A low n-6 to n-3 polyunsaturated fatty acid ratio diet improves hyperinsulinaemia by restoring insulin clearance in obese youth.

AIM: To examine the determinants and metabolic impact of the reduction in fasting and postload insulin levels after a low n-6 to n-3 polyunsaturated fatty acid (PUFA) ratio diet in obese youth. MATERIALS AND METHODS: Insulin secretion and clearance were assessed by measuring and modelling plasma insulin and C-peptide in 17 obese youth who underwent a nine-point, 180-minute oral glucose tolerance test (OGTT) before and after a 12-week, eucaloric low n-6:n-3 polyunsaturated fatty acid (PUFA) ratio diet. Hepatic fat content was assessed by repeated abdominal magnetic resonance imaging. RESULTS: Insulin clearance at fasting and during the OGTT was significantly increased after the diet, while body weight, glucose levels, absolute and glucose-dependent insulin secretion, and model-derived variables of ß-cell function were not affected. Dietary-induced changes in insulin clearance positively correlated with changes in whole-body insulin sensitivity and ß-cell glucose sensitivity, but not with changes in hepatic fat. Subjects with greater increases in insulin clearance showed a worse metabolic profile at enrolment, characterized by impaired insulin clearance, ß-cell glucose sensitivity, and glucose tolerance, and benefitted the most from the diet, achieving greater improvements in glucose-stimulated hyperinsulinaemia, insulin resistance, and ß-cell function. CONCLUSIONS: We showed that a 12-week low n-6:n-3 PUFA ratio diet improves hyperinsulinaemia by increasing fasting and postload insulin clearance in obese youth, independently of weight loss, glucose concentrations, and insulin secretion.

A Low ω-6 to ω-3 PUFA Ratio (n-6:n-3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth.

BACKGROUND: Recent literature suggests that the Western diet's imbalance between high ω-6 (n-6) and low ω-3 (n-3) PUFA intake contributes to fatty liver disease in obese youth. OBJECTIVES: We tested whether 12 wk of a low n-6:n-3 PUFA ratio (4:1) normocaloric diet mitigates fatty liver and whether the patatin-like containing domain phospholipase 3 (PNPLA3) rs738409 variant affects the response. METHODS: In a single-arm unblinded study, obese youth 9-19 y of age with nonalcoholic fatty liver disease were treated with a normocaloric low n-6:n-3 PUFA ratio diet for 12 wk. The primary outcome was change in hepatic fat fraction (HFF%), measured by abdominal MRI. Metabolic parameters included alanine aminotransferase (ALT), lipids, measures of insulin sensitivity, and plasma oxidized linoleic acid metabolites (OXLAMs). Outcomes were also analyzed by PNPLA3 rs738409 genotype. Wilcoxon's signed rank test, the Mann-Whitney U test, and covariance pattern modeling were used. RESULTS: Twenty obese adolescents (median age: 13.3 y; IQR: 10.5-16.4 y) were enrolled and 17 completed the study. After 12 wk of dietary intervention, HFF% decreased by 25.8% (P = 0.009) despite stable weight. We observed a 34.4% reduction in ALT (P = 0.001), 21.9% reduction in triglycerides (P = 0.046), 3.28% reduction in LDL cholesterol (P = 0.071), and a 26.3% improvement in whole body insulin sensitivity (P = 0.032). The OXLAMs 9-hydroxy-octadecandienoic acid (9-HODE) (P = 0.011), 13-HODE (P = 0.007), and 9-oxo-octadecadienoic acid (9-oxoODE) (P = 0.024) decreased after 12 wk. HFF% declined in both the not-at-risk (CC/CG) and at-risk (GG) PNPLA3 rs738409 genotype groups, with significant (P = 0.016) HFF% reduction in the GG group. Changes in 9-HODE (P = 0.023), 9-oxoODE (P = 0.009), and 13-oxoODE (P = 0.003) differed between the 2 genotype groups over time. CONCLUSIONS: These data suggest that, independently of weight loss, a low n-6:n-3 PUFA diet ameliorates the metabolic phenotype of adolescents with fatty liver disease and that response to this diet is modulated by the PNPLA3 rs738409 genotype.This trial was registered at clinicaltrials.gov as NCT01556113.

