Effective Translation of an Intensive Lifestyle Intervention for Hispanic Women With Prediabetes in a Community Health Center Setting

OBJECTIVE

The Diabetes Prevention Program (DPP) demonstrated that weight loss from intensive lifestyle intervention (ILI) in adults with prediabetes could decrease progression to type 2 diabetes. Inner-city, low-income Hispanic women are at high risk for developing type 2 diabetes; however, this type of intervention is not well established in this group. We hypothesized that a DPP intervention modified for a community health center (CHC) setting would decrease weight and improve metabolic measures in Hispanic women with prediabetes.

RESEARCH DESIGN AND METHODS

Women diagnosed with prediabetes on a screening oral glucose tolerance test were recruited from a CHC. Participants (90% of whom were Hispanic) were randomized to either usual care (age 43 ± 9.7 years, BMI 35.2 ± 7.3 kg/m²) or ILI (age 43.8 ± 10.8 years, BMI 35.4 ± 8.5 kg/m²), structured as 14 weeks of group sessions focused on food choices, behavior change, physical activity, and weight loss. One year after enrollment, 122 women repeated baseline measures.

RESULTS

Groups had similar baseline weight, BMI, and fasting and 2-h glucose. One year later, the ILI group had lost 3.8 kg (4.4%), while the usual care group had gained 1.4 kg (1.6%, P < 0.0001). Two-hour glucose excursion decreased 15 mg/dL (0.85 mmol/L) in the ILI and 1 mg/dL (0.07 mmol/L) in the usual care group (P = 0.03). Significant decreases favoring the ILI group were noted in BMI, percent body fat, waist circumference, and fasting insulin.

CONCLUSIONS

A 14-week ILI program based on the DPP can effectively be translated into a predominantly Hispanic CHC setting, resulting in decreased weight, improved fasting insulin, and smaller glucose excursions 1 year after enrolling in the program.     

Cross-sectional and Longitudinal Associations Between Objectively Measured Sedentary Time and Metabolic Disease: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

OBJECTIVE

Prolonged sedentary time (ST) might be contributing to the diabetes epidemic, but most studies have been cross-sectional and few have objectively measured ST. The purpose of this study was to evaluate cross-sectional and 5-year longitudinal relationships between ST and metabolic parameters and outcomes.

RESEARCH DESIGN AND METHODS

This was an analysis of 2,027 Coronary Artery Risk Development in Young Adults (CARDIA) study participants (aged 38–50 years, 57% female, and mean BMI of 29.0 ± 7.0 kg/m²) with accelerometry data (≥4 days with ≥10 h/day) measured at the year 20 follow-up exam (2005–2006). Metabolic variables (fasting glucose, fasting insulin, 2-h postchallenge glucose, HOMA of insulin resistance [HOMA-IR], and HbA_1c) and outcomes (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], prediabetes by HbA_1c, and diabetes) were assessed concurrently and 5 years later.

RESULTS

Average ST was 8.1 ± 1.7 h/day or 55 ± 10% of wear time. Each additional hour per day of ST was cross-sectionally associated with a 3% higher fasting insulin and HOMA-IR (both P < 0.01) but not 5-year changes in metabolic parameters. Having ≥10 h/day vs. <6 h/day of ST was associated with an odds ratio (OR) = 2.74 (95% CI 1.13, 6.62) for IGT and an OR = 3.80 (95% CI 1.39, 10.35) for diabetes. ST was not associated with prevalent IFG, prevalent prediabetes by HbA_1c, or 5-year incidence of any metabolic outcomes (all P > 0.05).

CONCLUSIONS

ST was independently related to insulin, HOMA-IR, and prevalent diabetes and IGT but did not predict 5-year changes in metabolic parameters or incidence of metabolic outcomes. These results suggest that higher ST may not be a risk factor for future metabolic outcomes, but more research with repeated ST measurement and longer follow-up is needed.     

Quantification of the Glycemic Response to Microdoses of Subcutaneous Glucagon at Varying Insulin Levels

OBJECTIVE

Glucagon delivery in closed-loop control of type 1 diabetes is effective in minimizing hypoglycemia. However, high insulin concentration lowers the hyperglycemic effect of glucagon, and small doses of glucagon in this setting are ineffective. There are no studies clearly defining the relationship between insulin levels, subcutaneous glucagon, and blood glucose.

RESEARCH DESIGN AND METHODS

Using a euglycemic clamp technique in 11 subjects with type 1 diabetes, we examined endogenous glucose production (EGP) of glucagon (25, 75, 125, and 175 μg) at three insulin infusion rates (0.016, 0.032, and 0.05 units/kg/h) in a randomized, crossover study. Infused 6,6-dideuterated glucose was measured every 10 min, and EGP was determined using a validated glucoregulatory model. Area under the curve (AUC) for glucose production was the primary outcome, estimated over 60 min.

RESULTS

At low insulin levels, EGP rose proportionately with glucagon dose, from 5 ± 68 to 112 ± 152 mg/kg (P = 0.038 linear trend), whereas at high levels, there was no increase in glucose output (19 ± 53 to 26 ± 38 mg/kg, P = NS). Peak glucagon serum levels and AUC correlated well with dose (r² = 0.63, P < 0.001), as did insulin levels with insulin infusion rates (r² = 0.59, P < 0.001).

CONCLUSIONS

EGP increases steeply with glucagon doses between 25 and 175 μg at lower insulin infusion rates. However, high insulin infusion rates prevent these doses of glucagon from significantly increasing glucose output and may reduce glucagon effectiveness in preventing hypoglycemia when used in the artificial pancreas.     

