Impaired glucose tolerance is common among obese adolescents, but the changes in insulin sensitivity and secretion that lead to this prediabetic state are unknown. We investigated whether altered ...partitioning of myocellular and abdominal fat relates to abnormalities in glucose homoeostasis in obese adolescents with prediabetes.
We studied 14 obese children with impaired glucose tolerance and 14 with normal glucose tolerance, of similar ages, sex distribution, and degree of obesity. Insulin sensitivity and secretion were assessed by the euglycaemichyperinsulinaemic clamp and the hyperglycaemic clamp. Intramyocellular lipid was assessed by proton nuclear magnetic resonance spectroscopy and abdominal fat distribution by magnetic resonance imaging.
Peripheral glucose disposal was significantly lower in individuals with impaired than in those with normal glucose tolerance (mean 35·4 SE 4·0
vs 60·6 7·2 moles per kg lean body mass per min; p=0·023) owing to a reduction in non-oxidative glucose disposal metabolism (storage). Individuals with impaired glucose tolerance had higher intramyocellular lipid content (3·04 0·43
vs 1·99 0·19%, p=0·03), lower abdominal subcutaneous fat (460 47
vs 626 39 cm
2, p=0·04), and slightly higher visceral fat than the controls (70 11
vs 47 6 cm
2, p=0·065), resulting in a higher ratio of visceral to subcutaneous fat (0·15 0·02
vs 0·07 0·01, p=0·002). Intramyocellular and visceral lipid contents were inversely related to the glucose disposal and non-oxidative glucose metabolism and positively related to the 2 h plasma glucose concentration.
In obese children and adolescents with prediabetes, intramyocellular and intra-abdominal lipid accumulation is closely linked to the development of severe peripheral insulin resistance.
Aims/hypothesis
The study aimed to compare participant characteristics, treatment modalities and clinical outcomes in registry participants less than 6 years old.
Methods
Participant characteristics, ...treatment modalities and clinical outcomes (HbA
1c
, severe hypoglycaemia SH and diabetic ketoacidosis DKA) as well as frequencies of attaining HbA
1c
goals in line with the International Society for Pediatric and Adolescent Diabetes (<7.5% <58 mmol/mol) and ADA (<8.5% <69 mmol/mol) were compared.
Results
Insulin pump use was more frequent (74% vs 50%,
p
< 0.001) and HbA
1c
levels lower in the Prospective Diabetes Follow-up Registry (DPV) than in the T1D Exchange (T1DX) (mean 7.4% vs 8.2%,
p
< 0.001). A lower HbA
1c
level was seen in the DPV compared with the T1DX for both pump users (
p
< 0.001) and injection users (
p
< 0.001). More children from DPV were meeting the recommended HbA
1c
goals, compared with children from T1DX (HbA
1c
<7.5%: 56% vs 22%,
p
< 0.001; HbA
1c
<8.5%: 90% vs 66%,
p
< 0.001). The adjusted odds of having an HbA
1c
level <7.5% or <8.5% were 4.2 (
p
< 0.001) and 3.6 (
p
< 0.001) higher for the DPV than the T1DX, respectively. The frequency of SH did not differ between registries or by HbA
1c
, whereas the frequency of DKA was higher for the T1DX and greater in those with higher HbA
1c
levels.
Conclusions/interpretation
DPV data indicate that an HbA
1c
of <7.5% can frequently be achieved in children with type 1 diabetes who are under 6 years old. An improved metabolic control of type 1 diabetes in young patients appears to decrease the risk of DKA without increasing SH. The greater frequency of suboptimal control in young patients in the T1DX compared with the DPV is not fully explained by a less frequent use of insulin pumps and may relate to the higher HbA
1c
targets that are recommended for this age group in the USA.
Across all age groups, management of type 1 diabetes (T1D) places substantial responsibility and emotional burden upon families. This study explored parent perceptions of the burdens of caring for ...very young children with T1D.
Semi-structured qualitative interviews were conducted with parents (85% mothers) of 79 children with T1D, aged 1 to <8 years old, from four diverse pediatric diabetes clinical centers. Interviews were transcribed, coded, and analyzed using hybrid thematic analysis to derive central themes.
Youth (77% White) had T1D for ≥6 months: age (M ± SD) 5.2 ± 1.5 years, diabetes duration 2.4 ± 1.3 years, and A1c 63 ± 10 mmol/mol (7.9 ± 0.9%); 66% used an insulin pump and 61% used CGM. Three major themes emerged related to diabetes burdens: (a) the emotional burden of diabetes on themselves and their children, (b) the burden of finding, training, and trusting effective secondary caregivers to manage the child's diabetes, and (c) suggestions for how more comprehensive, personalized diabetes education from healthcare providers for parents and secondary caregivers could help reduce parent burden and worry.
