Relationship of Insulin Sensitivity,Insulin Secretion,and Adiposity With Insulin Clearance in a Multiethnic Population: The Insulin Resistance Atherosclerosis Study

OBJECTIVE

We aimed to examine insulin clearance, a compensatory mechanism to changes in insulin sensitivity, across sex, race/ethnicity populations, and varying states of glucose tolerance.

RESEARCH DESIGN AND METHODS

We measured insulin sensitivity index (S_I), acute insulin response (AIR), and metabolic clearance rate of insulin (MCRI) by the frequently sampled intravenous glucose tolerance test in 1,295 participants in the Insulin Resistance Atherosclerosis Study.

RESULTS

MCRI was positively related to S_I and negatively to AIR and adiposity across sex, race/ethnicity populations, and varying states of glucose tolerance, adiposity, and family history of diabetes. Differences in MCRI by race/ethnicity (lower in African Americans and Hispanics compared with non-Hispanic whites) and glucose tolerance were largely explained by differences in adiposity, S_I, and AIR.

CONCLUSIONS

Insulin sensitivity, insulin secretion, and adiposity are correlates of insulin clearance and appear to explain differences in insulin clearance by race/ethnicity and glucose tolerance status.Reduced insulin clearance has been demonstrated in experimental models of insulin resistance (1) and conditions associated with insulin resistance (2–5). Insulin clearance partially explains the variability of fasting insulin independently of the effect of insulin resistance, insulin secretion, adiposity, and plasma glucose (6). In response to their higher insulin resistance, minority populations have lower insulin clearance than non-Hispanic whites (4,5,7). In these studies, however, results were not adjusted for insulin resistance. Therefore, we aimed to examine insulin clearance across sex, race/ethnicity populations, and varying states of glucose tolerance in the Insulin Resistance Atherosclerosis Study (IRAS) (8).     

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.     

Effectiveness of a Computerized Insulin Order Template in General Medical Inpatients With Type 2 Diabetes: A cluster randomized trial

OBJECTIVE

To determine whether an electronic order template for basal-bolus insulin ordering improves mean blood glucose in hospitalized general medical patients with hyperglycemia and type 2 diabetes.

RESEARCH DESIGN AND METHODS

We randomly assigned internal medicine resident teams on acute general medical floors to the use of an electronic insulin order template or usual insulin ordering. We measured diabetes care parameters for 1 month on all patients with type 2 diabetes and blood glucose <60 mg/dl or >180 mg/dl treated by these physicians.

RESULTS

Intervention group patients (n = 65) had mean glucose of 195 ± 66 mg/dl. Control group patients (n = 63) had mean glucose of 224 ± 57 mg/dl (P = 0.004). In the intervention group, there was no increase in hypoglycemia.

CONCLUSIONS

Access to a computer insulin order template was associated with improved mean glucose levels without increasing hypoglycemia in patients with type 2 diabetes.Physiological, basal-bolus insulin prescribing is safe, effective (1), and the standard of care in hospitalized patients with type 2 diabetes and hyperglycemia (2). Yet only about half of such patients are prescribed basal insulin in the hospital (3). Order templates to support basal-bolus insulin prescribing (usually as part of a comprehensive inpatient diabetes quality improvement program) have been effective in improving glycemia in observational trials (4–8). Randomized trials have shown more modest effects (9,10). Knowledge of appropriate insulin ordering is a barrier to ordering basal-bolus insulin among inpatient providers (11–13).We tested the hypothesis that giving internal medicine residents access to an electronic insulin order template would be more effective than usual insulin ordering in lowering mean blood glucose in medical inpatients with type 2 diabetes.     

In Vivo Insulin Sensitivity and Lipoprotein Particle Size and Concentration in Black and White Children

OBJECTIVE

To examine sex-specific black/white differences in lipoprotein profile and the role of visceral adiposity and to assess the relationship between insulin sensitivity and lipoprotein profiles in each group.

RESEARCH DESIGN AND METHODS

Fasting lipoprotein particle size and concentration and visceral adipose tissue (VAT) were determined in 226 children (117 black, 101 male) aged 8 to <18 years. The relationship between lipoproteins and insulin sensitivity was evaluated in a subset of 194 children (100 black, 88 male) who underwent a hyperinsulinemic-euglycemic clamp.

RESULTS

Black male children had smaller VLDL and black female children had larger HDL size than their white counterparts. Overall, blacks had larger LDL size with no sex-specific race differences. After adjusting for VAT and sex, only VLDL size and concentrations remained significantly favorable in blacks. Analysis of lipoprotein particle size and concentration across insulin sensitivity quartiles revealed that in both racial groups, the most insulin-resistant children had higher concentrations of small dense LDL, small HDL, and large VLDL and smaller LDL and HDL sizes than their more insulin-sensitive counterparts.

