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AIMS The extent that pre-diabetic fasting plasma glucose (FPG) levels influence the effectiveness of lifestyle interventions in preventing type 2 diabetes (T2DM) is uncertain. We aimed to determine if the outcome of lifestyle intervention in people with impaired glucose tolerance (IGT) differs in those with normal or impaired FPG levels. MATERIALS AND METHODS Data were used from the Da Qing Diabetes Prevention Outcome Study, which was a 30-year follow-up of a 6-year randomized trial of lifestyle intervention in 576 people with IGT. We then conducted a post-hoc analysis to compare the efficacy of intervention to reduce the incidence of T2DM and its complications in those with baseline FPG

We aimed to determine associations of regression to normal glucose tolerance (NGT), maintaining impaired glucose tolerance (IGT) or progression to diabetes with subsequent risks of CVD and microvascular disease among Chinese adults with IGT. We conducted an observational study among 540 participants in the Da Qing Diabetes Prevention Study, a 6 year lifestyle intervention trial in people with IGT, defined by 1985 WHO criteria as fasting plasma glucose

Prospective studies in informative populations are crucial to increasing our knowledge of disease. In this perspective, we describe a half century of studies in an American Indian population that transformed our understanding of kidney disease in type 2 diabetes, now recognized as the leading cause of kidney failure worldwide. Serial examinations conducted for many years that included the collection of data and samples across multiple domains captured an unprecedented volume of clinical, physiologic, morphometric, genomic, and transcriptomic data. This work permitted us to extensively characterize the course and determinants of diabetic kidney disease, its pathophysiologic underpinnings, and important secular trends of urgent concern to populations worldwide, including the emergence of youth-onset type 2 diabetes and its effect on development of diabetic kidney disease in midlife. By combining these data using the tools of integrative biology, we are developing new mechanistic insights into the development and progression of diabetic kidney disease in type 2 diabetes. These insights have already contributed to the identification and successful therapeutic targeting of a novel pathway in DKD. We anticipate that this work will continue to expand our understanding of this complex disease and influence its management in the coming years.

The global epidemic of type 2 diabetes has prompted numerous studies and public health efforts to reduce its development. A variety of interventions, including lifestyle modifications and pharmacological agents directed at ameliorating the major risk factors for type 2 diabetes, are of proven efficacy in reducing the development of type 2 diabetes in people with impaired glucose tolerance. While prevention of the hyperglycaemia characteristic of diabetes is arguably an important, clinically relevant outcome, a more compelling outcome with greater clinical significance is the prevention or reduction of the relatively diabetes-specific microvascular and less-specific cardiovascular disease (CVD) complications associated with diabetes. These complications cause the majority of morbidity and excess mortality associated with diabetes. Any reduction in diabetes should, logically, also reduce the occurrence of its long-term complications; however, most diabetes prevention trials have not been of sufficient duration to allow such an evaluation. The limited long-term data, largely from the Da Qing Diabetes Prevention Study (DQDPS) and the Diabetes Prevention Program (DPP) and their respective follow-up studies (DQDPOS and DPPOS), suggest a reduction in microvascular complications and amelioration of CVD risk factors. Only the DQDPOS and Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) studies have shown a reduction in CVD events and only DQDPOS has demonstrated a decrease in CVD and overall mortality. While these limited data are promising, whether diabetes prevention directly reduces complication-related morbidity and mortality remains unclear. Longer follow-up of prevention studies is needed to supplement the limited current clinical trial data, to help differentiate the effects of diabetes prevention itself from the means used to reduce diabetes development and to understand the balance among benefits, risks and costs of prevention.

Lifestyle interventions in persons with impaired glucose tolerance (IGT) delay the onset of diabetes, but freedom from complications is a major goal of diabetes prevention and management. The extent that lifestyle intervention can delay the onset of the common but serious complications of diabetes is ill-defined. We assessed freedom from any serious diabetes-related complication in the 30-year follow-up data from the Da Qing Diabetes Prevention study in which 576 adults with IGT, randomized to control or lifestyle intervention groups for six-years, were followed from the time of randomization to determine the onset of diabetes and occurrence of any serious diabetes-related complication defined as CVD events or death, severe retinopathy, nephropathy, neuropathy, or death due to acute diabetes complications or infection. We estimated differences between the intervention and control groups in the incidence and time free of serious complications. Lifestyle interventions significantly increased the time free of major serious diabetes-related complications (Table). The study provides yet further evidence supporting the value of implementing lifestyle interventions in persons with IGT. Disclosure Q. Gong: None. P. Zhang: None. J. Wang: None. Y. Chen: None. Y. An: None. X. Feng: None. Y.J. Cheng: None. J. Ma: None. P.H. Bennett: Advisory Panel; Self; World Health Organization. Stock/Shareholder; Self; Eli Lilly and Company, Pfizer Inc., Unilever, UnitedHealth Group. Other Relationship; Self; American Diabetes Association, European Association for the Study of Diabetes, European Diabetic Nephropathy Study Group, International Diabetes Federation, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. G. Li: None.

Prevalence of diabetes and obesity in Mexican Pima Indians is low, while prevalence is high in Pima Indians in the United States (US); although lifestyle likely accounts for much of the difference, the role of genetic factors is not well-explored. To examine this, we genotyped 359 single nucleotide polymorphisms, including established type 2 diabetes and obesity variants from genome-wide association studies (GWAS) and 96 random markers, in 342 Mexican Pimas. A multimarker risk score of obesity variants was associated with body mass index (BMI; β = 0.81 kg/m(2) per SD, P = 0.0066). The mean value of the score was lower in Mexican Pimas than in US Pimas (P = 4.3×10(−11)), and differences in allele frequencies at established loci could account for ~7% of the population difference in BMI; however, the difference in risk scores was consistent with evolutionary neutrality given genetic distance. To identify loci potentially under recent natural selection, allele frequencies at 283 variants were compared between US and Mexican Pimas, accounting for genetic distance. The largest differences were seen at HLA markers (e.g., rs9271720, difference = 0.75, P = 8.7×10(−9)); genetic distances at HLA were greater than at random markers (P = 1.6×10(−46)). Analyses of GWAS data in 937 US Pimas also showed sharing of alleles identical by descent at HLA that exceeds its genomic expectation (P = 7.0×10(−10)). These results suggest that, in addition to the widely-recognized balancing selection at HLA, recent directional selection may also occur, resulting in marked allelic differentiation between closely related populations.

