Multitissue insulin resistance despite near-normoglycemic remission in Africans with ketosis-prone diabetes

OBJECTIVE—To characterize insulin action in Africans with ketosis-prone diabetes (KPD) during remission.RESEARCH DESIGN AND METHODS—At Saint-Louis Hospital, Paris, France, 15 African patients with KPD with an average 10.5-month insulin-free near-normoglycemic remission period (mean A1C 6.2%) were compared with 17 control subjects matched for age, sex, BMI, and geographical origin. Insulin stimulation of glucose disposal, and insulin suppression of endogenous glucose production (EGP) and nonesterified fatty acids (NEFAs), was studied using a 200-min two-step (10 mU · m⁻² body surface · min⁻¹ and 80 mU · m⁻² · min ⁻¹ insulin infusion rates) euglycemic clamp with [6,6-²H₂]glucose as the tracer. Early-phase insulin secretion was determined during an oral glucose tolerance test.RESULTS—The total glucose disposal was reduced in patients compared with control subjects (7.5 ± 0.8 [mean ± SE] vs. 10.5 ± 0.9 mg · kg⁻¹ · min⁻¹; P = 0.018). EGP rate was higher in patients than control subjects at baseline (4.0 ± 0.3 vs. 3.0 ± 0.1 mg · kg⁻¹ · min⁻¹; P = 0.001) and after 200-min insulin infusion (10 mU · m⁻² · min⁻¹: 1.6 ± 0.2 vs. 0.6 ± 0.1, P = 0.004; 80 mU · m⁻² · min⁻¹: 0.3 ± 0.1 vs. 0 mg · kg⁻¹ · min⁻¹, P = 0.007). Basal plasma NEFA concentrations were also higher in patients (1,936.7 ± 161.4 vs. 1,230.0 ± 174.1 μmol/l; P = 0.002) and remained higher after 100-min 10 mU · m⁻² · min⁻¹ insulin infusion (706.6 ± 96.5 vs. 381.6 ± 55.9 μmol/l; P = 0.015).CONCLUSIONS—The triad hepatic, adipose tissue, and skeletal muscle insulin resistance is observed in patients with KPD during near-normoglycemic remission, suggesting that KPD is a form of type 2 diabetes.Impairment of insulin sensitivity is considered the background defect that interplays with the add-on progressive β-cell dysfunction to underlie the development of type 2 diabetes (1,2). An atypical form of diabetes, ketosis-prone diabetes (KPD), has been described over the past 2 decades and may represent a significant proportion of diabetes cases in people of sub-Saharan African origin (3,4). Patients with KPD present at onset with acute hyperglycemia, usually >30 mmol/l, and ketosis or ketoacidosis as type 1 diabetes but do not have autoimmune markers against the islet β-cell (3,5–7). The correction of those insulin-requiring acute-phase disorders is followed in >50% of cases by an insulin-free near-normoglycemic remission weeks to months later (8–10), thus resembling the course of type 2 diabetes. The pathogenesis and, consequently, the classification of KPD are still debated. It was classified under idiopathic type 1 diabetes or type 1B diabetes (11). However, growing evidence based on clinical and metabolic studies suggests its high phenotypical likeness to type 2 diabetes, and “ketosis-prone type 2 diabetes” has been proposed as a provisional name and is being used elsewhere (4,8,12). Metabolic studies have evidenced insulin secretion deficiency as the major determinant of the ketotic onset (8–10). This deficit is marked by a loss of acute-phase insulin secretion in response to intravenous glucose (10) or a decrease in C-peptide response to glucagon (9,10). The subsequent remission process is due to a restoration, at least partial, of the β-cell insulin secretory capacity after achievement of good metabolic control (8,10). Insulin action was assessed in three reports, but only toward glucose metabolism, and was found to be normal or decreased while patients were in good metabolic control (6,8,10). Moreover, most studies on KPD have been reported in African-Americans who are more overweight than native Africans and may be metabolically different from them, as suggested earlier (13).In this study, we aimed at characterizing all aspects of insulin action in Africans with KPD when in the near-normoglycemic state without insulin treatment compared with control subjects of the same geographic origin.     

Effects of an Intravenous Lipid Challenge and Free Fatty Acid Elevation on In Vivo Insulin Sensitivity in African American Versus Caucasian Adolescents

OBJECTIVE—African American youth have lower insulin sensitivity than their Caucasian peers, but the metabolic pathways responsible for this difference remain unknown. Free fatty acids (FFAs) are associated with insulin resistance through the Randle cycle. The present investigation determined whether elevating FFA is more deleterious to insulin sensitivity in African American than in Caucasian adolescents.RESEARCH DESIGN AND METHODS—Insulin sensitivity (3-h hyperinsulinemic-euglycemic clamp) was evaluated in 22 African American and 21 Caucasian adolescents on two occasions: 1) infusion of normal saline and 2) infusion of 20% intralipid.RESULTS—During intralipid infusion, fasting insulin and C-peptide concentrations increased while fasting glucose and basal glucose turnover did not change in either group. Insulin sensitivity decreased similarly in African American (normal saline 7.65 ± 0.61 vs. intralipid 5.15 ± 0.52 μmol · kg⁻¹ · min⁻¹ per pmol/l) and Caucasian subjects (normal saline 8.97 ± 0.85 vs. intralipid 5.96 ± 0.56 μmol · kg⁻¹ · min⁻¹ per pmol/l) (P < 0.001).CONCLUSIONS—African American and Caucasian adolescents respond to FFA elevation similarly through increased fasting insulin secretion to maintain fasting glucose homeostasis and reduced peripheral glucose uptake and insulin resistance. Thus, African American adolescents are not more susceptible to FFA-induced insulin resistance than Caucasian youth.Free fatty acids (FFAs) are implicated in insulin resistance development through the Randle cycle (1,2). In adults, elevating plasma FFA by infusing lipid emulsion inhibits glucose disposal and oxidation in normal-weight, obese, and type 2 diabetic patients (3–5). The only pediatric study was performed in Caucasian children and demonstrated that intralipid infusion decreased insulin sensitivity in pubertal adolescents, with no such effect in prepubertal children (6). Such data support that pubertal insulin resistance is driven by the Randle cycle/substrate competition (7,8).Insulin sensitivity is lower in African American children than in their Caucasian peers (9,10), but the metabolic pathways responsible for this contrast remain unknown. Lower insulin sensitivity correlates inversely with an increased fat-to-carbohydrate ratio in the diet of African American children (10,11). Thus, FFAs may be detrimental to insulin sensitivity in African American children. If race-related differences in the susceptibility to FFA-induced insulin resistance exist, then this is of increased importance during puberty when increased FFAs decrease glucose disposal (6). The present investigation, therefore, aimed to compare the effects of FFA elevation on fasting and insulin-stimulated glucose metabolism in African American and Caucasian adolescents. We hypothesized that increased concentrations of circulating FFAs result in a greater decrement in insulin sensitivity in African American than in Caucasian adolescents.     

Association of intrauterine exposure to maternal diabetes and obesity with type 2 diabetes in youth: the SEARCH Case-Control Study