In families with very young children with T1D, parental perceptions of the burden of managing diabetes are common and could be mitigated by tailored education programs that increase parent knowledge, bolster parents' confidence in themselves, and increase trust in their secondary caregivers to manage diabetes. Reduced parental burden and increased caregiver knowledge may positively impact child's glycemic control, as well as improve parent and child quality of life.
Given the extreme increase in prediabetes, type 2 diabetes, and the potential for metabolic syndrome in obese youth, identifying simplified indexes for assessing stimulated insulin sensitivity is ...critical. The purpose of this study was validation of two surrogate indexes of insulin sensitivity determined from the oral glucose tolerance test (OGTT): the composite whole body insulin sensitivity index (WBISI) and the insulin sensitivity index (ISI). An obese population (aged 8–18 yr) of normal and impaired glucose tolerance individuals was studied. One group (n = 38) performed both the euglycemic-hyperinsulinemic clamp and OGTT for comparison of insulin sensitivity measurements as well as 1H-magnetic resonance spectroscopy estimates of intramyocellular lipid content. Another larger (n = 368) cohort participated only in an OGTT. Both the WBISI and ISI represented good estimates (r = 0.78 and 0.74; P < 0.0005) for clamp-derived insulin sensitivity (glucose disposed, M-value), respectively. In the large cohort, the surrogate indexes demonstrated the shift toward poorer function and increased risk profile as a function of insulin resistance. Additionally, the WBISI and ISI correlated with intramyocellular lipid content (r = −0.74 and −0.71; P < 0.0001), a tissue marker for insulin resistance. Insulin sensitivity can be estimated using plasma glucose and insulin responses derived from the OGTT in obese youth with normal and impaired glucose tolerance.
Objective:
The aim was to formulate practice guidelines for determining settings where patients are most likely to benefit from the use of continuous glucose monitoring (CGM).
Participants:
The ...Endocrine Society appointed a Task Force of experts, a methodologist, and a medical writer.
Evidence:
This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence.
Consensus Process:
One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, the Diabetes Technology Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines.
Conclusions:
The Task Force evaluated three potential uses of CGM: 1) real-time CGM in adult hospital settings; 2) real-time CGM in children and adolescent outpatients; and 3) real-time CGM in adult outpatients. The Task Force used the best available data to develop evidence-based recommendations about where CGM can be beneficial in maintaining target levels of glycemia and limiting the risk of hypoglycemia. Both strength of recommendations and quality of evidence were accounted for in the guidelines.
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.
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).
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).
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.
Even under closed-loop (CL) conditions, meal-related blood glucose (BG) excursions frequently exceed target levels as a result of delays in absorption of insulin from the subcutaneous site of ...infusion. We hypothesized that delaying gastric emptying with preprandial injections of pramlintide would improve postprandial glycemia by allowing a better match between carbohydrate and insulin absorptions.
Eight subjects (4 female; age, 15-28 years; A1C, 7.5 ± 0.7%) were studied for 48 h on a CL insulin-delivery system with a proportional integral derivative algorithm with insulin feedback: 24 h on CL control alone (CL) and 24 h on CL control plus 30-μg premeal injections of pramlintide (CLP). Target glucose was set at 120 mg/dL; timing and contents of meals were identical on both study days. No premeal manual boluses were given. Differences in reference BG excursions, defined as the incremental glucose rise from premeal to peak, were compared between conditions for each meal.
CLP was associated with overall delayed time to peak BG (2.5 ± 0.9 vs. 1.5 ± 0.5 h; P < 0.0001) and reduced magnitude of glycemic excursion (88 ± 42 vs. 113 ± 32 mg/dL; P = 0.006) compared with CL alone. Pramlintide effects on glycemic excursions were particularly evident at lunch and dinner, in association with higher premeal insulin concentrations at those mealtimes.
Pramlintide delayed the time to peak postprandial BG and reduced the magnitude of prandial BG excursions. Beneficial effects of pramlintide on CL may in part be related to higher premeal insulin levels at lunch and dinner compared with breakfast.
Hemoglobin A1c (HbA1c) levels among individuals with type 1 diabetes (T1D) influence the longitudinal risk for diabetes-related complications. Few studies have examined HbA1c trends across time in ...children, adolescents, and young adults with T1D. This study examines changes in glycemic control across the specific transition periods of pre-adolescence-to-adolescence and adolescence-to-young adulthood, and the demographic and clinical factors associated with these changes.
Available HbA1c lab results for up to 10 yr were collected from medical records at 67 T1D Exchange clinics. Two retrospective cohorts were evaluated: the pre-adolescent-to-adolescent cohort consisting of 85 016 HbA1c measurements from 6574 participants collected when the participants were 8-18 yr old and the adolescent-to-young adult cohort, 2200 participants who were 16-26 yr old at the time of 17 279 HbA1c measurements.
