Minimal Contribution of Fasting Hyperglycemia to the Incidence of Type 2 Diabetes in Subjects With Normal 2-h Plasma Glucose

OBJECTIVE

To assess the relative contribution of increased fasting and postload plasma glucose concentrations to the incidence of type 2 diabetes in subjects with a normal 2-h plasma glucose concentration.

RESEARCH DESIGN AND METHODS

A total of 3,450 subjects with 2-h plasma glucose concentration <140 mg/dl at baseline were followed up in the San Antonio Heart Study (SAHS) and the Botnia Study for 7–8 years. The incidence of type 2 diabetes at follow-up was related to the fasting, 1-h, and 2-h plasma glucose concentrations.

RESULTS

In subjects with 2-h plasma glucose <140 mg/dl, the incidence of type 2 diabetes increased with increasing fasting plasma glucose (FPG) and 1-h and 2-h plasma glucose concentrations. In a multivariate logistic analysis, after adjustment for all diabetes risk factors, the FPG concentration was a strong predictor of type 2 diabetes in both the SAHS and the Botnia Study (P < 0.0001). However, when the 1-h plasma glucose, but not 2-h plasma glucose, concentration was added to the model, FPG concentration was no longer a significant predictor of type 2 diabetes in both studies (NS). When subjects were matched for the level of 1-h plasma glucose concentration, the incidence of type 2 diabetes markedly increased with the increase in 1-h plasma glucose, but the increase in FPG was not associated with a significant increase in the incidence of type 2 diabetes.

CONCLUSIONS

An increase in postload glycemia in the normal range is associated with an increase in the incidence of type 2 diabetes. After controlling for 1-h plasma glucose concentration, the increase in FPG concentration is not associated with an increase in the incidence of type 2 diabetes.Impaired fasting glucose (IFG) was introduced in 1997 by the American Diabetes Association (ADA) (1), and, analogous with impaired glucose tolerance (IGT), it was meant to represent an intermediate stage in the transition from normal glucose tolerance (NGT) to overt type 2 diabetes. Both IFG and IGT indicate an increased risk for future type 2 diabetes (2–4). Previously (5–7), we have shown that the 1-h plasma glucose concentration has better predictive power than either fasting plasma glucose (FPG) or 2-h plasma glucose, suggesting that the 1-h plasma glucose concentration may have greater utility in identifying subjects at increased risk for type 2 diabetes in routine clinical practice.Previous studies have reported that IFG and IGT represent separate clinical entities, which are characterized by distinct metabolic abnormalities (8–13). Subjects with IGT manifest insulin resistance in skeletal muscle (9–12) and impaired β-cell function (both early and late phases of insulin secretion) (10,14–16), whereas subjects with IFG are characterized by increased hepatic insulin resistance (9,16), impaired early insulin response (12), and decreased non–insulin-dependent glucose clearance (15). Because of the prominent role of progressive β-cell failure in the development of hyperglycemia (17), the impairment in β-cell function in subjects with IGT represents a major pathogenic factor for their increased risk for future type 2 diabetes. Although the increase in fasting plasma glucose is associated with a decrease in first-phase insulin secretion (11–13,18), subjects with IFG have robust second-phase insulin secretion, and, when related to their prevailing level of insulin resistance, they have second-phase insulin secretion comparable with that of subjects with NGT (12,13). Thus, impaired β-cell function cannot fully explain the increased incidence of type 2 diabetes associated with the increase in FPG concentration, e.g., in subjects with isolated IFG.Previously we have shown a strong correlation between insulin resistance in skeletal muscle and liver (16). Thus, a strong correlation between FPG and postload plasma glucose concentrations is anticipated. Therefore, we hypothesized that the increased type 2 diabetes risk associated with the increase in FPG, at least in part, is due to the increased postprandial plasma glucose concentration associated with the increase in FPG and is not due to the increase in FPG per se. The aim of this study was to test this hypothesis.     

Efficacy of Primary Prevention Interventions When Fasting and Postglucose Dysglycemia Coexist: Analysis of the Indian Diabetes Prevention Programmes (IDPP-1 and IDPP-2)

OBJECTIVE

Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have different pathophysiological abnormalities, and their combination may influence the effectiveness of the primary prevention tools. The hypothesis was tested in this analysis, which was done in a pooled sample of two Indian Diabetes Prevention Programmes (IDPP-1 and IDPP-2).

RESEARCH DESIGN AND METHODS

Researchers analyzed and followed up on the details of 845 of the 869 IGT subjects in the two studies for 3 years. Incidence of diabetes and reversal to normoglycemia (normal glucose tolerance [NGT]) were assessed in group 1 with baseline isolated IGT (iIGT) (n = 667) and in group 2 with IGT + IFG (n = 178). The proportion developing diabetes in the groups were analyzed in the control arm with standard advice (IDPP-1) (n = 125), lifestyle modification (LSM) (297 from both), metformin (n = 125, IDPP-1), and LSM + metformin (n = 121, IDPP-1) and LSM + pioglitazone (n = 298, IDPP-2). Cox regression analysis was used to assess the influence of IGT + IFG versus iIGT on the effectiveness of the interventions.

RESULTS

Group 2 had a higher proportion developing diabetes in 3 years (56.2 vs. 33.6% in group 1, P = 0.000) and a lower rate of reversal to NGT (18 vs. 32.1%, P = 0.000). Cox regression analysis showed that effectiveness of intervention was not different in the presence of fasting and postglucose glycemia after adjusting for confounding variables.

CONCLUSIONS

The effectiveness of primary prevention strategies appears to be similar in subjects with iIGT or with combined IGT + IFG. However, the possibility remains that a larger study might show that the effectiveness is lower in those with the combined abnormality.Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have a high potential to convert to type 2 diabetes. While an elevated basal hepatic glucose output and impaired early phase insulin secretion are the major abnormalities in IFG, IGT is characterized by more severe muscle insulin resistance (IR) and defects in late insulin secretion (1). Among Asian Indians, higher degrees of IR and β-cell dysfunction are seen in IFG than in IGT (2).Analysis of six prospective studies among subjects with IGT showed that the incidence of diabetes varied widely from 23 to 62% within two to twenty-seven years of follow-up (3). The incidence was higher among populations with high prevalence of diabetes than in white populations. Incidence rates of diabetes in subjects with IFG or IGT or with a combined abnormality were varied in different populations (4–8).Primary prevention studies have been done among subjects with IGT in different ethnic populations (9–14). Among these, only the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial (12) recruited subjects with either isolated IFG (iIFG) or isolated IGT (iIGT) or both. Rosiglitazone was found to be a potent agent in preventing diabetes in this trial (12). The Diabetes Prevention Programme (DPP) (9) recruited subjects with a fasting glucose in the range of 5.3–6.9 mmol/l (95–125 mg/dl) and 2-h postglucose of 7.8–11 mmol/l (140–199 mg/dl) and nearly one-third of the participants had IFG by the present criteria (15).Results of the Indian Diabetes Prevention Programme-1 (IDPP-1) showed that a moderate lifestyle modification (LSM) or a small dose of metformin (500 mg/day) reduced the risk of diabetes in a relatively nonobese but insulin resistant Asian Indian population (13). In the IDPP-2 study, we noted that pioglitazone did not improve the efficacy of LSM in Asian Indians (14). In both studies, subjects with persistent IGT and fasting glucose levels below 6.9 mmol/l were recruited. Therefore, some participants also had IFG. In view of the higher degree of biochemical abnormalities occurring when fasting and postprandial dysglycemia coexisted, it was considered important to study whether the combined abnormalities influenced the cumulative incidence of diabetes in comparison with subjects with iIGT. To increase the sample size, data from both IDPP studies were pooled. The participants'' baseline characteristics were identical in the two studies.     

Screening for Diabetes and Pre-Diabetes With Proposed A1C-Based Diagnostic Criteria

OBJECTIVE

An International Expert Committee (IEC) and the American Diabetes Association (ADA) proposed diagnostic criteria for diabetes and pre-diabetes based on A1C levels. We hypothesized that screening for diabetes and pre-diabetes with A1C measurements would differ from using oral glucose tolerance tests (OGTT).

RESEARCH DESIGN AND METHODS

We compared pre-diabetes, dysglycemia (diabetes or pre-diabetes), and diabetes identified by the proposed criteria (A1C ≥6.5% for diabetes and 6.0–6.4% [IEC] or 5.7–6.4% [ADA] for high risk/pre-diabetes) with standard OGTT diagnoses in three datasets. Non-Hispanic white or black adults without known diabetes who had A1C and 75-g OGTT measurements were included from the prospective Screening for Impaired Glucose Tolerance study (n = 1,581), and from the National Health and Nutrition Examination Survey (NHANES) III (n = 2014), and NHANES 2005–2006 (n = 1,111).

RESULTS

OGTTs revealed pre-diabetes in 35.8% and diabetes in 5.2% of combined study subjects. A1C provided receiver operating characteristic (ROC) curve areas for diabetes of 0.79–0.83, but ROC curve areas were ≤0.70 for dysglycemia or pre-diabetes. The proposed criteria missed 70% of individuals with diabetes, 71–84% with dysglycemia, and 82–94% with pre-diabetes. Compared with the IEC criteria, the ADA criteria for pre-diabetes resulted in fewer false-negative and more false-positive result. There were also racial differences, with false-positive results being more common in black subjects and false-negative results being more common in white subjects. With use of NHANES 2005–2006 data, ∼5.9 million non-Hispanic U.S. adults with unrecognized diabetes and 43–52 million with pre-diabetes would be missed by screening with A1C.