Schooling diabetes: Use of continuous glucose monitoring and remote monitors in the home and school settings.

BACKGROUND: Despite significant advances in type 1 diabetes (T1D) management, achieving targeted glycemic control in pediatric patients remains a struggle. Continuous glucose monitoring (CGM) with remote access holds the promise to address this challenge by allowing caregivers to monitor glucose, even when the child is not directly under their supervision. OBJECTIVE: To explore real-time and remote CGM practices in homes and schools, including caregiver expectations regarding this technology. SUBJECTS: Parents and daytime caregivers. METHODS: Respondents answered an anonymous survey assessing characteristics of CGM use. Cross-sectional data were collected and analyzed using quantitative and qualitative methods. RESULTS: Thirty-three parents and 17 daytime caregivers responded. Threshold alerts (alerts when patients reached certain pre-set high or low limits) were used most frequently, followed by rate of change alerts. Most parents and daytime caregivers responded to low- and high-threshold CGM alerts by confirming with a glucose meter prior to treatment; while about one-third endorsed treating lows without a confirmatory test. Most parents expected their child's daytime caregiver to respond to CGM alerts and daytime caregivers felt the parent's expectations of them were reasonable. All parents and most caregivers reported decreased overall worry/stress. Parents felt positive about CGM use and daytime caregivers felt comfortable with CGM. CONCLUSION: The positive and collaborative management reported by parents and daytime caregivers sets the stage for CGM to play an important role in the management of children with T1D both in the home and in the school settings.

Nighttime is the worst time: Parental fear of hypoglycemia in young children with type 1 diabetes.

BACKGROUND: Fear of hypoglycemia is common in parents of young children with type 1 diabetes (T1D), but little is known about the specific fears that parents most often experience. Hypoglycemia fear has been associated with poorer glycemic control in older children, though not yet studied in a large cohort of very young children. MATERIALS AND METHODS: Parents of 549 children <7 years (mean 5.2 ± 1.2 years [19% <3 years]) with a mean diabetes duration of 2.4 ± 1.0 years (range 1-6 years) and mean HbA1c 8.2% ± 1.1% (66 ± 12 mmol/mol) registered in the T1D Exchange completed the worry scale of the Hypoglycemia Fear Survey modified for parents (HFS-P). RESULTS: Mean parental fear of hypoglycemia worry score was 36.1 ± 23.1 (possible range 0-100), with most frequent worries related to the child having a low while asleep and the child not recognizing a low. The mean worry score was not associated with the child's age, glycemic control, or recent severe hypoglycemic event. Parental worries about lows while sleeping were significantly higher in pump users than non-users (61% vs. 45%; P < .001), and tended to be higher in CGM users than non-users (62% vs 51%; P = .02). CONCLUSIONS: The greatest worries of parents of young children with T1D were related to hypoglycemia during sleep and other times/circumstances during which it would be difficult to detect hypoglycemia. Using advanced diabetes technologies may be an effort to temper fears about hypoglycemia during sleep, though the directionality of this relationship is undetermined. Additional studies can clarify this association and leverage use of diabetes technologies to improve glycemic control.

POSTPRANDIAL DOSING OF BOLUS INSULIN IN PATIENTS WITH TYPE 1 DIABETES: A CROSS-SECTIONAL STUDY USING DATA FROM THE T1D EXCHANGE REGISTRY.