HbA1c in the 8-18 cohort increased over time after age 10 yr until ages 16-17; followed by a plateau. HbA1c levels in the 16-26 cohort remained steady from 16-18, and then gradually declined. For both cohorts, race/ethnicity, income, health insurance, and pump use were all significant in explaining individual variations in age-centered HbA1c (p < 0.001). For the 8-18 cohort, insulin pump use, age of onset, and health insurance were significant in predicting individual HbA1c trajectory.
Glycemic control among patients 8-18 yr old worsens over time, through age 16. Elevated HbA1c levels observed in 18 yr-olds begin a steady improvement into early adulthood. Focused interventions to prevent deterioration in glucose control in pre-adolescence, adolescence, and early adulthood are needed.
Recommendations from the Diabetes Control and Complications Trial (DCCT) indicate that adolescents with type 1 diabetes should be treated with intensive therapy involving multiple daily injections ...(MDI) of insulin or insulin pump therapy (continuous subcutaneous insulin infusion CSII to help obtain better metabolic control and prevent later complications. Interest has thus focused on insulin pump therapy to help adolescents meet this challenge. The purpose of this study was to examine responses to CSII and MDI in a large group of adolescents with established type 1 diabetes during a 12-month period and to determine whether either treatment regimen more favorably affected clinical and psychosocial outcomes.
One-third of 75 youths aged 12-20 years who were candidates for intensive therapy chose CSII as their mode of treatment. Patients received intensive treatment and education as described by the DCCT investigators. Psychosocial data (e.g., quality of life, depression, self-efficacy, and coping) were collected at baseline and at 6-month intervals, and clinical data (e.g., HbA1c levels, adverse events) were collected every 4-6 weeks.
Although both MDI- and CSII-treated adolescents initially exhibited improved metabolic control, this level of control was more difficult to sustain for 12 months in the MDI group (at 6 months HbA1c = 8.1, at 12 months HbA1c = 8.3), whereas average HbA1c levels in the CSII group continued to decrease during the 12 months of treatment (at 6 months HbA1c = 7.7, at 12 months HbA1c = 7.5). Despite lower HbA1c levels in CSII-versus MDI-treated patients, the rate of severe hypoglycemic events was reduced by almost 50% in the CSII group (P = 0.01). Self-reported questionnaires demonstrated that there was improvement in self-efficacy, depression, and quality of life in both MDI- and CSII-treated patients. Finally, adolescents using CSII found coping with diabetes to be less difficult than adolescents using MDI did.
CSII is an alternative means to lower HbA1c levels and reduce the risk of hypoglycemia without adversely affecting psychosocial outcomes in adolescents with type 1 diabetes.
The increasing prevalence of childhood overweight and obesity has led to a substantial increase in T2D in youth. The clinical course of youth-onset T2D is more aggressive than in adults, with a ...faster decline in beta‑cell function leading to worse glycemic control and an early onset of complications. The DINAMO trial compared the efficacy and safety of empagliflozin and linagliptin with placebo in 157 participants aged 10-17 years. Participants were randomized (1:1:1) to linagliptin 5 mg, empagliflozin 10 mg, or placebo. At Week 12, those in the empagliflozin group who did not attain HbA1c <7.0% were re‑randomized (1:1) to empagliflozin 10 or 25 mg. Responders were defined as having no rescue medication and a HbA1c change from baseline ≤-0.5% or attained HbA1c <7.0% at Week 26. Empagliflozin results were pooled. Significantly more participants responded to empagliflozin vs placebo (rate difference 23.6, 95% CI 4.3-41.4; p=0.01); this response was maintained to Week 52 by 40% of the group. Results for linagliptin vs placebo were not significant. Empagliflozin provided a clinically meaningful response even at higher HbA1c and FPG levels (Table). These results show that empagliflozin provides a clinically relevant, statistically significant, and durable improvement in glycemic control, suggesting SGLT2 inhibitors could be a new therapy for T2D in youth.
Disclosure
L. M. Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. T. Danne: Research Support; Abbott Diabetes, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Medtronic, Stock/Shareholder; DreaMed Diabetes, Ltd. W. V. Tamborlane: None. G. J. Klingensmith: Advisory Panel; Boehringer Ingelheim Inc., Consultant; AstraZeneca, Boehringer Ingelheim Inc., Novo Nordisk, Takeda Pharmaceutical Co., Ltd. D. Neubacher: Employee; Boehringer Ingelheim Pharma GmbH&Co. KG. I. Tartakovsky: Employee; Boehringer Ingelheim International GmbH. J. Marquard: Employee; Boehringer Ingelheim Inc. P. Zeitler: Consultant; Eli Lilly and Company, Boehringer Ingelheim Inc., Johnson & Johnson. S. M. Willi: Advisory Panel; Boehringer Ingelheim International GmbH, Medtronic.
Funding
Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance
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