CONCLUSIONS

The proposed A1C diagnostic criteria are insensitive and racially discrepant for screening, missing most Americans with undiagnosed diabetes and pre-diabetes.Diabetes affects >21 million American adults (1,2), with a lifetime risk ranging from 20 to 50+%, depending on sex and race (3). Identification of diabetes and its precursor, pre-diabetes, can permit management to prevent complications or delay progression from pre-diabetes to diabetes. Because most U.S. health care systems do not have systematic screening programs, many Americans have undiagnosed diabetes and pre-diabetes, and, therefore, these individuals are not initiating programs targeted at prevention (2).An International Expert Committee (IEC) recently proposed new diagnostic criteria based on measurement of A1C, with A1C ≥6.5% for diabetes and 6.0–6.4% for “high risk” of progression to diabetes (4). The American Diabetes Association (ADA) subsequently proposed A1C ≥6.5% for the diagnosis of diabetes and 5.7–6.4% for the highest risk to progress to diabetes (5).Because A1C testing is readily available in the U.S., is relatively well standardized, exhibits low intraindividual variation, and does not require fasting or restriction to certain times of the day (6), many clinicians might wish to use A1C measurements to screen for diabetes and pre-diabetes. However, the proposed diagnostic criteria were based largely on identification of diabetic retinopathy, and use of the proposed criteria as a screening test is not understood. The IEC A1C criteria have recently been compared with testing with fasting glucose or oral glucose tolerance tests (OGTTs) in various populations to diagnose diabetes (7–13) and high-risk/pre-diabetes (10,11,13), but the ADA A1C criteria have not been studied.We hypothesized that A1C diagnostic criteria would fail to identify many subjects with unrecognized diabetes or pre-diabetes. We evaluated the proposed criteria as screening tests in three populations, compared with the OGTT as a “gold standard” used for identification of diabetes and pre-diabetes around the world (14).     

A1C Between 5.7 and 6.4% as a Marker for Identifying Pre-Diabetes, Insulin Sensitivity and Secretion, and Cardiovascular Risk Factors: The Insulin Resistance Atherosclerosis Study (IRAS)

OBJECTIVE

A1C is an optional method for diagnosing diabetes and also for detecting individuals at increased risk of the disease. However, how A1C compares with fasting (FPG) and 2-h plasma glucose for detecting at-risk individuals is not well known.

RESEARCH DESIGN AND METHODS

A 2-h glucose tolerance test, frequently sampled intravenous glucose tolerance test, and A1C were obtained at the follow-up examination in 855 participants in the Insulin Resistance Atherosclerosis Study (IRAS). For this report, 385 individuals were at increased risk of diabetes as defined by A1C between 5.7 and 6.4%, impaired glucose tolerance (IGT), and/or impaired fasting glucose (IFG).

RESULTS

IFG and IGT identified 69.1 and 59.5% of all individuals at increased risk of diabetes, respectively. A1C 5.7–6.4% detected 23.6% of all at-risk individuals, although more African Americans (31.4%) and Hispanics (35.2%) than non-Hispanic whites (9.9%). Relative to A1C, FPG was more strongly related to fasting insulin (r = 0.38 vs. 0.26; P < 0.01), acute insulin response (r = – 0.20 vs. – 0.09; P < 0.01), and waist circumference (r = 0.43 vs. 0.25; P < 0.001) by the Spearman correlation test. Similarly, 2-h plasma glucose was more strongly related to Si (r = – 0.40 vs. – 0.27; P < 0.01) and triglycerides (r = 0.30 vs. 0.08; P < 0.001).

CONCLUSIONS

A1C 5.7–6.4% is less sensitive for detecting at-risk individuals than IFG and IGT, particularly among non-Hispanic whites. Single determinations of FPG and 2-h plasma glucose seem to be more precise correlates of insulin resistance and secretion than A1C and, in general, better for other metabolic disorders.A1C has been proposed by the American Diabetes Association (ADA) as an optional assay for diagnosing diabetes and also for detecting individuals at increased risk of the disease (1). A1C has been shown to predict future onset of diabetes (2–4) and is better than fasting plasma glucose (FPG) for predicting microvascular complications (1). A1C may be superior to FPG in predicting mortality and cardiovascular risk in nondiabetic individuals (5) but inferior to 2-h glucose concentration (2-h plasma glucose) in most studies (6–8), albeit not all (9). The A1C assay has advantages over the measurement of plasma glucose including convenience (not requiring fasting samples) and superior technical attributes (1). Conversely, the number of individuals diagnosed with diabetes by the 6.5% A1C threshold is significantly smaller than the number of those diagnosed by the 2003 American Diabetes Association (ADA) criteria (10–13). A1C, FPG, and 2-h plasma glucose assess different aspects of glucose metabolism (1), but differences in the relation of these three glycemic measures to insulin resistance, insulin secretion, and other metabolic abnormalities have not been described.A1C between 5.7 and 6.4% (A1C 5.7–6.4%) is now considered a category of increased risk for diabetes in addition to impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (1). However, studies that compare A1C 5.7–6.4% with IFG and IGT are lacking. Therefore, our aim was twofold: 1) to analyze A1C, FPG, and 2-h plasma glucose for their ability to identify individuals at increased risk of diabetes; and 2) to examine the relation of these glycemic measures to other metabolic abnormalities, particularly measured insulin resistance and secretion in nondiabetic subjects.     

Effect of case-based training for medical residents on inpatient glycemia

OBJECTIVE

To determine whether an educational intervention for medical house staff improves blood glucose (BG) in hospitalized patients.

RESEARCH DESIGN AND METHODS

All 116 medicine residents at an academic medical center were assigned to online or classroom training on inpatient dysglycemia in fall 2008. Both groups were offered an online refresher course in spring 2009 addressing gaps in clinical practice identified on chart review. We assessed event BG, the first BG of any 3-h period, on two teaching wards.

RESULTS

A total of 108 residents (93.1%) completed the initial training. The primary outcome, median event BG, decreased from 152 mg/dL in August 2008 to 139 mg/dL in December 2008 (P < 0.0001). Prevalence of event BG >200 mg/dL decreased from 25.5 to 22.7% (P = 0.0207), at the expense of more event BGs <70 mg/dL (2.0–3.9%, P = 0.0124).

CONCLUSIONS

A curriculum for medicine residents on inpatient glycemia led to lower inpatient BG.Inpatient hyperglycemia and hypoglycemia are associated with increased morbidity, mortality, and cost (1,2). Nonadherence to published guidelines (3), inadequate hypoglycemia precautions, delayed titration of insulin, and regular insulin sliding-scale use are widely prevalent practices associated with worse dysglycemia (4,5). Many residents (while acknowledging that inpatient dysglycemia is a common problem) profess limited knowledge and motivation to treat it (6,7).Clinician-driven quality improvement strategies including clinician-directed audit-and-feedback cycles improved outcomes in resident-treated ambulatory patients with diabetes (8,9). We designed an interactive course that increased resident confidence and knowledge (10) and studied its effect on inpatient glycemia.     

Two-step approach for the prediction of future type 2 diabetes risk

OBJECTIVE

To develop a model for the prediction of type 2 diabetes mellitus (T2DM) risk on the basis of a multivariate logistic model and 1-h plasma glucose concentration (1-h PG).

RESEARCH DESIGN AND METHODS

The model was developed in a cohort of 1,562 nondiabetic subjects from the San Antonio Heart Study (SAHS) and validated in 2,395 nondiabetic subjects in the Botnia Study. A risk score on the basis of anthropometric parameters, plasma glucose and lipid profile, and blood pressure was computed for each subject. Subjects with a risk score above a certain cut point were considered to represent high-risk individuals, and their 1-h PG concentration during the oral glucose tolerance test was used to further refine their future T2DM risk.

RESULTS

We used the San Antonio Diabetes Prediction Model (SADPM) to generate the initial risk score. A risk-score value of 0.065 was found to be an optimal cut point for initial screening and selection of high-risk individuals. A 1-h PG concentration >140 mg/dL in high-risk individuals (whose risk score was >0.065) was the optimal cut point for identification of subjects at increased risk. The two cut points had 77.8, 77.4, and 44.8% (for the SAHS) and 75.8, 71.6, and 11.9% (for the Botnia Study) sensitivity, specificity, and positive predictive value, respectively, in the SAHS and Botnia Study.

