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1.
J Clin Invest ; 101(1): 86-96, 1998 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-9421470

RESUMO

No studies are available that have compared early defects in glucose metabolism in the offspring of insulin-deficient and insulin-resistant probands with non-insulin-dependent diabetes mellitus (NIDDM). To investigate this issue, we evaluated insulin secretion capacity with oral and intravenous glucose tolerance tests and with the hyperglycemic clamp, and insulin action with the euglycemic insulin clamp in 20 offspring of NIDDM patients with low fasting C-peptide (+/-450 pmol/liter), reflecting deficient insulin secretion (IS-group), 18 offspring of NIDDM patients with high fasting C-peptide (>/= 880 pmol/liter), reflecting insulin resistance (IR-group), and 14 healthy control subjects without a family history of NIDDM. The frequency of impaired glucose tolerance was 45.0% in the IS-group and 50% in the IR-group. The IS-group had lower insulin-glucose response at 30 min in the oral glucose tolerance test (85.2+/-10.0 pmol insulin per mmol glucose) than the control group (136.4+/-23.1 pmol insulin per mmol glucose; P < 0.05) and the IR-group (115.6+/-11.8 pmol insulin per mmol glucose; P = 0.05). Furthermore, the acute insulin response during the first 10 min of an intravenous glucose tolerance test was lower in the IS-group than in the IR-group. Maximal insulin secretion capacity evaluated by C-peptide levels during the hyperglycemic clamp did not differ between the groups. The IR-group had lower rates of whole body glucose uptake (60.1+/-4.6 micromol per lean body mass per minute) than did the control group (84.2+/-5.0 micromol per lean body mass per minute; P < 0.001) or the IS-group (82.6+/-5.9 micromol per lean body mass per minute; P < 0.01) and this was due to reduced glucose nonoxidation. To conclude, both impaired insulin secretion and insulin action seem to be inherited and could represent the primary defects in glucose metabolism in the offspring of NIDDM probands.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina/fisiologia , Insulina/metabolismo , Tecido Adiposo/anatomia & histologia , Adulto , Idoso , Composição Corporal , Diabetes Mellitus Tipo 2/fisiopatologia , Metabolismo Energético , Ácidos Graxos não Esterificados/sangue , Feminino , Seguimentos , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Humanos , Secreção de Insulina , Ácido Láctico/sangue , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Oxirredução
2.
J Clin Invest ; 106(7): 897-906, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11018078

RESUMO

ATP-sensitive potassium channels play a major role in linking metabolic signals to the exocytosis of insulin in the pancreatic beta cell. These channels consist of two types of protein subunit: the sulfonylurea receptor SUR1 and the inward rectifying potassium channel Kir6.2. Mutations in the genes encoding these proteins are the most common cause of congenital hyperinsulinism (CHI). Since 1973, we have followed up 38 pediatric CHI patients in Finland. We reported previously that a loss-of-function mutation in SUR1 (V187D) is responsible for CHI of the most severe cases. We have now identified a missense mutation, E1506K, within the second nucleotide binding fold of SUR1, found heterozygous in seven related patients with CHI and in their mothers. All patients have a mild form of CHI that usually can be managed by long-term diazoxide treatment. This clinical finding is in agreement with the results of heterologous coexpression studies of recombinant Kir6.2 and SUR1 carrying the E1506K mutation. Mutant K(ATP) channels were insensitive to metabolic inhibition, but a partial response to diazoxide was retained. Five of the six mothers, two of whom suffered from hypoglycemia in infancy, have developed gestational or permanent diabetes. Linkage and haplotype analysis supported a dominant pattern of inheritance in a large pedigree. In conclusion, we describe the first dominantly inherited SUR1 mutation that causes CHI in early life and predisposes to later insulin deficiency.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Genes Dominantes , Hiperinsulinismo/congênito , Mutação de Sentido Incorreto , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/genética , Receptores de Droga/genética , Difosfato de Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Adolescente , Adulto , Sítios de Ligação , Glicemia/metabolismo , Criança , Pré-Escolar , Diazóxido/farmacologia , Diazóxido/uso terapêutico , Feminino , Finlândia , Humanos , Hiperinsulinismo/tratamento farmacológico , Masculino , Pâncreas/patologia , Linhagem , Polimorfismo Conformacional de Fita Simples , Canais de Potássio/efeitos dos fármacos , Receptores de Droga/efeitos dos fármacos , Receptores de Sulfonilureias , Tolbutamida/farmacologia
3.
Diabetes ; 48(6): 1295-9, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10342819

