Fasting Glucose Level and the Risk of Incident Atherosclerotic Cardiovascular Diseases

OBJECTIVE

Although diabetes increases the risk of cardiovascular disease (CVD) and mortality, the dose-response relationship between fasting glucose levels below those diagnostic of diabetes with cardiovascular events has not been well characterized.

RESEARCH DESIGN AND METHODS

A prospective cohort study of more than one million Koreans was conducted with a mean follow-up of 16 years. A total of 1,197,384 Korean adults with no specific medical conditions diagnosed were classified by baseline fasting serum glucose level. Associations of fasting glucose level with CVD incidence and mortality, stroke incidence and mortality, and all-cause mortality were analyzed using multivariate proportional hazards regression.

RESULTS

The relationships between fasting glucose levels and CVD risks generally followed J-shape curves, with lowest risk in the glucose range of 85–99 mg/dL. As fasting glucose levels increased to >100 mg/dL, risks for CVD, ischemic heart disease, myocardial infarction, and thrombotic stroke progressively increased, but risk for hemorrhagic stroke did not. Fasting glucose levels <70 mg/dL were associated with increased risk of all stroke (hazard ratio 1.06, 95% CI 1.01–1.11) in men and (hazard ratio 1.11, 1.05–1.17) in women.

CONCLUSIONS

Both low glucose level and impaired fasting glucose should be considered as predictors of risk for stroke and coronary heart disease. The fasting glucose level associated with the lowest cardiovascular risk may be in a narrow range.Diabetes is a well-established risk factor for cardiovascular disease (CVD) and all-cause mortality (1–3). Impaired fasting glucose (IFG), defined by the American Diabetes Association as having a fasting plasma glucose level of 100–125 mg/dL (5.6–7.0 mmol/L) or a 2-h value on the oral glucose tolerance test of 140–199 mg/dL (7.8–11.1 mmol/L) (4) was associated with CVD risk in several studies (1,5–7). The evidence is inconsistent, however, and the clinical relevance of IFG as a predictor of CVD is still unclear (8–11). In addition, the shape of the dose-response relationship between CVD risk and fasting glucose level has not been well characterized across the full range of fasting blood glucose values.It is unclear whether there is an optimum fasting glucose level associated with the lowest level of CVD risk (12,13), or whether risk increases at very low fasting glucose levels (14). Several studies have shown J-shape or U-shape relationships between fasting glucose levels and mortality (3,5,14,15).The Korean Cancer Prevention Study (16,17) (KCPS) is a cohort study of >1.3 million Korean adults designed to evaluate major risk factors for chronic diseases and mortality. The large sample size of this cohort facilitated detailed characterization of the dose-response relationship of fasting glucose level with the incidence of clinical CVD end points.     

Impaired Fasting Glucose and Risk of Cardiovascular Disease in Korean Men and Women: The Korean Heart Study

OBJECTIVE

The relationship between impaired fasting glucose (IFG) and risk of cardiovascular disease (CVD) or ischemic heart disease (IHD) varies widely according to sex and ethnicity. We evaluated the relationship between IFG and CVD or IHD among Korean men and women.

RESEARCH DESIGN AND METHODS

A total of 408,022 individuals who underwent voluntary private health examinations in 17 centers in South Korea were followed for 10 years. Data regarding CVD or IHD events were obtained from the Korean National Health Insurance database. IFG was categorized as grade 1 (fasting glucose 100–109 mg/dL) or grade 2 (110–125 mg/dL).

RESULTS

Incidence rates of CVD (per 100,000 person-years) were 2,203 for diabetes. Age-adjusted hazard ratios (HRs) for CVD were 1.17 (95% CI 1.13–1.20) for grade 1 IFG, 1.30 (1.24–1.35) for grade 2 IFG, and 1.81 (1.75–1.86) for diabetes. The increased risk for women was similar to that of men. Age-adjusted HRs for IHD and ischemic stroke were also significantly increased for men and women with IFG and diabetes. After multivariate adjustment of conventional risk factors (hypertension, dyslipidemia, smoking, obesity, and family history of CVD), the overall risk of CVD was greatly attenuated in all categories. However, the HRs for IHD and ischemic stroke remained significantly increased in men for grade 2 IFG but not in women.

CONCLUSIONS

In Korea, grade 2 IFG is associated with increased risk of IHD and ischemic stroke, independent of other conventional risk factors, in men but not in women.It is well-established that type 2 diabetes is associated with a marked increase in the risk of cardiovascular disease (CVD) and ischemic heart disease (IHD) (1–4). Studies suggest that atherosclerosis develops before the onset of clinical diabetes (5,6). Supporting this possibility, many studies have reported that impaired glucose tolerance (IGT) is associated with increased cardiovascular morbidity and mortality (7,8). However, the association between impaired fasting glucose (IFG) and risk of CVD and/or IHD remains unclear (7–18). Although some studies have reported that IFG was associated with a greater risk of IHD/CVD in women than in men (17,19), others have reported similar risks for men and women (18).There has also been considerable debate regarding the threshold glucose level associated with increased CVD risk. In 2003, the American Diabetes Association (ADA) lowered the fasting plasma glucose (FPG) cutoff point for IFG from 110 to 100 mg/dL (20). Some studies have reported that FPG levels of 110–125 mg/dL were associated with significantly higher rates CVD morbidity or mortality, but that FPG levels of 100–109 mg/dL were not (12,13). However, other investigators reported that the relationship between CVD risk and fasting glucose was continuous or J-shaped rather than showing a threshold effect at high glucose levels (18,21). However, most studies were based mainly on Caucasian populations, and only a few studies have assessed the relationship between IFG and CVD risk in Asian populations (13,14,18). Furthermore, most of these studies analyzed IHD and stroke together as CVD, whereas few studies have analyzed IHD, ischemic stroke, and hemorrhagic stroke separately (14,22).The primary purpose of this study was to determine whether IFG is associated with increased risk of CVD, IHD, and/or stroke in the Korean population. We also assessed potential sex differences, which have been shown in some previous studies (17,19). Finally, we evaluated whether the CVD risk associated with fasting serum glucose (FSG) levels of 100–109 mg/dL is similar to the risk associated with FSG levels of 110–125 mg/dL (the 1997 ADA definition of IFG).     

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.     

Glycemic Control and Cardiovascular Disease in 7,454 Patients With Type 1 Diabetes: An observational study from the Swedish National Diabetes Register (NDR)

OBJECTIVE

We assessed the association between A1C and cardiovascular diseases (CVDs) in an observational study of patients with type 1 diabetes followed for 5 years.

RESEARCH DESIGN AND METHODS

A total of 7,454 patients were studied from the Swedish National Diabetes Register (aged 20–65 years, diabetes duration 1–35 years, followed from 2002 to 2007).

RESULTS

Hazard ratios (HRs) for fatal/nonfatal coronary heart disease (CHD) per 1% unit increase in baseline or updated mean A1C at Cox regression analysis were 1.31 and 1.34 and 1.26 and 1.32, respectively, for fatal/nonfatal CVD (all P < 0.001 after adjustment for age, sex, diabetes duration, blood pressure, total and LDL cholesterol, triglycerides, BMI, smoking, and history of CVD). HRs were only slightly lower for CHD (P = 0.002) and CVD (P = 0.002–0.007) after also adjusting for albuminuria. Adjusted 5-year event rates of CHD and CVD increased progressively with higher A1C, ranging from 5 to 12%, as well as when subgrouped by shorter (1–20 years) or longer (21–35 years) duration of diabetes. A group of 4,186 patients with A1C 5–7.9% (mean 7.2) at baseline showed risk reductions of 41% (95% confidence intervals: 15–60) (P = 0.005) for fatal/nonfatal CHD and 37% (12–55) (P = 0.008) for CVD, compared with 3,268 patients with A1C 8–11.9% (mean 9.0), fully adjusted also for albuminuria.