CONCLUSIONS

A two-step model, based on the combination of the SADPM and 1-h PG, is a useful tool for the identification of high-risk Mexican-American and Caucasian individuals.The prevalence of type 2 diabetes mellitus (T2DM) has increased in recent decades to epidemic proportions (1). Because of the chronic course of T2DM, and the significant morbidity and mortality associated with the vascular complications of the disease, T2DM has become not only a serious public health threat but also a heavy economic burden on every health care system (2). Recent clinical trials have demonstrated that the incidence of T2DM can be reduced with lifestyle intervention (3,4) and pharmacotherapy (4,5) in subjects with impaired glucose tolerance (IGT). These results indicate that primary prevention of T2DM is a promising strategy to restrain the epidemic increase in disease prevalence and control the economic burden that it poses on health care expenditure.Accurate identification of subjects at increased risk of future T2DM is essential for every prevention program. It minimizes the number of subjects in the intervention program and improves its efficacy and cost-effectiveness. All previous intervention trials that have tested the efficacy of various prevention strategies have recruited subjects with IGT (3–5) and/or impaired fasting glucose (IFG). Although subjects with IGT are at increased risk for future T2DMt compared with individuals with normal glucose tolerance (NGT), only 35–50% of subjects with IGT convert to T2DM after 5–10 years (6–8), and, even after 20 years of follow-up, only ~50% of subjects with IGT convert to T2DM (8). Furthermore, ~30–40% of subjects who develop T2DM in prospective studies have NGT at baseline (7,8), suggesting that the future risk for T2DMis not similar among all subjects with IGT or NGT. Thus, by solely relying on IGT for the identification of subjects at increased T2DM risk, a large group of high-risk subjects with NGT remains unidentified (9).These limitations associated with the use of IGT to identify high-risk individuals have lead to the development of prediction models based on multivariate logistic models using risk factors for T2DM (e.g., age, sex, BMI, fasting plasma glucose [FPG], lipid profile, and blood pressure) (10–18). These predictive models have been shown to perform as well as IGT in predicting future T2DM risk. Because all of the measurements required for these models are taken during the fasting state, these models have been advocated to replace IGT for the identification of subjects at increased risk for future T2DM without the need to perform an oral glucose tolerance test (OGTT).Although multivariate prediction models have better sensitivity compared with IGT in identifying subjects at increased T2DM risk, they have relatively low specificity and positive predictive value (PPV). We previously (19–21) have shown that a plasma glucose concentration >155 mg/dL at 1 h during the OGTT identifies subjects at increased T2DM risk with relatively high sensitivity and specificity. We also demonstrated that the 1-h plasma glucose concentration (1-h PG) performs superiorly to both IGT and multivariate prediction models in the identification of high-risk individuals. Furthermore, we demonstrated that the addition of the 1-h PG to multivariate prediction models significantly improves their predictive power, indicating that the 1-h PG contains additional information about future T2DM risk compared with all known diabetes risk factors. However, similar to IGT, the 1-h PG requires a glucose load.In this study, we used data from the San Antonio Heart Study (SAHS) to develop a two-step model for the prediction of future T2DM risk. This model involves screening all nondiabetic subjects using the San Antonio Diabetes Prediction Model (SADPM) (14,19) and administering an oral glucose load to obtain the 1-h PG value, only in high-risk individuals, to further refine their future T2DM risk. We demonstrate that this two-step model decreases the number of subjects who require an oral glucose load and has high sensitivity, specificity, and PPV in identifying subjects at increased T2DM risk.     

Postchallenge Glucose, A1C, and Fasting Glucose as Predictors of Type 2 Diabetes and Cardiovascular Disease: A 10-year prospective cohort study

OBJECTIVE

A1C has been proposed as a new indicator for high risk of type 2 diabetes. The long-term predictive power and comparability of elevated A1C with the currently used high-risk indicators remain unclear. We assessed A1C, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) as predictors of type 2 diabetes and cardiovascular disease (CVD) at 10 years.

RESEARCH DESIGN AND METHODS

This prospective population-based study of 593 inhabitants from northern Finland, born in 1935, was conducted between 1996 and 2008. An oral glucose tolerance test (OGTT) was conducted at baseline and follow-up, and A1C was determined at baseline. Those with a history of diabetes were excluded from the study. Elevated A1C was defined as 5.7–6.4%. Incident type 2 diabetes was confirmed by two OGTTs. Cardiovascular outcome was measured as incident CVD or CVD mortality. Multivariate log-binomial regression models were used to predict diabetes, CVD, and CVD mortality at 10 years. Receiver operating characteristic curves compared predictive values of A1C, IGT, and IFG.

RESULTS

Incidence of diabetes during the follow-up was 17.1%. Two of three of the cases of newly diagnosed diabetes were predicted by a raise in ≥1 of the markers. Elevated A1C, IGT, or IFG preceded diabetes in 32.8, 40.6, and 21.9%, respectively. CVD was predicted by an intermediate and diabetic range of 2-h glucose but only by diabetic A1C levels in women.

CONCLUSIONS

A1C predicted 10-year risk of type 2 diabetes at a range of A1C 5.7–6.4% but CVD only in women at A1C ≥6.5%.Early detection of high risk for type 2 diabetes is fundamental for prevention of diabetes and associated cardiovascular complications. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are currently used for diagnosis of high-risk glucose levels below the diabetic range. The International Expert Committee proposed A1C ≥6.5% as a diagnostic tool for diabetes in 2009 (1) and in January 2010 an intermediate range of A1C 5.7–6.4% (elevated A1C) was proposed by the American Diabetes Association (ADA) to detect individuals at high risk for developing type 2 diabetes (2).To date, however, limited data exist to support the use of A1C in predicting type 2 diabetes (3–8). Importantly, the long-term predictive power of elevated A1C as defined above has not yet been investigated. Previous data on the association between A1C and incident type 2 diabetes in unselected populations have relied on self-reporting, fasting glucose measurements, and use of antidiabetes medication to determine the outcomes. An oral glucose tolerance test (OGTT) has not been used to determine the outcome (3–8).Deterioration of glucose homeostasis reflects a continuum of glycemia, some of which is reversible if detected early (9,10). Importantly, the risk of cardiovascular disease is increased already before glycemia reaches the levels of diabetes, and 2-h glucose appears to be a better predictor of cardiovascular disease (CVD) than fasting glucose (11). Recently, A1C was shown to be a better predictor of CVD than fasting glucose (12).Data directly comparing 2-h glucose and A1C as long-term predictors of new-onset cardiovascular disease are scarce, and results are controversial (13,14). Therefore, we compared A1C, 2-h glucose, and fasting glucose as predictors of type 2 diabetes, CVD, and CVD mortality during a prospective population-based study with a 10-year follow-up.     

Comparison of near-patient capillary glucose measurement and a risk assessment questionnaire in screening for type 2 diabetes in a high-risk population in rural India

OBJECTIVE

To assess the utility of a point-of-care (POC) capillary blood glucose measurement as compared with routine clinical parameters in predicting undiagnosed diabetes in a low-resource rural India setting.

RESEARCH DESIGN AND METHODS

Nine hundred and ninety-four participants aged >30 years and stratified by age and sex were randomly selected from 20 villages in India. A clinical questionnaire, sampling for laboratory venous fasting plasma glucose (FPG), and POC capillary blood glucose assay were performed simultaneously. Diabetes diagnosis was based on the World Health Organization (WHO) definition using FPG. The capacity of the POC glucose to predict the presence of diabetes was assessed and compared with the questionnaire using area under the receiver operating characteristic curves (AUCs).

RESULTS

The AUC for POC glucose alone in predicting diabetes was 0.869 (95% CI 0.810–0.929). This was significantly better (P < 0.001 for AUC comparison) than the models based upon clinical variables alone (AUC for the best clinical model including age, BMI, hypertension, waist circumference: 0.694 [95% CI 0.621–0.766]). POC glucose appropriately reclassified the risk of up to one-third of participants ranked according to the clinical models. Adding the clinical variables to the POC glucose assay did not significantly improve the discriminatory capability beyond that achieved with the POC glucose measurement alone (all P > 0.37).

CONCLUSIONS

POC glucose testing appears to be a simple and reliable tool for identifying undiagnosed diabetes in a high-risk, resource-poor rural population. However, studies evaluating the cost effectiveness of introducing POC glucose testing are needed prior to widespread implementation.The prevalence of type 2 diabetes is rapidly increasing around the world (1). Developing countries are facing the largest increases both in absolute and relative terms (1). It is predicted that this will have devastating consequences on the economies and health systems of these countries. Successful prevention and early management of diabetes is therefore a major health priority (1,2).In many regions, up to 50% of people with diabetes remain undiagnosed (1,3,4). Failure to improve these levels of detection will mean that the opportunity to improve health outcomes with early intervention will be lost. Early treatment with successful glucose control significantly reduces the morbidity and mortality associated with diabetes (5,6). Earlier detection of diabetes also allows for the implementation of other treatments that reduce the vascular complications of diabetes (5,6).Universal screening for diabetes is not currently recommended due to a lack of good evidence for an accurate test. However, targeted screening is advocated in certain ethnic groups deemed at increased risk of diabetes (2). For some ethnic groups, implementation of targeted screening may require the entire population to be screened. This applies for instance to Asian Indian populations, which are at greater risk of developing diabetes (7) and have a high prevalence of diabetes both in urban (4) and rural settings (3). However to successfully apply screening to such populations requires accurate, safe, and low-cost diagnostic strategies that are easy to implement (8).In resource-poor settings, clinical variables–based risk assessment questionnaires or point-of-care (POC) glucose analysis may be reasonable screening tools (9). Both require little expertise and allow an individual''s risk of having undiagnosed diabetes to be immediately determined so that only those at high risk require a confirmatory diagnostic test. However, the value of risk assessment questionnaires (9–13) and POC glucose analysis (14–16) in resource-poor settings remains unclear. Additionally the performance of these different screening methods has not been compared in rural Asian Indian populations.The aim of this study was to quantify and compare the accuracy of strategies based on POC glucose, clinical variables, and the combination of both in predicting undiagnosed diabetes in an asymptomatic, resource-poor rural Asian Indian population.     

