]: 84 [1.07] vs 137 [1.11] pmol min−1 m−2 (mmol/l)−1, p = 1.51 × 10−6). The same was seen for the 30 min insulin response (p = 4.17 × 10−7). The relationship remained after adding in the other four susceptibility loci (30 min insulin response and beta cell glucose
sensitivity, p < 0.001 and p = 0.003, respectively).
Conclusions/interpretation This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta
cell function in non-diabetic individuals.
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
17.
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
18.
A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans 总被引:1,自引:1,他引:0
A. Kotronen L. E. Johansson L. M. Johansson C. Roos J. Westerbacka A. Hamsten R. Bergholm P. Arkkila J. Arola T. Kiviluoto R. M. Fisher E. Ehrenborg M. Orho-Melander M. Ridderstråle L. Groop H. Yki-Järvinen 《Diabetologia》2009,52(6):1056-1060
Aims/hypothesis It has recently been suggested that the rs738409 G allele in PNPLA3, which encodes adiponutrin, is strongly associated with increased liver fat content in three different ethnic groups. The
aims of the present study were as follows: (1) to try to replicate these findings in European individuals with quantitative
measures of hepatic fat content; (2) to study whether the polymorphism influences hepatic and adipose tissue insulin sensitivity;
and (3) to investigate whether PNPLA3 expression is altered in the human fatty liver.
Methods We genotyped 291 Finnish individuals in whom liver fat had been measured using proton magnetic resonance spectroscopy. Hepatic
PNPLA3 expression was measured in 32 participants. Hepatic and adipose tissue insulin sensitivities were measured using a euglycaemic–hyperinsulinaemic
(insulin infusion 0.3 mU kg−1 min−1) clamp technique combined with infusion of [3-3H]glucose in 109 participants.
Results The rs738409 G allele in PNPLA3 was associated with increased quantitative measures of liver fat content (p = 0.011) and serum aspartate aminotransferase concentrations (p = 0.002) independently of age, sex and BMI. Fasting serum insulin and hepatic and adipose tissue insulin sensitivity were
related to liver fat content independently of genotype status. PNPLA3 mRNA expression in the liver was positively related to obesity (r = 0.62, p < 0.0001) and to liver fat content (r = 0.58, p = 0.025) in participants who were not morbidly obese (BMI < 40 kg/m2).
Conclusions/interpretation A common variant in PNPLA3 increases the risk of hepatic steatosis in humans.
A. Kotronen and L. E. Johansson contributed equally to this study. 相似文献
19.
Aims/hypothesis The physiological increase in muscle protein anabolism induced by insulin is blunted in healthy, glucose-tolerant older adults.
We hypothesised that the age-related defect in muscle protein anabolism is a true insulin resistance state and can be overridden
by supraphysiological hyperinsulinaemia.
Methods We used dye dilution, stable isotopic and immunoblotting techniques to measure leg blood flow, muscle protein synthesis, protein
kinase B/mammalian target of rapamycin (Akt/mTOR) signalling, and amino acid kinetics in 14 healthy, glucose-tolerant older
volunteers at baseline, and during an insulin infusion at postprandial (PD, 0.15 mU min−1 100 ml−1) or supraphysiologically high (HD, 0.30 mU min−1 100 ml−1) doses.
Results Leg blood flow, muscle protein synthesis, and Akt/mTOR signalling were not different at baseline. During hyperinsulinaemia,
leg blood flow (p < 0.01) and muscle protein synthesis increased in the HD group only (PD [%/h]: from 0.063 ± 0.006 to 0.060 ± 0.005; HD [%/h]:
from 0.061 ± 0.007 to 0.098 ± 0.007; p < 0.01). Muscle Akt phosphorylation increased in both groups, but the increase tended to be greater in the HD group (p = 0.07). The level of p70 ribosomal S6 kinase 1 (S6K1) phosphorylation increased in the HD group only (p < 0.05). Net amino acid balance across the leg improved in both groups, but a net anabolic effect was observed only in the
HD group (p < 0.05).
Conclusions/interpretation We conclude that supraphysiological hyperinsulinaemia is necessary to stimulate muscle protein synthesis and anabolic signalling
in healthy older individuals, suggesting the existence of a true age-related insulin resistance of muscle protein metabolism. 相似文献
20.
D. K. Coletta A. Sriwijitkamol E. Wajcberg P. Tantiwong M. Li M. Prentki M. Madiraju C. P. Jenkinson E. Cersosimo N. Musi R. A. DeFronzo 《Diabetologia》2009,52(4):723-732
Aims/hypothesis The molecular mechanisms by which thiazolidinediones improve insulin sensitivity in type 2 diabetes are not fully understood.
We hypothesised that pioglitazone would activate the adenosine 5′-monophosphate-activated protein kinase (AMPK) pathway and
increase the expression of genes involved in adiponectin signalling, NEFA oxidation and mitochondrial function in human skeletal
muscle.
Methods A randomised, double-blind, parallel study was performed in 26 drug-naive type 2 diabetes patients treated with: (1) pioglitazone
(n = 14) or (2) aggressive nutritional therapy (n = 12) to reduce HbA1c to levels observed in the pioglitazone-treated group. Participants were assigned randomly to treatment using a table of random
numbers. Before and after 6 months, patients reported to the Clinical Research Center of the Texas Diabetes Institute for
a vastus lateralis muscle biopsy followed by a 180 min euglycaemic–hyperinsulinaemic (80 mU m−2 min−1) clamp.
Results All patients in the pioglitazone (n = 14) or nutritional therapy (n = 12) group were included in the analysis. Pioglitazone significantly increased plasma adiponectin concentration by 79% and
reduced fasting plasma NEFA by 35% (both p < 0.01). Following pioglitazone, insulin-stimulated glucose disposal increased by 30% (p < 0.01), and muscle AMPK and acetyl-CoA carboxylase (ACC) phosphorylation increased by 38% and 53%, respectively (p < 0.05). Pioglitazone increased mRNA levels for adiponectin receptor 1 and 2 genes (ADIPOR1, ADIPOR2), peroxisome proliferator-activated receptor gamma, coactivator 1 gene (PPARGC1) and multiple genes involved in mitochondrial function and fat oxidation. Despite a similar reduction in HbA1c and similar improvement in insulin sensitivity with nutritional therapy, there were no significant changes in muscle AMPK
and ACC phosphorylation, or the expression of ADIPOR1, ADIPOR2, PPARGC1 and genes involved in mitochondrial function and fat oxidation. No adverse (or unexpected) effects or side effects were reported
from the study.
Conclusions/interpretations Pioglitazone increases plasma adiponectin levels, stimulates muscle AMPK signalling and increases the expression of genes
involved in adiponectin signalling, mitochondrial function and fat oxidation. These changes may represent an important cellular
mechanism by which thiazolidinediones improve skeletal muscle insulin sensitivity.
Trial registration: NCT 00816218
Funding: This trial was funded by National Institutes of Health Grant DK24092, VA Merit Award, GCRC Grant RR01346, Executive Research
Committee Research Award from the University of Texas Health Science Center at San Antonio, American Diabetes Association
Junior Faculty Award, American Heart Association National Scientist Development Grant, Takeda Pharmaceuticals North America
Grant and Canadian Institute of Health Research Grant.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献