Serum Paraoxonase 1 Activity and Oxidative Stress in Pediatric Patients with Pulmonary Tuberculosis

Objectives

The aim of this study was to determine the oxidative stress and paraoxonase 1 (PON1) levels in children with pulmonary tuberculosis (TB) compared to healthy controls, and to examine the association of demographical with oxidative stress.

Subjects and Methods

Forty children diagnosed with pulmonary TB and 40 age- and gender-matched healthy controls were enrolled in the study. Serum total antioxidant status (TAS), total oxidant status (TOS) and PON1 levels were measured. The oxidative stress index (OSI) was calculated to indicate the degree of oxidative stress.

Results

The TAS levels were lower (1.73 ± 0.5 vs. 2.54 ± 1.2 μmol Trolox Eq/l) while TOS levels were significantly higher (26.9 ± 14.4 vs. 13.4 ± 7.7 μmol H₂O₂ Eq/l) in the TB group than in the controls (p < 0.001). The OSI was significantly higher in the TB group than in the controls (21.2 ± 5.1 vs. 6.5 ± 4.9 units, p = 0.006). Serum PON1 levels were significantly lower in the TB group than in the controls (14.2 ± 13.2 vs. 28.4 ± 17.3 U/l, p < 0.001). The lower PON1 levels correlated with TAS and OSI levels but not with anthropometric parameters (r = 0.264, p = 0.018 and r = −0.255, p = 0.023, respectively).

Conclusion

The TOS and OSI levels were higher and the TAS and PON1 levels were lower in pediatric patients with pulmonary TB when compared to healthy controls. This indicates greater oxidative stress in the patients.Key Words: Total oxidant status, Paraoxonase 1, Tuberculosis, Oxidative stress     

Pathogenetic Mechanisms and Cardiovascular Risk: Differences between HbA1c and oral glucose tolerance test for the diagnosis of glucose tolerance

OBJECTIVE

To ascertain to which extent the use of HbA_1c and oral glucose tolerance test (OGTT) for diagnosis of glucose tolerance could identify individuals with different pathogenetic mechanisms and cardiovascular risk profile.

RESEARCH DESIGN AND METHODS

A total of 844 subjects (44% men; age 49.5 ± 11 years; BMI 29 ± 5 kg/m²) participated in this study. Parameters of β-cell function were derived from deconvolution of the plasma C-peptide concentration after a 75-g OGTT and insulin sensitivity assessed by homeostasis model assessment of insulin resistance (IR). Cardiovascular risk profile was based on determination of plasma lipids and measurements of body weight, waist circumference, and blood pressure. Glucose regulation categories by OGTT and HbA_1c were compared with respect to insulin action, insulin secretion, and cardiovascular risk profile.

RESULTS

OGTT results showed 42% of the subjects had prediabetes and 15% had type 2 diabetes mellitus (T2DM), whereas the corresponding figures based on HbA_1c were 38 and 11%, with a respective concordance rate of 54 and 44%. Subjects meeting both diagnostic criteria for prediabetes presented greater IR and impairment of insulin secretion and had a worse cardiovascular risk profile than those with normal glucose tolerance at both diagnostic methods. In a logistic regression analyses adjusted for age, sex, and BMI, prediabetic subjects, and even more T2DM subjects by OGTT, had greater chance to have IR and impaired insulin secretion.

CONCLUSIONS

HbA_1c identifies a smaller proportion of prediabetic individuals and even a smaller proportion of T2DM individuals than OGTT, with no difference in IR, insulin secretion, and cardiovascular risk profile. Subjects fulfilling both diagnostic methods for prediabetes or T2DM are characterized by a worse metabolic profile.The early identification of subjects at high risk for type 2 diabetes mellitus (T2DM) or with unknown DM is crucial to implement measures that may prevent or delay progression from prediabetes to T2DM and reduce the incidence of chronic complications. Diagnostic criteria for these categories of impaired glucose tolerance (IGT) have been classically based on glucose measurements, in particular after a glucose loading during an oral glucose tolerance test (OGTT). The OGTT, however, can be cumbersome, time consuming, and expensive, so that alternative diagnostic tools have been sought. The use of HbA_1c has been repeatedly considered for such a purpose, but the American Diabetes Association (ADA) has only recently proposed adoption of cutoff values of 5.7–6.4% and ≥6.5% for identification of individuals with prediabetes and overt diabetes, respectively (1). The World Health Organization has advocated a similar HbA_1c cutoff for the diabetes diagnosis, although no high-risk category has been identified (2).The performance of these criteria have been compared with determination of fasting plasma glucose levels and/or OGTT in various populations (3–9), but few data have explored whether the two criteria identify in the same individuals the prevalent pathogenetic mechanisms (i.e., insulin secretion and insulin action) and cardiovascular (CV) risk profile. Previous studies have shown that impaired β-cell function can be recognized in people at risk for diabetes even at the time they still have normal glucose tolerance (NGT) (10–13). A recent study, however, has reported that the relationship between β-cell function and HbA_1c can be quite different between those with impaired fasting glucose and those with altered 2-h postload glucose concentrations (14). This raises the possibility that individuals with impaired glucose regulation, as identified by HbA_1c or OGTT, also may differ in their pathogenetic mechanisms and, therefore, their CV risk profile. Therefore, the aim of the current study was to assess insulin secretion, insulin action, and CV risk profile based on different diagnostic criteria for abnormal glucose tolerance.     