Incident Dysglycemia and Progression to Type 1 Diabetes Among Participants in the Diabetes Prevention Trial�CType 1

OBJECTIVE

We studied the incidence of dysglycemia and its prediction of the development of type 1 diabetes in islet cell autoantibody (ICA)-positive individuals. In addition, we assessed whether dysglycemia was sustained.

RESEARCH DESIGN AND METHODS

Participants (n = 515) in the Diabetes Prevention Trial–Type 1 (DPT-1) with normal glucose tolerance who underwent periodic oral glucose tolerance tests (OGTTs) were followed for incident dysglycemia (impaired fasting glucose, impaired glucose tolerance, and/or high glucose levels at intermediate time points of OGTTs). Incident dysglycemia at the 6-month visit was assessed for type 1 diabetes prediction.

RESULTS

Of 515 participants with a normal baseline OGTT, 310 (60%) had at least one episode of dysglycemia over a maximum follow-up of 7 years. Dysglycemia at the 6-month visit was highly predictive of the development of type 1 diabetes, both in those aged <13 years (P < 0.001) and those aged ≥13 years (P < 0.01). Those aged <13 years with dysglycemia at the 6-month visit had a high cumulative incidence (94% estimate by 5 years). Among those who developed type 1 diabetes after a dysglycemic OGTT and who had at least two OGTTs after the dysglycemic OGTT, 33 of 64 (52%) reverted back to a normal OGTT. However, 26 (79%) of the 33 then had another dysglycemic OGTT before diagnosis.

CONCLUSIONS

ICA-positive individuals with normal glucose tolerance had a high incidence of dysglycemia. Incident dysglycemia in those who are ICA positive is strongly predictive of type 1 diabetes. Children with incident dysglycemia have an especially high risk. Fluctuations in and out of the dysglycemic state are not uncommon before the onset of type 1 diabetes.There is increasing evidence that impaired glucose tolerance (IGT) is a predictor and common precursor of type 1 diabetes (1–3). Still, little is known about the incidence of IGT and other forms of dysglycemia in individuals who have pancreatic autoantibodies and normal glucose tolerance. In addition, there is no information about the risk of type 1 diabetes when dysglycemia occurs in those individuals. Moreover, it is not known whether dysglycemia is sustained once it occurs.We used data from the Diabetes Prevention Trial–Type 1 (DPT-1) (4,5) to examine these questions. In addition to IGT, impaired fasting glucose (IFG) and high glucose values at intermediate times (between fasting and 2 h) during oral glucose tolerance tests (OGTTs), termed indeterminate glycemia (INDET), were included as other forms of dysglycemia in the analyses. Glucose levels at intermediate times have been shown to be predictive of type 1 diabetes (6,7).Information regarding the incidence of these various forms of dysglycemia and their prediction of type 1 diabetes should be helpful for understanding the pathogenesis and natural history of type 1 diabetes. Such information should also be useful for improving type 1 diabetes prevention trials.     

Changes in Insulin Secretion and Insulin Sensitivity in Relation to the Glycemic Outcomes in Subjects With Impaired Glucose Tolerance in the Indian Diabetes Prevention Programme-1 (IDPP-1)

OBJECTIVE

The Indian Diabetes Prevention Programme-1 (IDPP-1) showed that lifestyle modification (LSM) and metformin were effective for primary prevention of diabetes in subjects with impaired glucose tolerance (IGT). Among subjects followed up for 3 years (n = 502), risk reductions versus those for the control group were 28.5, 26.4, and 28.2% in LSM, metformin (MET), and LSM plus MET groups, respectively. In this analysis, the roles of changes in secretion and action of insulin in improving the outcome were studied.

RESEARCH DESIGN AND METHODS

For this analysis, 437 subjects (93 subjects with normoglycemia [NGT], 150 subjects with IGT, and 194 subjects with diabetes) were included. Measurements of anthropometry, plasma glucose, and plasma insulin at baseline and at follow-up were available for all of them. Indexes of insulin resistance (homeostasis model assessment of insulin resistance) and β-cell function (insulinogenic index [ΔI/G]: 30-min fasting insulin divided by 30-min glucose) were also analyzed in relation to the outcome.

RESULTS

Subjects with IGT showed a deterioration in β-cell function with time. Individuals with higher insulin resistance and/or low β-cell function at baseline had poor outcome on follow-up. In relation to no abnormalities, the highest incidence of diabetes occurred when both abnormalities coexisted (54.9 vs. 33.7%, χ² = 7.53, P = 0.006). Individuals having abnormal insulin resistance (41.1%) or abnormal ΔI/G (51.2%, χ² = 4.87, P = 0.027 vs. no abnormalities) had lower incidence. Normal β-cell function with improved insulin sensitivity facilitated reversal to NGT, whereas deterioration in both resulted in diabetes. The beneficial changes were better with intervention than in the control group. Intervention groups had higher rates of NGT and lower rates of diabetes.

CONCLUSIONS

In the IDPP-1 subjects, beneficial outcomes occurred because of improved insulin action and sensitivity caused by the intervention strategies.Primary prevention studies in diabetes have been done in subjects with a high risk for diabetes, such as those with impaired glucose tolerance (IGT) (1–6) or with a history of gestational diabetes mellitus (7). Lifestyle modification (LSM) (1–5) and/or pharmacological agents such as metformin (MET) (1,5) and glitazones (6) have been shown to be effective in reducing the rate of conversion of IGT to diabetes in different ethnic groups. The benefits are seen in association with weight reduction in the obese population (1,2) or without significant weight changes in relatively nonobese population (3,5). The mechanisms that result in the beneficial changes are associated with two important pathophysiological components, namely impaired secretion and impaired action of insulin.The Indian Diabetes Prevention Programme-1 (IDPP-1) had shown that moderate, but consistent, LSM or use of MET reduced the risk of deterioration of IGT to diabetes by 28% in relation to that in a control group who had no intervention in a 3-year follow-up period (5). Combining LSM with MET showed no added benefit.IGT, an intermediate state in the natural history of type 2 diabetes, is characterized by a worsening in insulin resistance and insulin secretion (8). Asian Indians have higher rates of insulin resistance than Europeans and other white populations despite being relatively nonobese (9,10).The chief pathophysiological components of type 2 diabetes, namely impaired secretion and action of insulin are detectable many years before the diagnosis of clinical diabetes (11). A combined occurrence of both defects due to gradual deterioration, eventually results in diabetes. This analysis was done to identify the changes in insulin secretion and insulin action that produced the improved outcome with the primary prevention strategies in the IDPP-1 cohort.     

Many Americans Have Pre-Diabetes and Should Be Considered for Metformin Therapy

OBJECTIVE

To determine the proportion of the American population who would merit metformin treatment, according to recent American Diabetes Association (ADA) consensus panel recommendations to prevent or delay the development of diabetes.

RESEARCH DESIGN AND METHODS

Risk factors were evaluated in 1,581 Screening for Impaired Glucose Tolerance (SIGT), 2,014 Third National Health and Nutrition Examination Survey (NHANES III), and 1,111 National Health and Nutrition Examination Survey 2005–2006 (NHANES 2005–2006) subjects, who were non-Hispanic white and black, without known diabetes. Criteria for consideration of metformin included the presence of both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), with ≥1 additional diabetes risk factor: age <60 years, BMI ≥35 kg/m², family history of diabetes, elevated triglycerides, reduced HDL cholesterol, hypertension, or A1C >6.0%.

RESULTS

Isolated IFG, isolated IGT, and IFG and IGT were found in 18.0, 7.2, and 8.2% of SIGT; 22.3, 6.4, and 9.4% of NHANES III; and 21.8, 5.0, and 9.0% of NHANES 2005–2006 subjects, respectively. In SIGT, NHANES III, and NHANES 2005–2006, criteria for metformin consideration were met in 99, 96, and 96% of those with IFG and IGT; 31, 29, and 28% of all those with IFG; and 53, 57, and 62% of all those with IGT (8.1, 9.1, and 8.7% of all subjects), respectively.

CONCLUSIONS

More than 96% of individuals with both IFG and IGT are likely to meet ADA consensus criteria for consideration of metformin. Because >28% of all those with IFG met the criteria, providers should perform oral glucose tolerance tests to find concomitant IGT in all patients with IFG. To the extent that our findings are representative of the U.S. population, ∼1 in 12 adults has a combination of pre-diabetes and risk factors that may justify consideration of metformin treatment for diabetes prevention.Diabetes is a public health epidemic (1) associated with high morbidity, mortality (1), and cost (2). Currently, an estimated 38 million Americans have the disease, nearly 40% of which is undiagnosed, and another 87 million have pre-diabetes: impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) (3). Diabetes develops insidiously over several years, during which time glucose metabolism progresses slowly from normal to pre-diabetes and then more rapidly to diabetes. Based on observational and prospective studies, ∼25–40% of individuals with pre-diabetes go on to develop diabetes over 3–8 years (4–6), and there is evidence of complications in 50% of patients at the time of diagnosis of diabetes (7).Because progression from pre-diabetes can be prevented or delayed by lifestyle change and/or medication (4–6), the American Diabetes Association (ADA) has issued a consensus statement recommending early identification and preventive treatment in high-risk individuals (8). The panel statement recommends that individuals with both IFG and IGT and one additional risk factor (age <60 years, BMI ≥35 kg/m², family history of diabetes in first-degree relative, elevated triglycerides, reduced HDL cholesterol, or A1C >6.0%) should be considered for treatment with metformin, in addition to lifestyle modification, which includes weight loss and physical activity.To determine what proportion of the American population presenting with either IFG or IGT would merit consideration for metformin treatment in accordance with the recent ADA recommendations, we evaluated healthy volunteers without known diabetes who were screened for diabetes/pre-diabetes by the 75-g oral glucose tolerance test (OGTT).     