OBJECTIVE: To assess the prevalence and characteristics of patients with type 1 diabetes (T1D) who dose bolus insulin postprandial (PostP) versus preprandial (PreP). METHODS: Data for this cross-sectional study were obtained from 21,533 participants in the T1D Exchange Registry. Data were drawn from the enrollment questionnaire. Patients who dosed 'immediately before meal' or 'several minutes before meal' were classified as PreP. Patients who dosed 'during meal' or 'after meal' were classified as PostP. Data reported (PostP vs. PreP) are mean ± SD and percentage, as appropriate. RESULTS: After exclusion of patients who did not answer the dose-timing question or who selected 'not given regularly' or 'depends on glucose level prior to meal,' (4,229 of 25,762), 21,533 patients were included in the study. Ninety-nine percent of patients used rapid-acting insulin analogues; 32% dosed insulin PostP. Compared to PreP, children <18 years of age dosing PostP were characterized by higher glycated hemoglobin (HbA1c) (8.7 ± 1.5% [72 ± 16.4 mmol/mol] vs. 8.4 ± 1.7% [68 ± 18.6 mmol/mol]), larger insulin dose (1.2 ± 0.7 IU/kg/day vs. 1.1 ± 0.7 IU/kg/day), greater prevalence of history of hypoglycemia, and diabetic ketoacidosis. Adults who dosed PostP were characterized by younger age (33.0 ± 15.3 years vs. 39.5 ± 16.6 years), higher HbA1c (8.3 ± 1.5% [67 ± 16.4 mmol/mol] vs. 7.8 ± 1.5% [62 ± 16.4 mmol/mol]), and larger insulin dose (1.0 ± 0.6 IU/kg/day vs. 0.9 ± 0.5 IU/kg/day) than PreP. CONCLUSION: This study reveals that a large proportion of patients dose bolus insulin PostP. Despite the use of current rapid-acting insulin analogues, patients who dose PostP are characterized by poorer glycemic control in all patients and a greater prevalence of history of severe hypoglycemia and diabetic ketoacidosis in children. ABBREVIATIONS: BMI = body mass index; CGM = continuous glucose monitoring; DKA = diabetic ketoacidosis; HbA1c = glycated hemoglobin; PostP = postprandial; PreP = preprandial; SMBG = self-monitored blood glucose; T1D = type 1 diabetes.

Long-term Continuous Glucose Monitor Use in Very Young Children With Type 1 Diabetes: One-Year Results From the SENCE Study.

OBJECTIVES: Achieving optimal glycemic outcomes in young children with type 1 diabetes (T1D) is challenging. This study examined the durability of continuous glucose monitoring (CGM) coupled with a family behavioral intervention (FBI) to improve glycemia. STUDY DESIGN: This one-year study included an initial 26-week randomized controlled trial of CGM with FBI (CGM+FBI) and CGM alone (Standard-CGM) compared with blood glucose monitoring (BGM), followed by a 26-week extension phase wherein the BGM Group received the CGM+FBI (BGM-Crossover) and both original CGM groups continued this technology. RESULTS: Time in range (70-180 mg/dL) did not improve with CGM use (CGM+FBI: baseline 37%, 52 weeks 41%; Standard-CGM: baseline 41%, 52 weeks 44%; BGM-Crossover: 26 weeks 38%, 52 weeks 40%). All three groups sustained decreases in hypoglycemia (<70 mg/dL) with CGM use (CGM+FBI: baseline 3.4%, 52 weeks 2.0%; Standard-CGM: baseline 4.1%, 52 weeks 2.1%; BGM-Crossover: 26 weeks 4.5%, 52 weeks 1.7%, P-values <.001). Hemoglobin A1c was unchanged with CGM use (CGM+FBI: baseline 8.3%, 52 weeks 8.2%; Standard-CGM: baseline 8.2%, 52 weeks 8.0%; BGM-Crossover: 26 weeks 8.1%, 52 weeks 8.3%). Sensor use remained high (52-week study visit: CGM+FBI 91%, Standard-CGM 92%, BGM-Crossover 88%). CONCLUSION: Over 12 months young children with T1D using newer CGM technology sustained reductions in hypoglycemia and, in contrast to prior studies, persistently wore CGM. However, pervasive hyperglycemia remained unmitigated. This indicates an urgent need for further advances in diabetes technology, behavioral support, and diabetes management educational approaches to optimize glycemia in young children.

Tobacco use patterns and clinical outcomes in the T1D exchange.