CONCLUSIONS

The previously reported favorable lipoprotein profiles in black versus white children is partly due to race differences in VAT. In both groups, however, the most insulin-resistant youths have a high-risk atherogenic profile of small dense LDL, small HDL, and large VLDL, akin to the atherogenic lipoprotein pattern in adults with coronary artery disease.Type 2 diabetes and insulin resistance in children are associated with dyslipidemia (1,2), characterized by elevated triglycerides and LDL cholesterol and low concentrations of HDL cholesterol (1–3). In addition to traditional lipid profiles, evidence suggests that insulin resistance and type 2 diabetes are associated with changes in lipoprotein particle size and subclass concentration (2,4). These are important to assess, as traditional lipid measurements only partially predict disease risk (5). Recently, the SEARCH for Diabetes in Youth study (2) reported that 36% of youth with type 2 diabetes and 62% of those with poorly controlled diabetes had small dense LDL. Similarly, low proportions of large and high proportions of small HDL particles are found in children with type 2 diabetes and overweight, insulin-resistant children (4). However, whereas some investigators reported associations between LDL (6,7), HDL (8), and VLDL (6) particle size and fasting insulin, others did not (9). High triglyceride and low HDL cholesterol concentrations together with small, dense LDL in children with type 2 diabetes and insulin resistance are similar to the atherogenic lipoprotein phenotype in adults with coronary artery disease (10,11).Black children, despite being insulin resistant and hyperinsulinemic (12,13) compared with their white counterparts, have favorable lipid concentrations including lower LDL and triglyceride and higher HDL concentrations (3,14,15), larger HDL and LDL and smaller VLDL particles, and favorable lipoprotein subclass concentrations (6,8). Why black children have favorable lipoprotein profiles despite insulin resistance is not clear. One explanation could be lower visceral adiposity in black than in white children despite similar overall adiposity (15). In black adults insulin resistance is not a good marker of triglyceride or HDL cholesterol concentrations or lipoprotein particle size (16). Thus, the relationship between in vivo insulin sensitivity and lipoprotein profiles in black and white children needs to be examined if at-risk children are to be identified for early treatments to improve lipoprotein profiles and if those treatments are to be pertinent in children of different ethnicity.In the present study, therefore, we determined lipoprotein particle size and subclass concentrations in black and white children and measured in vivo insulin sensitivity to test the following hypotheses: 1) the favorable lipoprotein phenotype in black children is probably due to lower visceral adipose tissue (VAT) than in whites and 2) the relationship between insulin sensitivity and lipoprotein profile is similar between black and white children.     

Racial and Ethnic Differences in an Estimated Measure of Insulin Resistance Among Individuals With Type 1 Diabetes

OBJECTIVE

Insulin resistance is greater in racial/ethnic minorities than in non-Hispanic whites (NHWs) for those with and without type 2 diabetes. Because previous research on insulin resistance in type 1 diabetes was limited to NHWs, racial/ethnic variation in an estimated measure of insulin resistance in type 1 diabetes was determined.

RESEARCH DESIGN AND METHODS

The sample included 79 individuals with type 1 diabetes diagnosed at age <18 years (32.9% NHWs, 46.8% non-Hispanic black [NHB], 7.6% other/mixed, and 12.7% Hispanic) and their families. Estimated glucose disposal rate (eGDR) (milligrams per kilogram per minute; a lower eGDR indicates greater insulin resistance) was calculated using A1C, waist circumference, and hypertension status.

RESULTS

Mean current age was 13.5 years (range 3.2–32.5) and diabetes duration was 5.7 years (0.1–19.9). eGDR was inversely associated with age. Compared with that in NHWs, age-adjusted eGDR was significantly lower among nonwhites (NHB, other/mixed, and Hispanic: Δ = −1.83, P = 0.0006). Age-adjusted eGDR was negatively associated with body fat, triglycerides, urinary albumin/creatinine, acanthosis nigricans, parental obesity, and parental insulin resistance and positively related to HDL and sex hormone–binding globulin. In multivariable analysis, lower eGDR was significantly associated with older age, nonwhite race/ethnicity, acanthosis, and lower HDL.

CONCLUSIONS

Minorities with type 1 diabetes are significantly more insulin resistant, as measured by eGDR, than NHWs. Exploring potential mechanisms, including disparities in care and/or physiological variation, may contribute to preventing racial/ethnic differences in insulin resistance–associated outcomes.Insulin resistance is common in type 2 diabetes (1) and seems to play a role in the natural history (2) and risk of complications (3) in type 1 diabetes as well. Measurement of insulin resistance in type 1 diabetes is difficult because methods used in nondiabetic and type 2 individuals, e.g., insulin or homeostasis model assessment (4), cannot be used in hypoinsulinemia. The euglycemic-hyperinsulinemic clamp has been used; however, it is labor-intensive and invasive and therefore is not suitable for population-based studies. In response, a derived measure of insulin resistance, the estimated glucose disposal rate (eGDR), has been developed using clinical measures and is strongly correlated with clamp-measured insulin resistance (5).Consistent with clamp studies in type 1 diabetes (2), lower eGDR is associated with older age (6), longer duration of diabetes (6), greater adiposity (6), family history of type 2 diabetes (5), poor glycemic control (5), and elevated lipids (6). Low eGDR predicts incident retinopathy (3), nephropathy (3,6), neuropathy (7), and cardiovascular disease in type 1 diabetes (3,6). These findings are primarily based on non-Hispanic white (NHW) adults.Previous research shows racial/ethnic differences in insulin resistance for healthy individuals and those with type 2 diabetes. For example, minority adults with and without type 2 diabetes were more insulin resistant than their NHW counterparts (1,8). Similarly, in nondiabetic youth, minorities were more insulin resistant than NHWs (9,10). Despite these findings, to our knowledge, there are no data on insulin resistance in minorities with type 1 diabetes.Therefore, we sought to determine 1) whether racial/ethnic differences in insulin resistance, as measured by eGDR, exist in type 1 diabetes and 2) whether the association of eGDR with factors traditionally related to insulin resistance differed by race/ethnicity. It was hypothesized that insulin resistance is greater in minorities than in whites and that associations with insulin resistance are consistent across race/ethnicity.     