OBJECTIVE—Limited data exist on the association between in utero exposure to maternal diabetes and obesity and type 2 diabetes in diverse youth. These associations were explored in African-American, Hispanic, and non-Hispanic white youth participating in the SEARCH Case-Control Study.RESEARCH DESIGN AND METHODS—A total of 79 youth with type 2 diabetes and 190 nondiabetic control youth aged 10–22 years attended a research visit. In utero exposures to maternal diabetes and obesity were recalled by biological mothers.RESULTS—Youth with type 2 diabetes were more likely to have been exposed to maternal diabetes or obesity in utero than were nondiabetic control youth (P < 0.0001 for each). After adjusting for offspring age, sex, and race/ethnicity, exposure to maternal diabetes (odds ratio [OR] 5.7 [95% CI 2.4–13.4]) and exposure to maternal obesity (2.8 [1.5–5.2]) were independently associated with type 2 diabetes. Adjustment for other perinatal and socioeconomic factors did not alter these associations. When offspring BMI was added, the OR for the association between in utero exposure to obesity and type 2 diabetes was attenuated toward the null (OR 1.1 [0.5–2.4]). Overall, 47.2% (95% CI 30.9–63.5) of type 2 diabetes in youth could be attributed to intrauterine exposure to maternal diabetes and obesity.CONCLUSIONS—Intrauterine exposures to maternal diabetes and obesity are strongly associated with type 2 diabetes in youth. Prevention efforts may need to target, in addition to childhood obesity, the increasing number of pregnancies complicated by obesity and diabetes.Type 2 diabetes has increasingly been reported in young adults and adolescents. The SEARCH for Diabetes in Youth Study found type 2 diabetes among youth of all major racial/ethnic groups, and high rates were noted among minority adolescents aged 15–19 years (1).A maternal diabetic intrauterine environment has consequences for future type 2 diabetes risk in the offspring (2). Among the Pima Indians, exposure to diabetes in utero was the strongest risk factor for development of type 2 diabetes in young offspring (3). This association was independent of maternal obesity, father''s diabetes, age at onset of diabetes in either parent, and offspring''s birth weight and later obesity (2,3).Recent studies have shown an association between maternal prepregnancy obesity and excessive neonatal growth and adiposity (4), independent of diabetes in pregnancy. There is increasing interest in the hypothesis that maternal obesity during pregnancy, even in the absence of frank diabetes, is also associated with lifelong metabolic abnormalities in offspring, such as the presence of obesity (5) and features of the metabolic syndrome (6). However, no study has specifically explored an association between exposure to maternal prepregnancy obesity and type 2 diabetes in youth.In the last decade an increase in the prevalence of overweight among obstetric populations has been reported (7). There is also an increasing incidence and a younger age at onset of type 2 diabetes in adults (8), and an increasing prevalence of gestational diabetes mellitus (GDM) in all major racial/ethnic groups (9). In this context, the Fifth International Workshop on Gestational Diabetes Mellitus (10) has recommended studies of in utero exposure to maternal diabetes and obesity and type 2 diabetes in youth in populations other than American Indians.Using data from the multiethnic (non-Hispanic white, African-American, and Hispanic) SEARCH Case-Control (SEARCH CC) Study, we hypothesized that youth with type 2 diabetes would be more likely to have been exposed to a diabetic and obese intrauterine environment compared with nondiabetic control youth. We also hypothesized that the association between exposure to maternal diabetes and offspring type 2 diabetes will be independent of other perinatal, early life, and familial socioeconomic factors; however, the association between maternal prepregnancy obesity and offspring type 2 diabetes will be, at least in part, accounted for by offspring BMI.     

Plasma adiponectin does not correlate with insulin resistance and cardiometabolic variables in nondiabetic Asian Indian teenagers

OBJECTIVE—The objectives of this study were to determine age- and sex-specific concentrations of adiponectin in Asian Indian teenagers and adults and to assess whether its blood levels correlated with insulin resistance and other cardiometabolic parameters.RESEARCH DESIGN AND METHODS—We studied 196 teenagers (94 boys, 102 girls) 12–18 years of age, selected from a cohort of 2,640 individuals from a cross-sectional school-based survey in Chennai, India. For comparison, adiponectin and plasma insulin were measured in 84 healthy adults. Correlation of adiponectin with plasma levels of insulin, proinsulin, insulin resistance, anthropometry, and family history of diabetes were studied.RESULTS—Adiponectin showed a sex dimorphism, with girls having higher values (in μg/ml) (10.3 ± 5.0) than boys (8.4 ± 3.5) (P < 0.0001), and it showed a positive correlation with HDL cholesterol in boys only and not with other lipid parameters, insulin resistance, proinsulin, anthropometry, and family history of diabetes. In the adults, adiponectin correlated with fasting glucose and inversely with triglycerides.CONCLUSIONS—In Asian Indian adults and teenagers, adiponectin did not correlate directly with measures of insulin sensitivity, overweight, and other cardiometabolic variables. This was at variance with several reports in other populations showing an inverse association of adiponectin with insulin resistance, proinsulin, and BMI, suggesting ethnic differences in the relationship of adiponectin with insulin sensitivity. The role of adiponectin in relation to action of insulin needs more detailed studies in Asian Indians.A variety of adipokines have been implicated in causation of insulin resistance, systemic inflammation, and atherosclerotic processes (1–5). Among these, Adiponectin is the most abundant and is shown to have insulin-sensitizing, antiatherogenic, and anti-inflammatory properties (3–5). Sex dimorphism is generally observed, with females having higher concentrations (5–7). Hypoadiponectinemia is common in obese adults (4), obese children and adolescents (5,6,8–10), and subjects having insulin resistance at all ages (3,9,10). Low adiponectin is shown to be predictive of future diabetes, in many populations, including the Asian Indians (7,11). Adiponectin is inversely related to proinsulin (9). Higher concentrations of proinsulin are associated with cardiovascular risk in adults (12,13) and also in adolescents (14). A raised proinsulin-to-insulin ratio, often found in diabetes, is considered an index of β-cell dysfunction.Our recent study in adolescents showed a high prevalence of insulin resistance and cardiovascular risk factors; 65% of normal weight and 85% of overweight children and adolescents showed presence of at least one cardiovascular risk factor (15). Whereas many studies in white teenagers had demonstrated such abnormalities in obese subjects (10), we observed these abnormalities even in nonobese subjects. In light of evidence showing an important role for adiponectin in regulation of insulin action and having antiatherogenic properties, we studied its association with cardiometabolic variables including insulin resistance and proinsulin in Asian Indian teenagers. A subsample from the cohort of our previous study (15) was used for this analysis.The objectives of the study were 1) to determine age- and sex-specific values of adiponectin and proinsulin in Asian Indian teenagers, 2) to assess the association of adiponectin with cardiometabolic risk variables, 3) to see if abnormal proinsulin-to-insulin ratio suggestive of early β-cell dysfunction was present in association with other abnormalities, and 4) to see if positive family history of diabetes influenced the levels of adiponectin, insulin, proinsulin, and proinsulin/insulin.     

Euglycemic hyperinsulinemia alters the response to orthostatic stress in older adults with type 2 diabetes

OBJECTIVE—Insulin has opposing influences on blood pressure by simultaneously increasing adrenergic activity and vasodilatating peripheral blood vessels. In this study, we sought to determine whether hyperinsulinemia affects tilt table responses in older adults with type 2 diabetes not complicated by orthostatic hypotension.RESEARCH DESIGN AND METHODS—Twenty-two older adults (mean age 71.7 ± 1.1) with diet-controlled or oral hypoglycemic drug–controlled type 2 diabetes were recruited. All subjects with orthostatic hypotension, diabetic nephropathy, and sensory neuropathy were excluded. Subjects underwent euglycemic-hyperinsulinemic clamp and placebo “sham clamp” sessions. Sequential euglycemic-hyperinsulinemic clamps were performed for 2 h at 40 mU · m⁻² · min⁻¹ (low dose) and 2 h at 80 mU · m⁻² · min⁻¹ (high dose), and each was followed by a head-up tilt table test at 70°C for 10 min.RESULTS—There were no incidents of presyncope during the sham clamp, whereas there were four presyncopal events during both the low-dose and high-dose tilts. Although the low-dose clamp showed no difference in the response between sessions (two-way ANOVA), subjects demonstrated a significantly larger decrease in mean arterial pressure (P = 0.005) and diastolic blood pressure (P = 0.08) during the high-dose tilt. Doppler measures of middle cerebral artery velocity were no different between the two sessions at either dose.CONCLUSIONS—The vasodilatory response to insulin can unmask orthostatic intolerance in older adults with type 2 diabetes, resulting in presyncopal symptoms. This could contribute to orthostatic hypotension in combination with other factors such as hyperthermia, hypovolemia, and adverse effects from medications.Orthostatic hypotension is common in older adults with (1) and without diabetes (2) and is usually attributed to autonomic neuropathy or age-related comorbidities (3). Insulin has profound cardiovascular properties, resulting in simultaneous adrenergic (4) and vasodilatory (5,6) responses that have opposing influences on blood pressure. Depending on the relative magnitude of sympathetic activation and vasodilation in older adults, insulin administration might be a contributing factor in orthostatic intolerance and syncope.Epidemiological studies have demonstrated that the use of insulin is a risk factor for syncope in older adults (7) and that insulin hypersensitivity is a predisposing factor for vasovagal syncope in young women (8). Previous work in young adults with type 1 diabetes has shown that insulin has no impact on standing blood pressure unless their diabetes is already complicated by autonomic neuropathy (9). However, the aging process itself is associated with a reduction in adrenergic sensitivity (10). Insensitivity to an insulin-mediated increase in adrenergic activity could allow the vasodilatory response to predominate and potentially uncover “latent” orthostatic hypotension in older adults with uncomplicated diabetes, similar to that demonstrated previously in young hyperthermic adults with diabetes (11).In the current study, we examined in older adults with type 2 diabetes (without baseline orthostatic hypotension) the impact of hyperinsulinemia (12) on arterial blood pressure and Doppler measures of cerebral blood flow during upright tilt. We hypothesized that in older adults with type 2 diabetes, the cardiovascular effects of insulin would precipitate orthostatic intolerance not present at baseline.     