Obstructive Sleep Apnea,Glucose Tolerance,and β-Cell Function in Adults With Prediabetes or Untreated Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study

OBJECTIVEObstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet β-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with β-cell function in overweight/obese adults with prediabetes or recently diagnosed, treatment-naive type 2 diabetes.RESEARCH DESIGN AND METHODSTwo hundred twenty-one adults (57.5% men, age 54.5 ± 8.7 years, BMI 35.1 ± 5.5 kg/m²) completed 1 week of wrist actigraphy and 1 night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA_1c, OGTT-derived outcomes, and clamp-derived outcomes were evaluated with adjusted regression models.RESULTSMean ± SD objective sleep duration by actigraphy was 6.6 ± 1.0 h/night. OSA, defined as an apnea-hypopnea index (AHI) of five or more events per hour, was present in 89% of the participants (20% mild, 28% moderate, 41% severe). Higher AHI was associated with higher HbA_1c (P = 0.007). However, OSA severity, measured either by AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or <6 vs. ≥6 h) were not associated with fasting glucose, 2-h glucose, insulin sensitivity, or β-cell responses.CONCLUSIONSIn this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA_1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or β-cell responses.     

Increased Skeletal Muscle Capillarization After Aerobic Exercise Training and Weight Loss Improves Insulin Sensitivity in Adults With IGT

OBJECTIVE

Transcapillary transport of insulin is one determinant of glucose uptake by skeletal muscle; thus, a reduction in capillary density (CD) may worsen insulin sensitivity. Skeletal muscle CD is lower in older adults with impaired glucose tolerance (IGT) compared with those with normal glucose tolerance and may be modifiable through aerobic exercise training and weight loss (AEX+WL). We tested the hypothesis that 6-month AEX+WL would increase CD to improve insulin sensitivity and glucose tolerance in older adults with IGT.

RESEARCH DESIGN AND METHODS

Sixteen sedentary, overweight-obese (BMI 27–35 kg/m²), older (63 ± 2 years) men and women with IGT underwent hyperinsulinemic-euglycemic clamps to measure insulin sensitivity, oral glucose tolerance tests, exercise and body composition testing, and vastus lateralis muscle biopsies to determine CD before and after 6-month AEX+WL.

RESULTS

Insulin sensitivity (M) and 120-min postprandial glucose (G₁₂₀) correlated with CD at baseline (r = 0.58 and r = −0.60, respectively, P < 0.05). AEX+WL increased maximal oxygen consumption (VO_2max) 18% (P = 0.02) and reduced weight and fat mass 8% (P < 0.02). CD increased 15% (264 ± 11 vs. 304 ± 14 capillaries/mm², P = 0.01), M increased 21% (42.4 ± 4.0 vs. 51.4 ± 4.3 µmol/kg FFM/min, P < 0.05), and G₁₂₀ decreased 16% (9.35 ± 0.5 vs. 7.85 ± 0.5 mmol/L, P = 0.008) after AEX+WL. Regression analyses showed that the AEX+WL-induced increase in CD independently predicted the increase in M (r = 0.74, P < 0.01) as well as the decrease in G₁₂₀ (r = −0.55, P < 0.05).

CONCLUSIONS

Six-month AEX+WL increases skeletal muscle CD in older adults with IGT. This represents one mechanism by which AEX+WL improves insulin sensitivity in older adults with IGT.     

HbA1c Diagnostic Categories and β-Cell Function Relative to Insulin Sensitivity in Overweight/Obese Adolescents

OBJECTIVE

The recommended HbA_1c diagnostic categories remain controversial and their utility in doubt in pediatrics. We hypothesized that alterations in the pathophysiologic mechanisms of type 2 diabetes may be evident in the American Diabetes Association recommended at-risk/prediabetes category (HbA_1c 5.7 to <6.5%).

RESEARCH DESIGN AND METHODS

We compared in vivo hepatic and peripheral insulin sensitivity by [6,6-²H₂] glucose and a 3-h hyperinsulinemic-euglycemic clamp and β-cell function by a 2-h hyperglycemic clamp (∼225 mg/dL) in overweight/obese (BMI ≥85th percentile) adolescents with prediabetes (HbA_1c 5.7 to <6.5%) (n = 160) to those with normal HbA_1c (<5.7%) (n = 44). β-Cell function was expressed relative to insulin sensitivity (i.e., the disposition index = insulin sensitivity × first-phase insulin).

RESULTS

In the prediabetes versus normal HbA_1c category, fasting glucose, insulin, and oral glucose tolerance test (OGTT) area under the curve for glucose and insulin were significantly higher; hepatic and peripheral insulin sensitivity were lower; and β-cell function relative to insulin sensitivity was lower (366 ± 48 vs. 524 ± 25 mg/kg/min; P = 0.005). A total of 27% of youth in the normal HbA_1c category and 41% in the prediabetes HbA_1c category had dysglycemia (impaired fasting glucose and/or impaired glucose tolerance) by a 2-h OGTT.

CONCLUSIONS

Overweight/obese adolescents with HbA_1c in the at-risk/prediabetes category demonstrate impaired β-cell function relative to insulin sensitivity, a metabolic marker for heightened risk of type 2 diabetes. Thus, HbA_1c may be a suitable screening tool in large-scale epidemiological observational and/or interventional studies examining the progression or reversal of type 2 diabetes risk.Glycated hemoglobin (HbA_1c) is used to monitor diabetes control in diagnosed patients (1). In 2009, an international expert committee recommended that HbA_1c also be used for diagnosis of diabetes and risk of diabetes (1). Subsequently, HbA_1c diagnostic cutoffs were incorporated into the 2010 American Diabetes Association (ADA) guidelines for diabetes (HbA_1c ≥6.5%) and prediabetes (HbA_1c 5.7 to <6.5%) (2). Unlike glycemic measures (e.g., fasting glucose, oral glucose tolerance test [OGTT]), the HbA_1c may be performed in the nonfasting state (2). However, adoption of these proposed criteria continues to be debated (3–8). In cross-sectional studies of adults, the HbA_1c criteria had lower sensitivity for diabetes diagnosis compared with OGTT (6) or a single fasting plasma glucose (9). But, the sensitivity of the HbA_1c criteria improved when compared with repeated fasting plasma glucose samples (3 years apart), and the combination of fasting glucose and HbA_1c provided the greatest predictive value for 10-year diabetes risk compared with fasting glucose alone (single or repeated) (9). Furthermore, in a longitudinal study, HbA_1c identified fewer cases of prediabetes at baseline, but had similar predictive value for progression to diabetes as fasting glucose (∼5-year follow-up) (10). Accordingly, recent pediatric studies indicate that HbA_1c identifies fewer adolescents with diabetes/prediabetes compared with glycemic measures (4,5,11). However, similar to adults, HbA_1c improved the predictive value of glycemic measures alone after a 2-year follow-up in adolescents (5). Because glycemic measures of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are linked to impaired insulin secretion relative to insulin sensitivity, conferring an increased risk of type 2 diabetes (12,13), we hypothesized that alterations in the pathophysiologic mechanisms of type 2 diabetes could be detected in the ADA recommended at-risk/prediabetes category (HbA_1c 5.7 to <6.5%). Therefore, we aimed to evaluate in vivo insulin sensitivity and β-cell function in overweight/obese youth categorized according to the 2010 ADA HbA_1c criteria (2) as normal versus prediabetes.     

Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized,Double-Blind,Placebo-Controlled,Phase 2 Trial

OBJECTIVEInsulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium–glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance.RESEARCH DESIGN AND METHODSIn this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m²) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain.RESULTSWe identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat.CONCLUSIONSOur results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.     

Frequency of Interruptions to Sitting Time: Benefits for Postprandial Metabolism in Type 2 Diabetes

OBJECTIVETo determine whether interrupting sitting with brief bouts of simple resistance activities (SRAs) at different frequencies improves postprandial glucose, insulin, and triglycerides in adults with medication-controlled type 2 diabetes (T2D).RESEARCH DESIGN AND METHODSParticipants (n = 23, 10 of whom were female, with mean ± SD age 62 ± 8 years and BMI 32.7 ± 3.5 kg · m⁻²) completed a three-armed randomized crossover trial (6- to 14-day washout): sitting uninterrupted for 7 h (SIT), sitting with 3-min SRAs (half squats, calf raises, gluteal contractions, and knee raises) every 30 min (SRA3), and sitting with 6-min SRAs every 60 min (SRA6). Net incremental areas under the curve (iAUC_net) for glucose, insulin, and triglycerides were compared between conditions.RESULTSGlucose and insulin 7-h iAUC_net were attenuated significantly during SRA6 (glucose 17.0 mmol · h · L⁻¹, 95% CI 12.5, 21.4; insulin 1,229 pmol · h · L⁻¹, 95% CI 982, 1,538) in comparison with SIT (glucose 21.4 mmol · h · L⁻¹, 95% CI 16.9, 25.8; insulin 1,411 pmol · h · L⁻¹, 95% CI 1,128, 1,767; P < 0.05) and in comparison with SRA3 (for glucose only) (22.1 mmol · h · L⁻¹, 95% CI 17.7, 26.6; P = 0.01) No significant differences in glucose or insulin iAUC_net were observed in comparison of SRA3 and SIT. There was no statistically significant effect of condition on triglyceride iAUC_net.CONCLUSIONSIn adults with medication-controlled T2D, interrupting prolonged sitting with 6-min SRAs every 60 min reduced postprandial glucose and insulin responses. Other frequencies of interruptions and potential longer-term benefits require examination to clarify clinical relevance.     

25-Hydroxyvitamin D in Obese Youth Across the Spectrum of Glucose Tolerance From Normal to Prediabetes to Type 2 Diabetes

OBJECTIVE

To 1) determine if plasma 25-hydroxyvitamin D (25[OH]D) concentrations differ among obese youth with normal glucose tolerance (NGT) versus prediabetes versus type 2 diabetes and 2) assess the relationships between 25(OH)D and in vivo insulin sensitivity and β-cell function in this cohort.

RESEARCH DESIGN AND METHODS

Plasma 25(OH)D concentrations were examined in banked specimens in 9- to 20-year-old obese youth (n = 175; male 42.3%, black 46.3%) (NGT, n = 105; impaired glucose tolerance [IGT], n = 43; type 2 diabetes, n = 27) who had in vivo insulin sensitivity and secretion measured by hyperinsulinemic-euglycemic and hyperglycemic clamp techniques and had an assessment of total body composition and abdominal adiposity.

RESULTS

The mean age and BMI of the subjects were 14.3 ± 2.1 years and 35.7 ± 5.6 kg/m², respectively. BMI, plasma 25(OH)D, and the proportion of vitamin D–deficient and –insufficient children did not differ across the three groups. Furthermore, there was no association between 25(OH)D and in vivo insulin sensitivity or β-cell function relative to insulin sensitivity (disposition index) in all groups combined or in each group separately.

CONCLUSIONS

Our data in obese youth show 1) no differences in plasma 25(OH)D concentrations across the glucose tolerance groups and 2) no relationship between 25(OH)D and in vivo insulin sensitivity and β-cell function relative to insulin sensitivity in any of the groups. It remains uncertain if enhancement of the vitamin D status could improve pathophysiological mechanisms of prediabetes and type 2 diabetes in obese youth.The role of vitamin D in glucose homeostasis remains controversial. The reported relationships between vitamin D and glucose homeostasis have been inconsistent (1–6). Differences in study populations (glucose tolerant vs. intolerant; obese vs. nonobese; children vs. adults), the methodological approaches to the assessment of insulin sensitivity and secretion (surrogate indices vs. clamp studies), and adiposity measures (BMI vs. direct measures of total and/or regional adiposity) may explain some of the inconsistent findings among these studies. In healthy, glucose-tolerant, nonobese and obese youth, we found no independent relationships between plasma 25-hydroxyvitamin D (25[OH]D) and in vivo insulin sensitivity and β-cell function relative to insulin sensitivity (5). However, it remains to be determined if the vitamin D–glucose homeostasis relationships differ under pathophysiological conditions of glucose intolerance. Therefore, we 1) examined if plasma 25(OH)D concentrations differ among obese youth with normal glucose tolerance (NGT) versus prediabetes versus type 2 diabetes and 2) assessed the relationships between 25(OH)D and the pathophysiological components of type 2 diabetes, in vivo insulin sensitivity, and β-cell function.     