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.     

Dietary Phylloquinone and Menaquinones Intakes and Risk of Type 2 Diabetes

OBJECTIVE

To investigate whether dietary phylloquinone and menaquinones intakes are related to risk of type 2 diabetes.

RESEARCH DESIGN AND METHODS

We used data from a prospective cohort study in 38,094 Dutch men and women, aged 20–70 years. Dietary phylloquinone and menaquinones intakes were assessed using a validated food frequency questionnaire. Diabetes case patients were ascertained mainly via self-report and verified against medical records.

RESULTS

During 10.3 years of follow-up, 918 incident cases of diabetes were documented. In a multivariate model adjusting for diabetes risk factors and dietary factors, phylloquinone intake tended to be associated (P = 0.08) with a reduced risk of type 2 diabetes with a hazard ratio (HR) of 0.81 (95% CI 0.66–0.99) for the highest versus the lowest quartile. For menaquinones intake, a linear, inverse association (P = 0.038) with risk of type 2 diabetes was observed with an HR of 0.93 (0.87–1.00) for each 10-μg increment in the multivariate model.

CONCLUSIONS

This study shows that both phylloquinone and menaquinones intakes may be associated with a reduced risk of type 2 diabetes.Vitamin K is a fat-soluble vitamin occurring in two biologically active forms; vitamin K₁ (phylloquinone) and vitamin K₂ (menaquinones). Phylloquinone, the most common form, is present in green, leafy vegetables and certain vegetable oils (1), whereas menaquinones occur in animal products such as meat, eggs, and cheese (2). However, strong regional differences in the amount and forms of menaquinones intake exist (2). Vitamin K functions as a cofactor in the γ-carboxylation of certain glutamic acid (Gla) residues of vitamin K-dependent proteins for their activation (3). Vitamin K was known mainly as a cofactor to carboxylate clotting factors such as prothrombin (3). More recently, it became apparent that vitamin K also carboxylates other proteins such as osteocalcin, a regulator of bone mineral maturation (3).A recent study showed that osteocalcin concentrations may also affect insulin sensitivity and type 2 diabetes by regulating the expression of insulin genes and β-cell proliferation markers (4). In mice, osteocalcin was shown to increase insulin secretion and insulin sensitivity and decrease the severity of type 2 diabetes (4). This animal study suggested a specific role for the uncarboxylated form of osteocalcin (4), contradicting a role for vitamin K. Subsequent human studies, however, observed relations between high total or carboxylated osteocalcin and improved insulin sensitivity (5,6). These latter studies suggest that vitamin K could reduce insulin resistance and risk of type 2 diabetes by carboxylating osteocalcin.To date, no studies have investigated the relation between vitamin K intake and risk of type 2 diabetes and only a few have explored relations with insulin sensitivity. In rats, vitamin K deficiency delayed the insulin response and decreased plasma glucose (7). Similar results have been shown in small-scale human studies among young men with a low risk of diabetes (8). Recently, two larger studies investigated the relation between dietary phylloquinone and insulin sensitivity. An observational study showed that high phylloquinone intake was associated with improved insulin sensitivity and glycemic control (9). A randomized controlled trial showed improved insulin sensitivity after phylloquinone supplementation among men (10). Whether dietary phylloquinone or menaquinones intakes are associated with a reduced risk of type 2 diabetes is unknown. Therefore, we investigated whether dietary phylloquinone and menaquinones intakes are inversely associated with type 2 diabetes in a prospective cohort of Dutch men and women. Because previous studies suggested relations between vitamin K and inflammatory factors or blood lipid profile (11–14), we explored relations between phylloquinone and menaquinones intakes and high-sensitivity C-reactive protein (CRP), blood lipid profile, and A1C as a marker of diabetes risk.     

Depressive symptoms, antidepressant medication use, and insulin resistance: the PPP-Botnia Study

OBJECTIVE

Although insulin resistance (IR) may underlie associations between depressive symptoms and diabetes, previous findings have been contradictory. We examined whether depressive symptoms associate with IR and insulin secretion, and, additionally, whether antidepressant medication use may modulate such associations.

RESEARCH DESIGN AND METHODS

A total of 4,419 individuals underwent an oral glucose tolerance test (OGTT). Participants with previously or newly diagnosed diabetes are excluded from this sample. The homeostasis model assessment of IR (HOMA-IR) and corrected insulin response (CIR) were calculated. Depressive symptoms and antidepressant medication use were self-reported.

RESULTS

After controlling for confounding factors, depressive symptoms were associated with higher fasting and 30-min insulin during the OGTT and higher HOMA-IR but not CIR. Antidepressant medication use failed to modify these associations.

CONCLUSIONS

Depressive symptoms are associated with IR but not with changes in insulin response when corrected for IR in individuals without previously or newly diagnosed diabetes.Depressive symptoms are associated with type 2 diabetes (1) and the metabolic syndrome (2,3), and insulin resistance (IR) is thought to be the underlying factor. However, previous findings have been conflicting because depressive symptoms have been reported to be associated with both higher IR (4) and lower IR (5), whereas some studies have reported null associations (6,7). We examined associations of depressive symptoms with IR and insulin secretion in individuals without diabetes. We also tested if antidepressant medications modulated these associations, as one study suggests that antidepressant medication, such as the use of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, may improve insulin sensitivity (8). Yet, one study reported that antidepressant medications and insulin sensitivity are not related (9), whereas some studies have reported that antidepressant medications may decrease insulin sensitivity and increase the risk of type 2 diabetes (10,11).     