��-Cell�CMediated Signaling Predominates Over Direct ��-Cell Signaling in the Regulation of Glucagon Secretion in Humans

OBJECTIVE

Given evidence of both indirect and direct signaling, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans.

RESEARCH DESIGN AND METHODS

We measured plasma glucagon concentrations before and after ingestion of a formula mixed meal and, on a separate occasion, ingestion of the sulfonylurea glimepiride in 24 basal insulin-infused, demonstrably β-cell–deficient patients with type 1 diabetes and 20 nondiabetic, demonstrably β-cell–sufficient individuals; the latter were infused with glucose to prevent hypoglycemia after glimepiride.

RESULTS

After the mixed meal, plasma glucagon concentrations increased from 22 ± 1 pmol/l (78 ± 4 pg/ml) to 30 ± 2 pmol/l (103 ± 7 pg/ml) in the patients with type 1 diabetes but were unchanged from 27 ± 1 pmol/l (93 ± 3 pg/ml) to 26 ± 1 pmol/l (89 ± 3 pg/ml) in the nondiabetic individuals (P < 0.0001). After glimepiride, plasma glucagon concentrations increased from 24 ± 1 pmol/l (83 ± 4 pg/ml) to 26 ± 1 pmol/l (91 ± 4 pg/ml) in the patients with type 1 diabetes and decreased from 28 ± 1 pmol/l (97 ± 5 pg/ml) to 24 ± 1 pmol/l (82 ± 4 pg/ml) in the nondiabetic individuals (P < 0.0001). Thus, in the presence of both β-cell and α-cell secretory stimuli (increased amino acid and glucose levels, a sulfonylurea) glucagon secretion was prevented when β-cell secretion was sufficient but not when β-cell secretion was deficient.

CONCLUSIONS

These data indicate that, among the array of signals, indirect reciprocal β-cell–mediated signaling predominates over direct α-cell signaling in the regulation of glucagon secretion in humans.The regulation of pancreatic islet α-cell glucagon secretion is complex (1–10). It involves direct signaling of α-cells (1) and indirect signaling of α-cells by β-cell (2–6) and δ-cell (7) secretory products, the autonomic nervous system (8,9), and gut incretins (10).Appropriate glucagon secretory responses occur from the perfused pancreas (3,5) and perifused islets (2). Low plasma glucose concentrations stimulate glucagon secretion from the transplanted (i.e., denervated) human pancreas (11) and the denervated dog pancreas (12). Therefore, we have focused on the intraislet regulation of glucagon secretion. Furthermore, because selective destruction of β-cells results in loss of the glucagon response to hypoglycemia in type 1 diabetes (13), and partial reduction of the β-cell mass in minipigs results in impaired postprandial suppression of glucagon secretion (14), we have focused on the role of β-cell–mediated signaling in the regulation of glucagon secretion.Findings from studies of the perfused rat (3,4) and human (5) pancreas, rats in vivo (6), rat islets (2), isolated rat α-cells (2), and humans (15–18) have been interpreted to indicate that a β-cell secretory product or products tonically restrains basal α-cell glucagon secretion during euglycemia and that a decrease in β-cell secretion, coupled with low glucose concentrations at the α-cells, signals an increase in glucagon secretion in response to hypoglycemia. Parenthetically, the relative roles of the candidate β-cell secretory products (insulin, zinc, γ-aminobutyric acid, and amylin, among others) (2) that normally restrain α-cell glucagon secretion remain to be determined. However, that interpretation rests, in part, on results of studies in isolated rat α-cells (2), which are debated (1), and on the evidence that the islet microcirculation flows from β-cells to α-cells to δ-cells (4), which is also debated (19). Furthermore, it does not address the plausible possibility that a decrease in intraislet δ-cell somatostatin secretion might also signal an increase in α-cell glucagon secretion during hypoglycemia (7).Given that interpretation, it follows that an increase in β-cell secretion would signal a decrease in glucagon secretion in the postprandial state (14). The concept is an interplay of indirect reciprocal β-cell–mediated signaling of α-cells and of direct α-cell signaling in the regulation of glucagon secretion.There is, in our view, compelling evidence that, among other mechanisms, both indirect reciprocal β-cell–mediated signaling of α-cells (2–6) and direct α-cell signaling (1) are involved in the regulation of glucagon secretion by nutrients, hormones, neurotransmitters, and drugs. Given that premise, we posed the question: Which of these predominates in humans? Accordingly, we tested the hypothesis that increased β-cell–mediated signaling of α-cells negates direct α-cell signaling in the regulation of glucagon secretion in humans. To do so, we measured plasma glucagon responses to ingestion of a mixed meal and, on a separate occasion, to ingestion of the sulfonylurea glimepiride in patients with type 1 diabetes and in nondiabetic individuals. We conceptualized patients with type 1 diabetes as a model of α-cells isolated from β-cells because their β-cells had been destroyed but they have functioning α-cells. (Their α-cells are not, of course, isolated from other islet cells, including δ-cells.) Increased plasma amino acid and glucose levels after a mixed meal and sulfonylureas normally stimulate β-cell secretion; increased plasma amino acid and perhaps glucose (2) levels after a mixed meal and sulfonylureas (1) stimulate α-cell secretion. Our hypothesis predicts that such factors that normally stimulate both β-cells and α-cells would stimulate glucagon secretion in patients with type 1 diabetes but not in nondiabetic individuals, i.e., in the virtual absence and the presence of β-cell function, respectively. Indeed, a mixed meal (20,21) and the secretagogues tolbutamide (22), glyburide (23), and repaglinide (23) have been reported to raise plasma glucagon concentrations in patients with type 1 diabetes, but all of those studies lacked nondiabetic control subjects.     

From Pre-Diabetes to Type 2 Diabetes in Obese Youth: Pathophysiological characteristics along the spectrum of glucose dysregulation

OBJECTIVE

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are considered pre-diabetes states. There are limited data in pediatrics in regard to their pathophysiology. We investigated differences in insulin sensitivity and secretion among youth with IFG, IGT, and coexistent IFG/IGT compared with those with normal glucose tolerance (NGT) and type 2 diabetes.

RESEARCH DESIGN AND METHODS

A total of 24 obese adolescents with NGT, 13 with IFG, 29 with IGT, 11 with combined IFG/IGT, and 30 with type 2 diabetes underwent evaluation of hepatic glucose production ([6,6-²H₂]glucose), insulin-stimulated glucose disposal (R_d, euglycemic clamp), first- and second-phase insulin secretion (hyperglycemic clamp), body composition (dual-energy X-ray absorptiometry), abdominal adiposity (computed tomography), and substrate oxidation (indirect calorimetry).

RESULTS

Adolescents with NGT, pre-diabetes, and type 2 diabetes had similar body composition and abdominal fat distribution. R_d was lower (P = 0.009) in adolescents with type 2 diabetes than in those with NGT. Compared with adolescents with NGT, first-phase insulin was lower in those with IFG, IGT, and IFG/IGT with further deterioration in those with type 2 diabetes (P < 0.001), and β-cell function relative to insulin sensitivity (glucose disposition index [GDI]) was also lower in those with IFG, IGT, and IFG/IGT (40, 47, and 47%, respectively), with a further decrease (80%) in those with type 2 diabetes (P < 0.001). GDI was the major determinant of fasting and 2-h glucose levels.

CONCLUSIONS

Obese adolescents who show signs of glucose dysregulation, including abnormal fasting glucose, glucose intolerance or both, are more likely to have impaired insulin secretion rather than reduced insulin sensitivity. Given the impairment in insulin secretion, they are at high risk for progression to type 2 diabetes. Further deterioration in insulin sensitivity or secretion may enhance the risk for this progression.Pre-diabetes, defined as the presence of elevated fasting glucose, abnormal glucose tolerance, or both, is associated with an enhanced risk for development of type 2 diabetes in adults (1), but there are limited data to define the significance in children. A recent change in the definition of the abnormal fasting glucose to a lower level (100–125 mg/dl) has increased the prevalence of pre-diabetes in both adults and youth (2–4). It is unclear from the literature what role a defect in insulin secretion or an abnormality of insulin sensitivity might play in the impairment of glucose regulation, leading to glucose intolerance or elevated fasting plasma glucose.Epidemiological studies suggest that subjects with impaired fasting glucose (IFG) have lower insulin sensitivity and higher insulin secretion (5,6) based largely on fasting indexes of insulin sensitivity and an oral glucose tolerance (OGTT)–derived single index of insulin secretion (5). Adult studies reveal similar or lower insulin sensitivity in subjects with impaired glucose tolerance (IGT) compared with those with IFG who have lower insulin secretion (7,8). These studies are contrasted with clamp studies in Pima Indians showing similar insulin sensitivity in subjects with IFG and IGT but lower insulin secretion in those with fasting dysglycemia (9).Pediatric data are limited. In overweight Latino children with a family history of type 2 diabetes (10), children with impaired versus normal fasting glucose had no significant differences in insulin sensitivity or acute insulin response. However, the glucose disposition index (GDI), or insulin secretion relative to insulin sensitivity, was significantly reduced (15% lower) in children with IFG. A more recent study in obese adolescents revealed that subjects with IFG had decreased glucose sensitivity of first-phase insulin secretion and liver insulin sensitivity, whereas those with IGT had more severe degrees of peripheral insulin resistance compared with subjects with normal glucose tolerance (NGT) (11). We recently demonstrated that insulin secretion relative to insulin sensitivity shows a significantly declining pattern: highest in youth with NGT, intermediate in youth with IGT, and lowest in youth with type 2 diabetes (12).In an attempt to clarify the controversy concerning the metabolic derangements in the different categories of the pre-diabetes state, the aims of the present study were to 1) to investigate the metabolic characteristics of insulin sensitivity and secretion in obese youth, with IFG versus IGT, of similar body composition and abdominal adiposity and 2) to compare them not only with those with NGT but also with children with type 2 diabetes.     