RESUMO

Sympathetic activation has been considered as a link between insulin resistance, hyperinsulinemia, and hypertension. However, little is known about the association between insulin sensitivity and autonomic regulation or about the effect of acute hyperinsulinemia on cardiac sympathovagal balance. The aim of this study was to investigate heart rate variability (HRV) during the euglycemic-hyperinsulinemic clamp in nondiabetic offspring of patients with type 2 diabetes. We studied 35 nondiabetic offspring of patients with type 2 diabetes and 19 control subjects. Probands were chosen from a 10-year follow-up study of patients with well-characterized type 2 diabetes according to their fasting C-peptide level (selected from both ends of the distribution) and from control subjects to form three groups: 1) a group including subjects who were offspring of type 2 diabetic patients with low C-peptide levels (deficient insulin secretion group [IS group], n = 17), 2) a group including subjects who were offspring of type 2 diabetic patients with high C-peptide levels (insulin-resistant group [IR group], n = 18), and 3) a control group without a history of type 2 diabetes in first-degree relatives (n = 19). HRV was assessed at baseline and at the steady state during the euglycemic-hyperinsulinemic clamp. Rates of whole-body glucose uptake (M value) were lower in the IR group than in the IS group and the control group (41+/-3 vs. 54+/-2 vs. 60+/-4 micromol x kg(-1) x min(-1), P < 0.01 and P < 0.01, respectively). In all groups, heart rate increased significantly during hyperinsulinemia. In the IR group, insulin infusion increased total power of HRV [from 7.70+/-0.15 to 8.05+/-0.15 ln(ms2), P < 0.01] and the low frequency-to-high frequency ratio (from 0.62+/-0.14 to 1.14+/-0.18, P < 0.01) and decreased power of the high frequency spectral component (from 5.73+/-0.17 to 5.43+/-0.16 ln(ms2), P < 0.05), whereas in other groups, changes in HRV were not significant. We conclude that the HRV response to acute hyperinsulinemia in the offspring of type 2 diabetic probands was likely to be modulated by the type 2 diabetic phenotype of the parent. In insulin-resistant subjects, autonomic dysfunction may be an earlier defect than hitherto acknowledged.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Diabetes Mellitus Tipo 2/genética , Frequência Cardíaca , Hiperinsulinismo/fisiopatologia , Resistência à Insulina , Adulto , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo/etiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fumar
4.
J Mol Med (Berl) ; 78(7): 372-9, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11043380

RESUMO

The endothelial nitric oxide synthase (eNOS) gene is responsible for constitutive nitric oxide synthesis and arterial vasodilatation. Recently two polymorphisms, the 27-bp repeat sequence in intron 4 and the Glu298Asp substitution in exon 7 of the eNOS gene have been reported to be related to coronary heart disease (CHD). We screened these polymorphisms of the eNOS gene in 308 unrelated nondiabetic subjects with CHD, in 251 unrelated patients with type 2 diabetes with CHD, and in 110 randomly selected healthy subjects without CHD. The 4a and Asp298 allele frequencies of the eNOS gene were 0.19 and 0.36 in nondiabetic patients with CHD, 0.21 and 0.27 in type 2 diabetic patients with CHD, and 0.16 and 0.31 in nondiabetic subjects without CHD (n.s. between the groups). The Asp298 allele in exon 7 of the eNOS gene was not associated with elevated blood pressure in any of the study groups. Among type 2 diabetic patients with CHD the 4a allele in intron 4 of the eNOS gene was associated with elevated levels of systolic (P=0.035) and mean arterial blood pressure (P=0.040). In nondiabetic subjects these associations were not statistically significant. When all study groups were pooled in statistical analysis the 4a allele of the eNOS gene was associated with elevated diastolic (P=0.032) and mean (P=0.030) arterial blood pressure even after adjustment for confounding factors. We conclude that the 4a allele of the eNOS gene is not associated with CHD or type 2 diabetes, but that it is related to elevated blood pressure levels particularly among type 2 diabetic patients with CHD.


Assuntos
Doença das Coronárias/complicações , Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Hipertensão/complicações , Hipertensão/genética , Óxido Nítrico Sintase/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Glicemia/análise , Pressão Sanguínea/genética , Éxons , Feminino , Genótipo , Técnica Clamp de Glucose , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Óxido Nítrico Sintase Tipo III , Reação em Cadeia da Polimerase , Fatores de Risco
5.
J Mol Med (Berl) ; 79(12): 732-7, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11862316

RESUMO

The relationship of two apolipoprotein (apo) E gene polymorphisms and coronary heart disease (CHD) was investigated in 118 Finnish families with premature CHD and in 110 healthy control subjects. Affected siblings and probands with premature CHD had higher frequencies of the T allele of the -219G/T promoter polymorphism and the epsilon 4 allele (genotypes epsilon 4/3 or epsilon 4/4) of the apo epsilon 2/epsilon 3/ epsilon 4 polymorphism than those of healthy control subjects. Additionally, when the two apo E gene polymorphisms were combined, affected siblings and probands had a higher frequency of the -219T allele and the epsilon 4 allele combinations than did healthy controls. The -219T and the epsilon 4 alleles both separately and together were associated with higher levels of 2-h glucose in an oral glucose tolerance test. These results indicate that the two polymorphisms of the apo E gene have similar effects on the risk of coronary atherosclerosis in families with premature CHD. This risk was not explained by the effect of apo E gene polymorphisms on cholesterol metabolism, but their effect on cardiovascular risk factor clustering with insulin resistance may be of importance. We conclude that in addition to the epsilon 4 allele, also the -219G/T promoter polymorphism of the apo E gene is associated with early onset CHD.