A Higher-Complex Carbohydrate Diet in Gestational Diabetes Mellitus Achieves Glucose Targets and Lowers Postprandial Lipids: A Randomized Crossover Study

OBJECTIVE

The conventional diet approach to gestational diabetes mellitus (GDM) advocates carbohydrate restriction, resulting in higher fat (HF), also a substrate for fetal fat accretion and associated with maternal insulin resistance. Consequently, there is no consensus about the ideal GDM diet. We hypothesized that, compared with a conventional, lower-carbohydrate/HF diet (40% carbohydrate/45% fat/15% protein), consumption of a higher-complex carbohydrate (HCC)/lower-fat (LF) Choosing Healthy Options in Carbohydrate Energy (CHOICE) diet (60/25/15%) would result in 24-h glucose area under the curve (AUC) profiles within therapeutic targets and lower postprandial lipids.

RESEARCH DESIGN AND METHODS

Using a randomized, crossover design, we provided 16 GDM women (BMI 34 ± 1 kg/m²) with two 3-day isocaloric diets at 31 ± 0.5 weeks (washout between diets) and performed continuous glucose monitoring. On day 4 of each diet, we determined postprandial (5 h) glucose, insulin, triglycerides (TGs), and free fatty acids (FFAs) following a controlled breakfast meal.

RESULTS

There were no between-diet differences for fasting or mean nocturnal glucose, but 24-h AUC was slightly higher (∼6%) on the HCC/LF CHOICE diet (P = 0.02). The continuous glucose monitoring system (CGMS) revealed modestly higher 1- and 2-h postprandial glucose on CHOICE (1 h, 115 ± 2 vs. 107 ± 3 mg/dL, P ≤ 0.01; 2 h, 106 ± 3 vs. 97 ± 3 mg/dL, P = 0.001) but well below current targets. After breakfast, 5-h glucose and insulin AUCs were slightly higher (P < 0.05), TG AUC was no different, but the FFA AUC was significantly lower (∼19%; P ≤ 0.01) on the CHOICE diet.

CONCLUSIONS

This highly controlled study randomizing isocaloric diets and using a CGMS is the first to show that liberalizing complex carbohydrates and reducing fat still achieved glycemia below current treatment targets and lower postprandial FFAs. This diet strategy may have important implications for preventing macrosomia.     

Influence of Apolipoproteins on the Association Between Lipids and Insulin Sensitivity: A cross-sectional analysis of the RISC Study

OBJECTIVE

We evaluated whether the association of insulin sensitivity with HDL cholesterol (HDL) and triglycerides is influenced by major plasma apolipoproteins, as suggested by recent experimental evidence.

RESEARCH DESIGN AND METHODS

This study included a cross-sectional analysis of the RISC Study, a multicenter European clinical investigation in 1,017 healthy volunteers balanced in sex (women 54%) and age strata (range 30–60 years). Insulin sensitivity (M/I in µmol ⋅ min⁻¹ ⋅ kg_FFM⁻¹ ⋅ nM⁻¹) was measured by the clamp technique and apolipoproteins (ApoB, -C3, -A1, and -E) by Multiplex Technology.

RESULTS

The center-, sex-, and age-adjusted standardized regression coefficients (STDβ) with M/I were similar for HDL and triglycerides (+19.9 ± 1.9 vs. −20.0 ± 2.0, P < 0.0001). Further adjustment for triglycerides (or HDL), BMI, and adiponectin (or nonesterified fatty acid) attenuated the strength of the association of M/I with both HDL (STDβ +6.4 ± 2.3, P < 0.01) and triglycerides (−9.5 ± 2.1, P < 0.001). Neither ApoA1 nor ApoE and ApoB showed any association with M/I independent from plasma HDL cholesterol and triglycerides. ApoC3, in contrast, in both men and women, was positively associated with M/I independently of plasma lipids. A relative enrichment of plasma lipids with ApoC3 is associated with lower body fat percentage and lower plasma alanine amino transferase.

