Impaired maximum microvascular hyperaemia in patients with MODY 3 (hepatocyte nuclear factor-1alpha gene mutations)

Lee, B. C.; Appleton, Maggie; Shore, Angela C.; Tooke, JE; Hattersley, Andrew T.

doi:10.1046/j.1464-5491.1999.00129.x

Cited by 10 publications

(5 citation statements)

References 28 publications

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“…An impaired skin maximum hyperaemic (MH) response to local heating has been observed in type 1 [2, 3], type 2 [4], and MODY3 diabetic subjects [5] who are highly prone to both macro- and microcirculation complications. This reduced vasodilatory capacity predates diabetes as it is present in those at risk of developing type 2 diabetes mellitus, for example in subjects with fasting hyperglycaemia [6], in women with previous gestational diabetes [7], and in 3-month-old infants of low birth weight [8].…”

Section: Introductionmentioning

confidence: 99%

Maximum Skin Hyperaemia Induced by Local Heating: Possible Mechanisms

et al. 2006

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Background: Maximum skin hyperaemia (MH) induced by heating skin to ≧42°C is impaired in individuals at risk of diabetes and cardiovascular disease. Interpretation of these findings is hampered by the lack of clarity of the mechanisms involved in the attainment of MH. Methods: MH was achieved by local heating of skin to 42–43°C for 30 min, and assessed by laser Doppler fluximetry. Using double-blind, randomized, placebo-controlled crossover study designs, the roles of prostaglandins were investigated by inhibiting their production with aspirin and histamine, with the H₁ receptor antagonist cetirizine. The nitric oxide (NO) pathway was blocked by the NO synthase inhibitor, N^G-nitro-L-arginine methyl esther (L-NAME), and enhanced by sildenafil (prevents breakdown of cGMP). Results: MH was not altered by aspirin, cetirizine or sildenafil, but was reduced by L-NAME: median placebo 4.48 V (25th, 75th centiles: 3.71, 4.70) versus L-NAME 3.25 V (3.10, 3.80) (p = 0.008, Wilcoxon signed rank test). Inhibition of NO production (L-NAME) resulted in a more rapid reduction in hyperaemia after heating (p = 0.011), whereas hyperaemia was prolonged in the presence of sildenafil (p = 0.003). The increase in skin blood flow was largely confined to the directly heated area, suggesting that the role of heat-induced activation of the axon reflex was small. Conclusion: NO, but not prostaglandins, histamine or an axon reflex, contributes to the increase in blood flow on heating and NO is also a component of the resolution of MH after heating.

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Section: Introductionmentioning

confidence: 99%

Maximum Skin Hyperaemia Induced by Local Heating: Possible Mechanisms

et al. 2006

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“…This may be a consequence of the fact that our MODY patients were characterized by a relatively young age at the examination and their lack of some other risk factors, such as hyperlipidemia or obesity. While no earlier study had approached FMD measurements in monogenic diabetes, one previous study reported of microvascular function in HNF1A-MODY, which showed impaired maximum microvascular hyperemia in these patients (21). The relatively high prevalence of hypertension in both our diabetic cohorts should be treated with caution, as one criterion for diagnosis was the introduction of antihypertensive treatment.…”

Section: Discussionmentioning

confidence: 77%

Intima-media thickness and endothelial dysfunction in GCK and HNF1A-MODY patients