Assuntos
Apolipoproteínas E/genética , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Idade de Início , Idoso , Alelos , Doença das Coronárias/etiologia , Feminino , Finlândia/epidemiologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
6.
J Clin Endocrinol Metab ; 86(6): 2591-9, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11397859

RESUMO

The prevalence of polycystic ovaries (PCO) and clinical, endocrine, and metabolic features were investigated in women with previous gestational diabetes (GDM). Thirty-three women with a history of GDM and 48 controls were studied. Glucose and insulin secretion capacity was evaluated by means of the oral glucose tolerance test (OGTT), and insulin action was determined by means of a euglycemic insulin clamp. Compared with control women, women with previous GDM more often had significantly abnormal OGTT, a higher prevalence of PCO (39.4% vs. 16.7%; P = 0.03), higher serum concentrations of cortisol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate and a greater area under the glucose curve. Women with previous GDM showed a lowered early phase insulin response to glucose and impaired insulin sensitivity, which was accounted for mainly by decreased glucose nonoxidation. They also demonstrated a significantly lower fasting serum C peptide/insulin ratio than the controls, indicating that women with previous GDM have impaired hepatic insulin extraction, which tended to be more marked among women with PCO. This may explain why women with PCO and previous GDM were significantly more hyperinsulinemic than women with normal ovaries. In conclusion, our data demonstrate that women with previous GDM often have PCO and abnormal OGTT. They are insulin resistant as a result of lowered glucose nonoxidation and show inappropriately low insulin responses to glucose, reflecting impaired beta-cell function. They also have higher adrenal androgen secretion, which may be associated with abdominal obesity.


Assuntos
Diabetes Gestacional/complicações , Diabetes Gestacional/fisiopatologia , Hormônios/sangue , Síndrome do Ovário Policístico/complicações , Adulto , Diabetes Gestacional/dietoterapia , Diabetes Gestacional/tratamento farmacológico , Glândulas Endócrinas/fisiopatologia , Feminino , Intolerância à Glucose/etiologia , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Resistência à Insulina , Ácido Láctico/sangue , Prontuários Médicos , Síndrome do Ovário Policístico/epidemiologia , Gravidez , Prevalência
7.
J Clin Endocrinol Metab ; 85(9): 3161-8, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10999803

RESUMO

Metformin, a biguanide antihyperglycemic drug, has been shown to improve ovarian function and glucose metabolism in women with polycystic ovary syndrome (PCOS), but results concerning its effects on insulin sensitivity are controversial. Oral contraceptive pills are commonly used in the treatment of PCOS; but, like metformin, their influence on insulin sensitivity is not well known. We randomized 32 obese (body mass index > 27 kg/m2) women with PCOS, either to metformin (500 mg x 2 daily for 3 months, then 1,000 mg x 2 daily for 3 months) or to ethinyl estradiol (35 microg)-cyproterone acetate (2 mg) oral contraceptive pills (Diane Nova) for 6 months. Metformin significantly decreased the waist-to-hip ratio, serum testosterone, fasting free fatty acid, and insulin concentrations and improved oxidative glucose utilization and menstrual cyclicity, with slight (but nonsignificant) improvements in insulin hepatic extraction and insulin sensitivity. Diane Nova significantly decreased serum testosterone and increased serum sex hormone-binding globulin concentrations and glucose area under the curve during oral glucose tolerance test. It is concluded that metformin, probably by way of its effect on adipose tissue, leads to reduction of hyperinsulinemia and concomitant improvement in the menstrual pattern; and therefore, it offers a useful alternative treatment for obese, anovulatory women with PCOS. Despite slight worsening of glucose tolerance, Diane Nova is an efficient treatment for women with hyperandrogenism and hirsutism.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Acetato de Ciproterona/uso terapêutico , Congêneres do Estradiol/uso terapêutico , Etinilestradiol/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Obesidade/tratamento farmacológico , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Área Sob a Curva , Glicemia/metabolismo , Calorimetria , Gorduras/metabolismo , Feminino , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Hormônios/sangue , Humanos , Insulina/sangue , Resistência à Insulina/fisiologia , Obesidade/sangue , Obesidade/etiologia , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações
8.
Eur J Endocrinol ; 139(6): 598-604, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9916864

RESUMO

OBJECTIVE: To investigate whether there are differences in serum leptin levels between the offspring of non-insulin-dependent diabetes mellitus (NIDDM) patients representing different phenotypes of NIDDM, and furthermore to investigate the role of different fat tissue (subcutaneous fat area (SCFAT) and intra-abdominal fat area (IAFAT)) and insulin sensitivity on serum leptin levels. DESIGN: Twenty non-diabetic offspring of NIDDM patients with insulin secretion deficient phenotype (IS-group), 18 non-diabetic offspring of NIDDM patients with insulin resistant phenotype (IR-group) and 14 healthy control subjects without a family history of diabetes were studied. METHODS: Serum leptin levels were measured by RIA. SCFAT and IAFAT were measured by computed tomography. the total fat mass (TFM) by bioelectrical impedance and the whole body glucose uptake (WBGU) by the euglycemic hyperinsulinemic clamp technique. RESULTS: Subjects of the control group (P = 0.003) and the IS-group (P<0.001) had lower serum leptin levels than subjects of the IR-group even after adjustment for gender (P<0.001). TFM (P = 0.009), fasting plasma insulin (P = 0.003) and for IAFAT (P<0.001). The differences weakened after adjustments for SCFAT (P = 0.028) or WBGU (P = 0.040) and disappeared after adjustment for both SCFAT and WBGU (P = 0.058). In the stepwise multiple regression analyses SCFAT. WBGU and gender explained 58% of the variation of serum leptin levels whereas IAFAT failed to be a significant determinant of serum leptin levels. CONCLUSIONS: The higher serum leptin levels in the IR-group was markedly, but not solely, explained by lower rates of WBGU and higher SCFAT. SCFAT was shown to be a more important determinant of serum leptin levels than IAFAT among these study groups.