CONCLUSIONS

This observational study of patients in modern everyday clinical practice demonstrates progressively increasing risks for CHD and CVD with higher A1C, independently of traditional risk factors, with no J-shaped risk curves. A baseline mean A1C of 7.2% showed considerably reduced risks of CHD and CVD compared with A1C 9.0%, emphasizing A1C as a strong independent risk factor in type 1 diabetes.Patients with type 1 diabetes have long been considered to have increased risks of cardiovascular disease (CVD) and mortality (1,2), and this has recently been confirmed in two studies (3,4) from the General Practice Research Database in the U.K. Based on data from 1992 to 1999, risks of CVD and mortality were four to eight times higher in men and women with type 1 diabetes than nondiabetic individuals (3,4).While the association between glycemia and microvascular complications is established (5,6), there have been no long-term randomized clinical studies satisfactorily examining the relationship with macrovascular complications in type 1 diabetes, and epidemiological studies have shown conflicting results (7–14). The Epidemiology of Diabetes Interventions and Complications (EDIC) Study showed that patients who had previously been subjected to intensive glucose control during the Diabetes Control and Complications Trial (DCCT) had a considerably lower risk of CVD than patients receiving standard treatment (1983–1993) (7). A small study from Finland on late-onset type 1 diabetic patients without albuminuria showed increased risk of coronary heart disease (CHD) with poor glycemic control (9), but the EURODIAB Prospective Complications Study (PCS), the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study, and the Wisconsin Epidemiologic Study of Diabetic Retinopathy did not demonstrate a significant relationship between glycemia and CHD after controlling for other cardiovascular risk factors (10–13). However, a recent study (14) from the Pittsburgh EDC showed that change in A1C was related to coronary artery disease, whereas baseline A1C was not.With this background, we assessed the association between A1C and CHD, stroke, and CVD in a large cohort of patients with type 1 diabetes, aged 20–65 years, treated in everyday clinical practice from 2002 to 2007. Data were used from the Swedish National Diabetes register (NDR), a quality-assurance tool in diabetes care with nationwide coverage with recently published reports regarding type 1 and type 2 diabetes (15–17).     

Effect of Ranolazine on A1C and Glucose Levels in Hyperglycemic Patients With Non-ST Elevation Acute Coronary Syndrome

OBJECTIVE

We determined the relationships between glycemia at randomization, concurrent antidiabetic therapy, and change in A1C and fasting plasma glucose (FPG) in patients with diabetes receiving standard treatment for diabetes and randomized to ranolazine or placebo within the MERLIN-TIMI-36 (MERLIN) study. Ranolazine is a novel first-in-class drug approved for treating angina pectoris.

RESEARCH DESIGN AND METHODS

Randomization and 4-month glycemic and antidiabetes drug usage data from MERLIN were analyzed using Spotfire and SAS version 9.1 software.

RESULTS

In patients with diabetes and A1C of ≥8–10% at randomization (n = 171), there was an absolute A1C reduction in the ranolazine group of 1.2% (95% CI −1.4 to −1.0), and the placebo-adjusted (n = 182) decrease in A1C by ranolazine was 0.59% (95% CI −0.99 to −0.20, P < 0.001). In patients with FPG of 150–400 mg/dl at randomization, ranolazine (n = 131) compared with placebo (n = 147) reduced FPG by 25.7 mg/dl (95% CI −43.3 to −8.1, P = 0.001). When changes in either A1C or FPG were correlated to A1C or FPG at randomization, the slopes were significantly steeper for ranolazine than placebo (A1C, P = 0.046; FPG, P < 0.001), indicating that lowering of A1C and FPG by ranolazine is related to hyperglycemia at randomization. Ranolazine, compared with placebo, was not associated with serious hypoglycemic events, associated with significant changes in concurrent antidiabetic therapy, or dependent on a history of angina.

CONCLUSIONS

Ranolazine, when added to concurrent antidiabetes treatment, lowers FPG and A1C in patients with cardiovascular disease and poorly controlled diabetes.Diabetes is an established risk factor for cardiovascular disease, and the risk of cardiovascular disease increases with worsening hyperglycemia (1–3). Furthermore, coronary artery disease is the most common cause of death in patients with diabetes (4). Patients with coronary artery disease and a recent myocardial infarction or acute coronary syndrome (ACS) have an increased incidence of impaired fasting plasma glucose (FPG) and new-onset diabetes (5–7). Management of diabetes in patients with cardiovascular disease is complicated by the fact that the cardiovascular safety of some oral glucose–lowering agents has been questioned, and outcome data are lacking (8).Ranolazine is a first-in-class anti-anginal drug with cardioprotective properties without effects on heart rate or blood pressure (9). The drug inhibits the cardiac late sodium current (10,11). The late sodium current is enhanced during ischemia and in the failing heart and contributes to the Na+-dependent cellular calcium overload associated with these pathological conditions (10,11). Ranolazine has been shown effective in treating chronic angina both as a monotherapy (MARISA trial) and in combination with commonly prescribed cardiovascular drugs (CARISA and ERICA trials) (12–14), with no increase in mortality in patients with established coronary artery disease, including those with diabetes (15,16).Post hoc analysis of data from the CARISA study demonstrated that ranolazine lowered A1C, a long-term biomarker of glucose control, in patients with chronic angina and diabetes, in a dose-dependent manner (17). While the mechanism of glycemic improvement remains incompletely understood, preliminary studies using isolated rat and human pancreatic islets suggest ranolazine may promote glucose-stimulated insulin secretion (18).In the MERLIN-TIMI-36 (MERLIN) study, the effects of ranolazine to lower A1C and glucose were confirmed using prespecified glycemic end points (16). In this study, patients with diabetes were receiving standard of care treatment for diabetes with mean A1C levels of 7.5% at randomization. Despite the relatively low mean A1C at randomization, ranolazine was found to significantly reduce A1C in patients with diabetes and to reduce the incidence of newly elevated A1C in initially normoglycemic patients (16). The mean placebo-corrected reductions in A1C with ranolazine treatment at 4 months were 0.42% (P < 0.001) and 0.18% (P < 0.001) for patients with and without diabetes, respectively. There were no differences in the reported incidence of hypoglycemia between placebo and ranolazine.The glucose-lowering response to multiple antidiabetic therapies is greater in patients with higher baseline A1C and glucose values (19). Therefore, the current analysis of the MERLIN data was undertaken to evaluate the effects of ranolazine on FPG and A1C in diabetic patients with moderate or severe hyperglycemia, defined as an A1C of 6 to <8% or ≥8–10%, or FPG <150 or ≥150–400 mg/dl, respectively, at randomization. Additionally, MERLIN data were assessed as to whether effects of ranolazine on glycemia were influenced by concurrent antidiabetic therapy.     

Translating the A1C assay into estimated average glucose values

OBJECTIVE

The A1C assay, expressed as the percent of hemoglobin that is glycated, measures chronic glycemia and is widely used to judge the adequacy of diabetes treatment and adjust therapy. Day-to-day management is guided by self-monitoring of capillary glucose concentrations (milligrams per deciliter or millimoles per liter). We sought to define the mathematical relationship between A1C and average glucose (AG) levels and determine whether A1C could be expressed and reported as AG in the same units as used in self-monitoring.

RESEARCH DESIGN AND METHODS

A total of 507 subjects, including 268 patients with type 1 diabetes, 159 with type 2 diabetes, and 80 nondiabetic subjects from 10 international centers, was included in the analyses. A1C levels obtained at the end of 3 months and measured in a central laboratory were compared with the AG levels during the previous 3 months. AG was calculated by combining weighted results from at least 2 days of continuous glucose monitoring performed four times, with seven-point daily self-monitoring of capillary (fingerstick) glucose performed at least 3 days per week.

RESULTS

Approximately 2,700 glucose values were obtained by each subject during 3 months. Linear regression analysis between the A1C and AG values provided the tightest correlations (AG_mg/dl = 28.7 × A1C − 46.7, R² = 0.84, P < 0.0001), allowing calculation of an estimated average glucose (eAG) for A1C values. The linear regression equations did not differ significantly across subgroups based on age, sex, diabetes type, race/ethnicity, or smoking status.