AIMS: This study examined associations between tobacco use and diabetes outcomes using the T1D Exchange Registry. METHODS: Adult participants (N = 933) completed standardized questionnaires including self-reported outcomes: past year serious hypoglycemic and diabetic ketoacidosis episodes, diabetes self-care, diabetes distress, and self-monitoring of blood glucose. Chart-extracted outcomes included HbA1c, nephrology and neuropathy diagnoses, and BMI. We examined the relation of tobacco use status (never, former, current) and frequency of use (daily versus less than daily) to these outcomes. RESULTS: The majority had never used tobacco (55%, n = 515); 27% (n = 252) were former users and 18% (n = 166) were current users (with 31% using daily). Tobacco status was associated with HbA1c, BMI, self-care, distress, and blood glucose monitoring frequency. Across most outcomes, current users evidenced worse values relative to never users, and former users were largely similar to never users. Daily use was associated with significantly worse outcomes on HbA1c, diabetes self-care, and distress scores relative to less than daily use. CONCLUSIONS: These cross-sectional comparisons suggest that current tobacco use is associated with worse status on important clinical diabetes indicators. Former users did not evidence these deleterious associations. Findings point to potential diabetes-specific motivators that could inform tobacco cessation interventions.

Alcohol Use and Clinical Outcomes in Adults in the Type 1 Diabetes Exchange.

OBJECTIVES: Alcohol consumption has serious potential consequences for persons with type 1 diabetes. This cross-sectional study examined associations between drinking status and diabetes-related outcomes. METHODS: Participants included 934 adults at Type 1 Diabetes Exchange Registry clinics who responded to an e-mail invitation to complete an electronic survey with items on alcohol consumption; glycated hemoglobin (A1C) and body mass index (BMI) were extracted from medical charts. Participants were an average 38±16 years of age, 61% were women and 90% were non-Hispanic white; A1C was 7.8%±1.5%. The sample was made up of 11% (n=103) never drinkers, 9% (n=89) former drinkers, 61% (n=567) current (past year) nonbinge drinkers and 19% (n=174) current binge drinkers. RESULTS: After controlling for covariates, diabetes distress was lower among never drinkers compared with former and nonbinge drinkers (p<0.009). Never drinkers compared with former drinkers had lower odds of past-year severe hypoglycemia (p=0.001) and lower odds of a neuropathy diagnoses (p=0.006). There were omnibus model trends toward associations between drinking status and diabetes self-care (p=0.10) and between drinking status and BMI (p=0.06). Never drinkers did not differ from other groups on daily frequency of blood glucose self-monitoring, A1C or past-year diabetic ketoacidosis (p>0.05). CONCLUSIONS: These results suggest complex relationships between drinking and diabetes-related distress, and that recent severe hypoglycemia and the presence of neuropathy may motivate some to stop drinking. Prospective studies may improve understanding of these findings.

Sources and Valence of Information Impacting Parents' Decisions to Use Diabetes Technologies in Young Children <8 Years Old with Type 1 Diabetes.

There are multiple information sources available to assist families in learning about rapidly advancing diabetes technologies as care options for their children. This study explored where and from whom families of young children with type 1 diabetes get information about diabetes technologies and the valence (positive vs. negative) of that information. Semi-structured interviews were conducted with parents (86% mothers) of 79 youth <8 years old with type 1 diabetes for ≥6 months, ([mean ± standard deviation] age 5.2 ± 1.5 years, diabetes duration 2.4 ± 1.3 years, 77% white, A1c 63 ± 10 mmol/mol [7.9 ± 0.9%], 66% pump-treated, 58% using continuous glucose monitors [CGMs]). Interviews were transcribed and underwent content analysis to derive central themes. Most parents reported learning about new technologies from three direct sources: diabetes care providers, people with diabetes, and caregivers of children with diabetes. Parents also cited three indirect sources of information: online forums, publications, and diabetes-specific conferences. Parents reported hearing primarily positive things about technologies. Families not using pump and/or CGM noted reluctance to use technology due to family-specific concerns (e.g., cost, child's unwillingness to wear device) rather than information from outside sources. In this subset of parents, many still expressed willingness to initiate use once family-specific concerns were resolved. Parents of young children received largely positive information about diabetes technologies, primarily from health care providers and others familiar with using devices personally or for their children. To maximize diabetes technology use in young children, it is incumbent upon providers to ensure families receive balanced realistic information about benefits and barriers.