Assuntos
Diabetes Mellitus Tipo 2/genética , Saúde da Família , Resistência à Insulina/genética , Obesidade/sangue , Proteínas/metabolismo , Tecido Adiposo/fisiologia , Adulto , Idoso , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Feminino , Técnica Clamp de Glucose , Humanos , Insulina/metabolismo , Secreção de Insulina , Leptina , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fenótipo
9.
Eur J Endocrinol ; 150(5): 705-14, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15132728

RESUMO

OBJECTIVE AND METHODS: To study the effects of hormone replacement therapy on glucose metabolism, 31 obese (body mass index > or =27 kg/m(2)) postmenopausal women were randomized to treatment with tibolone (2.5 mg once daily; TIB; n=16) or to oestradiol valerate (2 mg daily)-dydrogesterone (20 mg daily for 2 weeks every 3 months; ED; n=15) for 12 months. Oral (OGTTs) and intravenous glucose tolerance tests (IVGTTs) and a euglycaemic hyperinsulinaemic clamp were performed before and at 6 and 12 months of treatment. RESULTS: TIB decreased the rates of whole body glucose uptake (WBGU) at 6 (P=0.04) and 12 months (P<0.001), but it did not have a significant effect on glucose tolerance. In OGTTs, serum insulin and C-peptide concentrations 2 h after the oral glucose load were increased (P<0.001 and P=0.05 respectively) at 12 months of treatment with TIB, but no changes in the areas under the curve (AUC) of insulin or C-peptide were observed. Furthermore, TIB did not have a significant effect on insulin secretion, the metabolic clearance rate (MCR) of insulin or hepatic insulin extraction. Treatment with ED did not modify the rates of WBGU, but it increased the MCR of insulin (P=0.017) and hepatic insulin extraction (P<0.001) and tended to decrease the insulin AUC (P=0.07). Moreover, glucose tolerance slightly deteriorated during this treatment (P=0.02). Although early phase insulin secretion evaluated by the serum C-peptide response at 30 min in the OGTT increased (P=0.046), the first-phase insulin response during the IVGTT decreased (P=0.05) during ED treatment. CONCLUSIONS: Despite the impairment in peripheral insulin sensitivity, TIB treatment had a neutral effect on glucose tolerance, possibly due to a compensatory decrease in endogenous glucose production. The increased demand on insulin induced by ED, due to both a stimulatory effect on pancreatic beta cells and increased insulin metabolism, may explain the slightly detrimental effect on glucose tolerance with this treatment.


Assuntos
Moduladores de Receptor Estrogênico/uso terapêutico , Terapia de Reposição de Estrogênios , Glucose/metabolismo , Norpregnenos/uso terapêutico , Obesidade/metabolismo , Pós-Menopausa , Área Sob a Curva , Glicemia/análise , Quimioterapia Combinada , Didrogesterona/uso terapêutico , Estradiol/uso terapêutico , Ácidos Graxos não Esterificados/sangue , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Secreção de Insulina , Modelos Lineares , Metabolismo dos Lipídeos , Pessoa de Meia-Idade , Oxirredução
10.
Eur J Endocrinol ; 143(2): 251-60, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10913945

RESUMO

OBJECTIVE: The purpose of this work was to study whether there are differences in plasma proinsulin levels and proinsulin-to-specific insulin ratio in the offspring of patients with different phenotypes of type II diabetes. DESIGN: Eleven glucose-tolerant offspring of type II diabetic patients with deficient insulin secretion phenotype (IS group), nine glucose-tolerant offspring of patients with insulin-resistant phenotype (IR group), and fourteen healthy control subjects without a family history of diabetes were studied. METHODS: Plasma specific insulin, plasma proinsulin, and plasma C-peptide levels were measured during a 2-h oral glucose tolerance test and during hyperglycemic clamp. RESULTS: Plasma proinsulin levels during the oral glucose tolerance test and the hyperglycemic clamp did not differ among the study groups. The IR group had a lower fasting plasma proinsulin-to-specific insulin ratio (10.3+/-1.7%) than the control group (15.4+/-1.4%; P<0.05) and the IS group (18.6+/-2.7%; P<0.05). Furthermore, the IR group had lower plasma proinsulin-to-specific insulin ratio at 30, 60 and 90 min after the oral glucose load than the IS group. However, there were no significant differences in proinsulin-to-C-peptide ratio during the oral glucose tolerance test among the study groups. In stepwise multiple regression analysis, hepatic specific insulin extraction in the fasting state (beta =0.65; P<0.001) and fasting blood glucose (beta =0.32; P<0.05) together explained 52% of the variation in fasting plasma proinsulin-to-specific insulin ratio. CONCLUSIONS: Hyperproinsulinemia is not a characteristic finding in glucose-tolerant offspring of type II diabetic probands with deficient insulin secretion or insulin-resistant phenotype. The differences in proinsulin-to-specific insulin ratios were most likely explained by different hepatic extraction among the study groups.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Fenótipo , Proinsulina/sangue , Adulto , Glicemia/análise , Peptídeo C/sangue , Jejum , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Cinética , Modelos Lineares , Pessoa de Meia-Idade , Análise de Regressão
11.
Diabetologia ; 49(7): 1560-6, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16752174