CONCLUSIONS

A1C levels can be expressed as eAG for most patients with type 1 and type 2 diabetes.The A1C assay is widely accepted and used as the most reliable means of assessing chronic glycemia (1–3). Its close association with risk for long-term complications, established in epidemiologic studies and clinical trials (4–6), has lead to the establishment of specific A1C targets for diabetes care with the goal of preventing or delaying the development of long-term complications (2,7–9). Diabetes treatment is adjusted based on the A1C results, expressed as the percentage of hemoglobin that is glycated. The vast majority of assays have been standardized worldwide, through the National Glycohemoglobin Standardization Program (10), to the assay used in the Diabetes Control and Complications Trial (DCCT), which established the relationship between A1C levels and risk for long-term diabetes complications (4,5).A new, more stable and specific method of standardization of the A1C assay, which is not intended for use in routine assays, has been developed and proposed to be used for global standardization by the International Federation of Clinical Chemists (11,12). However, the new method results in values that are 1.5–2.0 percentage points lower than current National Glycohemoglobin Standardization Program values (13), potentially causing confusion for patients and health care providers. Moreover, the International Federation of Clinical Chemists results would be expressed in new units (millimoles per mole), which would add to the confusion. Chronic glycemia (A1C) is usually expressed as a percentage of hemoglobin that is glycated, whereas the day-to-day monitoring and therapy of diabetes are based on acute glucose levels expressed as milligrams per deciliter or millimoles per liter. This discrepancy has always been problematic. If we could reliably report chronic metabolic control and long-term management goals as average glucose (AG), i.e., in the same units of measurement as acute glycemia, it would eliminate these potential sources of confusion.The relationship between A1C and chronic glycemia has been explored in several studies that have supported the association of A1C with AG levels over the preceding 5–12 weeks (14–21). However, the older studies have been limited, including relatively small homogeneous cohorts of patients, usually with type 1 diabetes (14–19). Moreover, almost all of the prior studies have relied on infrequent measures of capillary glucose levels, calling into question the validity of their assessment of chronic glycemia. We performed an international multicenter study to examine the relationship between average glucose, assessed as completely as possible with a combination of continuous glucose monitoring and frequent fingerstick capillary glucose testing, and A1C levels over time to estimate the relationship between the two.     

Disposition Index, Glucose Effectiveness, and Conversion to Type 2 Diabetes: The Insulin Resistance Atherosclerosis Study (IRAS)

OBJECTIVE

Disposition index (DI) and glucose effectiveness (S_G) are risk factors for diabetes. However, the effect of DI and S_G on future diabetes has not been examined in large epidemiological studies using direct measures.

RESEARCH DESIGN AND METHODS

Insulin sensitivity index (S_I), acute insulin response (AIR), and S_G were measured in 826 participants (aged 40–69 years) in the Insulin Resistance Atherosclerosis Study (IRAS) by the frequently sampled intravenous glucose tolerance test. DI was expressed as S_I × AIR. At the 5-year follow-up examination, 128 individuals (15.5%) had developed diabetes.

RESULTS

The area under the receiver operating characteristic curve of a model with S_I and AIR was similar to that of DI (0.767 vs. 0.774, P = 0.543). In a multivariate logistic regression model that included both DI and S_G, conversion to diabetes was predicted by both S_G (odds ratio × 1 SD, 0.61 [0.47–0.80]) and DI (0.68 [0.54–0.85]) after adjusting for demographic variables, fasting and 2-h glucose concentrations, family history of diabetes, and measures of obesity. Age, sex, race/ethnicity, glucose tolerance status, obesity, and family history of diabetes did not have a significant modifying impact on the relation of S_G and DI to incident diabetes.

CONCLUSIONS

The predictive power of DI is comparable to that of its components, S_I and AIR. S_G and DI independently predict conversion to diabetes similarly across race/ethnic groups, varying states of glucose tolerance, family history of diabetes, and obesity.Both insulin sensitivity and first-phase insulin secretion are independent determinants of conversion to diabetes in different ethnic groups and varying states of glucose tolerance, family history of diabetes, and obesity (1). First-phase insulin secretion compensates for the worsening of insulin sensitivity (2). In studies using direct methods, such as the frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis, this relationship is hyperbolic (2) and similar across glucose tolerance categories (3). Known as the disposition index (DI), the product of measures of insulin sensitivity and first-phase insulin secretion, it has been shown to predict conversion to diabetes (4–6). The evidence, however, comes from studies that have enrolled relatively few participants or targeted persons from a single ethnic group. Since direct methods have demanding technical requirements, the product of measures of insulin sensitivity and insulin secretion derived from the oral glucose tolerance test has attracted interest. This product has been shown to have a modest correlation with minimal model–derived DI, to decrease as glucose tolerance status deteriorates, and to predict the development of diabetes independent of other risk factors including fasting and 2-h glucose concentrations (7,8). It includes the incretin effect and therefore may not always follow the hyperbolic law (7–9). The hyperbolic paradigm of the minimal model–derived DI has also been criticized (10). Furthermore, its predictive power has not been tested for large epidemiological studies.In addition to the insulin-dependent component of glucose tolerance (or DI), the insulin-independent component (glucose effectiveness [S_G]) has already been explored in mice (11) and humans (12). S_G is the capacity of glucose to enhance its own cellular uptake and to suppress endogenous glucose production. Although reduced in individuals with impaired glucose tolerance (IGT) and diabetes (4,13), S_G contributes to glucose tolerance even in conditions of significant insulin resistance, including diabetes (13). Reduced S_G has also been described in healthy individuals following the infusion of cortisol or glucagon, individuals in states of very low caloric intake, women with polycystic ovary syndrome, and the elderly (13–15). Contrary to the insulin sensitivity index (S_I), S_G may not be influenced by exercise (16) or weight loss interventions (17). In relatively small studies, S_G has been shown to predict future diabetes (4,5,18), but its contribution to the development of diabetes remains largely unknown.Since the hyperbolic paradigm has not been tested in large epidemiological studies, our first objective was to analyze the risk of future diabetes associated with minimal model-derived DI relative to its components, S_I, and acute insulin response (AIR). The second objective was to assess the relative contribution of the insulin-independent component of glucose tolerance, S_G, to the development of diabetes. To meet these aims, we used data from the Insulin Resistance Atherosclerosis Study (IRAS), a multicenter observational epidemiological study of different ethnic groups and varying states of glucose tolerance (19).     

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 Pharmacological Treatment of Depression on A1C and Quality of Life in Low-Income Hispanics and African Americans With Diabetes: A randomized, double-blind, placebo-controlled trial

OBJECTIVE

To determine whether pharmacological treatment of depression in low-income minorities with diabetes improves A1C and quality of life (QOL).

RESEARCH DESIGN AND METHODS

This was a 6-month, randomized, double-blind, placebo-controlled trial. Patients were screened for depression using Whooley''s two-question tool at a county diabetes clinic. Depression was confirmed (or not) with the Computerized Diagnostic Interview Survey (CDIS) software program, and the severity of depression was assessed monthly by the Hamilton Depression Scale (HAM-D). Depressed subjects with A1C levels ≥8.0% were randomly assigned to receive either sertraline or placebo. Diabetes care was provided by nurses following detailed treatment algorithms who were unaware of therapy for depression.

RESULTS

A total of 150 subjects answered positively to at least one question on Whooley''s questionnaire. The positive predictive value for depression diagnosed by CDIS was 69, 67, and 84% for positive answers to question 1 only, question 2 only, or both, respectively. Of the 89 subjects who entered the study, 75 completed. An intention-to-treat analysis revealed significant differences between baseline and 6 months in HAM-D and pain scores, QOL, and A1C and systolic blood pressure levels in both groups, with no differences between groups for the first three but a significantly greater decrease with sertraline in A1C and systolic blood pressure levels. Changes in HAM-D scores and A1C levels were significantly correlated in all subjects (P = 0.45 [P < 10⁻⁶]).