Despite its growing prevalence in China, the extent to which diabetes leads to excess mortality and its underlying causes are ill-defined. Six-hundred and six persons with newly diagnosed diabetes (NDD) and a comparison group of 494 with normal glucose tolerance (NGT) were identified in 1986 by screening 110,660 adults aged 25-74 years who agreed to participate in The Da Qing IGT and Diabetes study. A follow-up study of the original study participants was conducted in 2016. We compared death rates and causes of death between the two groups during 30 years of follow-up. Four-hundred and forty (71.7%) participants with NDD and 153 (31.0%) with NGT died. Overall mortality (rates/1,000 person-years + 95% CI) were much higher in those with NDD than with NGT, 40.8 (35.6-46.5) vs.15.8 (13.0-19.1) in men (P< 0.0001), and 30.4 (26.4-34.9) vs. 6.9 (5.0-9.3) in women (P In conclusion, diabetes is associated with substantially increased risks of death in Chinese adults, especially from CVD, renal failure, infection and cancer. Earlier age at diagnosis leads to greater relative risk of death. Disclosure Y. An: None. P. Zhang: None. J. Wang: None. Q. Gong: None. B. Zhang: None. Y. Chen: None. E. Gregg: None. P.H. Bennett: Consultant; Self; World Health Organization. Stock/Shareholder; Self; Becton, Dickinson and Company, Eli Lilly and Company, Pfizer Inc., UnitedHealth Group Inc. Other Relationship; Self; American Diabetes Association, Centers for Disease Control and Prevention, European Association for the Study of Diabetes, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. G. Li: None. Funding Centers for Disease Control and Prevention/Chinese Center for Disease Control and Prevention (5U19GH000636-05)

Responses to lifestyle interventions in people with impaired glucose tolerance (IGT) may differ during the intervention phase: some progress to diabetes, some regress to normal glucose tolerance (NGT) and some retain IGT. Whether these different responses to intervention influence subsequent outcomes is uncertain. In 1986, 576 persons with IGT in Da Qing, China, were randomized to control or intervention (diet, exercise, diet plus exercise) groups for a six-year lifestyle intervention. In 1992, of 540 participants who completed the intervention, 252 (46.7%) had progressed to diabetes, 174 (32.2%) regressed to NGT, and 114 (21.1%) remained as having IGT. In 2016, we conducted a 30-year follow-up study to assess the intervention effect on CVD events, defined as the first occurrence of non-fatal or fatal stroke, myocardial infarction or heart failure, and composite microvascular complications, defined as the first occurrence of severe retinopathy, nephropathy or neuropathy. We compared the difference in those outcomes between the three groups. The 30-year cumulative incidence of CVD was 65.6% (95% CI 58.7-71.5) in the participants with diabetes, 46.1% (95% CI 48.0-53.8) in those with NGT, and 50.6% (95% CI 40.5-59.9) in those with IGT. The corresponding incidence of microvascular complications was 44.3% (95% CI 36.8-51.4), 23.1%, (95% CI 15.7-31.4), and 31.2% (95% CI 21.1-41.7). Adjusting for age and sex, those who had developed diabetes had significantly higher risks than those who had reverted to NGT for both CVD (HR = 1.57, 95% CI 1.18-2.07, P = 0.002) and composite microvascular complications (HR = 2.53, 95% CI 1.62-3.93, P < 0.0001). Our results indicate that delaying the development of diabetes in people with IGT is likely to reduce the incidence of both macro and microvascular adverse outcomes. Disclosure Y. Chen: None. P. Zhang: None. J. Wang: None. Q. Gong: None. Y. An: None. E. Gregg: None. P.H. Bennett: Consultant; Self; World Health Organization. Stock/Shareholder; Self; Becton, Dickinson and Company, Eli Lilly and Company, Pfizer Inc., UnitedHealth Group Inc. Other Relationship; Self; American Diabetes Association, Centers for Disease Control and Prevention, European Association for the Study of Diabetes, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. G. Li: None. Funding Centers for Disease Control and Prevention/Chinese Center for Disease Control and Prevention (5U19GH000636-05)

Summary Background Lifestyle interventions can delay the onset of type 2 diabetes in people with impaired glucose tolerance, but whether this leads subsequently to fewer complications or to increased longevity is uncertain. We aimed to assess the long-term effects of lifestyle interventions in people with impaired glucose tolerance on the incidence of diabetes, its complications, and mortality. Methods The original study was a cluster randomised trial, started in 1986, in which 33 clinics in Da Qing, China, were randomly assigned to either be a control clinic or provide one of three interventions (diet, exercise, or diet plus exercise) for 6 years for 577 adults with impaired glucose tolerance who usually receive their medical care from the clinics. Subsequently, participants were followed for up to 30 years to assess the effects of intervention on the incidence of diabetes, cardiovascular disease events, composite microvascular complications, cardiovascular disease death, all-cause mortality, and life expectancy. Findings Of the 577 participants, 438 were assigned to an intervention group and 138 to the control group (one refused baseline examination). After 30 years of follow-up, 540 (94%) of 576 participants were assessed for outcomes (135 in the control group, 405 in the intervention group). During the 30-year follow-up, compared with control, the combined intervention group had a median delay in diabetes onset of 3·96 years (95% CI 1·25 to 6·67; p=0·0042), fewer cardiovascular disease events (hazard ratio 0·74, 95% CI 0·59–0·92; p=0·0060), a lower incidence of microvascular complications (0·65, 0·45–0·95; p=0·025), fewer cardiovascular disease deaths (0·67, 0·48–0·94; p=0·022), fewer all-cause deaths (0·74, 0·61–0·89; p=0·0015), and an average increase in life expectancy of 1·44 years (95% CI 0·20–2·68; p=0·023). Interpretation Lifestyle intervention in people with impaired glucose tolerance delayed the onset of type 2 diabetes and reduced the incidence of cardiovascular events, microvascular complications, and cardiovascular and all-cause mortality, and increased life expectancy. These findings provide strong justification to continue to implement and expand the use of such interventions to curb the global epidemic of type 2 diabetes and its consequences. Funding US Centers for Disease Control and Prevention, WHO, Chinese Center for Disease Control and Prevention, World Bank, Ministry of Public Health of the People's Republic of China, Da Qing First Hospital, China–Japan Friendship Hospital, and National Center for Cardiovascular Diseases & Fuwai Hospital.