Fasting insulin level is positively associated with incidence of hypertension among American young adults: a 20-year follow-up study

OBJECTIVE

Although hyperinsulinemia, a surrogate of insulin resistance, may play a role in the pathogenesis of hypertension (HTN), the longitudinal association between fasting insulin level and HTN development is still controversial. We examined the relation between fasting insulin and incidence of HTN in a large prospective cohort.

RESEARCH DESIGN AND METHODS

A prospective cohort of 3,413 Americans, aged 18–30 years, without HTN in 1985 (baseline) were enrolled. Six follow-ups were conducted in 1987, 1990, 1992, 1995, 2000, and 2005. Fasting insulin and glucose levels were assessed by a radioimmunoassay and hexokinase method, respectively. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs of incident HTN (defined as the initiation of antihypertensive medication, systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg).

RESULTS

During the 20-year follow-up, 796 incident cases were identified. After adjustment for potential confounders, participants in the highest quartile of insulin levels had a significantly higher incidence of HTN (HR 1.85 [95% CI 1.42–2.40]; P_trend < 0.001) compared with those in the lowest quartile. The positive association persisted in each sex/ethnicity/weight status subgroup. A similar dose-response relation was observed when insulin-to-glucose ratio or homeostatic model assessment of insulin resistance was used as exposure.

CONCLUSIONS

Fasting serum insulin levels or hyperinsulinemia in young adulthood was positively associated with incidence of HTN later in life for both men and women, African Americans and Caucasians, and those with normal weight and overweight. Our findings suggested that fasting insulin ascertainment may help clinicians identify those at high risk of HTN.Hypertension (HTN), a leading cause of cardiovascular morbidity and mortality, has become an important public health burden worldwide (1). It has been well established that HTN tends to coexist with diabetes (2,3), either preceding or being the complication of diabetes. In addition, the risk factors for HTN and diabetes are prone to cluster together, and it has been hypothesized that hyperinsulinemia, a surrogate measure of insulin resistance, might provide the pathophysiological mechanism underlying these observations (4).Some epidemiological studies, including both cross-sectional and longitudinal studies, have indicated that insulin levels are associated with blood pressure (BP) as well as incidence of HTN (5–7). However, inconsistent findings (8,9), especially in a specific sex or ethnic subgroup (10,11), made this topic a controversy. In addition, among the limited prospective studies on the association of insulin level with incidence of HTN (5,6,9,12–14), most have been conducted in only one sex or one ethnic group (9,12–14). Few studies have examined the association in both men and women, and African Americans (AAs) and Caucasians (5,6). Therefore, we prospectively examined fasting insulin level in relation to incidence of HTN in a large biracial cohort of American men and women over 20 years of follow-up using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study.     

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).     

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.     

Associations between media consumption habits, physical activity, socioeconomic status, and glycemic control in children, adolescents, and young adults with type 1 diabetes

OBJECTIVE

To evaluate the relationship between media consumption habits, physical activity, socioeconomic status, and glycemic control in youths with type 1 diabetes.

RESEARCH DESIGN AND METHODS

In the cross-sectional study, self-report questionnaires were used to assess media consumption habits, physical activity, and socioeconomic status in 296 children, adolescents, and young adults with type 1 diabetes. Clinical data and HbA_1c levels were collected. Risk factors were analyzed by multiple regression.

RESULTS

Youths with type 1 diabetes (aged 13.7 ± 4.1 years, HbA_1c 8.7 ± 1.6%, diabetes duration 6.1 ± 3.3 years) spent 2.9 ± 1.8 h per day watching television and using computers. Weekly physical activity was 5.1 ± 4.5 h. Multiple regression analysis identified diabetes duration, socioeconomic status, and daily media consumption time as significant risk factors for glycemic control.

CONCLUSIONS

Diabetes duration, socioeconomic status, and daily media consumption time, but not physical activity, were significant risk factors for glycemic control in youths with type 1 diabetes.The pivotal Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) study demonstrate that poor glycemic control is associated with an increased risk of developing complications in type 1 diabetes (1). Various factors contributing to glycemic control have been identified (2). Immutable parameters such as age, sex, diabetes duration, and socioeconomic status have a major effect on metabolic control (2–6). Lower socioeconomic status is an important determinant for poor glycemic control (4,5). Modifiable factors influencing metabolic control are diabetes-related knowledge, frequency of blood glucose monitoring, and daily insulin dose (3,4,6,7). Lastly, psychosocial parameters are important in achieving good glycemic control (3–5,8–10). The influence of physical activity on metabolic control is unclear (9,11,12).Recent research addresses the influence of modern life habits on general health. Youths spend more and more time watching television and using computers. Many studies suggest that sedentary behaviors such as watching television lead to obesity in children (13,14). In one study in youths with type 1 diabetes, Margeirsdottir et al. (15) showed that poor metabolic control was associated with extensive television watching. However, the authors did not examine other covariables, such as socioeconomic status, which is associated with both glycemic control and media consumption (4,5,16,17). Hence, the aim of this study was to examine the impact of media consumption habits, physical activity, and socioeconomic status on glycemic control in youths with type 1 diabetes.     