CONCLUSIONS

In this low-income minority population, pharmacological treatment of depression significantly improved A1C and systolic blood pressure levels compared with placebo.The prevalence of depression among people with diabetes is more than twice that of the general population (1). Coexistence of depression in persons with diabetes is associated with worse glycemic control (2), which may be due to less adherence to self-care behaviors and medications (3). Eventually, there is increased morbidity (4) and mortality (5) and higher medical costs (6).The prevalence of untreated depression in people with diabetes is higher in minorities (1). Yet, screening for and treating depression are less common in this population (7). Very little research has been published on diabetes and depression with a focus on minority populations, who have significant disparities in outcomes (8), such as higher A1C levels (9), increased rates of complications (10), and more severe depression (8).Depression is associated with worse glycemic control (2). Some studies have evaluated whether treatment of depression will improve A1C levels (11–20). However, these drug studies were open label, were of short duration, and/or were conducted in highly educated (more than high school education) Caucasian populations. Most showed that although depression was improved, A1C levels were not. We sought to determine whether use of antidepressants in a minority population with uncontrolled diabetes improved their A1C levels, quality of life (QOL), and depression compared with placebo.     

Cardiovascular Disease Mortality in Europeans in Relation to Fasting and 2-h Plasma Glucose Levels Within a Normoglycemic Range

OBJECTIVE

To study mortality in relation to fasting plasma glucose (FPG) and 2-h plasma glucose levels within the normoglycemic range.

RESEARCH DESIGN AND METHODS

Data from 19 European cohorts comprising 12,566 men and 10,874 women who had FPG <6.1 mmol/l and 2-h plasma glucose <7.8 mmol/l at baseline examination were analyzed. Multivariate-adjusted hazard ratios (HRs) and 95% CIs for deaths from cardiovascular disease (CVD), non-CVD, and all causes were estimated for individuals whose 2-h plasma glucose > FPG (group II) compared with those whose 2-h plasma glucose ≤ FPG (group I).

RESULTS

A total of 827 (246) CVD and 611 (351) non-CVD and 1,438 (597) all-cause deaths occurred in men (women). Group II was older and had higher BMI, blood pressure, and fasting insulin than group I. The multivariate-adjusted HRs (95% CIs) for CVD, non-CVD, and all-cause mortality were 1.22 (1.05–1.41), 1.09 (0.92–1.29), and 1.16 (1.04–1.30) in men and 1.40 (1.03–1.89), 0.99 (0.79–1.25), and 1.13 (0.94–1.35) in women, respectively, for group II as compared with group I. HRs were 1.25 (1.05–1.50), 1.09 (0.89–1.34), and 1.18 (1.03–1.35) in men and 1.60 (1.03–2.48), 1.05 (0.78–1.42), and 1.18 (0.93–1.51) in women, respectively, after additional adjustment for fasting insulin in a subgroup of individuals.

CONCLUSIONS

In individuals with both FPG and 2-h plasma glucose within the normoglycemic range, high 2-h plasma glucose was associated with insulin resistance and increased CVD mortality.It is well known that type 2 diabetes (1,2) and nondiabetic hyperglycemia such as impaired glucose tolerance are risk factors for cardiovascular disease (CVD) mortality (3–5). The relations of fasting plasma glucose (FPG) and 2-h plasma glucose with CVD mortality and morbidity have been extensively investigated during the last few decades (6–9). Evidence has shown that 2-h plasma glucose is a stronger risk predictor than FPG for incident coronary heart disease (6) and CVD mortality (7), but little is known about the impact of FPG versus 2-h plasma glucose in the normoglycemic range. It has been suggested that individuals with normoglycemia, whose 2-h plasma glucose did not return to the FPG levels during an oral glucose tolerance test (OGTT) had a significantly higher risk of developing type 2 diabetes (10) and a worse cardiovascular risk factor profile (11) than individuals whose 2-h plasma glucose returned to the FPG levels. In the current study, based on the data of the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study, we compared CVD mortality in individuals whose 2-h plasma glucose was higher than FPG with those whose 2-h plasma glucose was equal to or lower than FPG.     

Further Improvement in Postprandial Glucose Control With Addition of Exenatide or Sitagliptin to Combination Therapy With Insulin Glargine and Metformin: A proof-of-concept study

OBJECTIVE

To assess the effect of a 4-week adjunctive therapy of exenatide (EXE) (5–10 μg b.i.d.) or sitagliptin (SITA) (100 mg once daily) in response to a standardized breakfast meal challenge in 48 men or women with type 2 diabetes receiving insulin glargine (GLAR) + metformin (MET).

RESEARCH DESIGN AND METHODS

This was a single-center, randomized, open-label, active comparator–controlled study with a three-arm parallel group design, consisting of: screening, 4- to 8-week run-in period, 4-week treatment period, and follow-up. In all three groups, the GLAR dose was titrated according to an algorithm (fasting blood glucose ≤100 mg/dl).

RESULTS

The unadjusted 6-h postprandial blood glucose excursion of both GLAR + MET + EXE and GLAR + MET + SITA was statistically significantly smaller than that of GLAR + MET (606 ± 104 vs. 612 ± 133 vs. 728 ± 132 mg/dl/h; P = 0.0036 and 0.0008). A1C significantly decreased in all three groups (P < 0.0001), with the greatest reduction of −1.9 ± 0.7 under GLAR + MET + EXE (GLAR + MET + SITA −1.5 ± 0.7; GLAR + MET −1.2 ± 0.5%-points; GLAR + MET + EXE vs. GLAR + MET P = 0.0154). The American Diabetes Association A1C target of <7.0% was reached by 80.0, 87.5, and 62.5% of subjects, respectively. GLAR + MET + EXE had the highest number (47) of adverse events, mostly gastrointestinal (56%) with one dropout. GLAR + MET or GLAR + MET + SITA only had 10 and 12 adverse events, respectively, and no dropouts. Hypoglycemia (blood glucose <50 mg/dl) rates were low and comparable among groups. Weight decreased with GLAR + MET + EXE (−0.9 ± 1.7 kg; P = 0.0396) and increased slightly with GLAR + MET (0.4 ± 1.5 kg; NS; GLAR + MET + EXE vs. GLAR + MET P = 0.0377).

CONCLUSIONS

EXE or SITA added to GLAR + MET further substantially reduced postprandial blood glucose excursions. Longer-term studies in a larger population are warranted to confirm these findings.The UK Prospective Diabetes Study (UKPDS) demonstrated that good glycemic control in type 2 diabetes is associated with a reduced risk of diabetes complications (1). After lifestyle modifications (diet and exercise) and oral hypoglycemic agents (OHAs) the addition of basal insulin to OHAs is common practice (2), because this kind of regimen requires only a single injection in most cases and can improve glycemic control. Its use, however, may not adequately control postprandial hyperglycemia or may be associated with hypoglycemia and/or weight gain (3,4). Because obesity is frequently present in subjects with type 2 diabetes (5) and represents a factor contributing to insulin resistance (5) and cardiovascular risk (5), weight gain may be particularly undesirable.A significant advance in basal insulin therapy was the introduction of insulin glargine, a long-acting insulin analog with an extended duration of action of ∼24 h without exhibiting a pronounced peak (6,7). In subjects with type 2 diabetes, insulin glargine was shown to confer glycemic control at least equivalent to that of NHP insulin with a lower incidence of hypoglycemia (3,8,9). However, insulin glargine still has the drawbacks of insulin treatment such as weight gain (3,8,9) and a lower effect on postprandial glucose excursions (8) than on fasting glucose values.Exenatide is the first-in-class glucagon-like peptide 1 (GLP-1) receptor agonist (or incretin mimetic) approved in the U.S. and Europe (10). Compared with placebo, exenatide statistically reduced A1C, whereas there was no difference in A1C improvement between exenatide and insulin glargine or biphasic insulin aspart (11–14). However, postprandial glycemia as well as weight was further reduced with exenatide compared with insulin glargine or biphasic insulin, with a similar risk of hypoglycemia (12,13).Sitagliptin is an approved once-daily, potent, and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor (15). When added to metformin, sitagliptin, given at a dose of 100 mg once daily over 24 weeks, led to significant reductions in A1C, fasting, and 2-h postprandial plasma glucose and was weight-neutral (16).With this background, a therapy controlling both fasting blood glucose (FBG) and postprandial glucose excursions seems to be a promising approach for subjects with type 2 diabetes (17–21). Therefore, in the present study we investigated the influence of a 4-week adjunctive therapy of either a GLP-1 receptor agonist (exenatide) or a DPP-4 inhibitor (sitagliptin) to titrated basal insulin (insulin glargine) plus metformin versus the continuation with titrated insulin glargine plus metformin alone as active comparator in subjects with type 2 diabetes.     

