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ABSTRACT: This review describes the effect of lifestyle change or metformin compared with standard care on incident type 2 diabetes and cardiometabolic risk factors in the Diabetes Prevention Program and its Outcome Study. The Diabetes Prevention Program was a randomized controlled clinical trial of intensive lifestyle and metformin treatments versus standard care in 3234 subjects at high risk for type 2 diabetes. At baseline, hypertension was present in 28% of subjects, and 53% had metabolic syndrome with considerable variation in risk factors by age, sex, and race. Over 2.8 years, type 2 diabetes incidence fell by 58% and 31% in the lifestyle and metformin groups, respectively, and metabolic syndrome prevalence fell by one-third with lifestyle change but was not reduced by metformin. In placebo- and metformin-treated subjects, the prevalence of hypertension and dyslipidemia increased during the Diabetes Prevention Program, whereas lifestyle intervention slowed these increases significantly. During long-term follow-up using modified interventions, type 2 diabetes incidence decreased to ≈5% per year in all groups. This was accompanied by significant improvement in cardiovascular disease risk factors over time in all treatment groups, in part associated with increasing use of lipid-lowering and antihypertensive medications. Thus a program of lifestyle change significantly reduced type 2 diabetes incidence and metabolic syndrome prevalence in subjects at high risk for type 2 diabetes. Metformin had more modest effects.
Arteriosclerosis Thrombosis and Vascular Biology 09/2012; 32(9):2077-90. · 6.37 Impact Factor
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ABSTRACT: The C allele at the rs11212617 polymorphism in the ataxia-telangiectasia-mutated (ATM) gene has been associated with greater clinical response to metformin in people with type 2 diabetes. We tested whether this variant modified the effect of metformin in the Diabetes Prevention Program (DPP), in which metformin reduced diabetes incidence by 31% in volunteers with impaired glucose tolerance.
We genotyped rs11212617 in 2,994 DPP participants and analyzed its effects on diabetes incidence and related traits.
Contrary to expectations, C carriers enjoyed no preventive advantage on metformin; their hazard ratio, compared with A carriers, was 1.17 ([95% CI 0.96-1.42], P = 0.13) under metformin. There were no significant differences by genotype in metformin's effects on insulin sensitivity, fasting glucose, glycated hemoglobin, or disposition index.
The reported association of rs11212617 with metformin response was not confirmed for diabetes prevention or for effects on relevant physiologic parameters in the DPP.
Diabetes care 06/2012; 35(9):1864-7. · 8.09 Impact Factor
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Jose C Florez,
Kathleen A Jablonski,
Jarred B McAteer,
Paul W Franks,
Clinton C Mason, Kieren Mather,
Edward Horton,
Ronald Goldberg,
Dana Dabelea,
Steven E Kahn,
Richard F Arakaki,
Alan R Shuldiner,
William C Knowler
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ABSTRACT: Common genetic variants have been recently associated with fasting glucose and insulin levels in white populations. Whether these associations replicate in pre-diabetes is not known. We extended these findings to the Diabetes Prevention Program, a clinical trial in which participants at high risk for diabetes were randomized to placebo, lifestyle modification or metformin for diabetes prevention. We genotyped previously reported polymorphisms (or their proxies) in/near G6PC2, MTNR1B, GCK, DGKB, GCKR, ADCY5, MADD, CRY2, ADRA2A, FADS1, PROX1, SLC2A2, GLIS3, C2CD4B, IGF1, and IRS1 in 3,548 Diabetes Prevention Program participants. We analyzed variants for association with baseline glycemic traits, incident diabetes and their interaction with response to metformin or lifestyle intervention. We replicated associations with fasting glucose at MTNR1B (P<0.001), G6PC2 (P = 0.002) and GCKR (P = 0.001). We noted impaired β-cell function in carriers of glucose-raising alleles at MTNR1B (P<0.001), and an increase in the insulinogenic index for the glucose-raising allele at G6PC2 (P<0.001). The association of MTNR1B with fasting glucose and impaired β-cell function persisted at 1 year despite adjustment for the baseline trait, indicating a sustained deleterious effect at this locus. We also replicated the association of MADD with fasting proinsulin levels (P<0.001). We detected no significant impact of these variants on diabetes incidence or interaction with preventive interventions. The association of several polymorphisms with quantitative glycemic traits is replicated in a cohort of high-risk persons. These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program.
PLoS ONE 01/2012; 7(9):e44424. · 4.09 Impact Factor
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Kieren Mather
AJP Endocrinology and Metabolism 03/2009; 296(2):E398-9. · 4.75 Impact Factor
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Ronald B Goldberg,
Marinella Temprosa,
Steven Haffner,
Trevor J Orchard,
Robert E Ratner,
Sarah E Fowler, Kieren Mather,
Santica Marcovina,
Chris Saudek,
Margaret J Matulik,
David Price
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ABSTRACT: Although subjects with diabetes have increased risk for cardiovascular disease (CVD), the evolution of this increased risk as pre-diabetic individuals progress to diabetes is not understood. This study examines the longitudinal relationship between selected CVD risk factors (blood pressure, triglycerides, HDL and LDL cholesterol, and LDL peak particle density [PPD]) and glycemia in the three treatment groups of the Diabetes Prevention Program.
A total of 3,234 participants with impaired glucose tolerance (IGT) were followed for a mean of 3.2 years after randomization to intensive lifestyle intervention (ILS), metformin, or placebo. Using repeated-measures models, adjusted mean levels of risk factors were estimated for an annual change in glycemic status. Tests were also conducted to assess the risk factor trends with improvement or worsening of glycemic status.
CVD risk factor values and changes from baseline became more unfavorable as glucose tolerance status deteriorated but improved with reversion to normal glucose tolerance (NGT), especially in the ILS intervention group (trend test P < 0.001 for all risk factors except for LDL PPD [P = 0.02] in ILS and HDL cholesterol [P = 0.02] in placebo). Although there were few significant differences in the transition from IGT to diabetes, there were strong relationships between risk factors and continuous measures of glycemia.
Progression from IGT to diabetes is associated with mild deterioration, whereas reversion to NGT is associated with improvement in risk factors. Early intervention with ILS, but less so with metformin, in participants at high risk for diabetes improves the cardiovascular risk and glucose tolerance profile simultaneously.
Diabetes care 02/2009; 32(4):726-32. · 8.09 Impact Factor
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AJP Regulatory Integrative and Comparative Physiology 09/2005; 289(2):R305-R306. · 3.34 Impact Factor
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Steven Haffner,
Marinella Temprosa,
Jill Crandall,
Sarah Fowler,
Ronald Goldberg,
Edward Horton,
Santica Marcovina, Kieren Mather,
Trevor Orchard,
Robert Ratner,
Elizabeth Barrett-Connor
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ABSTRACT: Increases in subclinical inflammation (C-reactive protein [CRP]) and impaired coagulation have been associated with increased obesity and insulin resistance. Only a few small studies have examined the effect of lifestyle changes, such as weight loss, increased physical activity, and insulin-sensitizing intervention on inflammation and coagulation. The Diabetes Prevention Program (DPP) clinical trial studied the effect of an intensive lifestyle intervention or metformin on progression to diabetes relative to placebo in 3,234 adults with impaired glucose tolerance. The effects of these interventions on CRP and fibrinogen at 12 months are examined in this report. Metformin reduced CRP in women compared with the placebo group. In men, the median changes in CRP from baseline to 1 year were -33% in the lifestyle group, -7% in the metformin group, and +5% in the placebo group. In women, the changes in CRP from baseline to follow-up were -29% in the lifestyle group, -14% in the metformin group, and 0% in the placebo group. In the lifestyle group weight loss rather than increased physical activity seems to account for most of the changes in CRP. Only modest reductions (although significant) were seen in fibrinogen levels in the lifestyle group relative to the metformin and placebo group. Lifestyle intervention reduced levels of nontraditional cardiovascular risk factors relative to both placebo and to a lesser degree to metformin.
Diabetes 06/2005; 54(5):1566-72. · 8.29 Impact Factor
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ABSTRACT: Epidemiological associations are now well-established between insulin resistance, the metabolic syndrome and worsened cardiovascular outcomes. A direct role of insulin in vascular biology is also now broadly recognized. Specifically, insulin can directly stimulate the action of nitric oxide synthase, an effect that can be demonstrated both in vitro and in vivo. Insulin resistance, whether present endogenously or produced experimentally through exposure to fatty acids, glucosamine or tumour necrosis factor alpha, is associated with impaired endothelium-dependent vasodilation and, specifically, with impaired insulin-stimulated vasodilation. A number of potential molecular explanations for these observations are being pursued, with evidence to support a number of concurrent pathogenic mechanisms. These include insulin resistance-associated reductions in nitric oxide availability due to increases in oxidative stress (not requiring the presence of hyperglycemia), reduced availability of tetrahydrobiopterin and excess levels of asymmetrical dimethylarginine. A strong body of evidence also supports an excess of the vasoconstrictor endothelin, which may result directly from hyperinsulinemia and/or indirectly due to a loss of the suppressive effects of nitric oxide on endothelin production and action. The current leading edge of investigations into the association between insulin-resistant states and vascular dysfunction involves the expanding repertoire of adipocyte-derived hormones. Of these, particular interest has been focused on adiponectin, which has both vascular and metabolic actions, and may contribute importantly to the connection between metabolism and vascular function. Progress along these novel lines of investigation will continue to expand the understanding of the mechanisms linking insulin resistance, the metabolic syndrome and vascular disease.
The Canadian journal of cardiology 09/2004; 20 Suppl B:66B-76B. · 3.36 Impact Factor
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ABSTRACT: Endothelial dysfunction is a feature of a variety of clinical states of insulin resistance, and increasingly it is recognized that pre-diabetic states of insulin resistance are associated not only with insulin resistance but with increased cardiovascular risk. The metabolic syndrome which typically accompanies insulin resistance brings aberrations in a number of classical cardiovascular risk factors, but it appears that insulin resistance itself represents an additional, non-classical risk factor. Therefore, the approach to treating the endothelium in patients with the metabolic syndrome might include therapies targeting insulin resistance. In this review, we provide a detailed overview of the current state of knowledge regarding the biguanide metformin and its effects on the endothelium. Its mode of action is reviewed, along with the available data from laboratory and experimental studies related to vascular function in animals and in humans. Metformin has beneficial effects on endothelial function which appear to be mediated through its effects to improve insulin resistance. Therapeutically targeting insulin resistance appears to be a viable route to improving endothelial function in clinical states of insulin resistance.
Current Drug Targets - Cardiovascular & Hematological Disorders 04/2004; 4(1):53-63.
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Diabetes Care 04/2004; 27(3):831-3. · 8.09 Impact Factor