Pharmacologic treatment options for type 1 diabetes: what's new?

INTRODUCTION: The expanding variety of insulins, including biosynthetic human insulin and rapid and long-acting insulin analogs, have dramatically transformed the management of type 1 diabetes (T1D) over the past 25 years. Moreover, increasing interest in the use of novel drugs developed for the treatment of type 2 diabetes (T2D) as adjunctive therapies for T1D remains a work in progress. Areas Covered: We reviewed articles published up to December 2018 in PubMed and ClinicalTrials.gov for recent developments in the pharmacologic treatment of T1D, including inhaled insulin, ultrafast and ultralong-acting insulins and adjunctive therapies including pramlintide, metformin, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2, and SGLT1/2 inhibitors. Expert Opinion: With the creation of ultrafast-acting insulin analogs and very prolonged duration of action of basal insulins, it is possible to more closely mimic physiologic insulin secretion. Adjunctive therapies, likewise, may also overcome some of the abnormal physiology that is a hallmark of T1D. Therefore, individualized consideration of the efficacy of these agents must be measured alongside the potential adverse effects when choosing an adjunctive therapy.

Altered Patterns of Early Metabolic Decompensation in Type 1 Diabetes During Treatment with a SGLT2 Inhibitor: An Insulin Pump Suspension Study.

BACKGROUND: Enthusiasm for the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as an adjunctive treatment in type 1 diabetes (T1D) has been offset by the possible increased risk of diabetic ketoacidosis (DKA). Since pump-treated T1D patients are susceptible to DKA due to infusion site problems, this study was undertaken to assess how treatment with SGLT2i affects patterns of early metabolic decompensation following suspension of basal insulin. METHODS: Ten T1D participants (age 19-35 years, duration 10 ± 8 years, A1c 7.4% ± 0.8%) underwent overnight pump suspension studies before and after treatment with canagliflozin (CANA). On both nights, basal insulin was suspended at 3 AM and plasma glucose (PG), ß-hydroxybutyrate (BHB), free fatty acids (FFA), plasma insulin (PI), and glucagon were measured. Studies were terminated 6 h after suspension or if PG rose to >350 mg/dL or BHB >2.5 mmol/L. RESULTS: PI levels at the start of suspension were reduced by 30% after CANA treatment (44 ± 11 uU/mL vs. 31 ± 10 uU/mL, P < 0.01), but baseline PG, BHB, FFA, and glucagon levels were not significantly different. During the suspension, PG rose from 104 ± 10 to 301 ± 21 mg/dL before treatment, but only from 109 ± 8 to 195 ± 14 mg/dL after treatment (P = 0.002 vs. pretreatment values). On the other hand, CANA treatment did not significantly affect the magnitude of increases in FFA, BHB, and glucagon levels during the suspension study. CONCLUSION: These data indicate that SGLT2i do not accelerate the rate of ketogenesis following the interruption of basal insulin infusion in T1D. Rather, the failure of patients to promptly recognize early metabolic decompensation relates to the much more gradual rise in PG levels.

Insulin Pump Use in Young Children with Type 1 Diabetes: Sociodemographic Factors and Parent-Reported Barriers.

BACKGROUND: Managing type 1 diabetes (T1D) in young children presents challenges to families and caregivers. Pump therapy may reduce challenges and benefit glycemic control. However, pump use is not universal; parent-reported reasons for lack of uptake are not well described. METHODS: Parents of children <7, with T1D for ≥1 year, in the T1D Exchange registry completed surveys capturing demographic and clinical characteristics, as well as barriers to pump use. Data from pump users were compared to nonusers, and barriers were analyzed among parents who received pump recommendations, but decided against uptake. RESULTS: Young children (N = 515) from 41 sites were identified (mean age 5.2 ± 1.2 years, diabetes duration 2.4 ± 1.0 years, 46% female, and 78% Non-Hispanic White). Overall glycemic control was suboptimal (HbA1c 8.1% ± 1.0%). The majority were pump users (64%, n = 331; nonusers 36%, n = 184). Pump users had longer T1D duration (2.5 ± 1.1 years vs. 2.2 ± 1.0 years, P = 0.001), were more likely to have annual household incomes ≥$75,000 (62% vs. 36%, P < 0.001), have a parent with college education or higher (70% vs. 45%, P < 0.001), perform more frequent blood glucose monitoring (7.5 ± 2.5 times/day vs. 6.5 ± 2.3 times/day, P < 0.001), and use continuous glucose monitoring (CGM) (45% vs. 13%, P < 0.001). Only income, education, frequency of blood glucose monitoring, and CGM use remained significant in a multivariate model including age, sex, ethnicity, and duration of diabetes. Barriers to pump uptake included concerns with physical interference, therapeutic effectiveness, and to a lesser extent, financial burden. CONCLUSIONS: These findings provide an opportunity to address potentially modifiable parent-reported barriers to pump uptake through education and behavioral intervention.