Sex Differences in the Association Between Serum Ferritin and Fasting Glucose in Type 2 Diabetes Among South Asian Surinamese,African Surinamese,and Ethnic Dutch: The population-based SUNSET study

OBJECTIVE

Moderately elevated iron stores below the levels commonly associated with hemochromatosis have been implicated in the etiology of diabetes. Studies suggest that iron status (measured by serum ferritin) differs significantly according to sex, but inconsistent findings have been reported. Our aim is to test the association between serum ferritin and the prevalence of type 2 diabetes and fasting glucose concentrations in a population-based, multiethnic, cross-sectional study including men and women of African Surinamese, South Asian Surinamese, and ethnic Dutch origin.

RESEARCH DESIGN AND METHODS

We analyzed data on 508 ethnic Dutch, 597 African Surinamese, and 339 South Asian Surinamese aged 35–60 years. Type 2 diabetes was defined as a fasting plasma glucose level ≥7.0 mmol/L or a self-reported diagnosis.

RESULTS

Serum ferritin was positively associated with type 2 diabetes and fasting glucose, but differences in the associations according to sex were observed. Serum ferritin concentration was positively associated with type 2 diabetes among women in all ethnic groups (odds ratio [OR] ethnic Dutch: 1.07 [95% CI 1.01–1.13]; OR South Asian Surinamese: 1.05 [1.00–1.10]; OR African Surinamese: 1.05 [1.01–1.10]), but not among men. Serum ferritin was also more strongly associated with fasting glucose in women than in men. Moreover, the magnitude of sex differences in the association between serum ferritin and fasting glucose, but not type 2 diabetes, was more pronounced in the African Surinamese group than in the other ethnic groups (P for interaction ≤0.0001).

CONCLUSIONS

We found a positive association between serum ferritin and type 2 diabetes and fasting glucose in our multiethnic population, which appeared stronger among women than men. Further evaluation of the variation in sex differences between ethnic groups is warranted, particularly among the African Surinamese, to understand the mechanisms behind these sex differences.Moderately elevated iron stores below the levels commonly associated with hemochromatosis have been implicated in the etiology of type 2 diabetes (1–3). Although a mechanism linking iron concentrations and diabetes is yet to be established, it is known that iron is a catalyst in the formation of hydroxyl radicals (4), which may contribute initially to insulin resistance, subsequently to decreased insulin secretion, and ultimately to the development of type 2 diabetes (5). Animal models suggest that iron excess may result in β-cell oxidative stress and decreased insulin secretion (6). Levels of serum ferritin, a predominant iron-storage protein and a biomarker of iron stores, are elevated in persons with prevalent diabetes as compared with nondiabetic controls (7) and correlate with impaired fasting glucose levels (8), an early marker of type 2 diabetes. In addition, several cross-sectional or case-control studies and two prospective studies have identified an independent association between baseline elevations in iron stores and the occurrence of type 2 diabetes (2,5,9–12). However, several questions remain unanswered.It is yet unclear whether the association between serum ferritin and diabetes differs among men and women. Some have found that differences in iron status exist according to sex (8,13–16), which might have implications for the association with the etiology of diabetes (13). Others have suggested that sex differences might exist due to differences in iron accumulation in the peripheral muscles, which may cause derangement of muscle glucose uptake because of muscle damage (17,18). However, robust studies on the influence of sex on the association between serum ferritin and diabetes are rather inconsistent. Some have reported sex differences in the association (9,18), whereas others have not demonstrated this (19–21). Moreover, in those studies in which different associations between serum ferritin and type 2 diabetes were found for men and women, it appeared that the direction of the differences varied across studies (7–9).These discrepancies might be the result of differences in the ethnic composition of study populations. A first argument to support this is a study reporting variations in the serum ferritin and type 2 diabetes associations across men and women from different ethnic populations, including white, black, Hispanic, Asian, and Pacific Islander populations (9). This study reported that the association between serum ferritin and type 2 diabetes differed significantly between the ethnic groups among women but not among men. Unfortunately, other multiethnic studies have not considered differential sex effects across ethnic groups (10,19,20). Another argument for the potential role of ethnicity is a difference in body composition that may occur between ethnic groups. For instance, in the Netherlands, differences in waist circumference or waist-to-height ratio have been reported among ethnic Dutch, South Asian Surinamese, and African Surinamese (22,23). This is relevant, as body composition is suggested to affect the association between serum ferritin and the insulin resistance syndrome (17,18).The aim of this exploratory study is: 1) to test whether the association between serum ferritin and diabetes and fasting glucose differs between men and women of African Surinamese, South Asian Surinamese, and ethnic Dutch origin, and 2) to test whether the differences in the association between serum ferritin between men and women varies between these populations.     

Sex Differences in All-Cause and Cardiovascular Mortality,Hospitalization for Individuals With and Without Diabetes,and Patients With Diabetes Diagnosed Early and Late

OBJECTIVE

To compare risk of all-cause mortality, cardiovascular disease (CVD) mortality, acute myocardial infarction (AMI) mortality, stroke mortality, and hospitalizations for males and females with and without diabetes and those with diabetes diagnosed early and late.

RESEARCH DESIGN AND METHODS

We conducted a population-based retrospective cohort study including 73,783 individuals aged 25 years or older in Newfoundland and Labrador, Canada (15,152 with diabetes; 9,517 with late diagnoses).

RESULTS

Males and females with diabetes had an increased risk of all-cause mortality, CVD mortality, AMI mortality, and CVD hospitalizations compared with individuals without diabetes, and the risk was stronger in females than in males. For females, risks of all-cause mortality (hazard ratio [HR] 1.85 [95% CI 1.74–1.96]) and CVD hospitalizations (2.57 [2.24–2.94]) were significantly higher compared with their male counterparts (1.59 [1.51–1.69] and 1.92 [1.72–2.14]). Females with diabetes diagnosed late had an increased risk of CVD mortality (6.54 [4.80–8.91]) and CVD hospitalizations (5.22 [4.31–6.33]) compared with females without diabetes, and both were significantly higher compared with their male counterparts (3.44 [2.47–4.79]) and (3.33 [2.80–3.95]).