The above-referenced article contained an error in the far-right column heading in Table 2. The heading should read as follows: PPV % (TP/TP + …

After Brockenhurst Grammar School and national service in the Royal Air Force, Kenneth Raymond Gough (“Ken”) trained at Bristol University, where he played cricket and football for university first teams, and met his wife-to-be. After house …

OBJECTIVE To determine whether early administration of losartan slows progression of diabetic kidney disease over an extended period. RESEARCH DESIGN AND METHODS We conducted a 6-year clinical trial in 169 American Indians with type 2 diabetes and urine albumin/creatinine ratio RESULTS After completion of the clinical trial, treatment with renin-angiotensin system inhibitors was equivalent in both groups. During a median of 13.5 years following randomization, 29 participants originally assigned to losartan and 35 to placebo reached the primary GFR outcome with an HR of 0.72 (95% CI 0.44–1.18). CONCLUSIONS Long-term risk of GFR decline was not significantly different between persons randomized to early treatment with losartan and those randomized to placebo. Accordingly, we found no evidence of an extended benefit of early losartan treatment on slowing GFR decline in persons with type 2 diabetes.

Diabetes mellitus is one of the most important public health challenges of the twenty-first century. Until the past decade, it has been seriously underrated as a global health threat. Major gaps exist in efforts to comprehend the burden nationally and globally, especially in developing nations, due to a lack of accurate data for monitoring and surveillance. Early attempts to obtain accurate data, discussed in this article, seem to have been cast aside so, at present, these needs remain unmet. Existing international efforts to assemble information fall far short of requirements. Current estimates are imprecise, only providing a rough picture, and probably underestimate the disease burden. The methodologies that are currently used, and that are discussed in this Perspectives article, are inadequate for providing a complete and accurate assessment of the prevalence of diabetes mellitus. International consensus on uniform standards and criteria for reporting national data on diabetes mellitus prevalence as well as for common complications of diabetes mellitus and mortality need to be developed.

OBJECTIVE People with impaired glucose tolerance (IGT) have increased risk of mortality and a high risk of progression to diabetes, but the extent that the excess mortality is associated with IGT per se or is the result of subsequent diabetes is unclear. RESEARCH DESIGN AND METHODS We compared mortality before and after the development of diabetes among 542 persons with IGT initially who participated in a 6-year lifestyle diabetes prevention trial and were followed-up from 1986 to 2009. RESULTS During the 23-year follow-up, 174 (32.1%) died, with an overall death rate of 15.9/1,000 person-years. The majority of deaths (74.7%; 130 of 174) occurred after progression to type 2 diabetes, with age-adjusted death rates of 11.1/1,000 person-years (95% CI 8.2–12.0) before and 19.4/1,000 person-years (95% CI 11.9–23.3) after the development of type 2 diabetes. The cumulative mortality was 37.8% (95% CI 33.1–42.2%) in participants who developed type 2 diabetes during first 10 years of follow-up, 28.6% (95% CI 21.6–35.0%) in those who progressed to type 2 diabetes in 10–20 years, and 13.9% (95% CI 7.0–20.3%) in those who did not develop to type 2 diabetes within 20 years. Time-dependent multivariate Cox proportional hazards analyses, with adjustment for baseline age, sex, intervention, and other potential confounding risk factors, showed that the development of type 2 diabetes was associated with a 73% higher risk of death (hazard ratio 1.73 [95% CI 1.18–2.52]). CONCLUSIONS As elsewhere, IGT is associated with increased risk of mortality in China, but much of this excess risk is attributable to the development of type 2 diabetes.

The International Diabetes Federation estimates that 415 million adults worldwide now have diabetes and 318 million have impaired glucose tolerance. These numbers are expected to increase to 642 million and 482 million, respectively, by 2040. This burgeoning pandemic places an enormous burden on countries worldwide, particularly resource-poor regions. Numerous landmark trials evaluating both intensive lifestyle modification and pharmacological interventions have persuasively demonstrated that type 2 diabetes can be prevented or its onset can be delayed in high-risk individuals with impaired glucose tolerance. However, key challenges remain, including how to scale up such approaches for widespread translation and implementation, how to select appropriately from various interventions and tailor them for different populations and settings, and how to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors’ Expert Forum convened to discuss these issues. This article, an outgrowth of the forum, begins with a summary of seminal prevention trials, followed by a discussion of considerations for selecting appropriate populations for intervention and the clinical implications of the various diagnostic criteria for prediabetes. The authors outline knowledge gaps in need of elucidation and explore a possible new avenue for securing regulatory approval of a prevention-related indication for metformin, as well as specific considerations for future pharmacological interventions to delay the onset of type 2 diabetes. They conclude with descriptions of some innovative, pragmatic translational initiatives already under way around the world.

The combination of high diabetes prevalence, declining mortality trends and high chronic kidney disease (CKD) prevalence has raised concerns about the future burden of CKD in the American Indian population. We modeled the future prevalence of diabetes and CKD in a Southwestern American Indian population well-characterized for type 2 diabetes using data from research examinations conducted on 4,476 participants between 1965 and 2007. Diabetes was assessed by 2-hour glucose tolerance testing, CKD was defined by estimated GFR (eGFR) In conclusion, the model provides assessment of the future burden of diabetes and diabetes-related CKD, projecting a marked increase in the proportion of people with diabetes who will have CKD over the next two decades. Disclosure M.E. Pavkov: None. A. Hoyer: None. E.W. Gregg: None. R. Brinks: None. P.H. Bennett: None.