Mitigating Reductions in Glucose During Exercise on Closed-Loop Insulin Delivery: The Ex-Snacks Study.

OBJECTIVE: To assess whether snacking could be used with closed-loop (CL) insulin delivery to avoid exercise-induced reductions in plasma glucose (PG), as well as elevations in PG at the end of exercise. RESEARCH DESIGN AND METHODS: Twelve type 1 diabetes (T1D) subjects (age 13-36 years, duration 10.7 ± 8.4 years, A1c 7.4% ± 0.8% [57 ± 8.7 mmol/mol]) underwent two 105-min exercise studies while under CL control: CL alone and CL+snack. Exercise, commenced at 3 PM, consisted of four 15-min periods of brisk treadmill walking to 65%-70% HRmax (separated by three 5-min rest periods), followed by a 30-min recovery period. Fifteen to 30 g carbohydrate (Gatorade) was provided on snacking visits just before and midway through the exercise period. PG and insulin were measured every 15-20 min during the exercise studies. RESULTS: Baseline PG levels were similar for CL alone (164 ± 16 mg/dL) versus CL+snack (172 ± 11 mg/dL). During exercise, PG levels fell by 53 ± 10 mg/dL without snacking versus a modest 10 ± 13 mg/dL increase in PG with snacking (P = 0.0005); similar differences in the change in PG levels were observed at the end of recovery period. Hypoglycemia requiring rescue treatment (PG ≤60 mg/dL) during exercise occurred in three nonsnacking visits versus none with snacking. During the 75-min exercise period, insulin delivered was 1.8 ± 0.4 U for the CL+snack admission compared to 0.7 ± 0.1 U during CL alone (P = 0.002). CONCLUSION: These results support the use of a simple snacking strategy to avoid exercise-induced lowering of PG while on CL insulin delivery. Persistent insulin infusion during exercise with snacking also appears to be effective in limiting increases in PG at the end of exercise.

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/m(2)) or ILI (age 43.8 ± 10.8 years, BMI 35.4 ± 8.5 kg/m(2)), 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.

Mitigating Meal-Related Glycemic Excursions in an Insulin-Sparing Manner During Closed-Loop Insulin Delivery: The Beneficial Effects of Adjunctive Pramlintide and Liraglutide.

OBJECTIVE: Closed-loop (CL) insulin delivery effectively maintains glucose overnight but struggles when challenged with meals. Use of single-day, 30-µg/meal pramlintide lowers meal excursions during CL. We sought to further elucidate the potential benefits of adjunctive agents after 3-4 weeks of outpatient dose titration. RESEARCH DESIGN AND METHODS: Two CL studies were conducted: one evaluating adjunctive pramlintide and the other liraglutide. Ten subjects (age 16-23 years; A1C 7.2 ± 0.6% [55 ± 6.6 mmol/mol]) completed two 24-h sessions: one on CL alone and one on CL plus 60-µg pramlintide (CL + P), after a 3-4-week outpatient dose escalation. Eleven subjects (age 18-27 years; A1C 7.5 ± 0.9% [58 ± 9.8 mmol/mol]) were studied before and after treatment with 1.8 mg liraglutide (CL + L) after a similar 3-4-week dose escalation period. Timing and content of meals during CL were identical within experiments; meals were not announced. RESULTS: Pramlintide delayed the time to peak plasma glucose (PG) excursion (CL 1.6 ± 0.5 h vs. CL + P 2.6 ± 0.9 h, P < 0.001) with concomitant blunting of peak postprandial increments in PG (P < 0.0001) and reductions in postmeal incremental PG area under the curve (AUC) (P = 0.0002). CL + L also led to reductions in PG excursions (P = 0.05) and incremental PG AUC (P = 0.004), with a 28% reduction in prandial insulin delivery. Outpatient liraglutide therapy led to a weight loss of 3.2 ± 1.8 kg, with a 26% reduction in total daily insulin dose. CONCLUSIONS: Adjunctive pramlintide and liraglutide treatment mitigated postprandial hyperglycemia during CL control; liraglutide demonstrated the additional benefit of weight loss in an insulin-sparing manner. Further investigations of these and other adjunctive agents in long-term outpatient CL studies are needed.