Retinol-binding protein 4 and insulin resistance in polycystic ovary syndrome

OBJECTIVE—Polycystic ovary syndrome (PCOS) is an insulin-resistant state with insulin resistance being an established therapeutic target; however, measurement of insulin resistance remains challenging. We aimed to 1) determine serum retinol-binding protein 4 (RBP4) levels (purported to reflect insulin resistance) in women with PCOS and control subjects, 2) examine the relationship of RBP4 to conventional markers of insulin resistance, and 3) examine RBP4 changes with interventions modulating insulin resistance in overweight women with PCOS.RESEARCH DESIGN AND METHODS—At baseline, 38 overweight women (BMI >27 kg/m²) with PCOS and 17 weight-matched control subjects were compared. Women with PCOS were then randomly assigned to 6 months of a higher-dose oral contraceptive pill (OCP) (35 μg ethinyl estradiol/2 mg cyproterone acetate) or metformin (1 g b.i.d.). Outcome measures were insulin resistance (total insulin area under the curve) on an oral glucose tolerance test, RBP4, and metabolic/inflammatory markers.RESULTS—Overweight women with PCOS were more insulin resistant than control subjects, yet RBP4 levels were not different in women with PCOS versus those in control subjects (35.4 ± 4.3 vs. 28.9 ± 3.1 μg/ml, P = 0.36). RBP4 correlated with cholesterol and triglycerides but not with insulin resistance. Metformin improved insulin resistance by 35%, whereas the OCP worsened insulin resistance by 33%. However, RBP4 increased nonsignificantly in both groups (43.7 ± 6.3 vs. 42.6 ± 5.5 μg/ml, P = 0.92).CONCLUSIONS—Overweight women with PCOS were more insulin resistant than control subjects, but this finding was not reflected by RBP4 levels. RBP4 correlated with lipid levels but not with insulin resistance markers. RBP4 levels did not change when insulin resistance was reduced by metformin or increased by the OCP. These data suggest that RBP4 is not a useful marker of insulin resistance in PCOS but may reflect other metabolic features of this condition.Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in reproductive-age women and affects 7% of this group and up to 30% of obese women (1). Reproductive abnormalities are underpinned by insulin resistance, which has a significant etiological role in PCOS (1). Women with PCOS have increased insulin resistance compared with that in control subjects (matched for BMI and body fat distribution) (1,2), as well as increased incidence of metabolic syndrome (2), impaired glucose tolerance (IGT), and type 2 diabetes. However, insulin resistance is not included in the diagnostic criteria for PCOS. Challenges include inaccuracy of insulin assays, lack of clarity on optimal methods to assess insulin resistance, and ill-defined cutoff values to determine insulin resistance (2). A reproducible, accurate marker of insulin resistance that predicts outcomes and therapeutic responses would assist clinical management of PCOS.Retinol-binding protein 4 (RBP4), an adipocyte product, is a carrier for vitamin A in blood. Although the majority of insulin-stimulated glucose uptake occurs in muscle, in insulin-resistant states, adipose tissue (not skeletal muscle) GLUT4 is downregulated (3). Recent convincing data in mice suggest a strong causal link between RBP4 and insulin resistance. Adipose-specific GLUT4 knockout mice exhibit insulin resistance with increased adipose RBP4 (3). Overexpression of RBP4 in mice induces insulin resistance, whereas decreases in RBP4 reduce insulin resistance. Furthermore, RBP4 levels can be normalized by insulin sensitizers and fenretinide, which reverse insulin resistance in obese rodents. Increased RBP4 impairs insulin signaling in muscle and increases gluconeogenesis in mouse liver, suggesting that RBP4 is involved in the pathogenesis of insulin resistance and is a marker of insulin resistance in mice.In contrast, human data are equivocal, with high adipocyte and plasma RBP4 levels being reported inconsistently in insulin-resistant states, including obesity, IGT, type 2 diabetes, and PCOS (3–9). Relationships of RBP4 with features of the metabolic syndrome have also been inconsistently demonstrated (4,6,8). RBP4 has been shown to change with interventions that reduce insulin resistance, including weight loss (5,10), exercise (4), and insulin sensitizers, although results are variable (8,9). Methodological issues in the measurement of RBP4 may contribute to inconsistencies, with few studies using the recommended Western blot technique (11).It is increasingly clear that PCOS is an insulin-resistant state and insulin resistance per se is an important therapeutic target. Assessment of insulin resistance is likely to guide treatment with options including the oral contraceptive pill (OCP) (which can increase insulin resistance) or metformin (which reduces insulin resistance) (2,12). However, significant challenges remain in the measurement of insulin resistance (2). Although RBP4 shows promise as a marker of insulin resistance in mice, its role in humans remains unclear. We aimed to clarify the role of serum RBP4 (using the Western blot technique) in PCOS by comparing RBP4 levels in overweight women with and without PCOS. We also examined the relationship between serum RBP4 levels and conventional insulin resistance markers, other metabolic factors, and adiposity in women with PCOS. Finally, we examined the effect of therapeutic interventions that both increase and decrease insulin resistance in women with PCOS on serum RBP4 levels.     

Weight loss strategies associated with BMI in overweight adults with type 2 diabetes at entry into the Look AHEAD (Action for Health in Diabetes) trial

OBJECTIVE—Intentional weight loss is recommended for those with type 2 diabetes, but the strategies patients attempt and their effectiveness for weight management are unknown. In this investigation we describe intentional weight loss strategies used and those related to BMI in a diverse sample of overweight participants with type 2 diabetes at enrollment in the Look AHEAD (Action for Health in Diabetes) clinical trial.RESEARCH DESIGN AND METHODS—This was a cross-sectional study of baseline weight loss strategies, including self-weighing frequency, eating patterns, and weight control practices, reported in 3,063 women and 2,082 men aged 45–74 years with BMI ≥25 kg/m².RESULTS—Less than half (41.4%) of participants self-weighed ≥1/week. Participants ate breakfast 6.0 ± 1.8 days/week, ate 5.0 ± 3.1 meals/snacks per day, and ate 1.9 ± 2.7 fast food meals/week. The three most common weight control practices (increasing fruits and vegetables, cutting out sweets, and eating less high-carbohydrate foods) were reported by ∼60% of participants for ≥20 weeks over the previous year. Adjusted models showed that self-weighing less than once per week (B = 0.83), more fast food meals consumed per week (B = 0.14), and fewer breakfast meals consumed per week (B = −0.19) were associated (P < 0.05) with a higher BMI (R² = 0.24).CONCLUSIONS—Regular self-weighing and breakfast consumption, along with infrequent consumption of fast food, were related to lower BMI in the Look AHEAD study population.As the prevalence of obesity has increased in the U.S., so has that of type 2 diabetes (1). Because of the relationship between body weight and insulin resistance (2), intentional weight loss is an essential component of treatment for type 2 diabetes (3).Changing eating, physical activity, and other weight-related behaviors is critical for weight management (4). One behavioral technique believed to be key for successful weight management is frequent self-weighing (5). Regular self-weighing provides objective information on weight and on the success of specific eating and activity behaviors in reducing weight (6).Different eating patterns may also be important for weight control. Regular consumption of meals, especially breakfast, may aid in weight control by preventing overconsumption later in the day caused by excessive hunger (7). However, regular intake of fast food may negatively impact weight control, as fast food is high in energy and fat (8).National surveys have consistently found that the most prevalent weight control practice used by adults self-reporting an attempt to lose/maintain body weight is eating less, followed by being active (9,10). In adults without type 2 diabetes who have actually lost or maintained weight over time, specific weight control strategies associated with successful weight control include those that target reducing energy intake and use of these strategies consistently over time (11,12).Because little is known about intentional weight loss strategies used by individuals with type 2 diabetes, one aim of this investigation was to describe the occurrence of these strategies in a racially/ethnically diverse sample of overweight individuals with type 2 diabetes participating in the Look AHEAD (Action for Health in Diabetes) clinical trial. A second aim was to identify specific weight loss strategies related to baseline BMI. As medical nutrition therapy is an integral part of the self-management of diabetes (13), it was hypothesized that the use of more dietary-focused compared with activity-focused strategies would be significantly related to a lower baseline BMI. Thus, we hypothesized that frequent self-weighing; regular consumption of meals, particularly breakfast; and infrequent consumption of fast food would be associated with lower BMI. In addition, as persistent use of weight control practices that reduce energy intake has been related to actual weight loss and/or weight maintenance (11,12), we also hypothesized that a longer duration of practices that reduce energy intake would be related to lower BMI.     