Glucagon-Like Peptide 1 Reduces Endothelial Dysfunction,Inflammation, and Oxidative Stress Induced by Both Hyperglycemia and Hypoglycemia in Type 1 Diabetes

OBJECTIVE

Hyperglycemia and hypoglycemia currently are considered risk factors for cardiovascular disease in type 1diabetes. Both acute hyperglycemia and hypoglycemia induce endothelial dysfunction and inflammation, raising the oxidative stress. Glucagon-like peptide 1 (GLP-1) has antioxidant properties, and evidence suggests that it protects endothelial function.

RESEARCH DESIGN AND METHODS

The effect of both acute hyperglycemia and acute hypoglycemia in type 1 diabetes, with or without the simultaneous infusion of GLP-1, on oxidative stress (plasma nitrotyrosine and plasma 8-iso prostaglandin F2alpha), inflammation (soluble intercellular adhesion molecule-1 and interleukin-6), and endothelial dysfunction has been evaluated.

RESULTS

Both hyperglycemia and hypoglycemia acutely induced oxidative stress, inflammation, and endothelial dysfunction. GLP-1 significantly counterbalanced these effects.

CONCLUSIONS

These results suggest a protective effect of GLP-1 during both hypoglycemia and hyperglycemia in type 1 diabetes.Recent evidence suggests that hypoglycemia also may play an important role in favoring diabetic vascular complications (1). Hypoglycemia causes oxidative stress (2), inflammation (3,4), and endothelial dysfunction (5). Oxidative stress is considered the key player in the pathogenesis of diabetes complications (6). It is of interest that during hyperglycemia, oxidative stress is mainly produced at the mitochondrial level (6), similar to what happens in hypoglycemia (2). Therefore, oxidative stress might be considered the common factor linking hyperglycemia, hypoglycemia, and vascular complications of diabetes. Consistent with this hypothesis is the evidence that both hyperglycemia (7) and hypoglycemia produce endothelial dysfunction and inflammation through oxidative stress generation (5,8). Both endothelial dysfunction and inflammation are well-recognized pathogenic factors for vascular disease, particularly in diabetes (9).Glucagon-like peptide 1 (GLP-1) and its analogs are now being used in clinics to enhance insulin secretion and to reduce body weight in patients with type 2 diabetes (10) in whom a defect of GLP-1 secretion or action in response to the meal often has been reported (11). GLP-1 has been shown to lower postprandial and fasting glucose and HbA_1c, to suppress the elevated glucagon level, and to stimulate glucose-dependent insulin synthesis and secretion (10). Recently, a possible beneficial effect of GLP-1 analogs in the management of type 1 diabetes has been suggested (12). GLP-1, in addition to its insulin-tropic action in alleviating hyperglycemia, has beneficial effects in protecting progressive impairment of pancreatic β-cell function, preservation of β-cell mass, and suppression of glucagon secretion, gastric emptying, and appetite, which are all characteristics that could be beneficial for the management of type 1 diabetes (12).Apart from the well-documented incretin effect of GLP-1, its role in the cardiovascular system also arouses interest. GLP-1 effects on the cardiovascular system may include a direct action on the endothelium in which the presence of specific receptors for GLP-1 has been demonstrated (13). Consistently, GLP-1 has been demonstrated to improve endothelial function in diabetes (14,15). This protective effect should be exerted to improve the antioxidant defenses of the endothelium (16) and to decrease oxidative stress generation (15).The aim of this study is to test whether GLP-1 can protect endothelial function and reduce the generation of oxidative stress and inflammation during acute hyperglycemia and hypoglycemia in type 1 diabetes.     

Improved metabolic control in children and adolescents with type 1 diabetes: a trend analysis using prospective multicenter data from Germany and Austria

OBJECTIVE

To investigate the temporal trend of metabolic control and potential predictors in German and Austrian children and adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

This study is based on a large, multicenter database for prospective longitudinal documentation of diabetes care in Germany and Austria. Data from 30,708 patients documented in 305 diabetes centers between 1995 and 2009 were analyzed. Generalized linear mixed regression models were used to adjust trend analysis for relevant confounders.

RESULTS

Unadjusted mean HbA_1c decreased from 8.7 ± 1.8% in 1995 to 8.1 ± 1.5% in 2009. In multiple regression analysis, treatment year, age, sex, diabetes duration, migration background, BMI-SDS, and daily insulin dose were significant predictors of metabolic control (P < 0.001). After multiple adjustment, mean HbA_1c decreased significantly by 0.038% per year (95% CI 0.032–0.043%), average odds ratio (OR) per year for HbA_1c >7.5% (>9.0%) was 0.969 (95% CI 0.961–0.977) (0.948, 95% CI 0.941–0.956). Intensified insulin regimen was associated with lower frequency of poor metabolic control (HbA_1c >9%; P = 0.005) but not with average HbA_1c (P = 0.797). Rate of severe hypoglycemia and hypoglycemic coma decreased significantly (relative risk [RR] per year 0.948, 95% CI 0.918–0.979; RR 0.917, 95% CI 0.885–0.950) over the study period. Diabetic ketoacidosis rate showed no significant variation over time.