Altered Brain Response to Drinking Glucose and Fructose in Obese Adolescents.

Increased sugar-sweetened beverage consumption has been linked to higher rates of obesity. Using functional MRI, we assessed brain perfusion responses to drinking two commonly consumed monosaccharides, glucose and fructose, in obese and lean adolescents. Marked differences were observed. In response to drinking glucose, obese adolescents exhibited decreased brain perfusion in brain regions involved in executive function (prefrontal cortex [PFC]) and increased perfusion in homeostatic appetite regions of the brain (hypothalamus). Conversely, in response to drinking glucose, lean adolescents demonstrated increased PFC brain perfusion and no change in perfusion in the hypothalamus. In addition, obese adolescents demonstrated attenuated suppression of serum acyl-ghrelin and increased circulating insulin level after glucose ingestion; furthermore, the change in acyl-ghrelin and insulin levels after both glucose and fructose ingestion was associated with increased hypothalamic, thalamic, and hippocampal blood flow in obese relative to lean adolescents. Additionally, in all subjects there was greater perfusion in the ventral striatum with fructose relative to glucose ingestion. Finally, reduced connectivity between executive, homeostatic, and hedonic brain regions was observed in obese adolescents. These data demonstrate that obese adolescents have impaired prefrontal executive control responses to drinking glucose and fructose, while their homeostatic and hedonic responses appear to be heightened. Thus, obesity-related brain adaptations to glucose and fructose consumption in obese adolescents may contribute to excessive consumption of glucose and fructose, thereby promoting further weight gain.

Leptin is associated with exaggerated brain reward and emotion responses to food images in adolescent obesity.

OBJECTIVE: In the U.S., an astonishing 12.5 million children and adolescents are now obese, predisposing 17% of our nation's youth to metabolic complications of obesity, such as type 2 diabetes (T2D). Adolescent obesity has tripled over the last three decades in the setting of food advertising directed at children. Obese adults exhibit increased brain responses to food images in motivation-reward pathways. These neural alterations may be attributed to obesity-related metabolic changes, which promote food craving and high-calorie food (HCF) consumption. It is not known whether these metabolic changes affect neural responses in the adolescent brain during a crucial period for establishing healthy eating behaviors. RESEARCH DESIGN AND METHODS: Twenty-five obese (BMI 34.4 kg/m2, age 15.7 years) and fifteen lean (BMI 20.96 kg/m2, age 15.5 years) adolescents underwent functional MRI during exposure to HCF, low-calorie food (LCF), and nonfood (NF) visual stimuli 2 h after isocaloric meal consumption. RESULTS: Brain responses to HCF relative to NF cues increased in obese versus lean adolescents in striatal-limbic regions (i.e., putamen/caudate, insula, amygdala) (P < 0.05, family-wise error [FWE]), involved in motivation-reward and emotion processing. Higher endogenous leptin levels correlated with increased neural activation to HCF images in all subjects (P < 0.05, FWE). CONCLUSIONS: This significant association between higher circulating leptin and hyperresponsiveness of brain motivation-reward regions to HCF images suggests that dysfunctional leptin signaling may contribute to the risk of overconsumption of these foods, thus further predisposing adolescents to the development of obesity and T2D.