Alcohol consumption, mediating biomarkers, and risk of type 2 diabetes among middle-aged women

OBJECTIVE—The purpose of this study was to investigate whether adiponectin concentrations and biomarkers of inflammation, endothelial dysfunction, and insulin resistance mediate the association between alcohol consumption and diabetes.RESEARCH DESIGN AND METHODS—In a nested case-control study of 705 women with incident diabetes and 787 matched control subjects, we examined the adjusted relationship between baseline alcohol consumption and risk of diabetes before and after adjustment for markers of inflammation/endothelial dysfunction (C-reactive protein, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, tumor necrosis factor-α receptor 2, and interleukin-6), fasting insulin, and adiponectin concentrations.RESULTS—Alcohol consumption was associated with a decreased risk of diabetes (odds ratio per 12.5 g/day increment in alcohol use 0.58; 95% CI 0.49–0.69; P < 0.001). Adjustment for BMI attenuated the association by 25%. None of the markers of inflammation or fasting insulin appeared to account for >2% of the observed relationship. Without adjustment for BMI, these biomarkers individually explained slightly more of the association, but <10% in all cases. Adiponectin accounted for 25% in a fully adjusted model and for 29% without adjustment for BMI.CONCLUSIONS—In this population of women, alcohol consumption was inversely associated with risk of type 2 diabetes. Adiponectin appeared to be a mediator of this association, but circulating biomarkers of inflammation, endothelial dysfunction, and fasting insulin did not explain this association. These results suggest that further research is needed into the potentially mediating roles of other biomarkers affected by alcohol consumption.Moderate alcohol consumption is associated with a decreased risk of both coronary heart disease and type 2 diabetes compared with abstaining and heavier drinking (1,2). Approximately 50% of the association with coronary heart disease (CHD) appears to be attributable to an increase in HDL cholesterol (3), and fibrinogen and glycemia may account for a large part of the remainder (4).The underlying mechanism for the lower risk of type 2 diabetes among moderate drinkers is not entirely clear, but several factors may be involved. First, high concentrations of markers of both inflammation and endothelial dysfunction are directly related to risk of type 2 diabetes (5,6), and moderate alcohol consumption is associated with lower levels of markers of inflammation and endothelial dysfunction in both cross-sectional and intervention studies (7,8). Second, a randomized controlled trial (9) and cross-sectional studies (10) have shown improved insulin sensitivity with moderate alcohol consumption, but results of studies are not entirely consistent (11). These changes in insulin sensitivity could be mediated by an increase in adiponectin concentrations that has been consistently shown in several observational and randomized studies (11,12). Finally, BMI is the most important predictor of type 2 diabetes, particularly among women (13). Cross-sectional studies and a recent prospective study suggest that moderate alcohol consumption may be associated with lower BMI and less weight gain over time among women but not men (14,15).Whether and to what extent markers of inflammation, endothelial dysfunction, fasting insulin, and adiponectin concentrations explain the inverse association between moderate alcohol consumption and type 2 diabetes has not been investigated to date. To address these questions, we investigated these relations in a nested case-control study from the Nurses’ Health Study. Previous reports from this study have shown that moderate alcohol consumption, BMI, markers of inflammation and endothelial dysfunction, and fasting insulin are all associated with the risk of type 2 diabetes (5,6) in expected directions.     

Adipokines and incident type 2 diabetes in an Aboriginal Canadian [corrected] population: the Sandy Lake Health and Diabetes Project

OBJECTIVE—The aim of this study was to investigate associations of adiponectin, leptin, C-reactive protein (CRP), interleukin (IL)-6, and serum amyloid A (SAA), individually or in combinations, with risk of incident type 2 diabetes in a Canadian Aborigine population.RESEARCH DESIGN AND METHODS—Of the 606 Sandy Lake Health and Diabetes Project cohort subjects who were free of diabetes at baseline, 540 (89.1%) participated in 10-year follow-up assessments. Concentrations of fasting adiponectin, leptin, CRP, IL-6, SAA, and covariates were measured at baseline. Fasting glucose and a 75-g oral glucose tolerance test were obtained at baseline and follow-up to determine incident type 2 diabetes, defined as clinically diagnosed type 2 diabetes or as fasting plasma glucose ≥7.0 mmol/l or 2-h postload plasma glucose ≥11.1 mmol/l at follow-up.RESULTS—Low adiponectin, high leptin, and low adiponectin-to-leptin ratio at baseline were associated with increased risk of incident type 2 diabetes after adjustment for age, sex, triglycerides, HDL cholesterol, hypertension, and impaired glucose tolerance (odds ratio 0.63 [95% CI 0.48–0.83], 1.50 [1.02–2.21], and 0.54 [0.37–0.77], respectively). When the models were additionally adjusted for waist circumference or BMI, however, only low adiponectin remained significantly associated with increased incident diabetes (0.68 [0.51–0.90]). Combinations of leptin, CRP, IL-6, and/or SAA with adiponectin, assessed using either the ratio or joint effects, did not improve diabetes prediction.CONCLUSIONS—Low baseline adiponectin is associated with increased risk of incident type 2 diabetes independent of leptin, CRP, IL-6, SAA, and metabolic syndrome variables including obesity.Obesity is a major risk factor for insulin resistance and type 2 diabetes (1). The recent focus on adipose tissue as an endocrine organ secreting signaling proteins, collectively termed adipokines, has prompted current interests in associations of adipokines with insulin resistance and diabetes (1–2). Although underlying mechanisms have not been completely explained, adipokines have been linked with obesity-induced inflammation and signaling pathways that contribute to type 2 diabetes (1). Prospectively, adiponectin, an anti-inflammatory, anti-atherogenic, and insulin-sensitizing adipokine (2,3), has been inversely associated with the development of type 2 diabetes (4–7). Several studies associated increased baseline levels of inflammatory markers, including interleukin (IL)-6 (8,9) and C-reactive protein (CRP) (9), with incident type 2 diabetes, while others reported no association of IL-6 (4) and CRP (4,8) with the development of type 2 diabetes after adjustment for adiposity measures. In another prospective study, the association between leptin and diabetes risk was attenuated after adjustment for intra-abdominal fat (10).Recent studies have suggested that adipokines may interact in regulating metabolic homeostasis (11–12). In a cross-sectional study, evidence was presented for CRP inhibiting the binding of leptin to its receptors and leptin stimulating expression of CRP (11). Others identified the adiponectin-to-leptin (A/L) ratio as a reliable marker of insulin resistance (12).Nonetheless, limited population-based data are available on how adipokines in combinations may contribute to the etiology of diabetes. In addition, previous prospective investigations on associations of adipokines with diabetes provide inconsistent findings (4–10). Among those, only a few have reported data from studies of North American Aboriginal people (4,5), while no studies have been conducted among Aboriginal Canadians in whom diabetes is increasingly prevalent (13). The objective of this study was to investigate associations of baseline adiponectin, leptin, CRP, IL-6, and serum amyloid A (SAA), individually and/or in combinations, with the development of type 2 diabetes in a Canadian Aborigine population undergoing rapid cultural transition.     

Serum adipocyte fatty acid-binding protein levels are associated with nonalcoholic fatty liver disease in type 2 diabetic patients