Szopa

Osmenda

Wilk

et al. 2015

European Journal of Endocrinology

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Objective: Mutations in the glucokinase (GCK) gene, along with hepatocyte nuclear factor 1A (HNF1A) gene mutations, are the most frequent cause of maturity-onset diabetes of the young (MODY). GCK-MODY patients are typically characterized by a moderate fasting hyperglycemia; however, little is known about atherosclerosis and intermediate-related phenotypes in these subjects. Design: To examine carotid artery intima-media thickness (IMT) and endothelial function assessed by brachial artery flow-mediated dilatation (FMD) in GCK gene mutations carriers and HNF1A-MODY. Methods: A total of 64 subjects with GCK gene mutations, and 52 HNF1A gene mutation carriers as well as 53 nondiabetic controls were examined. IMT and FMD were assessed by ultrasonography. Appropriate statistical tests were performed to assess differences between the groups, and multivariate linear regression was done for the association with IMT and FMD. Results: The clinical characteristics of all groups were similar with the mean age at examination of 35.1, 41.1, and 39.5 years for GCK, HNF1A and the control group respectively. The highest mean IMT value was in the HNF1A-MODY group: 7.0G1.4 mm, whereas it reached 6.3G1.4 mm in GCK mutation carriers and 6.3G1.3 mm in controls (PZ0.008). After adjustment for possible clinical and biochemical cofounders, IMT remained higher in HNF1A-MODY patients as compared with GCK-MODY patients (PZ0.02) and controls (PZ0.0003). FMD was significantly lower in HNF1A (9.9G4.6%) and GCK-MODY (11.1G4.6%) patients in comparison with controls (13.9G4.7%; PZ0.0001). After adjustment, FMD remained lower in HNF1A-MODY (PZ0.0005) and GCK-MODY patients (PZ0.01) as compared with controls. Conclusions: Both examined MODY groups demonstrated evidence of endothelial dysfunction. In addition, HNF1-MODY patients seem to be more prone to an early atherosclerotic phenotype.

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“…In patients with the type 3 form of maturity-onset diabetes of the young (MODY3) which results from mutations in the betacell transcription factor hepatocyte nuclear factor-1α, we described an impaired skin microvascular hyperaemic response with characteristics similar to those previously seen in patients with Type I diabetes [10]. Several groups have investigated the vascular effects of insertion/deletion (I/D) polymorphisms of the angiotensin I converting enzyme (ACE) gene with conflicting results.…”

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confidence: 86%

Association of the calpain-10 gene with microvascular function

et al. 2002

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Aims/hypothesis. Genotype could influence vascular function. In some populations, Calpain 10 gene polymorphisms increase susceptibility to diabetes or insulin resistance. Alterations in microvascular function could contribute to insulin resistance. This study investigated whether polymorphisms in the Calpain-10 gene influence microvascular function. Methods. Skin maximum microvascular hyperaemia to local heating on the dorsum of the foot (30 min at 43°C) was measured by Laser Doppler Fluximetry in 37 healthy volunteers. All were normoglycaemic according to World Health Organisation criteria, normotensive and not on any medication.Four polymorphisms in the calpain-10 gene were typed: SNP-44, SNP-43, SNP-19, SNP-63. The SNP common to all the described high risk haplotypes is the G-allele at SNP-43. This intron 3 polymorphism appears to influence gene expression. Microvascular function was examined in relation to polymorphisms at this site alone as well as the effects of the known extended high risk haplotypes using the SNP's above. Results. Maximum microvascular hyperaemia was increased in the 21 subjects with G/G genotypes at SNP-43 compared to the combined group of subjects (G/A genotype at SNP-43 (n=12) + A/A genotype at SNP-43 (n=4)), and the minimum microvascular resistance was reduced 49.4 (39.6-94.2) vs 67.5 (39.1-107.3) mmHg/V, p=0.007). Haplotype analysis of the hyperaemic response revealed no significant differences between haplotypes. The two groups did not differ in terms of anthropometric measures, blood pressure, insulin resistance or glucose. Conclusions/interpretation. The polymorphism that confers susceptibility to Type II (non-insulin-dependent) diabetes mellitus in some populations is associated in United Kingdom Caucasians with enhanced microvascular function in the presence of normoglycaemia. [Diabetologia (2002) 45:899-904]

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Impaired maximum microvascular hyperaemia in patients with MODY 3 (hepatocyte nuclear factor-1alpha gene mutations)

Cited by 10 publications

References 28 publications

Maximum Skin Hyperaemia Induced by Local Heating: Possible Mechanisms

Maximum Skin Hyperaemia Induced by Local Heating: Possible Mechanisms

Intima-media thickness and endothelial dysfunction in GCK and HNF1A-MODY patients

Association of the calpain-10 gene with microvascular function

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