RESUMO

AIMS/HYPOTHESIS: The mechanisms by which the calpain-10 gene (CAPN10) affects the risk of type 2 diabetes are unclear. Therefore, we investigated the effects of four polymorphisms in CAPN10 (single nucleotide polymorphism [SNP]-43, SNP-44, Insertion/Deletion [Indel]-19 and SNP-63) on insulin secretion, insulin action and abdominal fat distribution in offspring of patients with type 2 diabetes. SUBJECTS AND METHODS: Insulin secretion was determined by an IVGTT, insulin action by the hyperinsulinaemic-euglycaemic clamp and abdominal fat distribution by computed tomography in 158 non-diabetic offspring (age 34.9+/-6.3 years [mean+/-SD], BMI 26.2+/-4.9 kg/m(2)) of type 2 diabetic patients. RESULTS: SNP-43 (p=0.009 over the three genotypes, adjusted for age, sex, BMI and family relationship) and haplotypes carrying the A allele of SNP-43 were associated with intra-abdominal fat area. The A allele of SNP-43 was associated with intra-abdominal fat area in men (p=0.014) but not in women. SNP-44, InDel-19 and SNP-63 were not associated with intra-abdominal fat area or insulin action. Furthermore, we demonstrated in a separate sample of middle-aged men (n=234) who had a history of type 2 diabetes in first-degree relatives that the A allele of SNP-43 was associated with a large waist circumference, and high insulin levels in an OGTT. CONCLUSIONS/INTERPRETATION: SNP-43 of CAPN10 may contribute to the risk of diabetes by regulating abdominal obesity in subjects with high risk of type 2 diabetes.


Assuntos
Gordura Abdominal , Calpaína/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Feminino , Finlândia , Teste de Tolerância a Glucose , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Risco
12.
Diabetologia ; 48(7): 1331-4, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15912394

RESUMO

AIMS/HYPOTHESIS: Decreased expression of the peroxisomal proliferator activated receptor gamma coactivator 1 alpha gene (PPARGC1A) is found in patients with type 2 diabetes, and variants in this gene have been linked with type 2 diabetes. Therefore, we investigated the effects of single nucleotide polymorphisms in PPARGC1A on body composition and glucose tolerance and on insulin sensitivity and secretion. METHODS: Non-diabetic offspring (n=156, age 34.9+/-0.5 years [mean+/-SEM], BMI 26.2+/-0.4 kg/m2) underwent an OGTT and an IVGTT and the hyperinsulinaemic-euglycaemic clamp. The promoter and coding regions of PPARGC1A were sequenced. RESULTS: Two haplotype blocks in PPARGC1A were observed, one in the promoter region (G-1774A, A-1679G, T-1422C, A-1278G, C-543A) and one in the coding region and 3' regions (Thr394Thr, Asp475Asp, Gly482Ser, Thr528Thr, Thr612Met, G+2381A). The coding region haplotype carrying the rare allele in codons 482 and 528 was associated with elevated glucose levels in an OGTT (p=0.024, adjusted for age, sex and BMI) and a haplotype carrying the rare alleles in codons 394 and 475 was associated with low BMI (p=0.033), high rates of whole-body glucose uptake (p=0.045) and low glucose levels in the OGTT (p=0.037). CONCLUSIONS/INTERPRETATION: We conclude that PPARGC1A is likely to contribute to the risk of diabetes in offspring of patients with type 2 diabetes.


Assuntos
Glicemia/genética , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Proteínas de Choque Térmico/genética , Fatores de Transcrição/genética , Índice de Massa Corporal , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Teste de Tolerância a Glucose , Humanos , Desequilíbrio de Ligação , Masculino , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Regiões Promotoras Genéticas
13.
Int J Obes (Lond) ; 29(12): 1464-70, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16044174