Lifestyle interventions can prevent or delay type 2 diabetes (T2DM) but their long-term effect on cardiovascular disease (CVD) remains unclear. We assessed the effect of lifestyle interventions on the incidence of CVD events among Chinese adults with impaired glucose tolerance (IGT) who participated in the Da Qing Diabetes Prevention Study (DQDPS) and who were followed for up to 30 years after randomization. DQDPS was a 6-year clinical trial conducted in Da Qing, China from 1986 to 1992 in which 576 adults with IGT were randomized by clinic to a control group (138) or one of three lifestyle intervention groups (438) (diet or exercise or both). After the 6-year active intervention, participants were followed to assess their first CVD events until December 31st 2016. CVD was defined as fatal or nonfatal CVD, which included myocardial infarction, congestive heart failure, stroke, and amputation. The intervention effect on CVD was assessed using Cox proportional hazards analysis. 542 (94.1%) of the original participants had data for CVD events. 192 in the combined intervention group and 79 in the control group had a first CVD event during the follow-up. The 30-year cumulative incidence of CVD was 51.8% (95% CI 47.1-56.5) in the intervention group and 65.7% (95% CI 57.8-73.6) in the control group. CVD incidence per 1000 person-years was 21.8 (95% CI 18.8-25.1) in the intervention group compared to 29.0 (95% CI 23.0-36.2) in the control. After accounting for clinic cluster, the intervention reduced the risk of the first CVD event by 27% (HR 0.73, 95% CI 0.55-0.96; p=0.024).Our study is the first to show that a lifestyle intervention program in persons with IGT significantly reduces the incidence of CVD. Our results provide further justification to adopt lifestyle interventions as public health measures to prevent T2DM. Disclosure Q. Gong: None. P. Zhang: None. J. Ma: None. J. Wang: None. Y. An: None. Y.J. Cheng: None. B. Zhang: None. H. Li: None. Y. Chen: None. Y. Hu: None. E.W. Gregg: None. P.H. Bennett: None. G. Li: None.

Background and aim We sought to determine the effect of regression to normal glucose tolerance (NGT) or progression to diabetes in early years of impaired glucose tolerance (IGT) on subsequent risk of stroke. Methods In 1986, 576 adults aged 25 years and older with impaired glucose tolerance in Da Qing, China, were randomly assigned by clinic to control, diet, exercise, or diet plus exercise intervention groups for a six-year period. Subsequently participants received medical care in their local clinics. We tracked participants for additional 17 years to ascertain stroke events and other outcomes. Results At the end of 6-year intervention trial follow-up, 272 (50.2%) had progressed to diabetes, 169 (31.2%) regressed to normal glucose tolerance, and 101 (18.6%) remained impaired glucose tolerance. During the subsequent 17-year follow-up, 173 (31.9%) developed a stroke, 26.7% of normal glucose tolerances, 30.7% of impaired glucose tolerances, and 36.1% of those with diabetes. After controlling for age, sex, baseline blood pressure, smoking, total cholesterol, previous cardiovascular disease and intervention group, those who developed diabetes in the first six years had a higher incidence of stroke than those who reverted to normal glucose tolerance (HR = 1.49, 95% CI 1.01–2.19, p = 0.04), whereas for those who remained impaired glucose tolerance compared to those who regressed to normal glucose tolerance the HR was 1.25 (95% CI 0.80–1.93; p = 0.30). A 1-mmol/L increase in both fasting and 2-h post-load plasma glucose from entry to end of the six-year trial was significantly associated with a higher risk of development of stroke in the subsequent 17 years, respectively (HR = 1.07, 95% CI 1.03–1.11, p Conclusions Among Chinese adults with impaired glucose tolerance, early progression to diabetes predicted a higher risk of stroke, compared those who regressed to normal glucose tolerance.

Background Lifestyle interventions delay the onset of type 2 diabetes in people with impaired glucose tolerance (IGT), but whether this leads subsequently to fewer complications or increases longevity is uncertain. We aimed to determine the long-term effects of lifestyle intervention in people with IGT on the incidence of diabetes, its complications, and mortality. Methods In 1986, 577 adults with IGT in Da Qing, China were randomly assigned by clinic to a control group or one of three interventions (diet, exercise, or diet plus exercise) for six years. Participants were then followed for 30 years to assess the effects of intervention on the incidence of diabetes, cardiovascular events, composite microvascular complications, cardiovascular death, and life expectancy. Findings During the 30-year follow-up, the intervention group, compared with controls, had a median delay of 3·96 years (95% CI, 1·25 to 6·67; P=0·0042) in diabetes-onset with 26% fewer cardiovascular events (hazard ratio, 0·74; 95% CI, 0·59 to 0·92; P=0·0060), 28% lower incidence of severe microvascular complications (hazard ratio, 0·72; 95% CI, 0·52 to 0·99; P=0·044), 33% fewer cardiovascular disease deaths (hazard ratio, 0·67; 95% CI ,0·48 to 0·94; P=0·022), and 26% fewer total deaths (hazard ratio, 0·74; 95% CI, 0·61 to 0·89; P=0·0015), and an average increase of 1·44 life years (95% CI, 0·20 to 2·68; P=0·023). Interpretation Lifestyle intervention in people with IGT delayed the onset of type 2 diabetes, reduced the incidence of cardiovascular events, microvascular complications, cardiovascular and all-cause mortality, and increased life expectancy. The study provides strong justification to continue to implement and expand use of such interventions to curb the global diabetes epidemic and its consequences. Funding: CDC/WHO and CDC/Chinese CDC Cooperative Agreements, World Bank, Ministry of Public Health of the People's Republic of China, Da Qing First Hospital, China-Japan Friendship Hospital, National Center of Cardiology & Fuwai Hospital. Declaration of Interest: No potential conflicts of interest relevant to this article have been reported. Ethical Approval: Institutional review boards at the Chinese Centers for Disease Control and Prevention and Fuwai Hospital approved the study.

OBJECTIVE The global epidemics of type 2 diabetes and obesity have been attributed to the interaction between lifestyle changes and genetic predisposition to these diseases. We compared the prevalences of type 2 diabetes and obesity in Mexican Pima Indians, presumed to have a high genetic predisposition to these diseases, to those in their non-Pima neighbors, both of whom over a 15-year period experienced a transition from a traditional to a more modern lifestyle. RESEARCH DESIGN AND METHODS Prevalence of diabetes, impaired fasting glucose, impaired glucose tolerance, and obesity in Mexican Pimas (n = 359) and non-Pima Mexicans (n = 251) were determined in 2010 using methods identical to those used in 1995. RESULTS During this 15-year period, age-adjusted diabetes prevalence was unchanged in Pima men (5.8% in 1995 vs. 6.1% in 2010) yet increased in non-Pima men from 0.0 to 8.6% (P < 0.05). Diabetes prevalence tended to increase in both Pima women (9.4 vs. 13.4%) and non-Pima women (4.8 vs. 9.5%). Age-adjusted prevalence of obesity increased significantly in all groups (6.6 vs. 15.7% in Pima men; 8.5 vs. 20.5% in non-Pima men; 18.9. vs 36.3% in Pima women; 29.5 vs. 42.9% in non-Pima women). CONCLUSIONS Type 2 diabetes prevalence increased between 1995 and 2010 in non-Pima men, and to a lesser degree in women of both groups, but it did not increase in Pima men. Prevalence of obesity increased among Pimas and non-Pimas of both sexes. These changes occurred concomitantly with an environmental transition from a traditional to a more modernized lifestyle.