CONCLUSIONS

Our results suggest that HDL cholesterol modulates insulin sensitivity through a mechanism that is partially mediated by BMI and adiponectin but not by ApoA1. Similarly, the influence of triglycerides on insulin sensitivity is in part mediated by BMI and is unrelated to ApoE or ApoB, but it is significantly modulated by ApoC3, which appears to protect from the negative effect of plasma lipids.The dyslipidemia characterized by elevated plasma triglycerides and low HDL cholesterol is one of the key components of the metabolic syndrome, and there is evidence that it is secondary to the presence of insulin resistance and obesity (1). However, recent data suggest that serum lipoproteins exert an influence on tissue insulin sensitivity both directly and through the activity of their major lipoproteins. HDL particles and apolipoprotein A-I (ApoA1) might indirectly modulate insulin sensitivity through their antioxidant and anti-inflammatory action (2), their effect on energy expenditure (3), and/or their close relationships with adiponectin (4,5). Apolipoproteins CIII (ApoC3) and E (ApoE), which are present both in VLDL and HDL particles, have the potential to modulate whole-body insulin sensitivity by regulating the transfer of plasma triglycerides and nonesterified fatty acids (FFAs) to tissues. ApoC3, the second most abundant apolipoprotein circulating in human plasma, is a natural lipoprotein lipase inhibitor (6–8). When exposed to a high-fat diet, APOC3 gene knockout mice display lower serum triglycerides but more severe obesity and insulin resistance, which are caused by excess FFA transfer from plasma to tissues (9).Data in humans are scarce and conflicting. Higher ApoC3 levels have been reported in subjects with increased triglycerides, insulin resistance, cardiovascular disease, and type 2 diabetes (10–12). However, the contribution of ApoC3, independent of triglycerides, remains unclear. Although studies on the human APOC3 gene have failed to show clear associations between mutations and altered lipid/lipoprotein metabolism (7), interestingly, APOC3 polymorphisms rs2854116 and rs2854117 are associated with a relative poverty of ApoC3 (with respect to serum triglycerides), increased liver triglyceride content, and insulin resistance (13). Similarly, in middle-aged men with the metabolic syndrome, lower ApoC3 levels were associated with a higher visceral fat mass and lower plasma triglycerides (14).Data from experimental animals suggest that ApoE is opposite to ApoC3, its lack being associated with resistance to the development of both diet-induced obesity and insulin resistance (15). In humans, elevated levels of ApoE are consistently found in obesity, insulin resistance, and dyslipidemia (16), and all these factors, in turn, have been shown to upregulate ApoE and VLDL production (17). Therefore, it is particularly difficult to evaluate whether ApoE modulates insulin sensitivity independently of serum triglycerides and obesity. Also the studies on ApoE ε2/ε3/ε4 polymorphisms have not reached consistent conclusions. The Framingham Offspring Study found that none of these polymorphisms was associated with insulin resistance (18), whereas other studies (19–21) have observed that the polymorphisms modify the strength of the associations between insulin resistance and dyslipidemia.In conclusion, although experimental data suggest a role for apolipoproteins in modulating insulin sensitivity, whether this holds true in humans remains unclear. Possible reasons are that in most previous studies, insulin sensitivity was not directly measured but only estimated through plasma insulin and glucose levels, and/or that the strategies to dissect the effect of the apolipoproteins from that of lipoprotein as well as from their confounders were not always appropriate.To directly address the question of whether ApoA1, ApoC3, and ApoE modulate the relationships of serum lipids with insulin sensitivity, we exploited the RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) Study (22), one of the largest collections of subjects in which insulin sensitivity was measured with the use of the gold standard technique (the euglycemic-hyperinsulinemic clamp).     

Restoring Insulin Secretion (RISE): Design of Studies of β-Cell Preservation in Prediabetes and Early Type 2 Diabetes Across the Life Span

OBJECTIVE

The Restoring Insulin Secretion (RISE) Consortium is testing interventions designed to preserve or improve β-cell function in prediabetes or early type 2 diabetes.

RESEARCH DESIGN AND METHODS

β-Cell function is measured using hyperglycemic clamps and oral glucose tolerance tests (OGTTs). The adult medication protocol randomizes participants to 12 months of placebo, metformin alone, liraglutide plus metformin, or insulin (3 months) followed by metformin (9 months). The pediatric medication protocol randomizes participants to metformin or insulin followed by metformin. The adult surgical protocol randomizes participants to gastric banding or metformin (24 months). Adult medication protocol inclusion criteria include fasting plasma glucose 95–125 mg/dL (5.3–6.9 mmol/L), OGTT 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA_1c 5.8–7.0% (40–53 mmol/mol), and BMI 25–40 kg/m². Adult surgical protocol criteria are similar, except for fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), BMI 30–40 kg/m², HbA_1c <7.0% (<53 mmol/mol), and diabetes duration <12 months. Pediatric inclusion criteria include fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA_1c ≤8.0% (≤64 mmol/mol), BMI >85th percentile and ≤50 kg/m², 10–19 years of age, and diabetes <6 months.

RESULTS

Primary outcomes are clamp-derived glucose-stimulated C-peptide secretion and maximal C-peptide response to arginine during hyperglycemia. Measurements are made at baseline, after 12 months on treatment, and 3 months after treatment withdrawal (medication protocols) or 24 months postintervention (surgery protocol). OGTT-derived measures are also obtained at these time points.

CONCLUSIONS

RISE is determining whether medication or surgical intervention strategies can mitigate progressive β-cell dysfunction in adults and youth with prediabetes or early type 2 diabetes.     

Is β-Thalassaemia Minor Associated with Metabolic Disorder?

Objective

To investigate the frequency of metabolic syndrome and its components in subjects with β-thalassaemia minor.

Subjects and Methods

A total of 194 subjects, i.e. 92 subjects with β-thalassaemia minor (study group) and 102 subjects without β-thalassaemia minor (control group), were enrolled into this case-control study. Haemoglobin electrophoresis was performed on all patients. The waist circumference and systolic and diastolic blood pressure of the subjects were recorded. Fasting blood glucose and serum lipid levels were measured.

Results

Both groups were similar in terms of age and sex (p > 0.05 for each). The percentages of haemoglobin A₂ (4.3 ± 0.4 vs. 2.0 ± 0.3) and haemoglobin F (3.38 ± 1.4 vs. 0.26 ± 0.4) and the mean corpuscular volumes (64 ± 4.7 vs. 81.5 ± 9.3) of the groups were statistically different (p < 0.001 for each). The frequency of metabolic syndrome and its components was similar in both groups (p > 0.05 for each). According to correlation analyses, the percentage of haemoglobin A₂ correlated with fasting insulin, fasting glucose, systolic blood pressure, high-density lipoprotein, and low-density lipoprotein levels (p < 0.05).