OBJECTIVE—Adipocyte fatty acid–binding protein (A-FABP) is a major cytoplasmic protein in adipocytes and macrophages and is closely associated with metabolic syndrome, type 2 diabetes, and atherosclerosis. Here, we investigated whether A-FABP was associated with nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes.RESEARCH DESIGN AND METHODS—We enrolled 181 type 2 diabetic patients. Clinical and biochemical metabolic parameters were measured. The severity of NAFLD was measured by ultrasound. A-FABP, adiponectin, and retinol-binding protein-4 (RBP-4) were determined by enzyme-linked immunosorbent assay.RESULTS—A-FABP levels, defined as more than a moderate degree of fatty liver compared with men, those without metabolic syndrome, and those without NAFLD, were higher in women, patients with metabolic syndrome, and patients with overt NAFLD, respectively. Adiponectin was decreased according to the severity of NAFLD, but RBP-4 showed no difference. Age- and sex-adjusted A-FABP showed positive correlations with BMI, waist-to-hip ratio, waist circumference, triglycerides, γ-glutamyltransferase, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), A1C, and C-reactive protein (CRP) but showed negative correlation with HDL cholesterol. The odds ratio (OR) for the risk of overt NAFLD with increasing levels of sex-specific A-FABP was significantly increased (OR 2.90 [95% CI 1.15–7.29] vs. 7.87 [3.20–19.38]). The OR in the highest tertile of A-FABP remained significant after adjustments for BMI, waist circumference, A1C, HDL cholesterol, triglycerides, HOMA-IR, CRP, and hepatic enzymes.CONCLUSIONS—Our study demonstrates that serum A-FABP is significantly associated with NAFLD in type 2 diabetes, independent of BMI, waist circumference, HOMA-IR, A1C, triglycerides, HDL cholesterol, and CRP.Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic elevation of hepatic enzymes in the general population without known liver disease. NAFLD is observed in 20–30% of the total population (1) and in 75% of type 2 diabetic patients (2,3) in developed countries. NAFLD is characterized by hepatic insulin resistance. In epidemiologic studies, NAFLD has been reported to be closely associated with obesity, dyslipidemia, and diabetes (4–6). In prospective studies, NAFLD was a risk factor for type 2 diabetes and cardiovascular disease independent of the classic risk factors (7,8). Hence, NAFLD is considered a hepatic manifestation of metabolic syndrome.Adipocyte fatty acid–binding protein (A-FABP; also known as FABP-4 or aP2) is a major cytoplasmic protein and is involved in the regulation of lipid metabolism. A-FABP is expressed abundantly in mature adipocytes and activated macrophages. A-FABP binds fatty acid ligands with high affinity and functions in intracellular fatty acid trafficking, regulation of lipid metabolism, and modulation of gene expression (9,10). In obese mice lacking A-FABP, dyslipidemia and peripheral insulin resistance are improved and β-cell function is preserved (11). Boord et al. (12) reported that combined adipocyte-macrophage fatty acid–binding protein deficiency improves glucose and lipid metabolism, reduces atherosclerosis, and improves survival in apoE^-/- mice. In cross-sectional studies, A-FABP was closely associated with obesity and metabolic syndrome (13,14). In prospective studies, A-FABP levels predicted the development of metabolic syndrome and type 2 diabetes (15,16). Furthermore, Yeung et al. (17) reported that A-FABP levels were independently associated with carotid atherosclerosis. Tuncman et al. (18) reported that individuals with an aP2 variant had lower triglycerides and a reduced risk of coronary heart disease and obesity-induced type 2 diabetes. These findings suggested that A-FABP is closely associated with insulin resistance and plays a central role in the development of metabolic syndrome, type 2 diabetes, and atherosclerosis. Maeda et al. (19) demonstrated protection against fatty liver disease in mice lacking aP2 and mal1 on high-fat diet. However, a relationship between A-FABP and NAFLD, a hepatic manifestation of metabolic syndrome, has not yet been established in a human study.We hypothesized that patients with NAFLD might have higher A-FABP levels and that A-FABP might show a positive correlation with the severity of NAFLD on ultrasound. To test this hypothesis, we investigated the relationship between serum A-FABP levels and NAFLD in type 2 diabetic patients.     

Comparison of once- versus twice-daily administration of insulin detemir, used with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes: assessment of detemir administration in a progressive treat-to-target trial (ADAPT)

OBJECTIVE—The purpose of this study was to compare effects of insulin detemir once daily versus twice a day in a basal-bolus insulin regimen.RESEARCH DESIGN AND METHODS—In this open-label, 7-month study, 520 patients with type 1 diabetes were randomly assigned to receive detemir once daily or twice daily with mealtime insulin aspart. Insulin doses were titrated over 1 month, with patients followed up over the subsequent 3 months. Thereafter, patients were able to switch from one regimen to the other, with an additional nonrandomized 3-month follow-up, to a total of 7 months. The primary end point was A1C at 4 months, with noninferiority defined as a difference <0.4% between groups.RESULTS—A1C at 4 months was 8.1 ± 0.9 versus 8.0 ± 1.0% with once- and twice-daily detemir, respectively, with an adjusted between-group difference of 0.12% (95% CI −0.01 to 0.25%), showing noninferiority for once-daily dosing. Similar results were found in the per protocol population. Improvement in A1C was similar in both groups (−0.4 ± 0.8 vs. −0.5 ± 0.8%; P = 0.09, NS) but with differences in the 7-point glucose profile. Detemir doses were lower (29 ± 18 vs. 39 ± 20 units/day, P < 0.001), but aspart doses were higher (34 ± 17 vs. 26 ± 14 IU/day, P < 0.001) with once-daily detemir. At 7 months, A1C decreased slightly in patients switched from once-daily to twice-daily administration (8.2 ± 0.8 vs. 8.0 ± 0.8%; P = 0.34, NS) in association with increased total insulin doses (P < 0.05), but A1C increased in those switched from twice-daily to once-daily administration (7.2 ± 0.9 vs. 7.6 ± 0.8%, P < 0.05) in association with decreased doses (P < 0.05).CONCLUSIONS—Although some individuals may benefit from twice-daily dosing, the most suitable routine starting schedule for detemir in a basal-bolus regimen for type 1 diabetes is once-daily injection.The basal insulin analog insulin detemir (detemir) differs from human insulin by a single amino acid deletion and the acylation of myristic acid to the B terminus of the molecule. These changes affect the pharmacokinetics of the insulin, prolonging absorption from a subcutaneous depot through a unique mechanism involving self-association of detemir molecules and reversible binding to albumin (1). The result is a more prolonged, less peaked absorption (and hence pharmacodynamic) profile compared with that of NPH insulin (NPH) (2). Another property of detemir, believed to result from albumin binding, is reduced intrasubject variability of the pharmacodynamic profile (3) compared with those of both NPH (4,5) and insulin glargine (4,6). In theory, reduced intrasubject variability should reduce the risk of hypoglycemia (4,7). This theory was confirmed clinically in comparative trials against NPH involving basal-bolus therapy in type 1 diabetes in which detemir demonstrated similar efficacy but consistent reductions in the frequency of hypoglycemia during the night, when the absence of mealtime bolus insulin unmasks differences in the pharmacodynamics of basal insulins (8). Detemir has also been consistently associated with reduced weight gain compared with NPH (9).Most initial studies of detemir in type 1 diabetes involved a twice-daily regimen, but recent pharmacological analyses (6,7) suggest that detemir has a pharmacodynamic profile similar to that of insulin glargine, a basal insulin that is routinely injected once daily. Using a standard definition for duration of action, detemir has been reported to endure for a mean of close to 24 h in type 1 diabetes and longer in type 2 diabetes (7). In addition, data from the large-scale observational Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation (PREDICTIVE) study show that a majority of patients have been using detemir once daily and achieving clinically important improvements in glycemic control (10), although this was not a comparative trial. A recent analysis of basal insulin studies by DeVries et al. (11) suggested that, although a percentage of patients may benefit from twice-daily basal insulin dosing, the routine use of twice-daily basal regimens tends to drive up the total unit dose of insulin without corresponding gains in glycemic control. These observations call into question the routine of twice-daily dosing of detemir in most patients. The present study is the first specifically designed to assess whether routine use of twice-daily detemir in basal-bolus therapy for type 1 diabetes offers any clinical advantages over once-daily administration.     

Adult metabolic syndrome and impaired glucose tolerance are associated with different patterns of BMI gain during infancy: Data from the New Delhi Birth Cohort

OBJECTIVE—The purpose of this study was to describe patterns of infant, childhood, and adolescent BMI and weight associated with adult metabolic risk factors for cardiovascular disease.RESEARCH DESIGN AND METHODS—We measured waist circumference, blood pressure, glucose, insulin and lipid concentrations, and the prevalence of metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III definition) in 1,492 men and women aged 26–32 years in Delhi, India, whose weight and height were recorded every 6 months throughout infancy (0–2 years), childhood (2–11 years), and adolescence (11 years–adult).RESULTS—Men and women with metabolic syndrome (29% overall), any of its component features, or higher (greater than upper quartile) insulin resistance (homeostasis model assessment) had more rapid BMI or weight gain than the rest of the cohort throughout infancy, childhood, and adolescence. Glucose intolerance (impaired glucose tolerance or diabetes) was, like metabolic syndrome, associated with rapid BMI gain in childhood and adolescence but with lower BMI in infancy.CONCLUSIONS—In this Indian population, patterns of infant BMI and weight gain differed for individuals who developed metabolic syndrome (rapid gain) compared with those who developed glucose intolerance (low infant BMI). Rapid BMI gain during childhood and adolescence was a risk factor for both disorders.Approximately 10% of urban Indian men and women aged 40–49 years have type 2 diabetes, and a rising prevalence is predicted to produce 80 million diabetic patients in India by 2030 (1–3). Cardiovascular disease is also rising (4). Similar trends, thought to reflect increasing obesity, are occurring in other developing countries undergoing economic transition, and interventions to prevent disease are urgently needed.Research in high-income countries has shown that factors linked to weight gain in early life contribute to the risk of developing diabetes and cardiovascular disease. Low birth weight (5,6) and accelerated gain in BMI during childhood and adolescence predict increased risk (7,8). The optimal pattern of infant weight gain (the first 1–2 postnatal years) is unclear; studies of adults suggest that low infant weight gain is a risk factor for later disease (7–9), whereas studies of children suggest the opposite (10,11). There are few data from developing countries.In the New Delhi birth cohort (12,13), children were measured at birth and every 6 months throughout infancy, childhood, and adolescence. We reported earlier that low BMI in infancy and rapid childhood BMI gain were associated with an increased risk of adult diabetes or impaired glucose tolerance (IGT) (12). We have now examined other cardiovascular risk factors and the cluster of risk factors known as the metabolic syndrome.     