RESUMO

OBJECTIVE: To investigate the relative contribution of total body fat mass (TFM) and intra-abdominal fat mass (IAFM) to metabolic consequences of obesity in offspring of type 2 diabetic parents. DESIGN: Cross-sectional study of 129 nondiabetic offspring of diabetic parents (59 men, 70 women, age 35.7 +/- 6.3 y, body mass index 26.2 +/- 4.6 kg/m2). Study subjects were grouped according to TFM (assessed with bioelectrical impedance) and IAFM (assessed with CT). Insulin sensitivity was assessed with the euglycemic hyperinsulinemic clamp, insulin secretion with the intravenous glucose tolerance test and energy expenditure with indirect calorimetry. Furthermore, C-reactive protein (CRP) and adiponectin levels were measured. RESULTS: Insulin resistance, low rates of oxidative and nonoxidative glucose disposal, high rates of lipid oxidation and reduced energy expenditure during hyperinsulinemia were associated with high IAFM, independently of TFM. Adiponectin level was reduced and CRP level increased in subjects with high IAFM. CONCLUSIONS: The metabolic changes relating to obesity are largely attributable to high IAFM, and are present even in normal weight subjects with high IAFM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Adiponectina/sangue , Adulto , Glicemia/metabolismo , Distribuição da Gordura Corporal , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/genética , Metabolismo Energético , Feminino , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina/fisiologia , Masculino , Obesidade/genética , Linhagem
14.
Hum Reprod ; 15(6): 1266-74, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10831553

RESUMO

To study the contributions of body mass, body fat distribution and family history of type 2 diabetes mellitus to hyperinsulinaemia, insulin secretion and resistance in polycystic ovarian syndrome (PCOS), 17 lean (LC) and 17 obese (OC) healthy control subjects, and 15 lean (LPCOS) and 28 obese (OPCOS) women with PCOS were investigated. Waist:hip ratio (WHR), serum concentrations of sex steroids, glucose and insulin during a 75 g oral glucose tolerance test (OGTT), and insulin and C-peptide early phase secretion, and insulin sensitivity index using a euglycaemic hyperinsulinaemic clamp were assessed. The PCOS subjects had a higher mean WHR than the controls. A trend towards hyperinsulinaemia and impairment of insulin sensitivity (including the rates of both glucose oxidation and non-oxidation) was observed in LPCOS subjects, but only in OPCOS subjects were these changes significant. Early phase insulin secretion but not the early phase C-peptide secretion was increased in PCOS subjects compared to controls, suggesting that peripheral hyperinsulinaemia in PCOS women was mainly due to the observed lowered hepatic insulin extraction and insulin resistance in skeletal muscle. Moreover, the presence of a family history of type 2 diabetes did not affect early phase insulin or C-peptide secretion in the PCOS group. These results confirm and strengthen earlier contentions, that insulin resistance is a characteristic defect in PCOS and is worsened particularly by abdominal obesity.


Assuntos
Hormônios/metabolismo , Resistência à Insulina , Insulina/metabolismo , Síndrome do Ovário Policístico/fisiopatologia , Adulto , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/genética , Glândulas Endócrinas/metabolismo , Ácidos Graxos não Esterificados/sangue , Feminino , Glucose/metabolismo , Glucose/fisiologia , Humanos , Secreção de Insulina , Metabolismo dos Lipídeos , Prontuários Médicos , Obesidade/complicações , Oxirredução , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/metabolismo , Valores de Referência
15.
Eur J Clin Invest ; 31(4): 302-8, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11298776

RESUMO

BACKGROUND: Insulin resistance in the most common familial dyslipidemia, familial combined hyperlipidemia (FCHL), could be due to variations in the hormone sensitive lipase (HSL) gene. MATERIALS AND METHODS: The coding region of the HSL gene was screened with the single strand conformation polymorphism analysis in probands of 27 FCHL families with 228 members. In addition, the C-60G promoter substitution of the HSL gene was determined by the restriction fragment length polymorphism analysis in these subjects. RESULTS: No variants in the coding region of the HSL gene were found and the allele frequencies of the C-60G promoter substitution and the silent variant (G3138A) in the 3' untranslated region did not differ between 110 control subjects and 27 probands with FCHL. However, in control women the C-60G substitution was associated with high body mass index [30.6 +/- 0.9 kg m(-2) (mean +/- SD) in subjects with the C/G genotype and 24.8 +/- 4.6 in subjects with the C/C genotype, P = 0.012], and in control men with high rates of insulin-stimulated whole body glucose uptake (70.1 +/- 14.7 vs. 56.7 +/- 14.2 micromol kg(-1) min(-1), P = 0.014). In 228 FCHL family members this substitution was associated with high low-density lipoprotein cholesterol levels in men (4.51 +/- 1.12 vs. 5.17 +/- 1.28 mmol L(-1), P = 0.049), but not in women. CONCLUSIONS: The HSL gene is not a major gene for FCHL. However, the - 60G allele of this gene may affect body weight, insulin sensitivity and serum cholesterol levels.


Assuntos
Hiperlipidemia Familiar Combinada/genética , Resistência à Insulina/genética , Esterol Esterase/genética , Adulto , Alelos , Feminino , Testes Genéticos , Técnica Clamp de Glucose , Humanos , Hiperlipidemia Familiar Combinada/enzimologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Regiões Promotoras Genéticas/genética
16.
Arterioscler Thromb Vasc Biol ; 20(1): 164-70, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10634813