Conclusions

No association was found between β-thalassaemia minor and metabolic syndrome despite insulin resistance, which was shown in subjects with β-thalassaemia minor.Key Words: β-Thalassaemia minor, Metabolic syndrome, Metabolic syndrome components, Insulin resistance     

Enhanced Absorption of Insulin Aspart as the Result of a Dispersed Injection Strategy Tested in a Randomized Trial in Type 1 Diabetic Patients

OBJECTIVE

We investigated the impact of two different injection strategies on the pharmacokinetics and pharmacodynamics of insulin aspart in vivo in an open-label, two-period crossover study and verified changes in the surface-to-volume ratio ex vivo.

RESEARCH DESIGN AND METHODS

Before the clinical trial, insulin aspart was injected ex vivo into explanted human abdominal skin flaps. The surface-to-volume ratio of the subcutaneous insulin depot was assessed by microfocus computed tomography that compared 1 bolus of 18 IU with 9 dispersed boluses of 2 IU. These two injection strategies were then tested in vivo, in 12 C-peptide–negative type 1 diabetic patients in a euglycemic glucose clamp (glucose target 5.5 ± 1.1 mmol/L) for 8 h after the first insulin administration.

RESULTS

The ex vivo experiment showed a 1.8-fold higher mean surface-to-volume ratio for the dispersed injection strategy. The maximum glucose infusion rates (GIR) were similar for the two strategies (10 ± 4 vs. 9 ± 4; P = 0.5); however, times to reach maximum GIR and 50% and 10% of the maximum GIR were significantly reduced by using the 9 × 2 IU strategy (68 ± 33 vs. 127 ± 93 min; P = 0.01; 38 ± 9 vs. 49 ± 16 min; P < 0.01; 23 ± 6 vs. 30 ± 10 min; P < 0.05). For 9 × 2 IU, the area under the GIR curve was greater during the first 60 min (219 ± 89 vs. 137 ± 75; P < 0.01) and halved until maximum GIR (242 ± 183 vs. 501 ± 396; P < 0.01); however, it was similar across the whole study period (1,361 ± 469 vs. 1,565 ± 527; P = 0.08).

CONCLUSIONS

A dispersed insulin injection strategy enhanced the effect of a fast-acting insulin analog. The increased surface-to-volume ratio of the subcutaneous insulin depot can facilitate insulin absorption into the vascular system.Fast-acting insulin analogs have been developed to avoid postprandial glucose peaks (1,2). Some studies suggest that postprandial hyperglycemia can contribute to elevated levels of hemoglobin A_1c (3,4) and lead to the development of short- and long-term diabetes complications (5,6). Although currently available fast-acting insulin analogs have been designed for a better match with meal-induced glucose excursions, insulin absorption and insulin action still lag behind (7,8). Even bolus administration of fast-acting insulin analogs immediately before meals does not completely avoid postprandial glucose peaks. Modern fast-acting insulin analogs still only insufficiently mimic physiological insulin profiles; however, their effect could be further improved by accelerating insulin absorption from the injection site into the vascular system.Accelerated insulin absorption in response to an increased blood flow has been described for heated injection sites (9) or coadministered adjuvants such as hyaluronidase (10–12) but also for a larger distribution of the subcutaneous insulin depot achieved with a modified injection strategy. Human insulin absorption has been tested with a “sprinkler needle” that has 14 holes in its walls and a sealed tip, thus dispersing the insulin bolus at the injection site. With the sprinkler needle, insulin was absorbed more rapidly and glucose levels were less raised relative to a regular injection needle (13). A dispersed insulin bolus should have an increased surface-to-volume ratio and could further contribute to even faster insulin absorption of modern already fast-acting insulin analogs.The aim of our study was to test whether the absorption rate of a fast-acting insulin analog (insulin aspart) could be further accelerated through the dispersion of a single predefined insulin bolus into nine separate insulin injections. We compared the two different injection strategies ex vivo by using microfocus computed tomography (micro-CT) to assess the increase in the surface-to-volume ratio and in vivo by assessing the pharmacokinetic and pharmacodynamic response in a clinical trial.     

Correlates of Treatment Patterns Among Youth With Type 2 Diabetes

OBJECTIVE

To describe treatment regimens in youth with type 2 diabetes and examine associations between regimens, demographic and clinical characteristics, and glycemic control.

RESEARCH DESIGN AND METHODS

This report includes 474 youth with a clinical diagnosis of type 2 diabetes who completed a SEARCH for Diabetes in Youth study visit. Diabetes treatment regimen was categorized as lifestyle alone, metformin monotherapy, any oral hypoglycemic agent (OHA) other than metformin or two or more OHAs, insulin monotherapy, and insulin plus any OHA(s). Association of treatment with demographic and clinical characteristics (fasting C-peptide [FCP], diabetes duration, and self-monitoring of blood glucose [SMBG]), and A1C was assessed by χ² and ANOVA. Multiple linear regression models were used to evaluate independent associations of treatment regimens and A1C, adjusting for demographics, diabetes duration, FCP, and SMBG.

RESULTS

Over 50% of participants reported treatment with metformin alone or lifestyle. Of the autoantibody-negative youth, 40% were on metformin alone, while 33% were on insulin-containing regimens. Participants on metformin alone had a lower A1C (7.0 ± 2.0%, 53 ± 22 mmol/mol) than those on insulin alone (9.2 ± 2.7%, 77 ± 30 mmol/mol) or insulin plus OHA (8.6 ± 2.6%, 70 ± 28 mmol/mol) (P < 0.001). These differences remained significant after adjustment (7.5 ± 0.3%, 58 ± 3 mmol/mol; 9.1 ± 0.4%, 76 ± 4 mmol/mol; and 8.6 ± 0.4%, 70 ± 4 mmol/mol) (P < 0.001) and were more striking in those with diabetes for ≥2 years (7.9 ± 2.8, 9.9 ± 2.8, and 9.8 ± 2.6%). Over one-half of those on insulin-containing therapies still experience treatment failure (A1C ≥8%, 64 mmol/mol).