Dipeptidyl peptidase-4 inhibition by vildagliptin and the effect on insulin secretion and action in response to meal ingestion in type 2 diabetes

OBJECTIVE—The purpose of this study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations.RESEARCH DESIGN AND METHODS—We measured insulin secretion and action as well as glucose effectiveness in 14 subjects with type 2 diabetes who received vildagliptin (50 mg b.i.d.) or placebo for 10 days in random order separated by a 3-week washout. On day 9 of each period, subjects ate a mixed meal. Insulin sensitivity (S_I), glucose effectiveness, and β-cell responsivity indexes were estimated using the oral glucose and C-peptide minimal models. At 300 min 0.02 unit/kg insulin was administered intravenously.RESULTS—Vildagliptin reduced postprandial glucose concentrations (905 ± 94 vs. 1,008 ± 104 mmol/6 h, P = 0.02). Vildagliptin did not alter net S_I (7.71 ± 1.28 vs. 6.41 ± 0.84 10⁻⁴ dl · kg⁻¹ · min⁻¹ · μU⁻¹ · ml⁻¹, P = 0.13) or glucose effectiveness (0.019 ± 0.002 vs. 0.018 ± 0.002 dl · kg⁻¹ · min⁻¹, P = 0.65). However, the net β-cell responsivity index was increased (35.7 ± 5.2 vs. 28.9 ± 5.2 10⁻⁹ min⁻¹, P = 0.03) as was total disposition index (381 ± 48 vs. 261 ± 35 10⁻¹⁴ dl · kg⁻¹ · min⁻² · pmol⁻¹ · l⁻¹, P = 0.006). Vildagliptin lowered postprandial glucagon concentrations (27.0 ± 1.1 vs. 29.7 ± 1.5 μg · l⁻¹ · 6 h⁻¹, P = 0.03), especially after administration of exogenous insulin (81.5 ± 6.4 vs. 99.3 ± 5.6 ng/l, P = 0.02).CONCLUSIONS—Vildagliptin lowers postprandial glucose concentrations by stimulating insulin secretion and suppressing glucagon secretion but not by altered insulin action or glucose effectiveness. A novel observation is that vildagliptin alters α-cell responsiveness to insulin administration, but the significance of this action is as yet unclear.Glucagon-like peptide-1 (GLP-1) is a peptide hormone produced by the enteroendocrine L cells of the intestinal mucosa and is released in response to caloric intake. The major form of secreted GLP-1, GLP-1-(7,36)-amide, is a powerful insulin secretagogue that also suppresses glucagon secretion in a glucose-dependent fashion and may increase insulin action (1). These characteristics would theoretically make the hormone ideal therapy for use in type 2 diabetes, a disorder characterized by defective insulin secretion and action.However, GLP-1 is rapidly inactivated by dipeptidyl peptidase-4 (DPP-4), a widely distributed enzyme, which converts the intact peptide to the metabolite GLP-1-(9,36)-amide. GLP-1–based therapy for type 2 diabetes has required the development of GLP-1 receptor agonists such as exenatide, which are resistant to the action of DPP-4, or, alternatively, compounds that inhibit DPP-4 and thereby raise endogenous concentrations of active GLP-1 (2). GLP-1 (3), GLP-1 receptor agonists (4), and DPP-4 inhibitors (2) all lower postprandial glucose concentrations.GLP-1 and its analogs delay gastric emptying (5), whereas DPP-4 inhibitors do not (6), indicating that the effects of the latter on postprandial glucose concentrations must occur via other mechanisms. It is uncertain whether the lack of gastrointestinal effects of DPP-4 inhibitors occurs because the resulting rise in peripheral active GLP-1 concentrations is not elevated or sustained, in marked contrast with concentrations observed during peripheral GLP-1 infusion. Another potential explanation is that DPP-4 inhibition may alter concentrations of other gut hormones with effects on appetite or motility (such as peptide YY), which neutralize the effect of GLP-1 (7). DPP-4 inhibitors, GLP-1, and its analogues decrease postprandial glucagon concentrations (2). In contrast with GLP-1 and GLP-1 receptor agonists, the effect of DPP-4 inhibition on insulin secretion has been more uncertain: placebo-controlled studies have demonstrated similar insulin concentrations in the presence or absence of DPP-4 inhibition, despite lower glucose concentrations (6). This result implies that such compounds also increase insulin secretion for a given glucose concentration, as has been demonstrated previously using model-based parameters of β-cell function (8).It is possible, however, that these agents lower postprandial glucose concentrations through changes in insulin action and glucose effectiveness. The direct effects of GLP-1 on the ability of glucose per se to stimulate its own uptake and suppress its own release (glucose effectiveness) are less clear (9). Some (10,11) but not all (12) studies have suggested that, when given in pharmacological doses, GLP-1 increases the ability of insulin and glucose to stimulate glucose uptake and to suppress glucose production. Similar controversy exists with regard to the effects of GLP-1 on insulin action (9). Given the known differences in DPP-4 inhibitors, in comparison with other GLP-1–based therapy, it is possible that these compounds also differ with regard to their direct effects on glucose metabolism.To gain greater insight into the mechanism(s) by which DPP-4 inhibitors lower postprandial glucose concentrations, we used a randomized, double-blind, placebo-controlled crossover design in which subjects received vildagliptin, a DPP-4 inhibitor, or placebo over a 10-day period. The disposition index, a measure of insulin secretion for the prevailing insulin action, was measured using the oral glucose (13) and oral C-peptide minimal models (14). Glucose effectiveness was also measured simultaneously. We report that whereas vildagliptin stimulated insulin secretion and enhanced suppression of glucagon, it had no effect on either insulin action or glucose effectiveness. Taken together with previous studies in the same subjects indicating that vildagliptin does not alter gastric emptying (6), these data indicate that DPP-4 inhibitors lower postprandial glucose concentrations solely by alterations of islet cell function.     

Impaired Hyperglycemia-Induced Delay in Gastric Emptying in Patients With Type 1 Diabetes Deficient for Islet Amyloid Polypeptide

OBJECTIVE—Slowing of gastric emptying by hyperglycemia, a physiological response to minimize postprandial hyperglycemia, may be impaired in patients with type 1 diabetes. The causes and consequences on glucose homeostasis are unknown.RESEARCH DESIGN AND METHODS—Consequences of euglycemia- and hyperglycemia-induced changes in gastric emptying on postprandial glucose fluxes and excursions were studied in 10 healthy subjects and 15 type 1 diabetic subjects after ingestion of a mixed meal using the double isotope approach ([6,6-²H₂] and [1-¹³C]glucose) and scintigraphic measurements of gastric emptying.RESULTS—Gastric emptying was greater in type 1 diabetic subjects (90–120 min, P < 0.03), and 50% retention times were comparable in healthy subjects and type 1 diabetic subjects (167 ± 8 vs. 152 ± 10, P = 0.32). Hyperglycemia markedly delayed gastric emptying in healthy subjects but did not alter it in type 1 diabetic subjects (50% retention time 222 ± 18 vs. 167 ± 8 min, P = 0.003 and 148 ± 9 vs. 152 ± 10 min, P = 0.51). Plasma islet amyloid polypeptide (IAPP) increased approximately fourfold in healthy subjects (P < 0.001), whereas it was undetectable in type 1 diabetic subjects. IAPP replacement, using the analog pramlintide, in type 1 diabetic subjects slowed gastric emptying to a comparable extent, as did hyperglycemia in healthy subjects (P < 0.14), and greatly reduced postprandial hyperglycemia (P < 00.1). Meal-derived glucose appearance in plasma (10.7 ± 0.5 vs. 6.8 ± 0.7 μmol · kg⁻¹ · min⁻¹, P < 0.001) was reduced, and splanchnic glucose sequestration increased (14.0 ± 3.0 vs. 25.0 ± 6.0%, P = 0.04).CONCLUSIONS—In patients with type 1 diabetes the ability to delay gastric emptying in response to hyperglycemia is impaired. This impairment contributes to exaggerated rates of meal-derived glucose appearance and, ultimately, postprandial glucose excursions.The importance of insulin and glucagon in maintaining postprandial glycemic excursions within a narrow range is well established (1). However, alterations in gastric emptying, another potentially important factor (2), are not generally considered to be of clinical significance for postprandial hyperglycemia in diabetes unless diabetes late complications, such as gastroparesis, have emerged (3,4).Gastroparesis is a relatively rare diabetes late complication resulting from irreversible intestinal nerve damage (5) and has to be distinguished from the physiological inhibitory effects of acute hyperglycemia on gastric motility (6,7). The latter has been proposed as a defense mechanism to minimize postprandial hyperglycemia by reducing the rate of efflux of glucose into the circulation from the gut (8). This process may be of special importance for patients with type 1 diabetes because they have been reported to have a reduced ability to delay gastric emptying in response to hyperglycemia (9).The pancreatic β-cell hormone islet amyloid polypeptide (IAPP) is cosecreted with insulin in a fixed molar ratio (10) and reduces gastric emptying. Thus, patients with type 1 diabetes even without concomitant enteric neuropathy should have increased rather than delayed rates of gastric emptying, because they are IAPP deficient (11). Accordingly, the present studies were undertaken to test the hypothesis that impairment in hyperglycemia-induced delay in gastric emptying should result in greater meal-derived glucose appearance in the systemic circulation and thus should contribute to postprandial hyperglycemia in patients with type 1 diabetes.     