Missense variants in KCNJ11 and ABCC8, which encode the KIR6.2 and SUR1 subunits of the β-cell KATP channel, have previously been implicated in type 2 diabetes, neonatal diabetes, and hyperinsulinemic hypoglycemia of infancy (HHI). To determine whether variation in these genes affects risk for type 2 diabetes or increased birth weight as a consequence of fetal hyperinsulinemia in Pima Indians, missense and common noncoding variants were analyzed in individuals living in the Gila River Indian Community. A R1420H variant in SUR1 (ABCC8) was identified in 3.3% of the population (N = 7,710). R1420H carriers had higher mean birth weights and a twofold increased risk for type 2 diabetes with a 7-year earlier onset age despite being leaner than noncarriers. One individual homozygous for R1420H was identified; retrospective review of his medical records was consistent with HHI and a diagnosis of diabetes at age 3.5 years. In vitro studies showed that the R1420H substitution decreases KATP channel activity. Identification of this loss-of-function variant in ABCC8 with a carrier frequency of 3.3% affects clinical care as homozygous inheritance and potential HHI will occur in 1/3,600 births in this American Indian population.

Background A growing number of serum filtration markers are associated with mortality and end-stage renal disease (ESRD) in adults. Whether β-trace protein (BTP) and β 2 -microglobulin (B2M) are associated with these outcomes in adults with type 2 diabetes is not known. Study Design Longitudinal cohort study. Setting & Participants 250 Pima Indians with type 2 diabetes (69% women; mean age, 42 years; mean diabetes duration, 11 years). Predictors Serum BTP, B2M, and glomerular filtration rate measured by iothalamate clearance (mGFR) or estimated using creatinine (eGFR cr ) or cystatin C level (eGFR cys ). Outcomes & Measurements Incident ESRD and all-cause mortality through December 2013. HRs were reported per interquartile range decrease of the inverse of BTP and B2M (1/BTP and 1/B2M) using Cox regression. Improvement in risk prediction with the addition of BTP or B2M level to established markers (eGFR cys with mGFR or eGFR cr ) was evaluated using C statistics, continuous net reclassification improvement, and relative integrated discrimination improvement (RIDI). Results During a median follow-up of 14 years, 69 participants developed ESRD and 95 died. Both novel markers were associated with ESRD in multivariable models. BTP level remained statistically significant after further adjustment for mGFR (1/BTP, 1.53 [95% CI, 1.01-2.30]; 1/B2M, 1.54 [95% CI, 0.98-2.42]). B2M level was associated with mortality in multivariable models and after further adjustment for mGFR (HR, 2.12; 95% CI, 1.38-3.26). The addition of B2M level to established markers increased the C statistic for mortality but only weakly when assessed by either continuous net reclassification improvement or RIDI; none was improved for ESRD by the addition of these markers. Limitations Small sample size, single measurements of markers. Conclusions In Pima Indians with type 2 diabetes, BTP and, to a lesser extent, B2M levels were associated with ESRD. B2M level was associated with mortality after adjustment for traditional risk factors and established filtration markers. Further studies are warranted to confirm whether inclusion of B2M level in a multimarker approach leads to improved risk prediction for mortality in this population.

Background In Caucasians, lower triglycerides (TG), total or LDL cholesterol and high HDL cholesterol are generally associated with lower mortality. However, low cholesterol is associated with higher mortality in some Asian populations. This study examines the relationship between serum lipids and mortality in American Indians. Methods 2125 American Indians aged ≥ 40 years were examined biennially between 1993 and 2007. Vital status was determined through 2011. Mortality rates, adjusted for age, sex and diabetes, were calculated using Poisson regression. Results The median baseline age was 46 years and 61% were women. Over a median follow-up of 10.1 years, 522 deaths occurred. Relationships between baseline lipids, except for HDL cholesterol, and all-cause mortality were negative and linear in persons without diabetes and U-shaped in persons with diabetes. For HDL cholesterol, the relationship was U-shaped in the total cohort. Cardiovascular mortality was positively associated with total, LDL and non-HDL cholesterol whereas lower lipid concentrations were adversely associated with mortality from liver disease or external causes, except for HDL cholesterol, where associations were positive. Conclusion The common belief that low cholesterol and TG are beneficial for health is not universally observed; evidence suggests increased mortality at both ends of the cholesterol and TG distributions.

Summary Background Lifestyle interventions among people with impaired glucose tolerance reduce the incidence of diabetes, but their effect on all-cause and cardiovascular disease mortality is unclear. We assessed the long-term effect of lifestyle intervention on long-term outcomes among adults with impaired glucose tolerance who participated in the Da Qing Diabetes Prevention Study. Methods The study was a cluster randomised trial in which 33 clinics in Da Qing, China—serving 577 adults with impaired glucose tolerance—were randomised (1:1:1:1) to a control group or lifestyle intervention groups (diet or exercise or both). Patients were enrolled in 1986 and the intervention phase lasted for 6 years. In 2009, we followed up participants to assess the primary outcomes of cardiovascular mortality, all-cause mortality, and incidence of diabetes in the intention-to-treat population. Findings Of the 577 patients, 439 were assigned to the intervention group and 138 were assigned to the control group (one refused baseline examination). 542 (94%) of 576 participants had complete data for mortality and 568 (99%) contributed data to the analysis. 174 participants died during the 23 years of follow-up (121 in the intervention group vs 53 in the control group). Cumulative incidence of cardiovascular disease mortality was 11·9% (95% CI 8·8–15·0) in the intervention group versus 19·6% (12·9–26·3) in the control group (hazard ratio [HR] 0·59, 95% CI 0·36–0·96; p=0·033). All-cause mortality was 28·1% (95% CI 23·9–32·4) versus 38·4% (30·3–46·5; HR 0·71, 95% CI 0·51–0·99; p=0·049). Incidence of diabetes was 72·6% (68·4–76·8) versus 89·9% (84·9–94·9; HR 0·55, 95% CI 0·40–0·76; p=0·001). Interpretation A 6-year lifestyle intervention programme for Chinese people with impaired glucose tolerance can reduce incidence of cardiovascular and all-cause mortality and diabetes. These findings emphasise the long-term clinical benefits of lifestyle intervention for patients with impaired glucose tolerance and provide further justification for adoption of lifestyle interventions as public health measures to control the consequences of diabetes. Funding Centers for Disease Control and Prevention, WHO, the China-Japan Friendship Hospital, Da Qing First Hospital.