CONCLUSIONS

Approximately half of youth with type 2 diabetes were managed with lifestyle or metformin alone and had better glycemic control than individuals using other therapies. Those with longer diabetes duration in particular commonly experienced treatment failures, and more effective management strategies are needed.     

Neuroendocrine responses to glucose ingestion in man. Specificity, temporal relationships, and quantitative aspects

The mechanisms of postprandial glucose counterregulation—those that blunt late decrements in plasma glucose, prevent hypoglycemia, and restore euglycemia—have not been fully defined. To begin to clarify these mechanisms, we measured neuroendocrine and metabolic responses to the ingestion of glucose (75 g), xylose (62.5 g), mannitol (20 g), and water in ten normal human subjects to determine for each response the magnitude, temporal relationships, and specificity for glucose ingestion. Measurements were made at 10-min intervals over 5 h. By multivariate analysis of variance, the plasma glucose (P < 0.0001), insulin (P < 0.0001), glucagon (P < 0.03), epinephrine (P < 0.0004), and growth hormone (P < 0.01) curves, as well as the blood lactate (P < 0.0001), glycerol (P < 0.001), and β-hydroxybutyrate (P < 0.0001) curves following glucose ingestion differed significantly from those following water ingestion. However, the growth hormone curves did not differ after correction for differences at base line. In contrast, the plasma norepinephrine (P < 0.31) and cortisol (P < 0.24) curves were similar after ingestion of all four test solutions, although early and sustained increments in norepinephrine occurred after all four test solutions. Thus, among the potentially important glucose regulatory factors, only transient increments in insulin, transient decrements in glucagon, and late increments in epinephrine are specific for glucose ingestion. They do not follow ingestion of water, xylose, or mannitol.

Following glucose ingestion, plasma glucose rose to peak levels of 156±6 mg/dl at 46±4 min, returned to base line at 177±4 min, reached nadirs of 63±3 mg/dl at 232±12 min, and rose to levels comparable to base line at 305 min, which was the final sampling point. Plasma insulin rose to peak levels of 150±17 μU/ml (P < 0.001) at 67±8 min. At the time glucose returned to base line, insulin levels (49±12 μU/ml) remained fourfold higher than base line (P < 0.01); thereafter they declined but never fell below base line. Plasma glucagon decreased from 95±14 pg/ml to nadirs of 67±11 pg/ml (P < 0.001) at 84±9 min and then rose progressively to peak levels of 114±17 pg/ml (P < 0.001 vs. nadirs) at 265±12 min. Plasma epinephrine, which was 18±4 pg/ml at base line, did not change initially and then rose to peak levels of 119±20 pg/ml (P < 0.001) at 271±13 min.

These data indicate that the glucose counterregulatory process late after glucose ingestion is not solely due to the dissipation of insulin and that sympathetic neural norepinephrine, growth hormone, and cortisol do not play critical roles. They are consistent with, but do not establish, physiologic roles for the counterregulatory hormones—glucagon, epinephrine, or both—in that process.

     

Mechanisms of Insulin Resistance in Aging

We have studied 17 elderly and 27 non-elderly, nonobese subjects (mean age 69±1 and 37±2 yr, respectively) to assess the mechanisms responsible for the abnormal carbohydrate tolerance associated with aging. Serum glucose and insulin levels were significantly elevated in the elderly subjects compared with the nonelderly subjects during a 75-g oral glucose tolerance test, suggesting an insulin resistant state. Peripheral insulin sensitivity was assessed in both groups using the euglycemic glucose clamp technique during an insulin infusion rate of 40 mU/m² per min. Similar steady-state serum insulin levels led to a peripheral glucose disposal rate of 151±17 mg/m² per min in the elderly compared with a value of 247±12 mg/m² per min in the nonelderly, thus documenting the presence of insulin resistance in the elderly subjects. Insulin binding to isolated adipocytes and monocytes was similar in the elderly and nonelderly groups (2.34±0.33 vs. 2.62±0.24% and 5.04±1.10 vs. 5.12±1.07%), respectively. Thus, insulin resistance in the presence of normal insulin binding suggests the presence of a postreceptor defect in insulin action. This was confirmed by performing additional euglycemic clamp studies using infusion rates of 15 and 1,200 mU/m² per min to assess the contours of the dose-response relationship. These studies revealed a 39 and 25% decrease in the glucose disposal rate in the elderly subjects, respectively. The results confirm the presence of a postreceptor defect as well as a rightward shift in the dose-response curve. Insulin's ability to suppress hepatic glucose output was less in the elderly subjects during the 15 mU/m² per min insulin infusion (77±5 vs. 89±4% suppression), but hepatic glucose output was fully and equally suppressed in both groups during the 40 and 1,200 mU/m² per min infusion. Finally, a significant inverse relationship was observed between the degree of glucose intolerance in the individual elderly subjects, as reflected by the 2-h serum glucose level during the oral glucose tolerance test, and the degree of peripheral insulin resistance as assessed by the glucose disposal rate during the 40 mU/m² per min insulin infusion (r = 0.59, P < 0.01).     

Baseline Adiponectin Levels Do Not Influence the Response to Pioglitazone in ACT NOW

OBJECTIVE

Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (S_I) and glucose tolerance status.

RESEARCH DESIGN AND METHODS

A total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years.

RESULTS

Pioglitazone reduced IGT conversion to diabetes by 72% in association with improved β-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 μg/mL (P < 0.001) and was strongly correlated with the improvement in S_I (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group.

CONCLUSIONS

Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin.