Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The association of the Pro12Ala polymorphism of the PPAR-gamma2 gene with the incidence of type 2 diabetes was investigated in 522 subjects with impaired glucose tolerance (IGT) participating in the Finnish Diabetes Prevention Study. Subjects were randomized to either an intensive diet and exercise group or a control group. By 3 years of intervention, the odds ratio of the development of type 2 diabetes for subjects with the Ala12 allele was 2.11-fold compared with that for subjects with the Pro12Pro genotype (95% CI 1.20-3.72). The risk for type 2 diabetes increased also in subjects who gained weight or belonged to the control group. In the intervention group, subjects with the Ala12Ala genotype lost more weight during the follow-up than subjects with other genotypes (Pro12Pro vs. Ala12Ala P = 0.043), and none of subjects with the Ala12Ala genotype developed type 2 diabetes in this group. In conclusion, the Ala12 allele may predispose to the development of type 2 diabetes in obese subjects with IGT. However, beneficial changes in diet, increases in physical activity, and weight loss may reverse, to some extent, the diabetogenic impact of the Ala12 allele, possibly due to an improved insulin sensitivity.
Diabetes 2002 Aug
PMID:Association of the Pro12Ala polymorphism in the PPAR-gamma2 gene with 3-year incidence of type 2 diabetes and body weight change in the Finnish Diabetes Prevention Study. 1214 74

The Pro12Ala polymorphism of the gene encoding the peroxisome proliferator-activated receptor (PPAR)-gamma2 has recently been shown to be associated with type 2 diabetes. In the present analysis, we investigated whether PPAR-gamma2 Pro12Ala was associated with microvascular complications of type 2 diabetes, such as albuminuria, end-stage renal failure (ESRF), or retinopathy. A total of 445 patients with type 2 diabetes who were enrolled in the Berlin Diabetes Mellitus Study and in whom we determined albuminuria and the presence of ESRF and retinopathy were genotyped for the PPAR-gamma2 Pro12Ala polymorphism. We also measured potentially important covariables, such as blood pressure, BMI, duration of diabetes, glycosylated hemoglobin, serum creatinine, and serum lipids. Among 445 patients with type 2 diabetes (mean age 59.3 years), the Pro12Ala genotype distribution was in Hardy-Weinberg equilibrium (P = 0.42). The Ala12 allele frequency was 0.14. With adjustment for covariables, the 118 Ala12 allele carriers had significantly lower urinary albumin excretion (UAE) than the 327 noncarriers (17.1 vs. 25.8 mg/d; P = 0.01). The percentage decrease in UAE observed in PPAR-gamma Ala12 allele carriers relative to noncarriers (P = 0.003) rose from 0.2% (P = 0.99) to 54% (P = 0.008) and to 70% (P = 0.01) when the duration of diabetes increased from <10 years to 10-19 years and to >or=20 years, respectively. Similarly, the odds ratios of having albuminuria decreased from 1.22 (P = 0.54) to 0.61 (P = 0.23) and to 0.11 (P = 0.007), respectively. Among patients with type 2 diabetes, PPAR-gamma2 Ala12 allele carriers had significantly lower UAE and tended to develop overt proteinuria less frequently. These observations suggest a protective effect of the Ala12 allele in relation to diabetic nephropathy.
Diabetes 2002 Aug
PMID:Peroxisome proliferator-activated receptor-gamma2 polymorphism Pro12Ala is associated with nephropathy in type 2 diabetes: The Berlin Diabetes Mellitus (BeDiaM) Study. 1214 84

The peroxisome-proliferator-activated receptor gamma2 (PPAR gamma2) is a transcriptional key regulator of adipocyte differentiation. PPAR gamma2 can be inactivated by phosphorylation of a serine residue at position 114. A point mutation leading to an amino acid exchange at position 115 (Pro115Gln) was shown to preclude serine phosphorylation and to consecutively accelerate adipocyte differentiation emphasizing the pathophysiological relevance of this mutation. So far, four markedly obese heterozygote carriers of the Pro115Gln mutation (body mass index 37.9-47.3 kgxm (-2)) have been identified in a circumscribed study population. In order to evaluate the epidemiological relevance of the Pro115Gln mutation in morbid obesity we screened the DNA of all subjects with a body mass index greater than 35 kgxm (-2) who had participated in a nationwide German epidemiological field survey. There was no homozygote or heterozygote carrier of the Pro115Gln polymorphism among them. We conclude that the Pro115Gln polymorphism within the PPAR gamma2 gene has no relevant epidemiological impact on morbid obesity in Germany. It needs further investigation whether this polymorphism might play a role in related metabolic disorders.
Exp Clin Endocrinol Diabetes 2002 Aug
PMID:The Pro115Gln polymorphism within the PPAR gamma2 gene has no epidemiological impact on morbid obesity. 1214 87

It has been suggested that the insulin resistance (IR) associated with reduced fetal growth results from interactions between genetic factors and an unfavorable fetal environment. In addition, the adipose tissue seems to play a key role in this association. We investigated whether polymorphisms in tumor necrosis factor (TNF)-alpha(G-308A), beta3 adrenoreceptor (ADRB3)(G+250C), and peroxisome proliferator-activated receptor (PPAR)-gamma2(Pro12Ala), key molecules of the adipose tissue, might affect the IR associated with reduced fetal growth. They were genotyped in 171 subjects who were born small for gestational age (SGA) and in 233 subjects who were born appropriate for gestational age (AGA) and underwent an oral glucose tolerance test (OGTT). The SGA group showed higher serum insulin concentrations than the AGA group at fasting (P = 0.03) and after stimulation (P = 0.0007), whereas no difference in serum glucose concentrations was observed. The frequencies of the alleles of these three polymorphisms were similar in both groups. In neither group did the polymorphisms affect glucose tolerance. In the SGA group, fasting insulin-to-glucose ratios were significantly higher in the TNF/-308A (P = 0.03), the PPAR/Ala12 (P = 0.01), and the ADRB3/+250G (P = 0.02) carriers than in the noncarriers. Results were comparable for fasting insulin concentration and insulin excursion under OGTT. No such amplification was observed in the AGA group. The effects of the PPAR/ProAla12 (P = 0.005) and the ADRB3/G+250G (P = 0.009) gene polymorphisms on IR indexes were significantly potentiated by BMI in the SGA group. In conclusion, our data exemplify the interaction between intrauterine environmental and genetic factors in the development of the IR associated with reduced fetal growth. They also point to the key role of adipose tissue in this association.
Diabetes 2002 Dec
PMID:Combined effects of genetic and environmental factors on insulin resistance associated with reduced fetal growth. 1245 2

The peroxisome proliferator-activated receptor (PPAR)-gamma2 gene polymorphism Pro12Ala has been associated with increased insulin sensitivity in some but not all studies. Little is known about its effect on the tracking of insulin resistance status over time. These aspects were examined in a community-based sample of 686 white young adults, aged 20-38 years, and 426 white children, aged 4-17 years, and a subsample of a cohort (n = 362) who participated both as children and adults, with an average follow-up period of 13.4 years. Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR) using fasting insulin and glucose. The frequency of the variant Ala12 allele was 0.104 in whites vs. 0.017 in blacks. After adjusting for sex, age, and BMI, adult subjects with the genotype Pro/Pro, Pro/Ala, and Ala/Ala, respectively, showed significant decreasing trends in fasting insulin (11.7, 10.3, and 8.8 micro U/ml; P = 0.002) and HOMA-IR (2.4, 2.1, and 1.7; P = 0.006). Similar but nonsignificant trends were noted in childhood. A significant genotype-BMI interaction effect on insulin (P = 0.020), glucose (P = 0.007), and HOMA-IR (P = 0.001) was found in adulthood, with carriers versus noncarriers showing attenuated association with BMI. The genotype-BMI interaction effect on these variables tended to be similar in childhood. With respect to tracking over time, of individuals in the top age- and sex-specific quartile of HOMA-IR in childhood, 48.7% (38/78) of noncarriers vs. 16.7% (2/12) of the carriers (P = 0.035) remained in the same quartile in adulthood. A similar trend was observed for insulin (2/13 vs. 35/77, P = 0.037). In conclusion, the Pro12Ala polymorphism of the PPAR-gamma2 gene beneficially influences insulin resistance and its tracking from childhood to adulthood. Further, the Ala12 allele attenuates the adverse association between adiposity and insulin resistance measures.
Diabetes 2003 May
PMID:The peroxisome proliferator-activated receptor-gamma2 gene polymorphism (Pro12Ala) beneficially influences insulin resistance and its tracking from childhood to adulthood: the Bogalusa Heart Study. 1271 62