Association of depressive symptoms with impaired glucose regulation, screen-detected, and previously known type 2 diabetes: findings from the Finnish D2D Survey

OBJECTIVE

To study the association between impaired glucose regulation (IGR), screen-detected type 2 diabetes, and previously known diabetes and depressive symptoms.

RESEARCH DESIGN AND METHODS

Altogether, 2,712 participants from three hospital districts in Finland attended a health examination. Cutoff scores ≥10 and ≥16 in the 21-item Beck Depression Inventory (BDI-21) were used for depressive symptoms. The participants were defined as having known diabetes if they reported diabetes. An oral glucose tolerance test was used to detect normal glucose regulation (NGR), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and screen-detected diabetes. The participants were defined as having IGR if they had IFG or IGT.

RESULTS

Prevalence of depressive symptoms, defined as a BDI-21 cutoff score ≥10, was 14.4% for those with NGR, 13.7% for those with IGR, 14.8% for those with screen-detected diabetes, and 26.4% for those with previously known diabetes. The corresponding prevalences for a cutoff score ≥16 were 3.4, 3.4, 4.2, and 7.5%, respectively. Compared with NGR and adjusted for demographic, lifestyle, and biological factors, the odds ratios for IGR, screen-detected diabetes, and previously known diabetes were 0.91 (95% CI 0.69–1.20), 0.70 (0.45–1.08), and 1.35 (0.84–2.15), respectively, for a cutoff score ≥10. For a cutoff score ≥16, the corresponding odds ratios were 1.05 (0.62–1.76), 0.87 (0.40–1.90), and 1.56 (0.69–3.50), respectively.

CONCLUSIONS

Participants with diagnosed diabetes had a higher prevalence of depressive symptoms than participants with NGR, IGR, and previously unknown diabetes. When potential confounding factors were included in the analysis, previously known diabetes was not significantly associated with depressive symptoms.It is widely recognized that depression is more common among people with diabetes than in the general population (1). However, previous studies (2–10) that have assessed the relationship between depressive symptoms and impaired glucose tolerance (IGT) or diabetes have been inconsistent. A German study (4) that included 4,597 subjects and a Dutch study (2) that included 4,747 participants found no association between type 2 diabetes and depressive symptoms. In a general-practice setting study that included 2,849 male and 3,160 female subjects, depression was not more prevalent in people with screen-detected diabetes or impaired glucose regulation (IGR) than in people with normal glucose regulation (NGR) (5). Contrary to these studies, within the Hertfordshire Cohort Study (6) there was a relationship between depression scores and diagnosed and previously undiagnosed diabetes. A U.S. study (8) including 4,293 U.S. veterans indicated that men with undiagnosed type 2 diabetes had nearly double the odds of major depression compared with those with normal fasting glucose.In 1992, it was stated about the relationship between depression and diabetes that “the etiology is unknown but is probably complex; and biological, genetic, and psychological factors remain as potential contributors. Several neuroendocrine and neurotransmitter abnormalities common to both depression and diabetes have been identified, adding to etiological speculations” (11). It has been suggested that stress-induced activation of the hypothalamic-pituitary-adrenal axis may result in the development of metabolic abnormalities and depression (12). In addition, possible neuroendocrine abnormalities associated with both diabetes and depressive symptoms may include abnormalities in vitamin B₁₂ and sex hormone–binding globulin (SHBG) levels. Low vitamin B₁₂ levels have been found to relate to type 2 diabetes (13) and depressive symptoms (14–16). Low levels of SHBG may predict diabetes (17). SHBG binds circulating sex hormones, which have been suggested to be associated with depressive symptoms (18). In addition to these biological factors, the observed association between diabetes and depressive symptoms could be a reflection of the burden of diabetes and comorbidities.In the present study, our aim was to analyze the prevalence of depressive symptoms in people with NGR, IGR (including impaired fasting glycemia and impaired glucose tolerance), screen-detected (previously unknown) diabetes, and previously known type 2 diabetes. Furthermore, our aim was to study the association between glucose tolerance and depressive symptoms, taking into account potential confounding demographic and biological factors as well as comorbidity.     

Effect of Rosiglitazone and Ramipril on ��-Cell Function in People With Impaired Glucose Tolerance or Impaired Fasting Glucose: The DREAM trial

OBJECTIVE

The objective of this study was to determine the degree to which ramipril and/or rosiglitazone changed β-cell function over time among individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) who participated in the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) Trial, which evaluated whether ramipril and/or rosiglitazone could prevent or delay type 2 diabetes in high-risk individuals.

RESEARCH DESIGN AND METHODS

The present analysis included subjects (n = 982) from DREAM trial centers in Canada who had oral glucose tolerance tests at baseline, after 2 years, and at the end of the study. β-Cell function was assessed using the fasting proinsulin–to–C-peptide ratio (PI/C) and the insulinogenic index (defined as 30–0 min insulin/30–0 min glucose) divided by homeostasis model assessment of insulin resistance (insulinogenic index [IGI]/insulin resistance [IR]).

RESULTS

Subjects receiving rosiglitazone had a significant increase in IGI/IR between baseline and end of study compared with the placebo group (25.59 vs. 1.94, P < 0.0001) and a significant decrease in PI/C (−0.010 vs. −0.006, P < 0.0001). In contrast, there were no significant changes in IGI/IR or PI/C in subjects receiving ramipril compared with placebo (11.71 vs. 18.15, P = 0.89, and −0.007 vs. −0.008, P = 0.64, respectively). The impact of rosiglitazone on IGI/IR and PI/C was similar within subgroups of isolated IGT and IFG + IGT (all P < 0.001). Effects were more modest in those with isolated IFG (IGI/IR: 8.95 vs. 2.13, P = 0.03; PI/C: −0.003 vs. −0.001, P = 0.07).

CONCLUSIONS

Treatment with rosiglitazone, but not ramipril, resulted in significant improvements in measures of β-cell function over time in pre-diabetic subjects. Although the long-term sustainability of these improvements cannot be determined from the present study, these findings demonstrate that the diabetes preventive effect of rosiglitazone was in part a consequence of improved β-cell function.Pancreatic β-cell dysfunction plays a central role the pathogenesis of type 2 diabetes (1). It is present in people at high risk for type 2 diabetes, including those with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (2,3), and it predicts the development of type 2 diabetes in prospective studies of people with these disorders (4,5). β-Cell function is also known to decline steadily over the course of type 2 diabetes, highlighting the progressive nature of this disorder (6). It is therefore crucial to understand the factors that erode or preserve β-cell function across the spectrum of glucose tolerance. Relatively little information is available, however, regarding the determinants of β-cell dysfunction in humans (1).Recent evidence suggests that thiazolidinediones (TZDs) and ACE inhibitors may preserve β-cell function (7,8). Although TZDs have been demonstrated to improve glucose control and β-cell function in type 2 diabetes (9–11), very little is known about the effect of TZDs on β-cell function in people with hyperglycemia in the nondiabetic range, namely those with IGT and/or IFG (12–15). Similarly, while it has been hypothesized that ACE inhibitors may lower glucose via direct effects on the β-cell (16), studies have not been conducted in people with IGT and/or IFG.The objectives of this study, therefore, were to determine the degree to which ramipril (an ACE inhibitor) and/or rosiglitazone (a TZD) changed β-cell function over time among individuals with IFG and/or IGT who participated in the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) Trial, which evaluated whether ramipril and/or rosiglitazone could prevent or delay diabetes in high-risk individuals. We also aimed to determine the degree to which changes in indexes of β-cell function over time were modified by baseline glucose tolerance status and whether ramipril and/or rosiglitazone''s effect on diabetes incidence was mediated by treatment-induced changes in β-cell function.     

Evaluation of nonfasting tests to screen for childhood and adolescent dysglycemia

OBJECTIVE

To assess performance of nonfasting tests to screen children for dysglycemia (prediabetes or diabetes).