CONCLUSIONS

This study showed a significant improvement in metabolic control in children and adolescents with type 1 diabetes during the past decade and a simultaneous decrease in hypoglycemic events. The improvement was not completely explained by changes in the mode of insulin treatment. Other factors such as improved patient education may have accounted for the observed trend.The Diabetes Control and Complications Trial (DCCT) showed that improved metabolic control reduces the risk of long-term complications in both adult and adolescent patients with type 1 diabetes (1,2). The observational follow-up study of the DCCT (the Epidemiology of Diabetes Interventions and Complications [EDIC] study) further proved that good glycemic control had persistent beneficial effects on long-term complications (3). Based on the results of the DCCT/EDIC study, it was recommended to optimize glycemic control as early and close to normal as possible in all patients with type 1 diabetes in order to prevent development and progression of microvascular complications.Diabetes treatment has been intensified in pediatric and adolescent patients during the past 15 years. Insulin therapy has changed from twice-daily injection regimen to intensified therapy with multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII). This has been reported from single-center and multicenter studies (4–10). In the 1990s, mainly an increased use of MDI was observed, whereas since 2000, pump therapy increased considerably, paralleled by a decrease in MDI therapy (11). With the intensification of insulin regimen, the frequency of daily self-monitoring of blood glucose (SMBG) increased continuously (5,10–12), as close glucose monitoring is a precondition for intensified insulin therapy with an appropriate dose adjustment. Likewise, the use of short-acting insulin analogs has continuously increased since the mid-1990s and the use of long-acting analogs since 2000 (4,5,10).Despite these far-ranging changes in diabetes therapy, the anticipated improvement in metabolic control in children and adolescents with type 1 diabetes has not been achieved in all settings. The multicenter Hvidoere studies did not observe any improvement in glycemic control during 1995–2005 (6–8). Other studies, however, reported a significant decrease in average HbA_1c level over the past two decades (4,5,10,11,13). Concordantly, several studies indicated a notable increase in the proportion of children and adolescents with good metabolic control (HbA_1c <7.5 or <8%) over the past years (11,13).In the DCCT study, the tradeoff with intensified insulin therapy was a marked increase in episodes of severe hypoglycemia (2). Several studies reported a higher hypoglycemia risk with lower HbA_1c level (4,6,7,10,14), but others did not (15,16). Results on the trend of severe hypoglycemic events over the past 15 years are also inconsistent (4,5,8,9,11).The aim of this study was to give a current update on the temporal trend of metabolic control in German and Austrian children and adolescents over the past 15 years (1995–2009), to identify potential determinants of metabolic control, and to analyze the simultaneous trend of severe hypoglycemic and diabetic ketoacidotic events.     

Early Diabetic Nephropathy: A complication of reduced insulin sensitivity in type 1 diabetes

OBJECTIVE

Diabetic nephropathy (DN) is a major cause of mortality in type 1 diabetes. Reduced insulin sensitivity is a well-documented component of type 1 diabetes. We hypothesized that baseline insulin sensitivity would predict development of DN over 6 years.

RESEARCH DESIGN AND METHODS

We assessed the relationship between insulin sensitivity at baseline and development of early phenotypes of DN—microalbuminuria (albumin-creatinine ratio [ACR] ≥30 mg/g) and rapid renal function decline (glomerular filtration rate [GFR] loss >3 mL/min/1.73 m² per year)—with three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations over 6 years. Subjects with diabetes (n = 449) and without diabetes (n = 565) in the Coronary Artery Calcification in Type 1 Diabetes study had an estimated insulin sensitivity index (ISI) at baseline and 6-year follow-up.

RESULTS

The ISI was lower in subjects with diabetes than in those without diabetes (P < 0.0001). A higher ISI at baseline predicted a lower odds of developing an ACR ≥30 mg/g (odds ratio 0.65 [95% CI 0.49–0.85], P = 0.003) univariately and after adjusting for HbA_1c (0.69 [0.51–0.93], P = 0.01). A higher ISI at baseline conferred protection from a rapid decline of GFR as assessed by CKD-EPI cystatin C (0.77 [0.64–0.92], P = 0.004) and remained significant after adjusting for HbA_1c and age (0.80 [0.67–0.97], P = 0.02). We found no relation between ISI and rapid GFR decline estimated by CKD-EPI creatinine (P = 0.38) or CKD-EPI combined cystatin C and creatinine (P = 0.50).

CONCLUSIONS

Over 6 years, a higher ISI independently predicts a lower odds of developing microalbuminuria and rapid GFR decline as estimated with cystatin C, suggesting a relationship between insulin sensitivity and early phenotypes of DN.Diabetic nephropathy (DN) is a common and serious complication of diabetes. Its incidence is rising rapidly (1), and it is the most common cause of end-stage renal disease in the U.S. and Europe (2). The 2011 U.S. Renal Data System showed that DN accounted for 44.5% of all cases of end-stage renal disease in 2009 (3). Despite improvements in the outlook of this complication in past decades, it continues to be one of the major causes of morbidity and mortality in type 1 diabetes (4,5). DN is an important risk factor for coronary artery disease (6–8) and overall mortality (6,9). These findings highlight the need for improved methods of identifying persons at high risk for DN (10).The role of insulin sensitivity in the development and progression of macro- (7,11,12) and microvascular complications (12,13) in type 1 diabetes is increasingly recognized. Reduced insulin sensitivity also is a plausible mechanism linking renal disease with excess mortality in type 1 diabetes. Historically, when glycemic control is poor, reduced insulin sensitivity was believed to be directly related to body weight and HbA_1c (14,15), but more recent data suggest that reduced insulin sensitivity cannot simply be explained by weight or poor glycemic control. In fact, reduced insulin sensitivity has been documented in type 1 diabetic subjects with normal BMI and HbA_1c compared with nondiabetic individuals (16). The Coronary Artery Calcification in Type 1 Diabetes (CACTI) longitudinal cohort study of adults with type 1 diabetes investigated the determinants of early and accelerated atherosclerosis and found that insulin sensitivity independently predicted coronary artery calcification (17,18). Reduced insulin sensitivity has also been shown to predict diabetic retinopathy, neuropathy, and nephropathy in subjects with type 1 diabetes (13).Despite advances in the estimation of insulin sensitivity (insulin sensitivity index [ISI]) (19) and glomerular filtration rate (GFR) (20), research in the association of insulin sensitivity with DN has been limited since the Pittsburgh Epidemiology of Diabetes Complications (EDC) cohort showed more than a decade ago that the estimated glucose disposal rate (eGDR) predicts overt nephropathy (13). To readdress this relationship with contemporary data and estimating equations, we hypothesized that higher insulin sensitivity measured by ISI at baseline would be associated with decreased odds of developing two early phenotypes of DN—microalbuminuria (albumin-creatinine ratio [ACR] ≥30 mg/g) and rapid renal function decline (GFR loss >3 mL/min/1.73 m² per year) (21–23)—calculated by the three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations (20) over 6 years in the CACTI study.     