Diabetes and obesity-related risks for pelvic reconstructive surgery in a cohort of Swedish twins

OBJECTIVE—To determine the diabetes- and obesity-related risks for surgically managed stress urinary incontinence and pelvic organ prolapse.RESEARCH DESIGN AND METHODS—This twin cohort study used the Swedish Twin Register to identify 8,443 female twin pairs born from 1926 through 1958. The association between diabetes and pelvic floor surgery was estimated while taking into account the correlated (twin) structure of the data.RESULTS—For type 1 and type 2 diabetes, no significant associations were observed for stress urinary incontinence (odds ratio [OR] 1.0 [95% CI 0.1–9.2] and 2.0 [1.0–4.0], respectively). There were no cases of prolapse surgery in type 1 diabetic subjects, and for type 2 diabetes the risk estimate was nonsignificant (1.6 [1.0–2.7]). BMI >25 kg/m², age ≥60 years, and childbirth were the strongest risk factors for having incontinence surgery.CONCLUSIONS—Our data suggest that diabetes is not associated with stress urinary incontinence or pelvic organ prolapse surgery.The estimated 11% lifetime risk of female pelvic reconstructive surgery in U.S. women mainly comprises stress urinary incontinence and pelvic organ prolapse surgery (1). In addition to the health-economic burden on society, pelvic floor disorders are associated with often severe implications regarding quality of life (2).Diabetes and obesity are often promoted as risk factors for urogenital disorders (3,4), but previous studies are limited by cross-sectional study designs (5–7). Some studies do not differentiate between diabetes or incontinence types (3), and genetic influences on the association are unknown.Genetic effects may contribute to the occurrence of both pelvic floor disorders and diabetes (8,9). Using twin data, the association between diabetes and development of pelvic floor disorders can be estimated while taking into account the genetically correlated (twin) structure of the data. We used the nationwide Swedish Twin Register to estimate the risk of diabetes and obesity on stress urinary incontinence and pelvic organ prolapse surgery.     

Changes in risk variables of metabolic syndrome since childhood in pre-diabetic and type 2 diabetic subjects: the Bogalusa Heart Study

OBJECTIVE—That type 2 diabetes is associated with the metabolic syndrome is known. However, information is lacking regarding the long-term and adverse changes of metabolic syndrome variables in the development of type 2 diabetes from childhood to adulthood.RESEARCH DESIGN AND METHODS—Observations were examined, retrospectively, in a community-based cohort of normoglycemic (n = 1,838), pre-diabetic (n = 90), and type 2 diabetic (n = 60) subjects followed serially for cardiovascular risk factors during childhood (4–11 years), adolescence (12–18 years), and adulthood (19–44 years).RESULTS—Diabetic subjects versus normoglycemic subjects had significantly higher levels of subscapular skinfold, BMI, triglycerides, glucose, insulin, and homeostasis model assessment of insulin resistance and lower levels of HDL cholesterol beginning in childhood and higher levels of mean arterial pressure (MAP) in adolescence and adulthood. In a multivariate model including BMI, MAP, HDL cholesterol, LDL cholesterol, triglycerides, glucose, and insulin, adjusted for age, age², race, sex, and race × sex interaction, adverse changes in glucose and LDL cholesterol were independently associated with pre-diabetic subjects, whereas adverse changes in BMI, glucose, and HDL cholesterol were associated with diabetic subjects. As young adults, pre-diabetic and diabetic groups displayed a significantly higher prevalence of obesity, hypertension, dyslipidemia, hyperinsulinemia, and metabolic syndrome.CONCLUSIONS—These findings indicate that adverse levels of risk variables of metabolic syndrome, adiposity, and measures of glucose homeostasis accelerating since childhood characterize the early natural history of type 2 diabetes and underscore the importance of early prevention and intervention on risk factors beginning in childhood.More than 19 million people have type 2 diabetes and another 54 million individuals show impaired fasting glucose as adults, which may represent a pre-diabetic state (1). This carbohydrate-insulin imbalance becomes one of the most common causes of death in the U.S. (2). It is also widely recognized that type 2 diabetes increases the risk for cardiovascular morbidity and premature death (3). On the basis of the progressive global epidemic of obesity, it is expected that the worldwide prevalence of type 2 diabetes will rise by 50% to >360 million people over the next 30 years (4). Because a much larger population can be classified as pre-diabetic, the additional risk of cardiovascular mortality becomes enormous (5).As for type 2 diabetes, the pathogenesis of pre-diabetes is linked to a relative insulin deficiency and/or tissue insulin resistance associated with elevated blood glucose levels, despite secondary hyperinsulinemia (6). According to the classification of the American Diabetes Association (7), pre-diabetes and type 2 diabetes represent the two categories of impaired glucose regulation and are associated with a constellation of disorders characteristic of the metabolic syndrome (8,9). However, most studies have been performed on single, baseline measurements at middle and older ages (10,11). Information is lacking on long-term, longitudinal, and progressive changes of the risk variables of the metabolic syndrome from childhood to younger adulthood. This study observed changes over a 21-year period beginning in childhood.     

Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes

OBJECTIVE—In a prospective birth cohort study, we followed infants who had a first-degree relative with type 1 diabetes to investigate the relationship between early growth and infant feeding and the risk of islet autoimmunity.RESEARCH DESIGN AND METHODS—Infants with a first-degree relative with type 1 diabetes were identified during their mother''s pregnancy. Dietary intake was recorded prospectively to determine duration of breast-feeding and age at introduction of cow''s milk protein, cereals, meat, fruit, and vegetables. At 6-month reviews, length (or height) and weight, antibodies to insulin, GAD65, the tyrosine phosphatase-like insulinoma antigen, and tissue transglutaminase were measured. Islet autoimmunity was defined as persistent elevation of one or more islet antibodies at consecutive 6-month intervals, including the most recent measure, and was the primary outcome measure.RESULTS—Follow-up of 548 subjects for 5.7 ± 3.2 years identified 46 children with islet autoimmunity. Weight z score and BMI z score were continuous predictors of risk of islet autoimmunity (adjusted hazard ratios 1.43 [95% CI 1.10–1.84], P = 0.007, and 1.29 [1.01–1.67], P = 0.04, respectively). The risk of islet autoimmunity was greater in subjects with weight z score >0 than in those with weight z score ≤0 over time (2.61 [1.26–5.44], P = 0.01). Weight z score and BMI z score at 2 years and change in weight z score between birth and 2 years, but not dietary intake, also predicted risk of islet autoimmunity.CONCLUSIONS—Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes.Identical twin studies and geographic and temporal variations in incidence argue for a critical role of the environment in the development of type 1 diabetes (1). Environmental influences potentially initiate or accelerate the autoimmune destruction of the pancreatic islets. The incidence of type 1 diabetes is increasing in populations worldwide with an earlier age of onset described in European and Oceania populations (1). This rise in childhood incidence parallels in time the overweight/obesity epidemic in Western childhood populations.The accelerator hypothesis proposes that weight and associated insulin resistance accelerate loss of β-cells in both type 1 and type 2 diabetes, such that they are distinguished only by their rate of progression (2). Proposed accelerators include genes, insulin resistance, and autoimmunity. Although the full implications of this hypothesis are being debated, there is increasing evidence of the importance of weight, BMI, and relative insulin insensitivity in the development of type 1 diabetes. Younger age of onset of type 1 diabetes is associated with higher BMI at diagnosis in large cohorts (3), and in one study, the association was seen only in children with lower fasting C-peptide levels (4). We and others have shown that surrogate markers of insulin resistance and BMI predict progression to type 1 diabetes in subjects with islet autoimmunity (5,6). These findings support weight and relative insulin insensitivity as accelerating β-cell loss after the development of islet autoimmunity when insulin secretion is falling rather than before. However, only prospective studies from birth can resolve this question.Retrospective case-control studies in Europe link increased linear growth and weight gain in childhood, particularly in the first 2 years of life, with later onset of type 1 diabetes (7–9). In one study, infant growth was related to detection of tyrosine phosphatase-like insulinoma antigen (insulinoma-associated protein 2 [IA2]) antibodies at diagnosis (9). Reports from Scandinavia, Germany, and Colorado in the U.S. and our own data have provided prospective data from birth (10–17), but there are no data examining the effect of weight gain on the development of islet autoimmunity or type 1 diabetes in birth cohort studies. Diet, in terms of introduction and intake of cow''s milk protein, cereals, ω-3 fatty acids, fruits, and root vegetables, is a putative influence on the development of islet autoimmunity (12–17).The Australian Baby Diab Study has prospectively followed from birth infants who have a first-degree relative with type 1 diabetes and live in Victoria or South Australia (10,11). We aimed to investigate the relationship between early growth (weight, length, and height gain) and infant feeding and the risk of development of islet autoimmunity.     

Increased daily walking improves lipid oxidation without changes in mitochondrial function in type 2 diabetes

OBJECTIVE—To determine whether increased daily physical activity improves mitochondrial function and/or lipid oxidation in type 2 diabetes.RESEARCH DESIGN AND METHODS—Volunteers with (n = 10) and without (n = 10) type 2 diabetes were matched for habitual physical activity, age, sex, and weight. Basal and maximal mitochondrial activity, physical activity, and resting substrate oxidation were measured at baseline and after 2 and 8 weeks of increased physical activity.RESULTS—Baseline physical activity (6,450 ± 851 vs. 7,638 ± 741 steps/day), basal ATP use (12 ± 1 vs. 12 ± 1 μmol · ml⁻¹ · min⁻¹), phosphocreatine recovery from exercise (31 ± 5 vs. 29 ± 3 s), and basal lipid oxidation (0.57 ± 0.07 vs. 0.65 ± 0.06 mg · kg body wt⁻¹ · min⁻¹) were similar in people with and without type 2 diabetes. There was a significant increase in physical activity after 8 weeks (12,322 ± 1,979 vs. 9,187 ± 1,159 steps/day, respectively). Following increased physical activity, there were no changes in basal ATP use or phosphocreatine recovery after exercise in either group. Basal lipid oxidation increased after 8 weeks of increased physical activity in people with type 2 diabetes (0.79 ± 0.08 mg · kg⁻¹ · min⁻¹) but not people without (0.68 ± 0.13 mg · kg body wt⁻¹ · min⁻¹).CONCLUSIONS—Resting and maximal ATP turnover are not impaired in people with well-controlled type 2 diabetes compared with control subjects matched for physical activity as well as age and weight. Increased unsupervised daily physical activity is sustainable and improves lipid oxidation independent of change in mitochondrial activity in people with type 2 diabetes.The potential role of the mitochondria in the development of insulin resistance and type 2 diabetes has recently attracted much interest. Muscle biopsies taken from people with type 2 diabetes demonstrate smaller mitochondria and lower activities of oxidative enzymes compared with those of lean individuals without diabetes (1). Insulin-resistant people with a family history of diabetes have reduced basal mitochondrial activity in skeletal muscle compared with insulin-sensitive individuals (2). These observations, in combination with others (3–6), raise the possibility that mitochondrial defects could underlie type 2 diabetes. Defects in oxidative function could possibly help explain the impaired fatty acid oxidation (7) and elevated intramyocellular lipid (IMCL) (8) characteristic of impaired insulin action and type 2 diabetes. The elevated intramuscular lipid may affect insulin signaling in skeletal muscle (5), exacerbating insulin resistance.However, other studies have not observed abnormalities in basal mitochondrial activity in skeletal muscle of people with type 2 diabetes (9). Recent biopsy work has also shown that differences in oxidative enzymes between people with and without type 2 diabetes disappear when corrected for mitochondrial density (10). These data raise the possibility that type 2 diabetes is associated with normal mitochondrial function but that the mitochondrial capacity is reduced. This is an important differentiation, as it holds implications for the therapeutic approach to type 2 diabetes.People with type 2 diabetes are more sedentary than those without diabetes (11). It is clear that reversing this sedentary lifestyle with physical activity and/or exercise can produce significant improvements in long-term glucose control (12). These benefits could be mediated, at least in part, by changes in mitochondrial function (13). In people with type 2 diabetes, moderate-intensity exercise combined with moderate weight loss produced a significant improvement in insulin sensitivity and mitochondrial density (14). However, such moderate intensity exercise programs are difficult to implement and usually require close supervision. In contrast, unsupervised walking has been shown to produce significant improvements in long-term glucose control and is a sustainable behavior over long periods of time (2 years) (15). Little is known about how low-intensity physical activity interventions such as walking influence muscle metabolism in people with type 2 diabetes.This study was designed to 1) determine whether there are differences in basal and stimulated mitochondrial activity in people with type 2 diabetes compared with physical activity–matched control subjects and 2) establish whether an increase in daily physical activity is associated with changes in mitochondrial ATP turnover and changes in lipid oxidation.     

Dietary patterns, insulin resistance, and incidence of type 2 diabetes in the Whitehall II Study

OBJECTIVE—The aim of this study was to identify a dietary pattern associated with insulin resistance and investigate whether this pattern was prospectively associated with type 2 diabetes.RESEARCH DESIGN AND METHODS—Analysis was based on 7,339 participants of the Whitehall II study. Dietary intake was measured using a 127-item food frequency questionnaire. We used the reduced rank regression method to determine dietary patterns using the homeostasis model assessment of insulin resistance as the intermediate or response variable. The association between the dietary pattern identified and incidence of type 2 diabetes was investigated using Cox proportional hazard regression models.RESULTS—We identified a dietary pattern characterized by high consumption of low-calorie/diet soft drinks, onions, sugar-sweetened beverages, burgers and sausages, crisps and other snacks, and white bread and low consumption of medium-/high-fiber breakfast cereals, jam, French dressing/vinaigrette, and wholemeal bread. Higher dietary pattern scores were associated with increased risk of type 2 diabetes (hazard ratio for top quartile 2.95 [95% CI 2.19–3.97]; adjusted for age, sex, and energy misreporting). This relationship was attenuated after adjustment for ethnicity, employment grade, health behaviors (smoking, alcohol use, and physical activity) but remained significant after further adjustment for blood pressure and BMI (1.51 [1.10–2.09]).CONCLUSIONS—A dietary pattern associated with insulin resistance predicts type 2 diabetes risk after adjustment for a range of confounders. This study adds to the evidence that dietary patterns are an important risk factor for type 2 diabetes.The worldwide prevalence of type 2 diabetes is alarmingly high (1). Diabetes is an important cause of morbidity and a major risk factor for cardiovascular disease (2). Dietary intake is a potentially modifiable risk factor (2), and although there is convincing evidence for the role of excess calorie intake in the development of type 2 diabetes, the evidence surrounding other diet-related risk factors is far less complete or convincing (3). Further research is required to identify optimal eating patterns for the prevention of type 2 diabetes and provide the evidence base for dietary targets.In much of the work surrounding diet and chronic disease, a single nutrient approach has been adopted. Increasingly, dietary patterns are thought to be important determinants of chronic disease (4). A dietary patterns approach recognizes that foods are consumed in many complex combinations and that nutrients may have interactive and synergistic effects (4).Approaches to studying dietary patterns fall into two categories, using either dietary scores determined by a priori dietary guidelines or multivariate statistical techniques (4). To date, multivariate statistical approaches have tended to use factor and cluster analysis techniques (4). However, a new approach to dietary pattern analysis has emerged that combines multivariate approaches with existing knowledge of diet-disease relationships (5). In reduced rank regression (RRR) analysis, variations in food intake are used to predict intermediate outcomes such as nutrient intakes, biomarkers of intakes, or biomarkers of the disease process and subsequently relationships between the identified dietary patterns and disease are investigated. This approach has been used to study obesity (6), diabetes (5,7,8), cardiovascular disease (9,10), and all-cause mortality (11). Previous studies of type 2 diabetes and dietary patterns using RRR relied on self-report of diabetes status without an oral glucose tolerance test (OGTT) to identify incident disease (5,7,8).The aim of this study was to identify a dietary pattern using RRR that is associated with insulin resistance, a phenotype closely associated with development of type 2 diabetes, and, subsequently, to investigate the prospective association between the dietary pattern and disease.