RESEARCH DESIGN AND METHODS

This was a cross-sectional study of 254 overweight or obese (BMI ≥85th percentile) children aged 10–17 years. Subjects came for two visits to a clinical research unit. For visit one, they arrived fasting and a 2-h glucose tolerance test and HbA_1c and fructosamine testing were performed. For visit two, they arrived nonfasting and had a random plasma glucose, a 1-h 50-g nonfasting glucose challenge test (1-h GCT), and urine dipstick performed. The primary end point was dysglycemia (fasting plasma glucose ≥100 mg/dL or a 2-h postglucose ≥140 mg/dL). Test performance was assessed using receiver operating characteristic (ROC) curves and calculations of area under the ROC curve.

RESULTS

Approximately one-half of children were female, 59% were white, and 30% were black. There were 99 (39%) cases of prediabetes and 3 (1.2%) cases of diabetes. Urine dipstick, HbA_1c (area under the curve [AUC] 0.54 [95% CI 0.47–0.61]), and fructosamine (AUC 0.55 [0.47–0.63]) displayed poor discrimination for identifying children with dysglycemia. Both random glucose (AUC 0.66 [0.60–0.73]) and 1-h GCT (AUC 0.68 [0.61–0.74]) had better levels of test discrimination than HbA_1c or fructosamine.

CONCLUSIONS

HbA_1c had poor discrimination, which could lead to missed cases of dysglycemia in children. Random glucose or 1-h GCT may potentially be incorporated into clinical practice as initial screening tests for prediabetes or diabetes and for determining which children should undergo further definitive testing.Rates of type 2 diabetes in the U.S. pediatric population are rising (1,2). Because type 2 diabetes can be asymptomatic at diagnosis and requires tight glycemic, blood pressure, and lipid control to delay the onset of microvascular and macrovascular complications, screening for type 2 diabetes in children is endorsed by the American Diabetes Association (ADA) and the American Academy of Pediatrics (3,4). There is also increasing interest in screening for prediabetes in the pediatric population (5,6), given its increasing prevalence (7) and the documented link between prediabetes in childhood and development of diabetes in young adulthood (8).The ADA guidelines (3) recommend that children with a BMI ≥85th percentile for age and sex and additional risk factors should be screened every 2 years starting at age 10 years or at onset of puberty and that either a fasting plasma glucose (FPG) or a 2-h glucose tolerance test be performed. However, these recommendations were based on expert opinion and were not evidence based, as acknowledged by the ADA in its Position Statement.Both FPG and 2-h postload glucose have traditionally been used as the gold standard tests for diagnosing diabetes, but both tests require that the individual be fasting, which is an important barrier to screening. Studies have found that only a minority (4–21%) of pediatric providers in the primary care setting have screening practices consistent with the ADA guidelines (9,10) and instead use nonfasting tests, such as HbA_1c, random glucose, or urinalysis.Furthermore, in 2009, the screening and diagnosis landscape changed when an international expert committee of individuals from the ADA and their international counterparts recommended that HbA_1c be exclusively used for the diagnosis of diabetes with eventual phase out of additional glucose measurements such as FPG and the 2-h postload glucose (11).Despite the frequent use of nonfasting tests by physicians in clinical practice and the recent guideline advocating HbA_1c as a diagnostic test for diabetes among children, there is a critical lack of data about the performance of nonfasting tests in children. Therefore, the objective of our study was to assess the test performance of nonfasting screening tests, including HbA_1c, urinalysis, fructosamine, a nonfasting 1-h glucose challenge test (1-h GCT), and a random blood glucose for identifying adolescents aged 10–17 years with dysglycemia. Empiric information about test performance for nonfasting diabetes tests is critical for the development of evidence-based screening recommendations for prediabetes and diabetes in overweight and obese children.     

Closed-Loop Insulin Delivery Using a Subcutaneous Glucose Sensor and Intraperitoneal Insulin Delivery: Feasibility study testing a new model for the artificial pancreas

OBJECTIVE

Attempts to build an artificial pancreas by using subcutaneous insulin delivery from a portable pump guided by an subcutaneous glucose sensor have encountered delays and variability of insulin absorption. We tested closed-loop intraperitoneal insulin infusion from an implanted pump driven by an subcutaneous glucose sensor via a proportional-integral-derivative (PID) algorithm.

RESEARCH DESIGN AND METHODS

Two-day closed-loop therapy (except for a 15-min premeal manual bolus) was compared with a 1-day control phase with intraperitoneal open-loop insulin delivery, according to randomized order, in a hospital setting in eight type 1 diabetic patients treated by implanted pumps. The percentage of time spent with blood glucose in the 4.4–6.6 mmol/l range was the primary end point.

RESULTS

During the closed-loop phases, the mean ± SEM percentage of time spent with blood glucose in the 4.4–6.6 mmol/l range was significantly higher (39.1 ± 4.5 vs. 27.7 ± 6.2%, P = 0.05), and overall dispersion of blood glucose values was reduced among patients. Better closed-loop glucose control came from the time periods excluding the two early postprandial hours with a higher percentage of time in the 4.4–6.6 mmol/l range (46.3 ± 5.3 vs. 28.6 ± 7.4, P = 0.025) and lower mean blood glucose levels (6.9 ± 0.3 vs. 7.9 ± 0.6 mmol/l, P = 0.036). Time spent with blood glucose <3.3 mmol/l was low and similar for both investigational phases.

CONCLUSIONS

Our results demonstrate the feasibility of intraperitoneal insulin delivery for an artificial β-cell and support the need for further study. Moreover, according to a semiautomated mode, the features of the premeal bolus in terms of timing and amount warrant further research.In patients with type 1 diabetes, the near-normal glucose control required to prevent long-term complications (1,2) remains difficult to achieve (3). Indeed, the incidence of hypoglycemia increases when glucose control approaches normal glucose levels (4). For this reason the development of an “artificial pancreas” has been a goal for >30 years (5,6).An artificial β-cell requires three elements: a continuous insulin delivery device, a continuous glucose monitoring system, and a control algorithm linking insulin delivery to glucose measurements (3,7,8). The recent development of better performing continuous glucose sensors renewed the potential feasibility of closed-loop insulin delivery (9–11). Short-term initiatives in the clinical research setting were reported in recent years but showed some limitations (12–14). Key limiting factors were, first, delays in the modulation of insulin action related to subcutaneous infusion and, second, time lags in glucose detection due to either the placement of the sensors in the interstitial compartment of subcutaneous tissue or the internal structure of implanted intravenous sensors (15). To reduce glucose deviations at mealtimes, a hybrid option of closed-loop insulin delivery includes a manual priming bolus (16).Reported benefits of intraperitoneal insulin infusion from implantable pumps include fast insulin action and low basal plasma insulin levels, resulting in tight glucose control and a low incidence of hypoglycemic events (17). The feasibility of automated closed-loop insulin delivery from implantable pumps has been demonstrated in clinical trials performed with the Long-Term Sensor System, which coupled these devices with an intravenous glucose sensor (18).Our approach to optimize closed-loop glucose control includes the use of closer to physiological intraperitoneal insulin delivery, subcutaneous glucose sensing, and a proportional-integral-derivative (PID) algorithm with a manual premeal bolus, resulting in a hybrid PID (HyPID) system. The objective of this study was to test the feasibility of such an approach. We investigated patients in the same controlled hospital setting while testing the HyPID system and when following their usual self-management. This approach marks a difference from the previously reported closed-loop trials, which considered home-use periods for comparison with in-clinic closed-loop studies (13,16).     

Physical Activity, Adiposity, and Diabetes Risk in Middle-Aged and Older Chinese Population: The Guangzhou Biobank Cohort Study

OBJECTIVE

Physical activity may modify the association of adiposity with type 2 diabetes. We investigated the independent and joint association of adiposity and physical activity with fasting plasma glucose, impaired fasting glucose, and type 2 diabetes in a Chinese population.

RESEARCH DESIGN AND METHODS

Middle-aged and older Chinese (n = 28,946, ≥50 years, 72.4%women) from the Guangzhou Biobank Cohort Study were examined in 2003–2008. Multivariable regression was used in a cross-sectional analysis.

RESULTS

BMI, waist circumference, and waist-to-hip ratio (WHR) were positively associated with type 2 diabetes after multiple adjustment, most strongly for WHR with odds ratio (OR) of 3.99 (95% CI 3.60–4.42) for highest compared with lowest tertile. Lack of moderate-to-vigorous physical activity, but not walking, was associated with diabetes with an OR of 1.29 (1.17–1.41). The association of moderate-to-vigorous activity with fasting glucose varied with WHR tertiles (P = 0.01 for interaction). Within the high WHR tertile, participants who had a lack of moderate-to-vigorous activity had an OR of 3.87 (3.22–4.65) for diabetes, whereas those who were active had an OR of 2.94 (2.41–3.59).