CONCLUSIONS

Females with diabetes have a greater risk of mortality than males with diabetes. CVD has a greater impact on females with diabetes than males, especially when diagnosed at a later stage. Different management strategies should be considered for males and females and those with early and late diagnoses of diabetes.Diabetes has become a health problem of increasing significance in the past two decades. The number of individuals with diabetes will reach 366 million in 2011 and will increase to 552 million by 2030 (1). In Canada, the age-standardized incidence and prevalence of diabetes have been increasing in recent years (2).A challenge with type 2 diabetes is the late diagnosis of the disease because many individuals who meet the criteria are often asymptomatic. Approximately 183 million people, or half of those who have diabetes, are unaware they have the disease (1). Furthermore, type 2 diabetes can be present for 9 to 12 years before being diagnosed and, as a result, complications are often present at the time of diagnosis (3). Insulin resistance and β-cell dysfunction are largely responsible for the development of diabetes and its related complications, and both are present very early in the natural history of diabetes (4). However, the potential does exist to prevent or at least delay the onset of type 2 diabetes because several randomized control trials have shown that both lifestyle and pharmacologic interventions in adults are effective (5–8). In addition to preventing diabetes, it is also possible to reduce diabetes-related complications through intensive blood glucose control. Results from the UK Prospective Diabetes Study (UKPDS) have shown that intensive blood glucose control reduces diabetes-related complications (6–9). Early detection of type 2 diabetes is critical because effective and active management is essential for those with newly diagnosed diabetes who have not developed complications.Cardiovascular disease (CVD) is the most common comorbidity associated with diabetes, and with 50% of those with diabetes dying of CVD it is the most common cause of death (1). Acute myocardial infarction (AMI) and stroke are other common comorbidities associated with diabetes. Individuals with diabetes have an increased risk of all-cause mortality and morbidity related to CVD, AMI, and stroke compared with individuals without diabetes (9–12). Although studies consistently have found that individuals with diabetes have a higher risk of mortality and hospitalizations compared with those without diabetes, results have been inconsistent when comparing males and females. Most studies have found that females with diabetes have a greater risk of mortality and hospitalizations than males with diabetes (9,10,12–17). Two previous meta-analyses found that diabetes is a stronger risk factor for CVD mortality in females than in males; however, studies that did not adjust for major CVD risk factors were included in these meta-analyses (18,19). A meta-analysis conducted by Kanaya et al. (20), which included studies that controlled for CVD risk factors, found that the risks associated with diabetes for coronary heart disease mortality, nonfatal myocardial infarction, and CVD were higher among females than males. However, the differences were not statistically significant.Newfoundland and Labrador has the highest age-standardized prevalence of diabetes in Canada (2), and the age-standardized mortality and hospitalization rates for CVD, AMI, and stroke are some of the highest in the country (21,22). A better understanding of mortality and hospitalizations associated with diabetes for males and females is important to support diabetes prevention and management. Therefore, the objectives of this study were to compare the risk of all-cause, CVD, AMI, and stroke mortality and hospitalizations for males and females with and without diabetes and those with early and late diagnoses of diabetes.     

Acute Effects of Decaffeinated Coffee and the Major Coffee Components Chlorogenic Acid and Trigonelline on Glucose Tolerance

OBJECTIVE

Coffee consumption has been associated with lower risk of type 2 diabetes. We evaluated the acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on glucose tolerance.

RESEARCH DESIGN AND METHODS

We conducted a randomized crossover trial of the effects of 12 g decaffeinated coffee, 1 g chlorogenic acid, 500 mg trigonelline, and placebo (1 g mannitol) on glucose and insulin concentrations during a 2-h oral glucose tolerance test (OGTT) in 15 overweight men.

RESULTS

Chlorogenic acid and trigonelline ingestion significantly reduced glucose (−0.7 mmol/l, P = 0.007, and −0.5 mmol/l, P = 0.024, respectively) and insulin (−73 pmol/l, P = 0.038, and −117 pmol/l, P = 0.007) concentrations 15 min following an OGTT compared with placebo. None of the treatments affected insulin or glucose area under the curve values during the OGTT compared with placebo.

CONCLUSIONS

Chlorogenic acid and trigonelline reduced early glucose and insulin responses during an OGTT.In prospective cohort studies, higher coffee consumption has been associated with a lower risk of type 2 diabetes (1,2). Associations have been similar for caffeinated and decaffeinated coffee (1,3–5), suggesting that coffee components other than caffeine have beneficial effects on glucose homeostasis. Coffee is a major source of the phenolic compound chlorogenic acid (6) and the vitamin B3 precursor trigonelline (7), which have been shown to reduce blood glucose concentrations in animal studies (5–8). This is the first study to investigate the acute effects of chlorogenic acid and trigonelline on glucose tolerance in humans.     

Glucose Variability Assessed by Low Blood Glucose Index Is Predictive of Hypoglycemic Events in Patients With Type 1 Diabetes Switched to Pump Therapy

OBJECTIVE

To determine whether subgroups of type 1 diabetic patients with different glucose variability indices respond differently to continuous subcutaneous insulin infusion (CSII) in terms of reduced hypoglycemic events.

RESEARCH DESIGN AND METHODS

We studied 50 adults with long-standing type 1 diabetes switched to CSII because of persistently high A1C or frequent hypoglycemia despite well-managed intensive basal-bolus therapy. We compared A1C, hypoglycemic events, and glucose variability from self-monitoring of blood glucose profiles at baseline and after 6 months of CSII. Regression analysis was performed to identify predictors of response.

RESULTS

In multivariate analysis, baseline low blood glucose index (LBGI) was the best independent predictor of hypoglycemia outcome on CSII (R² = 0.195, P = 0.0013). An ROC curve analysis demonstrated a sensitivity of 70.8% (95% CI 48.9–87.4) and specificity of 73.1% (52.2–88.4) by using the LBGI cutoff of 3.34 as predictor of reduction of hypoglycemia on CSII. By grouping patients by LBGI tertiles, we found a 23.3% reduction in hypoglycemic events (<60 mg/dL [3.3 mmol/L]) in the third tertile (range 4.18–9.34) without change in A1C (P < 0.05). Conversely, the first tertile (range 0.62–2.05) demonstrated the greatest A1C reduction, −0.99% (P = 0.00001), but with increasing hypoglycemia.

CONCLUSIONS

Baseline LBGI predicts the outcome of type 1 diabetic patients who switch to CSII in terms of hypoglycemia.Continuous subcutaneous insulin infusion (CSII) by pump is widely used for patients with type 1 diabetes with persistently high A1C or frequent, disabling, or severe hypoglycemia, despite well-managed intensive insulin therapy with multiple daily injections (MDIs) (1,2).For patients who fail to achieve A1C targets (3), numerous meta-analyses of randomized controlled trials support the effectiveness of CSII, with a mean decrease of 0.5% in A1C in comparison with MDI (4–13). The greatest improvements in glycemic control were in individuals with the highest A1C: patients with A1C levels ≥8.5% being treated with MDI may expect a decrease of ~1.0–1.5% with CSII (6,8,14–16).In contrast, the ability of CSII to reduce hypoglycemic episodes remains a matter of debate. While some trials or meta-analyses showed a reduction in severe (requiring third-party assistance) (11) and nonsevere (5) hypoglycemic episodes on CSII compared with MDI, others did not (6,7,10,12) or even reported a higher rate of mild hypoglycemic events compared with MDI (13).In everyday life, individuals with type 1 diabetes experience, on average, about two episodes of mild but symptomatic hypoglycemia per week (17). In the absence of impaired hypoglycemia awareness, mild hypoglycemia is, thus, far more frequent than severe hypoglycemia (average incidence of 1.0–1.7 episodes per year) and may exert harmful psychological effects and hamper an individual’s social life (18). These repeated events can be a limiting factor preventing improvement or maintenance of glycemic control through the deliberate avoidance of frequent episodes of low glucose levels (19,20). A recent history of hypoglycemia is also the cause of hypoglycemia-associated autonomic failure (HAAF), leading to defective glucose counterregulation and hypoglycemia unawareness and fueling the vicious cycle of recurrent hypoglycemia (20). However, while patients with frequent severe hypoglycemia may show improvement with CSII (8), clinical characteristics that could predict a reduction in overall hypoglycemia when switching from MDI to CSII are, to our knowledge, currently unknown.Consequently, the aim of this study was to identify factors predicting mild hypoglycemic events (defined as glucose value <60 mg/dL [3.3 mmol/L]) when switching from MDI to CSII. More specifically, we tested the hypothesis that patients with the highest baseline glucose variability would be those in whom CSII reduces it the most, translating into a significant reduction of hypoglycemic events.     

Hyperglycemia, Type 2 Diabetes, and Depressive Symptoms: The British Whitehall II study

OBJECTIVE

To examine the recent suggestion that impaired fasting glucose may protect against depression, whereas a diagnosis of diabetes might then result in depression.

RESEARCH DESIGN AND METHODS

Cross-sectional analysis of 4,228 adults (mean age 60.7 years, 73.0% men) who underwent oral glucose tolerance testing and completed the Center for Epidemiologic Studies Depression scale (CES-D).

RESULTS

After adjustment for demographic factors, health behaviors, and clinical measurements (BMI, waist circumference, lipid profile, and blood pressure), there was a U-shaped association between fasting glucose and depression (P_curve = 0.001), with elevated CES-D at low and very high glucose levels. This finding was replicable with 2-h postload glucose (P = 0.11) and A1C (P = 0.007).