AMP-activated protein kinase (AMPK) is a multisubstrate enzyme activated by increases in AMP during metabolic stress caused by exercise, hypoxia, lack of cell nutrients, as well as hormones, including adiponectin and leptin. Furthermore, metformin and rosiglitazone, frontline drugs used for the treatment of type II diabetes, activate AMPK. Mammalian AMPK is an alphabetagamma heterotrimer with multiple isoforms of each subunit comprising alpha1, alpha2, beta1, beta2, gamma1, gamma2, and gamma3, which have varying tissue and subcellular expression. Mutations in the AMPK gamma subunit cause glycogen storage disease in humans, but the molecular relationship between glycogen and the AMPK/Snf1p kinase subfamily has not been apparent. We show that the AMPK beta subunit contains a functional glycogen binding domain (beta-GBD) that is most closely related to isoamylase domains found in glycogen and starch branching enzymes. Mutation of key glycogen binding residues, predicted by molecular modeling, completely abolished beta-GBD binding to glycogen. AMPK binds to glycogen but retains full activity. Overexpressed AMPK beta1 localized to specific mammalian subcellular structures that corresponded with the expression pattern of glycogen phosphorylase. Glycogen binding provides an architectural link between AMPK and a major cellular energy store and juxtaposes AMPK to glycogen bound phosphatases.
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PMID:AMPK beta subunit targets metabolic stress sensing to glycogen. 1274 37

Recent research suggests that the Pro12Ala variant in peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) is associated with diabetes- and obesity-related traits, and that its effects may be modified by obesity status. We characterized this variant in a population-based sample of 1,441 middle-aged African-American individuals with respect to diabetes-, obesity-, and other cardiovascular-related traits, both cross-sectionally and prospectively. The overall frequency of Ala12 was 1.9% (95% CI 1.5-2.5%), significantly lower than in Caucasian populations. Consistent with previous findings in Caucasians, African Americans with type 2 diabetes tended to be less likely to have the Pro/Ala genotype than those without (odds ratio [OR] 0.64, 95% CI 0.34-1.20); however, this OR was not statistically significant. Among nonobese individuals, the Pro/Ala genotype was associated with significantly lower ln(insulin) (P = 0.001), lower ln(HOMA-IR) (homeostasis model assessment of insulin resistance) (P = 0.002), higher fasting glucose-to-insulin ratio (P = 0.005), and lower diastolic blood pressure (P = 0.02). Among overweight individuals (BMI 25-29.9 kg/m(2)), the Pro/Ala genotype was associated with greater BMI (P = 0.02), waist-to-hip ratio (P = 0.01), and waist circumference (P = 0.04). Among obese individuals, there was no association between any of the diabetes- or obesity-related traits and the Pro12Ala PPAR-gamma2 variant. We conclude that among nonobese African Americans, the Pro/Ala genotype is associated with markers of greater insulin sensitivity.
Diabetes 2003 Jun
PMID:Pro12Ala of the peroxisome proliferator-activated receptor-gamma2 gene is associated with lower serum insulin levels in nonobese African Americans: the Atherosclerosis Risk in Communities Study. 1276 72

In this study, the association of the Pro12Ala peroxisome proliferator-activated receptor gamma2 (PPARgamma2) polymorphism with atherosclerosis was examined in a Japanese Type 2 diabetic population. PPARgamma has been identified as a key regulator of adipogenesis. Recently, some studies reported that the Pro12Ala polymorphism was associated with resistance to Type 2 diabetes. It is well-known that Type 2 diabetes is closely related with disorder of lipid metabolism as well as impaired glucose homeostasis, resulting in atherosclerosis. We aimed to evaluate the association between carriers of the Pro12Ala PPARgamma2 mutation and clinical profiles concerning atherosclerosis besides plasma glucose and lipid concentrations. Screening for the mutation was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method among 154 Type 2 diabetic patients. The homozygotes of the Pro12 allele were 143 (93%), the heterozygotes of the Pro12 and Ala12 allele were 11 (7%) and the homozygote of the Ala12 allele was not detected. The group with the Ala12 allele had a significantly lower value of carotid artery intima-media thickness (IMT) than that without it, although there was no difference between two groups in sex, age or other clinical variables we examined. The Pro12Ala PPARgamma2 polymorphism may be associated with carotid artery IMT values in Type 2 diabetes mellitus.
Diabetes Res Clin Pract 2003 Oct
PMID:The association of Pro12Ala polymorphism in PPARgamma2 with lower carotid artery IMT in Japanese. 1458 Nov 58

The peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala polymorphism has been associated with a decreased risk of type 2 diabetes and a lower albumin excretion rate (AER) in patients with established diabetes. We performed a case-control study aiming to evaluate the association between the Pro12Ala polymorphism and diabetic nephropathy. Genomic DNA was obtained from 104 type 2 diabetic patients (case subjects) with chronic renal insufficiency (78 on dialysis and 26 with proteinuria [AER >or=200 microg/min] and serum creatinine >or=2.0 mg/dl) and 212 normoalbuminuric patients (AER <20 microg/min) with known diabetes duration >or=10 years (control subjects). The genotypic distribution of the PPARgamma2 Pro12Ala polymorphism in these diabetic patients was in Hardy-Weinberg equilibrium, and the Ala allele frequency was 9%. The frequency of Ala carriers (Ala/Ala or Ala/Pro) was 20.3% in control subjects and 10.6% in case subjects (P = 0.031). The odds ratio of having diabetic nephropathy for Ala carriers was 0.465 (95% CI 0.229-0.945; P = 0.034). Carriers of the Ala allele were not different from noncarriers (Pro/Pro) regarding sex (38.9 vs. 44.1% males) or ethnicity (77.4 vs. 71.7% white) distribution, age (61 +/- 10 vs. 61 +/- 10 years), known diabetes duration (17 +/- 7 vs. 16 +/- 7 years), BMI (27 +/- 4 vs. 28 +/- 5 kg/m(2)), fasting plasma glucose (184 +/- 81 vs. 176 +/- 72 mg/dl), HbA(1c) (6.7 +/- 2.3 vs. 6.9 +/- 2.4%; high-performance liquid chromatography reference range: 2.7-4.3%), and systolic (145 +/- 27 vs. 0.144 +/- 24 mmHg) or diastolic (87 +/- 14 vs. 85 +/- 14 mmHg) blood pressure, respectively. In conclusion, the presence of the Ala allele may confer protection from diabetic nephropathy in patients with type 2 diabetes.
Diabetes 2003 Dec
PMID:The human peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala polymorphism is associated with decreased risk of diabetic nephropathy in patients with type 2 diabetes. 1463 65

It has been proposed that type 1 and 2 diabetes might share common pathophysiological pathways and, to some extent, genetic background. However, to date there has been no convincing data to establish a molecular genetic link between them. We have genotyped three single nucleotide polymorphisms associated with type 2 diabetes in a large type 1 diabetic family collection of European descent: Gly972Arg in the insulin receptor substrate 1 (IRS1) gene, Glu23Lys in the potassium inwardly-rectifying channel gene (KCNJ11), and Pro12Ala in the peroxisome proliferative-activated receptor gamma2 gene (PPARG2). We were unable to confirm a recently published association of the IRS1 Gly972Arg variant with type 1 diabetes. Moreover, KCNJ11 Glu23Lys showed no association with type 1 diabetes (P > 0.05). However, the PPARG2 Pro12Ala variant showed evidence of association (RR 1.15, 95% CI 1.04-1.28, P = 0.008). Additional studies need to be conducted to confirm this result.
Diabetes 2004 Mar
PMID:Analysis of the type 2 diabetes-associated single nucleotide polymorphisms in the genes IRS1, KCNJ11, and PPARG2 in type 1 diabetes. 1498 78


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