Hepatic and peripheral insulin sensitivity and diabetes remission at 1 month after Roux-en-Y gastric bypass surgery in patients randomized to omentectomy

OBJECTIVE

Early after Roux-en-Y gastric bypass (RYGB), there is improvement in type 2 diabetes, which is characterized by insulin resistance. We determined the acute effects of RYGB, with and without omentectomy, on hepatic and peripheral insulin sensitivity. We also investigated whether preoperative diabetes or postoperative diabetes remission influenced tissue-specific insulin sensitivity after RYGB.

RESEARCH DESIGN AND METHODS

We studied 40 obese (BMI 48 ± 8 kg/m²) participants, 17 with diabetes. Participants were randomized to RYGB alone or in conjunction with omentectomy. Hyperinsulinemic-euglycemic clamps with isotopic-tracer infusion were completed at baseline and at 1 month postoperatively to assess insulin sensitivity.

RESULTS

Participants lost 11 ± 4% of body weight at 1 month after RYGB, without an improvement in peripheral insulin sensitivity; these outcomes were not affected by omentectomy, preoperative diabetes, or remission of diabetes. Hepatic glucose production (HGP) and the hepatic insulin sensitivity index improved in all subjects, irrespective of omentectomy (P ≤ 0.001). Participants with diabetes had higher baseline HGP values (P = 0.003) that improved to a greater extent after RYGB (P = 0.006). Of the 17 participants with diabetes, 10 (59%) had remission at 1 month. Diabetes remission had a group × time effect (P = 0.041) on HGP; those with diabetes remission had lower preoperative and postoperative HGP.

CONCLUSIONS

Peripheral insulin sensitivity did not improve 1 month after RYGB, irrespective of omentectomy, diabetes, or diabetes remission. Hepatic insulin sensitivity improved at 1 month after RYGB and was more pronounced in patients with diabetes. Improvement in HGP may influence diabetes remission early after RYGB.Of the estimated 26 million people in the U.S. with type 2 diabetes and the 79 million with prediabetes (1), ∼80% are overweight or obese. Roux-en-Y gastric bypass (RYGB) surgery for treatment of obesity leads to long-term diabetes remission in ∼80% of patients (2), whereas very limited effects are observed with lifestyle intervention (3). Improvements in diabetes are reported to occur immediately after RYGB (4), with ∼30% of patients being discharged from the hospital with discontinuation of all diabetes medications (5).Impaired insulin sensitivity (insulin resistance) at the liver and in the periphery (primarily skeletal muscle) is an underlying mechanism of and precursor to diabetes (6). Several studies have described a long-term improvement in peripheral and hepatic insulin sensitivity 6 months to 1 year after RYGB (7–9), which is considered to occur secondary to weight loss. The mechanisms of the immediate improvement in diabetes after RYGB, before substantial weight loss, are not well delineated. Improvements in insulin sensitivity are reported early after RYGB, by hyperglycemic clamp at 1 and 4 weeks postoperatively (10) or by intravenous glucose tolerance tests (11) and homeostasis model assessment (HOMA) during the first week postoperatively (11,12). These approaches to measure insulin sensitivity, however, cannot distinguish between peripheral and hepatic insulin sensitivity. The hyperinsulinemic-euglycemic clamp method in conjunction with isotopically labeled tracer infusion allows measurement of peripheral (primarily skeletal muscle) insulin sensitivity as well as hepatic glucose production (HGP) and hepatic insulin sensitivity. Two studies have used this technique to assess insulin sensitivity early after RYGB, and interestingly, did not find a significant improvement in peripheral insulin sensitivity 2 to 4 weeks after RYGB; however, hepatic insulin sensitivity was not assessed (13,14). Recently, Camastra et al. (7) reported that peripheral and hepatic insulin sensitivity did not change at 2 weeks after RYGB in patients with and without diabetes.Increased visceral fat is considered an important risk factor for diabetes and insulin resistance (15). We recently reported, however, that surgical removal of the greater omentum (omentectomy) in conjunction with RYGB did not augment the improvement in insulin sensitivity long-term after RYGB (8). Here we report the acute effects of RYGB with or without omentectomy on hepatic and skeletal muscle insulin sensitivity. This was assessed by hyperinsulinemic-euglycemic clamp with tracer infusion at 1 month after RYGB. We also tested the hypothesis that an early remission of diabetes after RYGB is associated with improved hepatic and peripheral insulin sensitivity.     