CONCLUSIONS

The U-shaped association between blood glucose and CES-D, with the lowest depression risk seen among those in the normoglycemic range of A1C, did not support the hypothesized protective effect of hyperglycemia.The association between type 2 diabetes and depression, both major public health challenges, remains unclear (1–8). In a recent U.S. report, people with type 2 diabetes had an increased risk of depressive symptoms, whereas in nondiabetic individuals higher impaired fasting glucose (IFG) appeared to confer protection against depression (8). Although an increased prevalence of depression in people receiving a diagnosis of a pernicious chronic disease such as type 2 diabetes is perhaps unsurprising, the apparent counterintuitive protective effect of IFG warrants further scrutiny.     

Impact of Glucose Tolerance Status,Sex, and Body Size on Glucose Absorption Patterns During OGTTs

OBJECTIVE

We studied whether patterns of glucose absorption during oral glucose tolerance tests (OGTTs) were abnormal in individuals with impaired glucose regulation and whether they were related to sex and body size (height and fat-free mass). We also examined how well differences in insulin sensitivity and β-cell function measured by gold-standard tests were reflected in the corresponding OGTT-derived estimates.

RESEARCH DESIGN AND METHODS

With validated methods, various aspects of glucose absorption were estimated from 12-point, 3-h, 75-g OGTTs in 66 individuals with normal glucose tolerance (NGT), isolated impaired fasting glucose (i-IFG), or isolated impaired glucose tolerance (i-IGT). Insulin sensitivity and β-cell function were measured with the euglycemic-hyperinsulinemic clamp and intravenous glucose tolerance tests, respectively. Surrogate markers of both conditions were calculated from OGTTs.

RESULTS

More rapid glucose absorption (P ≤ 0.036) and reduced late glucose absorption (P ≤ 0.039) were observed in the i-IFG group relative to NGT and i-IGT groups. Women with i-IGT had a lower early glucose absorption than did men with i-IGT (P = 0.041); however, this difference did not persist when differences in body size were taken into account (P > 0.28). Faster glucose absorption was related to higher fasting (P = 0.001) and lower 2-h (P = 0.001) glucose levels and to greater height and fat-free mass (P < 0.001). All OGTT-derived measures of insulin sensitivity, but only one of three measures of β-cell function, reflected the differences for these parameters between those with normal and impaired glucose regulation as measured by gold-standard tests.

CONCLUSIONS

Glucose absorption patterns during an OGTT are significantly related to plasma glucose levels and body size, which should be taken into account when estimating β-cell function from OGTTs in epidemiological studies.Individuals with the prediabetic conditions of impaired fasting glycemia (IFG) and impaired glucose tolerance (IGT) have a higher risk of developing type 2 diabetes than do individuals with normal glucose tolerance (NGT) (1,2). Several studies have shown that men in general have higher fasting plasma glucose (FPG) levels and a higher prevalence of isolated IFG (i-IFG) than do women (3–6). In contrast, women often exhibit higher glucose levels after a standard 75-g oral glucose tolerance test (OGTT) and consequently have a higher prevalence of isolated IGT (i-IGT) (3,4,6) than do men. We and others have previously suggested that the difference in post-OGTT glucose concentration is a consequence of the relatively higher dose of glucose given to women compared with men when seen in relation to their body size (3,4,7). Specifically, it has been shown that there are no sex differences in post-OGTT 2-h plasma glucose (2hPG) levels after adjustment for body height (3,4,7). It has also been suggested, however, that the higher 2hPG levels in women may be attributed to differences in glucose absorption patterns between men and women (8). Healthy women with NGT seem to have lower glucose absorption from the gut during the first hour of an OGTT than do their male counterparts, whereas glucose absorption is higher in women than in men during the last hour of a 3-h OGTT (8). Whether such sex differences in glucose absorption patterns can be explained by differences in body size has not been previously determined.Several factors influence blood glucose concentrations after a meal or an OGTT. In addition to gastric emptying and small intestine digestion and absorption, peripheral insulin sensitivity and the amount of insulin secreted in response to glucose and incretin hormones are major determinants of postprandial or post-OGTT glucose concentration (9–11). The relative contributions of these various factors remains uncertain and controversial (10). More than 20 years ago it was shown that the amount of glucose absorbed in response to varying glucose loads is diminished in individuals with type 2 diabetes (12). Furthermore, a recent study showed that pregnant women with gestational diabetes mellitus had markedly lower glucose absorption than pregnant women with NGT (13). The mechanisms underlying these associations are not well understood. Moreover, it is unclear whether defects in glucose absorption are already present in individuals with slightly elevated blood glucose levels, those with IFG or IGT.Through the use of OGTTs, many methods for estimating β-cell function and insulin sensitivity have been suggested (14–16). These estimates reflect discrete aspects of β-cell function (first phase, second phase, static, dynamic) and more or less specific sites of insulin sensitivity (liver, periphery, whole body), but none of them take into account potential differences in glucose absorption patterns among the tested persons. In this study, we examined whether patterns of glucose absorption during OGTTs differed between individuals with normal and impaired glucose regulation and whether they were related to sex and body size. In addition, we examined how well the differences in insulin sensitivity and β-cell function between normal and impaired glucose regulation as estimated by gold-standard tests were reflected in the corresponding OGTT-derived estimates.     

Lifestyle counseling in routine care and long-term glucose, blood pressure, and cholesterol control in patients with diabetes

OBJECTIVE

In clinical trials, diet, exercise, and weight counseling led to short-term improvements in blood glucose, blood pressure, and cholesterol levels in patients with diabetes. However, little is known about the long-term effects of lifestyle counseling on patients with diabetes in routine clinical settings.

RESEARCH DESIGN AND METHODS

This retrospective cohort study of 30,897 patients with diabetes aimed to determine whether lifestyle counseling is associated with time to A1C, blood pressure, and LDL cholesterol control in patients with diabetes. Patients were included if they had at least 2 years of follow-up with primary care practices affiliated with two teaching hospitals in eastern Massachusetts between 1 January 2000 and 1 January 2010.

RESULTS

Comparing patients with face-to-face counseling rates of once or more per month versus less than once per 6 months, median time to A1C <7.0% was 3.5 versus 22.7 months, time to blood pressure <130/85 mmHg was 3.7 weeks versus 5.6 months, and time to LDL cholesterol <100 mg/dL was 3.5 versus 24.7 months, respectively (P < 0.0001 for all). In multivariable analysis, one additional monthly face-to-face lifestyle counseling episode was associated with hazard ratios of 1.7 for A1C control (P < 0.0001), 1.3 for blood pressure control (P < 0.0001), and 1.4 for LDL cholesterol control (P = 0.0013).

CONCLUSIONS

Lifestyle counseling in the primary care setting is strongly associated with faster achievement of A1C, blood pressure, and LDL cholesterol control. These results confirm that the findings of controlled clinical trials are applicable to the routine care setting and provide evidence to support current treatment guidelines.Diabetes is increasingly common in the U.S. and worldwide (1,2). Elevated blood glucose, blood pressure, and LDL cholesterol are associated with increased risk for micro- and macrovascular complications, and their reduction decreases the risk (3–8). Nevertheless, most patients with diabetes do not have A1C, blood pressure, and LDL cholesterol under control (9,10).American and European guidelines widely recommend diet, exercise, and weight counseling with follow-up for patients with diabetes (11,12). Many short-term randomized clinical trials have shown that intensive lifestyle counseling interventions of up to 1 year in duration can lead to lower blood glucose (13–16) and blood pressure (17–21), but long-term data on the efficacy of lifestyle counseling are lacking (22–24). Furthermore, clinical trials typically involve resource-intensive interventions that may not be feasible in routine care, and the efficacy of lifestyle counseling in everyday clinical practice remains questionable (25–27). Consequently, further evidence is needed to establish that lifestyle counseling as practiced in routine care improves the outcomes of patients with diabetes.We therefore conducted a retrospective study of over 30,000 patients with diabetes and hyperglycemia, hypertension, and/or hyperlipidemia who received care in a primary care setting to test the hypothesis that higher rates of lifestyle counseling in routine care are associated with better diabetes control.     