Angiotensin receptor blockers are renoprotective in hypertensive azotemic patients with type 2 diabetes, but their efficacy in early diabetic kidney disease is uncertain. We performed a 6-year randomized clinical trial in 169 American Indians with type 2 diabetes and normoalbuminuria (albumin/creatinine ratio [ACR]

The International Diabetes Federation estimates that 415 million adults worldwide now have diabetes and 318 million have impaired glucose tolerance. These numbers are expected to increase to 642 million and 482 million, respectively, by 2040. This burgeoning pandemic places an enormous burden on countries worldwide, particularly resource-poor regions. Numerous landmark trials evaluating both intensive lifestyle modification and pharmacological interventions have persuasively demonstrated that type 2 diabetes can be prevented or its onset can be delayed in high-risk individuals with impaired glucose tolerance. However, key challenges remain, including how to scale up such approaches for widespread translation and implementation, how to select appropriately from various interventions and tailor them for different populations and settings, and how to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors' Expert Forum convened to discuss these issues. This article, an outgrowth of the forum, begins with a summary of seminal prevention trials, followed by a discussion of considerations for selecting appropriate populations for intervention and the clinical implications of the various diagnostic criteria for prediabetes. The authors outline knowledge gaps in need of elucidation and explore a possible new avenue for securing regulatory approval of a prevention-related indication for metformin, as well as specific considerations for future pharmacological interventions to delay the onset of type 2 diabetes. They conclude with descriptions of some innovative, pragmatic translational initiatives already under way around the world.

Insulin resistance is a major risk factor for the development of type 2 diabetes in Pima Indians, a population with the highest prevalence of type 2 diabetes mellitus in the world. Their Mexican counterpart, living a traditional lifestyle in the mountains of Sonora, have at least 5 times less diabetes than the U.S. Pima Indians.We evaluated whether Mexican Pima Indians had lower insulin resistance than U.S. Pima Indians.We compared fasting insulin and homeostasis model assessment for insulin resistance (HOMA-IR) in 194 Mexican Pima Indians (100 females, 94 males) and 449 U.S. Pima Indians (246 females, 203 males) with normal glucose tolerance from a cross-sectional study. Adjusted differences of log-transformed outcomes (fasting insulin and HOMA-IR) between groups were evaluated using multiple linear regression models and paired t test in a matched subset.Unadjusted fasting insulin and HOMA-IR were much lower in the Mexican Pima Indians than in their U.S. counterparts. After adjusting by obesity, age, and sex, mean (95% confidence interval) for fasting insulin was 6.22 (5.34-7.24) vs. 13.56 μU/ml (12.27-14.97) and for HOMA-IR 1.40 (1.20-1.64) vs. 3.07 (2.77-3.40), respectively, for Mexican Pima and U.S. Pima Indians. Results were confirmed in subset matched for age, sex, and body fat.Our results indicate that Mexican Pima Indians have lower insulin resistance in comparison with their genetically related U.S. counterparts, even after controlling for differences in obesity, age, and sex. This finding underscores the importance of lifestyle factors as protecting factors against insulin resistance in individuals with a high propensity to develop diabetes.

Objectives Understanding why prolonged Bazett-corrected QT interval (QTc) is a risk factor for mortality is difficult, because QTc is positively correlated with heart rate. To optimally distinguish the effects of QT interval and heart rate on mortality, QT interval and heart rate were modeled separately and jointly in Pima Indians. Methods The effects of QT and heart rate on all-cause and cause-specific mortality were assessed in the overall study population and according to the presence or absence of diabetes using multivariable time-dependent proportional hazards models. Results Among 1488 nondiabetic and 990 diabetic subjects ≥25 years old, 81 nondiabetic and 149 diabetic subjects died during a median follow-up of 7.3 years. When included in the same regression model, QT and heart rate each predicted all-cause mortality [hazard ratios per standard deviation (SD) (95% confidence interval) = 1.31 (1.10–1.57) and 1.57 (1.32–1.87) respectively]. In nondiabetic subjects, hazard ratios for all-cause mortality were 1.54 (1.19–1.99) for QT and 1.86 (1.46–2.37) for heart rate. In diabetic subjects, hazard ratios for all-cause mortality were lower, 1.27 (1.00–1.62) for QT and 1.41 (1.12–1.78) for heart rate. In the overall study population, neither QT nor heart rate significantly predicted cardiovascular disease (CVD) mortality [hazard ratios = 1.13 (0.77–1.64) and 1.46 (0.98–2.19)] when adjusted for each other. Heart rate unadjusted for QT, however, predicted CVD mortality [hazard ratio = 1.34 (1.00–1.79)] in a separate model. Conclusions QT prolongation and high heart rate both predict all-cause mortality in Pima Indians, but heart rate was consistently the stronger predictor of the two.