Effect of elevated basal insulin on cancer incidence and mortality in cancer incident patients: the Israel GOH 29-year follow-up study

OBJECTIVE

Diabetes is associated with many forms of cancer. Recent evidence has suggested that some treatments for diabetes are associated with an increased cancer risk. Less is known about the association between endogenous insulin in the prediabetes state and cancer risk.

RESEARCH DESIGN AND METHODS

We investigated cumulative cancer incidence and cancer incidence density over 29 years, according to basal insulin, in a cohort of 1,695 nondiabetic men and women of four ethnic origins, aged 51.8 ± 8.0 years at baseline. Total mortality among the 317 subjects (18.7%) who developed cancer at least 2 years after baseline was assessed.

RESULTS

In a Cox proportional hazards model, the all-site hazard ratio of cancer incidence comparing the highest insulin quartile with the other three quartiles was 1.09 (95% CI 0.85–1.40), adjusted for age, sex, and ethnicity. BMI, smoking, and fasting blood glucose were not statistically significant in this model. Basal insulin level was not significantly associated with cancer of specific sites (breast, prostate, colon/rectum, or bladder). Fasting insulin in the upper quartile conferred a 37% increased risk for total mortality among cancer patients, adjusting for age, sex, and ethnic origin (95% CI 0.94–2.00, P = 0.097) compared with that of the lower quartiles. Male sex, older age, and North African origins were associated with a greater risk of mortality during follow-up time.

CONCLUSIONS

This long-term cohort study may suggest a role for basal elevated insulin levels, mainly as a negative predictor in cancer prognosis.The American Diabetes Association and the American Cancer Society recently issued a consensus report showing cancer incidence to be associated with diabetes (1). Type 2 diabetes has been associated with increased incidence, in the range of 1.2–2.5 of cancers of the pancreas (2), breast (3), colon (4), and bladder (5). In addition, a recent meta-analysis of 23 studies found diabetes to be associated with an increased mortality hazard ratio (HR) of 1.41 (95% CI 1.28–1.55) among individuals with cancer (6). Furthermore, some treatments for diabetes have been implicated in increasing the risk of malignancy (7). The development of some types of insulin has been discontinued secondary to increased mitogenic side effects (8). The affinity of binding to the IGF-1 receptor (IGF-1R) has been implicated.We and others have shown basal hyperinsulinemia to predict type 2 diabetes (9,10). Further, elevated levels of circulating insulin and C-peptide have been associated with an increased risk of colorectal and pancreatic cancers (11). Though the risk of breast cancer was less certain in the latter study, two recent analyses of the Women''s Health Initiative found a positive association between insulin levels and breast cancer (12,13).Studies in animals (14–17) and in vitro (18,19) suggest a role for insulin in tumor progression. Glucose tolerance status from 2-h glucose tolerance tests has been shown to associate with the risk of cancer mortality (4). However, the effect of elevated basal insulin on cancer prognosis has not been investigated in vivo.The current study examined the effect, up to 29 years later (mean follow-up time 21.7 ± 6.5 years), of elevated levels of basal insulin on the cumulative incidence of cancer and on cancer survival in a cohort of the Jewish population, representing the four main ethnic origins of immigration to Israel.     

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.     

A Study of Dapagliflozin in Patients With Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers: Applicability of a novel insulin-independent treatment

OBJECTIVE

To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs).

RESEARCH DESIGN AND METHODS

This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]).

RESULTS

At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated −0.70 and −0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C ≥0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and −9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were −1.9, −4.5, and −4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group.

CONCLUSIONS

In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.Treatment of hyperglycemia in patients with type 2 diabetes remains a challenge, particularly in those who require insulin as the disease progresses (1,2). Various combinations of insulin with oral antidiabetic agents (OADs) have been investigated (2–8). Often, these combination therapies become less effective in controlling hyperglycemia over time, particularly as a result of weight gain and worsening insulin resistance as well as progressive failure of insulin secretion.Hypoglycemia, weight gain, and subsequent increased insulin resistance are significant factors that limit optimal titration and effectiveness of insulin (2). Weight gain with insulin therapy, used alone or with OADs (7–9), is in part a consequence of reducing glucosuria (10,11). Among commonly used OADs, thiazolidinediones (TZDs) and sulfonylureas intrinsically contribute to weight gain, whereas metformin causes weight loss and dipeptidyl peptidase-4 inhibitors are weight neutral. Overall, there is a need for novel agents that can be safely administered to help achieve glycemic targets without increasing the risks of weight gain or hypoglycemia.A novel approach to treating hyperglycemia targets receptors for renal glucose reabsorption (12). Agents that selectively block sodium-glucose cotransporter 2 (SGLT2), located in the proximal tubule of the kidney, inhibit glucose reabsorption and induce its elimination through urinary excretion (13). Preclinical models have shown that SGLT2 inhibition lowers blood glucose independently of insulin (14–17). Dapagliflozin, a highly selective inhibitor of SGLT2, has demonstrated efficacy, alone or in combination with metformin, in reducing hyperglycemia in patients with type 2 diabetes (18,19) but has not been tested in patients requiring insulin. This study was designed to determine whether dapagliflozin is effective in lowering blood glucose in patients with type 2 diabetes who have not responded adequately to insulin combined with oral therapies that act through insulin-dependent mechanisms.