Impact of Metabolic Syndrome Compared With Impaired Fasting Glucose on the Development of Type 2 Diabetes in a General Japanese Population: The Hisayama study

OBJECTIVE

We examined whether metabolic syndrome predicts incident type 2 diabetes more effectively than impaired fasting glucose (IFG) in a general Japanese population.

RESEARCH DESIGN AND METHODS

A total of 1,935 nondiabetic subjects aged 40–79 years were followed-up prospectively for a mean of 11.8 years.

RESULTS

During the follow-up, 286 subjects developed type 2 diabetes. Compared with those without metabolic syndrome, the multivariate-adjusted hazard ratio (HR) for incident type 2 diabetes was significantly higher in subjects of both sexes with metabolic syndrome, even after adjustment for confounding factors, age, family history of diabetes, total cholesterol, alcohol intake, smoking habits, and regular exercise (men: HR 2.58 [95% CI 1.85–3.59]; women: 3.69 [2.58–5.27]). The multivariate-adjusted HR of metabolic syndrome for type 2 diabetes was slightly lower in men and similar in women compared with that of IFG. The multivariate-adjusted HR for type 2 diabetes rose progressively as the number of metabolic syndrome components increased in both subjects with and without IFG. In stratified analysis, the multivariate-adjusted risk of type 2 diabetes was significantly higher in subjects with metabolic syndrome alone (2.37 [1.45–3.88]) or IFG alone (3.49 [2.57–4.74]) and markedly increased in subjects with both metabolic syndrome and IFG (6.76 [4.75–9.61]) than in subjects with neither metabolic syndrome nor IFG. Furthermore, the multivariate-adjusted risk for type 2 diabetes was also significantly higher in subjects with both metabolic syndrome and IFG than in those with either one alone (both P < 0.001).

CONCLUSIONS

Our findings suggest that metabolic syndrome significantly increases the risk of incident type 2 diabetes, independent of IFG, and is therefore a valuable tool to identify individuals at high risk of type 2 diabetes.Metabolic syndrome consists of a clustering of cardiovascular risk factors, such as central obesity, elevated blood pressure, glucose intolerance, and dyslipidemia, and individuals with this condition have an elevated risk of developing cardiovascular diseases (1–5) and type 2 diabetes in different ethnic populations (1–4,6–11). Thus, the concept of metabolic syndrome could be used to reduce the incidence of these diseases worldwide. However, a number of experts in the field of diabetes have questioned whether the idea of metabolic syndrome is useful and valuable (12–14). Because all of the criteria sets for metabolic syndrome have included the component of impaired fasting glucose (IFG), which is a powerful predictor of type 2 diabetes, detractors have questioned whether the more complex definition of metabolic syndrome is better than a simple measurement of fasting plasma glucose (FPG). However, reported findings concerning this issue are controversial: a cohort study has shown that the ability of metabolic syndrome to predict type 2 diabetes was superior to that of IFG alone (3), whereas in other studies, the value of metabolic syndrome was comparable or inferior to that of IFG alone (2,6,7). Furthermore, most of these epidemiological studies were performed in Western populations, and this subject has not been assessed sufficiently in Asian populations.The purpose of the present study was to investigate the association between metabolic syndrome and the development of type 2 diabetes in a prospective study of a defined Japanese population, taking into account comprehensive risk factors. In addition, we compared which of the two measures, metabolic syndrome or IFG, better predicted incident type 2 diabetes.     

Metabolic Syndrome and Diabetes, Alone and in Combination, as Predictors of Cardiovascular Disease Mortality Among Men

OBJECTIVE

To examine cardiovascular disease (CVD) mortality risk in men with diabetes only, metabolic syndrome only, and concurrent metabolic syndrome and diabetes.

RESEARCH DESIGN AND METHODS

We examined CVD mortality risk by metabolic syndrome and diabetes status in men from the Aerobics Center Longitudinal Study (ACLS) (mean ± SD age 45.1 ± 10.2 years). Participants were categorized as having neither diabetes nor metabolic syndrome (n = 23,770), metabolic syndrome only (n = 8,780), diabetes only (n = 532), or both (n = 1,097). The duration of follow-up was 14.6 ± 7.0 years with a total of 483,079 person-years of exposure and 1,085 CVD deaths.

RESULTS

Age-, examination year–, and smoking-adjusted CVD death rates (per 1,000 man-years) in men with neither metabolic syndrome nor diabetes, metabolic syndrome only, diabetes only, and both were 1.9, 3.3, 5.5, and 6.5, respectively. CVD mortality was higher in men with metabolic syndrome only (hazard ratio 1.8 [95% CI 1.5–2.0]), diabetes only (2.9 [2.1–4.0]), and both (3.4 [2.8–4.2]) compared with men with neither. The presence of metabolic syndrome was not associated (1.2 [0.8–1.7]) with higher CVD mortality risk in individuals with diabetes. In contrast, the presence of diabetes substantially increased (2.1 [1.7–2.6]) CVD mortality risk in individuals with metabolic syndrome.

CONCLUSIONS

The presence of diabetes was associated with a threefold higher CVD mortality risk, and metabolic syndrome status did not modify this risk. Our findings support the fact that physicians should be aggressive in using CVD risk–reducing therapies in all diabetic patients regardless of metabolic syndrome status.Approximately 7.8% of the U.S. population has diabetes, and it is estimated that the number of adults with diabetes will increase to 48.3 million by 2050 in the U.S. and to 300 million worldwide in the year 2025, representing a 122% rise compared with 1995 (1–3). The public health importance is great, considering that individuals with diabetes have more than twice the risk for premature death, heart disease, and stroke compared with individuals without diabetes (1). Although clinical definitions differ slightly, metabolic syndrome is generally characterized as a clustering of abnormal levels of blood lipids (low HDL and high triglycerides), impaired fasting glucose, elevated blood pressure, and excess abdominal obesity (4–7). Approximately 25% of Americans and >50% of those aged >50 years meet the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III definition of metabolic syndrome (8). Similar to individuals with diabetes, individuals with metabolic syndrome have an increased risk for premature death, heart disease, and stroke (9–12).Metabolic syndrome and diabetes share many common characteristics, so it is not surprising that 65–85% of individuals with diabetes also have metabolic syndrome (13–15). However, relativity few studies have examined the effect of the combination of metabolic syndrome and diabetes on cardiovascular disease (CVD) risk (11,13,14). A cross-sectional study using National Health and Nutrition Examination Survey data reported that the prevalence of coronary heart disease (CHD) among individuals with diabetes and without metabolic syndrome was similar to that in those without diabetes or metabolic syndrome (7.5 vs. 8.7%, respectively) (14). However, individuals with concurrent diabetes and metabolic syndrome had a substantially greater prevalence (19.2%) compared with these groups. This finding suggests that in individuals with diabetes there is an increased risk for CHD only when metabolic syndrome also is present. Similarly, in a prospective study Hunt et al. (16) reported that within individuals with diabetes, those with metabolic syndrome have an increased risk for CVD mortality, whereas individuals with diabetes but not metabolic syndrome do not. However, this study was relatively small (n = 2,815) with only 117 CVD deaths. Finally, the UK Prospective Diabetes Study (UKPDS) reported that in individuals with type 2 diabetes, the presence of metabolic syndrome (NCEP) increased the risk of CVD events (17). However, it was noted from a clinical perspective that the presence of metabolic syndrome in individuals with diabetes provided little information for detecting who has an increased risk of CVD.Given the high prevalence of both metabolic syndrome and diabetes, it is of great clinical and public health importance that we develop a better understanding of the interactions of diabetes and metabolic syndrome on the risk of CVD. The primary aim of the current investigation is to examine the risk of CVD mortality in individuals with metabolic syndrome only, diabetes only, and concurrent metabolic syndrome and diabetes in a large prospective study population.