RESUMO

Insulin resistance has been associated with hypertriglyceridemia, combined hyperlipidemia, and familial combined hyperlipidemia (FCHL). Whether all FCHL patients with different types of dyslipidemia have low insulin sensitivity has not been evaluated. We measured insulin sensitivity by the hyperinsulinemic euglycemic clamp with indirect calorimetry in 110 healthy controls and in 105 nondiabetic, FCHL family members: in 50 without dyslipidemia, in 19 with hypercholesterolemia (total cholesterol >/=7.7 mmol/L), in 22 with hypertriglyceridemia (total triglycerides >/=2.4 mmol/L in men 2.4 mmol/L in women), and in 14 with combined hyperlipidemia. During the hyperinsulinemic clamp, FCHL family members had higher free fatty acid levels than did controls (0.06+/-0.06 [mean+/-SD] in controls versus 0.16+/-0.11 in relatives without dyslipidemia versus 0.15+/-0. 07 in hypercholesterolemic patients versus 0.29+/-0.14 in hypertriglyceridemic patients versus 0.27+/-0.17 mmol/L in patients with combined hyperlipidemia; P<0.001 after adjustment for age, sex, and body mass index). Relatives without dyslipidemia (16.4+/-4.4 micromol. kg(-1). min(-1), P=0.001) and patients with hypertriglyceridemia (12.8+/-3.8 micromol. kg(-1). min(-1), P<0.001) and with combined hyperlipidemia (13.7+/-3.1 micromol. kg(-1). min(-1), P<0.001) had lower rates of insulin-stimulated glucose oxidation than did controls (19.4+/-4.7 micromol. kg(-1). min(-1)). Also, the rates of nonoxidative glucose disposal were lower in patients with hypertriglyceridemia (P=0.001) and combined hyperlipidemia (P=0.011) than in controls. In contrast, subjects with hypercholesterolemia and control subjects had similar rates of insulin-stimulated glucose uptake. We conclude that a defect in free fatty acid suppression during hyperinsulinemia, probably located in adipose tissue, is characteristic for all FCHL patients with varying types of dyslipidemia, whereas insulin resistance in skeletal muscle is observed only in FCHL patients with elevated triglyceride levels.


Assuntos
Ácidos Graxos não Esterificados/sangue , Hiperlipidemia Familiar Combinada/sangue , Hipertrigliceridemia/sangue , Resistência à Insulina/fisiologia , Insulina/sangue , Adulto , Glicemia/metabolismo , Estudos de Casos e Controles , Feminino , Técnica Clamp de Glucose , Humanos , Lipídeos/sangue , Lipoproteínas/sangue , Masculino , Oxirredução
17.
J Mol Cell Cardiol ; 31(11): 2031-6, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10591029

RESUMO

Defects in seven genes encoding sarcomere proteins have been shown to cause hypertrophic cardiomyopathy. To date, only one study reporting defects in the cardiac troponin I gene associated with hypertrophic cardiomyopathy has been published, and the proportion of hypertrophic cardiomyopathy cases caused by defects in this gene is unknown. Therefore, the authors screened 37 unrelated Finnish patients with hypertrophic cardiomyopathy for variants in the cardiac troponin I gene. Exons 1-8 of the troponin I gene were screened with the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method. Five different variants (four intron variants and one silent exon variant) were found. Most variants were also present in control samples and none of the variants co-segregated with the disease in families. The results of the present study indicate that defects in the cardiac troponin I gene do not cause hypertrophic cardiomyopathy in patients from Eastern Finland.


Assuntos
Cardiomiopatia Hipertrófica/genética , Variação Genética , Miocárdio/metabolismo , Troponina I/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Ecocardiografia , Éxons , Família , Feminino , Finlândia , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples
18.
Diabetologia ; 43(1): 69-78, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10663218

RESUMO

AIMS/HYPOTHESIS: This study was undertaken to investigate metabolic and genetic characteristics of latent autoimmune diabetes in adults (LADA). METHODS: We evaluated insulin secretory capacity with oral and intravenous glucose tolerance tests (early insulin response) and hyperglycaemic clamp (insulin secretory capacity) and the rates of whole body glucose uptake with the euglycaemic clamp, HLA-DQB1 genotypes (time-resolved fluorescence) and islet cell antibodies (ICA) (immunofluorescence) and antibodies to glutamic acid decarboxylase (GAD) (radio-immunoprecipitation) in 36 non-diabetic offspring (LADA-offspring) of patients with Type II (non-insulin-dependent) diabetes mellitus who tested positive for ICA and/or GAD antibodies during the 10-year follow-up from the diagnosis and in 19 healthy control subjects without a family history of diabetes. RESULTS: The early insulin response during the first 10 min of an intravenous glucose tolerance test was about 40% lower in the LADA-offspring than in the control group (p = 0.008). Insulin secretory capacity in the hyperglycaemic clamp was also about 30% lower in the LADA-offspring (p = 0.048). The rates of whole body glucose uptake were similar in both groups. The frequency of low risk HLA-DQB1 genotypes was higher in the LADA-offspring than among Finnish healthy blood donors (p = 0.033). The risk conferring genotypes were associated with the lowest tertile of insulin secretory capacity in the LADA-offspring (p = 0.032). There were no associations between the autoantibodies and early insulin response or insulin secretory capacity within the study groups. CONCLUSION/INTERPRETATION: We conclude that LADA is a familial disease involving most likely gene defects leading to a slow progressive beta-cell destruction and insulin deficiency.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/genética , Insulina/metabolismo , Tecido Adiposo/anatomia & histologia , Adulto , Autoanticorpos/sangue , Glicemia/metabolismo , Constituição Corporal , Peptídeo C/sangue , Calorimetria Indireta , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/fisiopatologia , Metabolismo Energético , Ácidos Graxos não Esterificados/sangue , Feminino , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Glutamato Descarboxilase/imunologia , Humanos , Insulina/sangue , Secreção de Insulina , Ilhotas Pancreáticas/imunologia , Estudos Longitudinais , Masculino , Núcleo Familiar
19.
Diabet Med ; 14(9): 748-56, 1997 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9300224