Angiotensin receptor blockers are renoprotective in hypertensive azotemic patients with type 2 diabetes, but their efficacy in early diabetic kidney disease is uncertain. We performed a 6-year randomized clinical trial in 169 American Indians with type 2 diabetes and normoalbuminuria (albumin/creatinine ratio [ACR]30 mg/g; n = 91) or microalbuminuria (ACR 30-299 mg/g; n = 78) at baseline. The primary outcome was decline in glomerular filtration rate (GFR) to ≤60 mL/min or to half the baseline value in subjects who entered with GFR120 mL/min. Another outcome was differences in glomerular structure at end of treatment. Subjects received 100 mg losartan or placebo daily. GFR was measured annually; 111 subjects underwent kidney biopsies. Only nine subjects reached the GFR outcome, and the unadjusted hazard ratio (losartan vs. placebo) was 0.50 (95% CI, 0.12-1.99). Differences in mesangial fractional volume were not estimated in the combined albuminuria groups because of an interaction with treatment assignment. In separate analyses, mesangial fractional volume was lower in subjects treated with losartan in the microalbuminuria group (18.8 vs. 25.6%; P = 0.02), but not in the normoalbuminuria group (19.6 vs. 17.8%; P = 0.86). Treatment with losartan may preserve some features of kidney structure in American Indians with type 2 diabetes and microalbuminuria.

OBJECTIVE We examined secular trends in the frequency distribution of albuminuria and estimated glomerular filtration rate (eGFR) in subjects with type 2 diabetes in 1982–1988 and 2001–2006, two periods associated with major changes in the management of diabetes. RESEARCH DESIGN AND METHODS The cross-sectional study included Pima Indians ≥15 years old with type 2 diabetes and measures of serum creatinine and urinary albumin-to-creatinine ratios (ACR). The continuous probability density distributions of ACR and eGFR were compared for the two time periods. eGFR was calculated using the Modification of Diet in Renal Disease Study equation. RESULTS The overall standardized distribution of ACR shifted toward lower values between time periods (P = 0.001), whereas the standardized distribution of eGFR did not (P = 0.45). In the first period, eGFR was CONCLUSIONS The distribution of albuminuria changed significantly among diabetic Pima Indians over the past 20 years, as treatment with medicines to control hyperglycemia and hypertension increased. The distribution of eGFR, however, remained unchanged. Consequently, the frequency of chronic kidney disease characterized by normoalbuminuria and low eGFR doubled.

Abstract Many protocols have been used in clinical and research settings for collecting systolic blood pressure (SBP) measurements to calculate the ankle–brachial index (ABI); however, it is not known how useful it is to replicate measurements and which measures best reflect cardiovascular risk. Standardized measurements of ankle and arm SBP from 5140 overweight or obese individuals with type 2 diabetes were used to estimate sources of variation. Measurement characteristics of leg-specific ABI, as calculated using a standard algorithm based on the highest SBP of the dorsalis pedis or posterior tibial arteries, were projected using simulations. Coefficients of variability ranged from 2% to 3% when single SBP measurements were used and ABI was overestimated by 2–3%. Taking two SBP measurements at each site reduced standard errors and bias each by 30–40%. The sensitivity of detecting low ABI ranges exceeded 90% for ABI within 0.05 of the 0.90 clinical cut-point. The average and the minimum of the two (i.e. right and left) leg-specific ABI values had similar U-shaped relationships with Framingham risk scores; however, the average leg ABI had slightly greater precision. Replicating SBP measurements reduces the error and bias of ABI. Averaging leg-specific values may increase power for characterizing cardiovascular disease risk.

Background To determine whether historic albuminuria measurements provide additional predictive value for diabetic end-stage renal disease (ESRD) and natural mortality over the most recent measurement, ie, whether "regression" from high albuminuria has a different prognosis than stability at the lower level. Study Design Observational longitudinal study. Setting & Participants Pima Indians 15 years or older with type 2 diabetes and at least 2 consecutive measurements of urinary albumin-creatinine ratio (ACR) within 6 years. Predictors Sequential measurements of urinary ACR. Outcomes & Measurements Proportional hazards analyses were used to estimate the risk of ESRD and natural death associated with the first and second ACR measurement. The ability of these highly correlated variables to predict outcome was compared with receiver operating characteristic curves calculated by means of the generalized c statistic. Results In 983 subjects, 136 developed ESRD and 180 died of natural causes during a maximum follow-up of 12.6 years. Each doubling in the second ACR was associated with a 1.71-fold greater incidence of ESRD (95% confidence interval, 1.54 to 1.89) and 1.16-fold greater natural mortality (95% confidence interval, 1.07 to 1.27) adjusted for age, sex, diabetes duration, and antihypertensive medication. The addition of the first ACR measurement to the model did not add to the predictive value for ESRD or mortality. In pairwise comparisons of c statistics, the second ACR was a significantly better predictor of ESRD than the first ACR. Limitations The predictive value of ACR measurements is decreased to the extent that its precision is based on a single measure. Conclusion The predictive power of the latest ACR for ESRD and natural mortality in patients with diabetes is not enhanced by knowledge of the preceding ACR. Therefore, ACR changes over time, ie, regression or progression, add minimal predictive value beyond the latest measurement in the series.

Zimmet P, Alberti K George MM, Kaufman F, Tajima N, Silink M, Arslanian S, Wong G, Bennett P, Shaw J, Caprio S; IDF Consensus Group. The metabolic syndrome in children and adolescents – an IDF consensus report. Pediatric Diabetes 2007: 8: 299–306. Paul Zimmet, K George MM Alberti, Francine Kaufman, Naoko Tajima, Martin Silink, Silva Arslanian, Gary Wong, Peter Bennett, Jonathan Shaw and Sonia Caprio; IDF Consensus Group International Diabetes Institute, Melbourne, Victoria, Australia; Department of Endocrinology and Metabolic Medicine, St Mary’s Hospital, London, UK; Center for Diabetes, Endocrinology and Metabolism, Children’s Hospital, Los Angeles, CA, USA; Division of Diabetes, Metabolism and Endocrinology, Jikei University School of Medicine, Tokyo, Japan; Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia; Division of Endocrinology, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA; Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong; Phoenix Epidemiology and Clinical Research Branch, NIDDK, National Institutes of Health, Phoenix, AZ, USA; and Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA

OBJECTIVE—Type 2 diabetes and obesity have genetic and environmental determinants. We studied the effects of different environments on these diseases in Pima Indians in Mexico and the U.S. RESEARCH DESIGN AND METHODS—Adult Pima-Indian and non-Pima populations in the Sierra Madre mountains of Mexico were examined using oral glucose tolerance tests and assessments for obesity, physical activity, and other risk factors. Results were compared with those from Pima Indians in Arizona. Both Pima populations were typed for DNA polymorphisms to establish their genetic similarity. RESULTS—The age- and sex-adjusted prevalence of type 2 diabetes in the Mexican Pima Indians (6.9%) was less than one-fifth that in the U.S. Pima Indians (38%) and similar to that of non-Pima Mexicans (2.6%). The prevalence of obesity was similar in the Mexican Pima Indians (7% in men and 20% in women) and non-Pima Mexicans (9% in men and 27% in women) but was much lower than in the U.S. Pima Indians. Levels of physical activity were much higher in both Mexican groups than in the U.S. Pima Indians. The two Pima groups share considerable genetic similarity relative to other Native Americans. CONCLUSIONS—The much lower prevalence of type 2 diabetes and obesity in the Pima Indians in Mexico than in the U.S. indicates that even in populations genetically prone to these conditions, their development is determined mostly by environmental circumstances, thereby suggesting that type 2 diabetes is largely preventable. This study provides compelling evidence that changes in lifestyle associated with Westernization play a major role in the global epidemic of type 2 diabetes.

Background The association between electrocardiographic (ECG) abnormalities and deaths from cardiovascular diseases (CVD) and ischemic heart disease (IHD) has been reported in the general population, but there is little information regarding persons with type 2 diabetes. Methods Minor and major ECG abnormalities were identified and classified according to the Minnesota Code in a longitudinal study of 1605 Pima Indians aged ≥35 years with type 2 diabetes. Underlying causes of death were determined by review of all available clinical records, autopsy reports, medical examiners' findings, and death certificates. Results During a median follow-up of 14.1 years (range 0.1 to 33.8 years), there were 190 CVD deaths, 135 (71.1%) of which were attributable to IHD. The age-adjusted CVD death rates in men with none, minor, and major ischemic ECG abnormalities were 7.3, 12.2 and 27.8, and in women, 4.3, 4.8 and 12.5 per 1000 person-years, respectively. After adjustment for other co-variables in a multiple proportional hazards model, subjects with minor and major ischemic abnormalities on ECG had 1.22 (95% CI, 0.76-1.97) and 1.83 (95% CI, 1.21-2.76) times the CVD death rate, and 1.32 (95% CI, 0.70-2.50) and 2.12 (95% CI, 1.26-3.57) times the IHD death rate of those with no ischemic ECG abnormalities, respectively. Conclusions The CVD and IHD death rates were higher in men and in subjects with major ischemic ECG abnormalities. Major ischemic abnormalities on ECG predicted death after accounting for other cardiovascular risk factors, including proteinuria.

Secular trends over 34 years (1965-1998) in overall and cause-specific mortality were examined in 4,623 Pima Indiansor=35 years old.The underlying and contributing causes of the 1,363 deaths were determined from a review of all available clinical records; 540 of the deaths occurred in the 2,528 nondiabetic participants and 823 in the 2,095 participants who had diabetes during all or part of the study period. Age/sex-adjusted death rates were calculated across four 8.5-year time intervals.In the nondiabetic participants, the rate of death from natural causes declined gradually over time (20.4, 17.3, 17.3, and 16.0 deaths per 1,000 persons/year; P=.11); deaths from ischemic heart disease (IHD) were uncommon (n=22), and the rate did not change appreciably, remaining as the fifth leading natural cause of death. In the diabetic participants, the rate of death from natural causes was unchanged over time, but the rate of death from IHD (n=141) increased nearly twofold (3.3, 4.2, 6.4, and 6.4 deaths per 1,000 persons/year; P.01), becoming the leading cause of death in the third and fourth time intervals.The rate of death from IHD remained stable in nondiabetic Pima Indians but increased among those with diabetes. This finding suggests that, in the absence of diabetes, the underlying susceptibility to IHD in this population has not changed.

Predominant effect of kidney disease on mortality in Pima Indians with or without type 2 diabetes.BackgroundWe examined the effect of kidney disease (KD) on mortality in nondiabetic and diabetic Pima Indians aged ≥45 years old.MethodsDeaths and person-years of follow-up were stratified in a time-dependent fashion into categories of (1) no proteinuria and normal serum creatinine (SCr); (2) proteinuria and normal SCr; (3) high SCr [SCr ≥133 μmol/L (1.5 mg/dL) in men, ≥124 μmol/L (1.4 mg/dL) in women] but not on renal replacement therapy (RRT); or (4) RRT.ResultsAmong 1993 subjects, 55.8% had type 2 diabetes at baseline. Overall death rates increased with declining kidney function in both the nondiabetic and diabetic subjects (P < 0.0001). Death rates were similar in nondiabetic and diabetic subjects with comparable levels of kidney function, although the number of deaths among nondiabetic subjects with advanced KD was small. Infections and malignancy were the leading causes of death in nondiabetic subjects with KD. Among diabetic subjects, overall mortality increased with diabetes duration (P = 0.0001) and was highest in those on RRT (P < 0.0001). High SCr was associated with higher death rates from cardiovascular disease (CVD), diabetic nephropathy (DN), infections, and malignancy.ConclusionDeath rates increased comparably with worsening kidney function in both nondiabetic and diabetic subjects and were similar in nondiabetic and diabetic subjects without KD. KD was associated with excess mortality from DN, CVD, infections, and malignancy in diabetic subjects, and from infections in those without diabetes.

OBJECTIVE—To estimate the global number of excess deaths due to diabetes in the year 2000. RESEARCH DESIGN AND METHODS—We used a computerized generic formal disease model (DisMod II), used by the World Health Organization to assess disease burden through modeling the relationships between incidence, prevalence, and disease-specific mortality. Baseline input data included population structure, age- and sex-specific estimates of diabetes prevalence, and available published estimates of relative risk of death for people with diabetes compared with people without diabetes. The results were validated with population-based observations and independent estimates of relative risk of death. RESULTS—The excess global mortality attributable to diabetes in the year 2000 was estimated to be 2.9 million deaths, equivalent to 5.2% of all deaths. Excess mortality attributable to diabetes accounted for 2–3% of deaths in poorest countries and over 8% in the U.S., Canada, and the Middle East. In people 35–64 years old, 6–27% of deaths were attributable to diabetes. CONCLUSIONS—These are the first global estimates of mortality attributable to diabetes. Globally, diabetes is likely to be the fifth leading cause of death.