CONCLUSIONS

In this population, WHR was a better measure of adiposity-related diabetes risk than BMI or waist circumference. Higher moderate-to-vigorous activity was associated with lower diabetes risk, especially in abdominally obese individuals.Type 2 diabetes is a worldwide cause of morbidity and mortality. Adiposity, especially abdominal adiposity, seems to be at the core of development of hyperglycemia and type 2 diabetes (1). Increased physical activity may mitigate some of the diabetogenic impact of adiposity (2–4). Individuals who are obese but fit could even have a lower risk of mortality than those who are normal weight but unfit (5,6). However, being physically active does not completely abolish the obesity-related risk for cardiovascular disease and associated mortality (7). Adiposity is still the main risk factor for the development of type 2 diabetes (2–4,8). Although increased physical activity has been shown to be associated with reduced type 2 diabetes risk independent of adiposity, the protective effects may differ by the level of adiposity. However, the group that could benefit most from physical activity for the prevention of diabetes is still unclear (2–4,8–10).Understanding the relationship between adiposity and physical activity is important to stratify risk groups for the development of effective diabetes prevention strategies from public health and clinical perspectives. Most of the studies relate to Caucasians (2–4,8–10), whereas Asians, including Chinese and Indians, are possibly more vulnerable to insulin resistance (11). The number of Chinese adults with type 2 diabetes was estimated to be ∼28.1 million in 2000 and may double by 2030, with China being second only to India (12). The purpose of this study was to investigate the independent and joint association of adiposity and physical activity with fasting plasma glucose, impaired fasting glucose (IFG), and type 2 diabetes in 28,946 middle-aged and older Chinese participants in the Guangzhou Biobank Cohort Study.     

Circulating Fibroblast Growth Factor-21 Is Elevated in Impaired Glucose Tolerance and Type 2 Diabetes and Correlates With Muscle and Hepatic Insulin Resistance

OBJECTIVE

Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates hepatic glucose production and lipid metabolism in rodents. However, its role in the pathogenesis of type 2 diabetes in humans remains to be defined. The aim of this study was to quantitate circulating plasma FGF-21 levels and examine their relationship with insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance.

RESEARCH DESIGN AND METHODS

Forty-one subjects (8 lean with normal glucose tolerance [NGT], 9 obese with NGT, 12 with impaired fasting glucose [IFG]/impaired glucose tolerance [IGT], and 12 type 2 diabetic subjects) received an oral glucose tolerance test (OGTT) and a hyperinsulinemic-euglycemic clamp (80 mU/m² per min) combined with 3-[³H] glucose infusion.

RESULTS

Subjects with type 2 diabetes, subjects with IGT, and obese subjects with NGT were insulin resistant compared with lean subjects with NGT. Plasma FGF-21 levels progressively increased from 3.9 ± 0.3 ng/ml in lean subjects with NGT to 4.9 ± 0.2 in obese subjects with NGT to 5.2 ± 0.2 in subjects with IGT and to 5.3 ± 0.2 in type 2 diabetic subjects. FGF-21 levels correlated inversely with whole-body (primarily reflects muscle) insulin sensitivity (r = −0.421, P = 0.007) and directly with the hepatic insulin resistance index (r = 0.344, P = 0.034). FGF-21 levels also correlated with measures of glycemia (fasting plasma glucose [r = 0.312, P = 0.05], 2-h plasma glucose [r = 0.414, P = 0.01], and A1C [r = 0.325, P = 0.04]).

CONCLUSIONS

Plasma FGF-21 levels are increased in insulin-resistant states and correlate with hepatic and whole-body (muscle) insulin resistance. FGF-21 may play a role in pathogenesis of hepatic and whole-body insulin resistance in type 2 diabetes.Fibroblast growth factors (FGFs) represent a group of peptides that regulate diverse biological functions, including cell differentiation, cell growth, and angiogenesis (1,2). Recently, a subfamily of FGFs that interact with nuclear receptors has been identified that plays an important role in liver, bone, and adipose tissue metabolism (3,4). This subfamily contains FGF-19, which regulates energy expenditure (5,6); FGF-23, which regulates phosphate metabolism and excretion (7); and the recently described FGF-21, which regulates glucose homeostasis (8,9).FGF-21 is a novel protein that has been implicated in the regulation of lipid and glucose metabolism under fasting and ketotic conditions (9,10). In murine models, FGF-21 was reported to be expressed predominantly in liver (11), but its expression has also been reported in adipose tissue and pancreatic β-cells (12). In a primate model of diabetes, Kharitonenkov et al. (9) reported a reduction in plasma glucose, insulin, triglycerides, LDL cholesterol, and HDL cholesterol levels following 6 weeks of recombinant FGF-21 administration. In diet-induced obese mice, FGF-21 reversed hepatic steatosis and improved insulin sensitivity (13). In adipose tissue, FGF-21 was shown to increase glucose uptake (9). Based on these observations, FGF-21 has been proposed as a potential therapeutic agent for type 2 diabetes in humans (14). However, few studies in humans have examined the relationship between FGF-21 and glucose/lipid metabolism. Chen et al. (15) reported that patients with newly diagnosed type 2 diabetes had significantly higher plasma FGF-21 concentrations than nondiabetic control subjects, and FGF-21 negatively correlated with fasting plasma glucose. More recently, Zhang et al. (16) found that FGF-21 concentrations are elevated in obese nondiabetic individuals compared with lean healthy control subjects and that the circulating levels correlated positively with adiposity and fasting insulin and negatively with HDL cholesterol. Conversely, in patients with anorexia nervosa, plasma FGF-21 concentrations are decreased and increased following weight gain (17). In the present study, we examined the relationship between plasma FGF-21 concentrations and direct measurements of peripheral and hepatic insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance.     

Insulin sensitivity, β-cell function, and incretin effect in individuals with elevated 1-hour postload plasma glucose levels

OBJECTIVE

Individuals with normal glucose tolerance (NGT), whose 1-h postload plasma glucose is ≥155 mg/dL (NGT 1h-high), have an increased risk of type 2 diabetes. The purpose of this study was to characterize their metabolic phenotype.

RESEARCH DESIGN AND METHODS

A total of 305 nondiabetic offspring of type 2 diabetic patients was consecutively recruited. Insulin secretion was assessed using both indexes derived from oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp.

RESULTS

Compared with individuals with a 1-h postload plasma glucose <155 mg/dL (NGT 1h-low), NGT 1h-high individuals exhibited lower insulin sensitivity after adjustment for age, sex, and BMI. Insulin secretion estimated from the OGTT did not differ between the two groups of individuals. By contrast, compared with NGT 1h-low individuals, the acute insulin response during an IVGTT and the disposition index were significantly reduced in NGT 1h-high individuals after adjustment for age, sex, and BMI. Incretin effect, estimated as the ratio between total insulin responses during OGTT and IVGTT, was higher in NGT 1h-high individuals compared with NGT 1h-low individuals.

CONCLUSIONS

NGT 1h-high individuals may represent an intermediate state of glucose intolerance between NGT and type 2 diabetes characterized by insulin resistance and reduced β-cell function, the two main pathophysiological defects responsible for the development of type 2 diabetes. Postload hyperglycemia is the result of an intrinsic β-cell defect rather than impaired incretin effect.Impaired glucose tolerance (IGT) identifies individuals with a dysglycemic condition intermediate between normal glucose tolerance (NGT) and type 2 diabetes (1). Individuals with IGT are at high risk for the future development of type 2 diabetes, and several clinical trials have shown that both lifestyle changes and pharmacological intervention prevent/halt the progression from IGT to overt type 2 diabetes (2–5). The results of these intervention studies highlight the importance of identifying individuals at high risk for type 2 diabetes in order to offer them an intervention program to reduce the incidence of the disease, and recently new guidelines for the screening of individuals for type 2 diabetes risks and diabetes prevention have been developed by a European multidisciplinary consortium (the Development and Implementation of a European Guideline and Training Standards for Diabetes Prevention [IMAGE] project) to provide evidence-based recommendations for health care practitioners, organizations, and funders on the prevention of type 2 diabetes in European health care settings (6,7). It is important to note that all clinical trials that have evaluated the impact of intervention strategies for preventing type 2 diabetes have recruited subjects with IGT (2–5). However, longitudinal studies have demonstrated that over one-third of individuals who develop type 2 diabetes have NGT at baseline (8), indicating that the use of IGT or impaired fasting glucose (IFG) categories as the sole means of identifying individuals at high risk for type 2 diabetes may overlook a considerable proportion of individuals who will develop type 2 diabetes over time. Recently, it has been reported that a cutoff of 155 mg/dL for 1-h postload plasma glucose during an oral glucose tolerance test (OGTT) can identify individuals at high risk for development of type 2 diabetes among those who have NGT (NGT 1h-high) (9–11). Addition of HbA_1c levels to 1-h postload plasma glucose levels significantly increased their respective power in predicting development of type 2 diabetes risk, indicating that additional information about type 2 diabetes risk is embedded in HbA_1c (12). Importantly, NGT 1h-high individuals exhibit early signs of subclinical organ damage including vascular atherosclerosis (13), reduced estimated glomerular filtration rate (14), left ventricular hypertrophy (15), and left ventricular diastolic dysfunction (16). The metabolic abnormalities responsible for 1-h postload hyperglycemia remain to be elucidated. Impaired insulin sensitivity and failure of pancreatic β-cells to compensate for the enhanced insulin demand are the principal factors responsible for the development and progression of type 2 diabetes. It is possible that defects in β-cells function and/or in the incretin effect occur at an earlier stage than IGT, i.e., in individuals who are considered to have NGT according to current diagnostic criteria. To gain a more deep insight into the metabolic abnormalities characterizing NGT 1h-high individuals, we evaluated insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp as well as insulin secretion and the incretin effect by using both OGTT and intravenous glucose tolerance test (IVGTT) in a cohort of nondiabetic offspring of type 2 diabetic patients.