RESUMO

We analysed a well-characterized group of 83 patients (43 men, 40 women; mean age +/- SEM: 65.5 +/- 0.6 years at the 10-year examination) with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and in 123 control subjects (56 men, 67 women; mean age +/- 0.9 years) retrospectively for the relationship of apolipoprotein E (apo E) genotypes (E2/3, E3/3 vs E3/4, E4/4) to the incidence of clinical macrovascular disease and its risk factors and the incidence of microvascular complications of diabetes during the first 10 years of NIDDM, as well as carotid intima-media thickness measured by B-mode ultrasound at the 10-year examination. In patients with NIDDM, apo E4 genotype showed no relationship to clinical events or carotid intima-media thickness. However, in the control subjects with apo E4, the incidence of non-fatal myocardial infarction during the follow-up was increased (apo E4 positivity: 17.1%; apo E4 negativity 5.1%; p = 0.035) and they had higher common carotid intima-media thickness than those with apo E2/3 or apo E3/3 (1.15 +/- 0.05 mm vs 1.01 +/- 0.03 mm, p = 0.008). Apo E genotype groups showed no relationship to microvascular complications of diabetes, although control subjects with apo E4 positivity showed a higher frequency of microalbuminuria than those lacking apo E4. We conclude that apo E4 was a marker of vascular disease and increased atherosclerosis in non-diabetic subjects, whereas in the diabetic patients these relationships were absent. It is likely that NIDDM per se influences the vascular risk so overwhelmingly that the effects of other risk factors are obscured.


Assuntos
Apolipoproteínas E/genética , Arteriosclerose/epidemiologia , Transtornos Cerebrovasculares/epidemiologia , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/epidemiologia , Infarto do Miocárdio/epidemiologia , Polimorfismo Genético , Alelos , Arteriosclerose/genética , Arteriosclerose/patologia , Artéria Carótida Primitiva/diagnóstico por imagem , Artéria Carótida Primitiva/patologia , Transtornos Cerebrovasculares/genética , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/patologia , Feminino , Seguimentos , Frequência do Gene , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Estudos Retrospectivos , Fatores de Risco , Ultrassonografia
20.
Arterioscler Thromb Vasc Biol ; 20(7): 1789-95, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10894818

RESUMO

Low activity of hepatic lipase (HL) has been associated with high levels of triglycerides and high density lipoproteins, but the association of the HL promoter variants with insulin sensitivity has not been investigated. Therefore, in this study, the relationship of the G-250A promoter variant of the HL gene to the rates of insulin-stimulated glucose uptake measured by the hyperinsulinemic euglycemic clamp was investigated in 110 control subjects (82 men and 28 women, aged 50.7+/-7.6 [mean+/-SD] years, body mass index 26. 1+/-3.6 kg/m(2)) and in 105 first-degree relatives (65 men and 40 women, aged 47.8+/-16.0 years, body mass index 26.9+/-5.3 kg/m(2)) of 34 families with familial combined hyperlipidemia (FCHL). The A-250 allele of the HL promoter was associated with low rates of insulin-stimulated whole-body nonoxidative glucose disposal in control subjects (41.1+/-12.7 micromol. kg(-1). min(-1) in subjects with the G-250G genotype, 36.9+/-13.1 micromol. kg(-1). min(-1) in subjects with the G-250A genotype, and 29.9+/-13.5 micromol. kg(-1). min(-1) in subjects with the A-250A genotype; P=0.012 adjusted for age and sex) and with low rates of insulin-stimulated whole-body glucose oxidation in FCHL family members (16.7+/-4.2 versus 15.0+/-4. 4 versus 14.1+/-4.4 micromol. kg(-1). min(-1), P=0.024). In addition, the A-250 allele was associated with high levels of fasting insulin (P=0.047), very low density lipoprotein cholesterol (P=0.007), and total (P=0.009) and very low density lipoprotein (P=0.005) triglycerides in control subjects and with high levels of low density lipoprotein triglycerides (P=0.001) in FCHL family members (n=340). We conclude that the G-250A promoter variant of the HL gene is associated with dyslipidemia and insulin resistance. Mechanisms via which this polymorphism could affect insulin sensitivity remain to be elucidated.


Assuntos
Substituição de Aminoácidos , Hiperlipidemia Familiar Combinada/genética , Resistência à Insulina/genética , Lipase/genética , Regiões Promotoras Genéticas/genética , Adulto , Calorimetria Indireta , Jejum/fisiologia , Feminino , Técnica Clamp de Glucose , Humanos , Hiperlipidemia Familiar Combinada/enzimologia , Hipertrigliceridemia/enzimologia , Hipertrigliceridemia/genética , Insulina/sangue , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
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