Predictors of glycemic worsening in the next year in adults with screen-detected type 2 diabetes.

Background and Aims: Identifying simple markers of risk for worsening glucose can allow care providers to target therapeutic interventions according to risk of worsening glycemic control. We aimed to determine which routine clinical measures herald near-term glycemic worsening in early type 2 diabetes(T2D). Methods: The Early Diabetes Intervention Program (EDIP) was a clinical trial in individuals with screendetected T2D [HbA1C 6.3+0.63%(45+5mmol/mol)]. During the trial some participants experienced worsening fasting blood glucose (FBG). We investigated the time course of FBG, HbA1c, weight, and other clinical factors to determine which might herald glycemic worsening over the next year. Results: Progressors (62/219, 28.5%) had higher FBG than non-progressors at baseline [118 vs 130mg/dL (6.6 vs 7.2 mmol/L), p=<0.001]. FBG was stable except in the year of progression, when progressors exhibited a large 1-year rise [mean change 14.2mg/dL(0.79 mmol/L)]. Current FBG and antecedent year change in FBG were associated with progression(p<0.01), although the magnitude of change was too small to be of clinical utility (0.19 mg/dL; 0.01 mmol/L). Current or antecedent year change in HbA1c, weight, TG or HDL were not associated with progression. In the year of glycemic worsening, rising glucose was strongly associated with a concurrent increase in weight (p<0.001). Conclusions: Elevated FBG but not HbA1c identified individuals at risk for imminent glycemic worsening; the subsequent large rise in glucose was associated with a short-term increase in weight. Glucose and weight surveillance provide actionable information for those caring for patients with early diabetes.

A co-designed, community-based intensive health behavior intervention promotes participation and engagement in youth with risk factors for type 2 diabetes.

Background: Obesity among youth (children and adolescents) is associated with increased risk for youth-onset type 2 diabetes. Lifestyle change can delay or prevent the development of type 2 diabetes, yet real-world implementation of health behavior recommendations is challenging. We previously engaged youth with risk factors for type 2 diabetes, their caregivers, and professionals in a human-centered design study to co-design a lifestyle change program. Here we report the outcomes for this 16-week co-designed lifestyle change program for youth at risk for T2D and their caregivers. Research design and methods: This single-arm family-based cohort study included youth aged 7-18 years, with BMI ≥85th percentile (overweight or obese) and at least one additional risk factor for type 2 diabetes, and their caregivers. Clinical (BMI, HbA1c), self-reported physical activity, and quality of life outcomes were evaluated at baseline (B), post-intervention (M4), and 1 year (M12) following the intervention. Results: Seventy-eight youth (mean age 12.4 ± 2.7y, 67% female, 37.8% white) and 65 caregivers were included in the data analysis. Youth baseline BMI z-scores (2.26 ± 0.47) and HbA1c (5.3 ± 0.3) were unchanged at follow up time points [BMI z-scores M4 (2.25 ± 0.52), M12 (2.16 ± 0.58), p-value 0.46], [HbA1c M4 (5.3 ± 0.3), M12 (5.2 ± 0.3), p-value (0.04)]. Youth reported increased physical activity at M4 (p = 0.004), but not at M12. Youth quality of life scores increased at M12 (p=0.01). Families who attended at least one session (n=41) attended an average of 9 out of 16 sessions, and 37 percent of families attended 13 or more sessions. Conclusion: A co-designed, community-based lifestyle intervention promotes increased physical activity, improved quality of life, maintenance of BMI z-scores and HbA1c, and engagement in youth with risk factors for T2D.

Low-Carbohydrate Diets in Children and Adolescents With or at Risk for Diabetes.

Carbohydrate restriction is increasingly popular as a weight loss strategy and for achieving better glycemic control in people with diabetes, including type 1 and type 2 diabetes. However, evidence to support low-carbohydrate diets in youth (children and adolescents 2-18 years of age) with obesity or diabetes is limited. There are no guidelines for restricting dietary carbohydrate consumption to reduce risk for diabetes or improve diabetes outcomes in youth. Thus, there is a need to provide practical recommendations for pediatricians regarding the use of low-carbohydrate diets in patients who elect to follow these diets, including those with type 1 diabetes and for patients with obesity, prediabetes, and type 2 diabetes. This clinical report will: Provide background on current dietary patterns in youth, describe how moderate-, low-, and very low-carbohydrate diets differ, and review safety concerns associated with the use of these dietary patternsReview the physiologic rationale for carbohydrate reduction in youth with type 1 diabetes and for youth with obesity, prediabetes, and type 2 diabetesReview the evidence for low-carbohydrate diets in the management of youth with type 1 diabetesReview the evidence for low-carbohydrate diets in the management of youth with obesity, prediabetes, and type 2 diabetesProvide practical information for pediatricians counseling families and youth on carbohydrate recommendations for type 1 diabetes and for obesity, prediabetes, and type 2 diabetes.

Approach to the Patient: Youth-Onset Type 2 Diabetes.

Youth-onset type 2 diabetes is a growing epidemic with a rising incidence worldwide. Although the pathogenesis and diagnosis of youth-onset type 2 diabetes are similar to adult-onset type 2 diabetes, youth-onset type 2 diabetes is unique, with greater insulin resistance, insulin hypersecretion, and faster progression of pancreatic beta cell function decline. Individuals with youth-onset type 2 diabetes also develop complications at higher rates within short periods of time compared to adults with type 2 diabetes or youth with type 1 diabetes. The highest prevalence and incidence of youth-onset type 2 diabetes in the United States is among youth from minoritized racial and ethnic groups. Risk factors include obesity, family history of type 2 diabetes, comorbid conditions and use of medications associated with insulin resistance and rapid weight gain, socioeconomic and environmental stressors, and birth history of small-for-gestational-age or pregnancy associated with gestational or pregestational diabetes. Patients with youth-onset type 2 diabetes should be treated using a multidisciplinary model with frequent clinic visits and emphasis on addressing of social and psychological barriers to care and glycemic control, as well as close monitoring for comorbidities and complications. Intensive health behavior therapy is an important component of treatment, in addition to medical management, both of which should be initiated at the diagnosis of type 2 diabetes. There are limited but growing pharmacologic treatment options, including metformin, insulin, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors. Although long-term outcomes are not fully known, metabolic/bariatric surgery in youth with type 2 diabetes has led to improved cardiometabolic outcomes.

Weight loss and ß-cell responses following gastric banding or pharmacotherapy in adults with impaired glucose tolerance or type 2 diabetes: a randomized trial.

OBJECTIVE: The extent to which weight loss contributes to increases in insulin sensitivity (IS) and ß-cell function after surgical or medical intervention has not been directly compared in individuals with impaired glucose tolerance or newly diagnosed type 2 diabetes. METHODS: The Restoring Insulin Secretion (RISE) Study included adults in the Beta-Cell Restoration Through Fat Mitigation Study (n = 88 randomized to laparoscopic gastric banding or metformin [MET]) and the Adult Medication Study (n = 267 randomized to placebo, MET, insulin glargine/MET, or liraglutide + MET [L + M]). IS and ß-cell responses were measured at baseline and after 12 months by modeling of oral glucose tolerance tests and during arginine-stimulated hyperglycemic clamps. Linear regression models assessed differences between and within treatments over time. RESULTS: BMI decreased in all treatment groups, except placebo, at 12 months. IS increased in all arms except placebo and was inversely correlated with changes in BMI. L + M was the only treatment arm that enhanced multiple measures of ß-cell function independent of weight loss. Insulin secretion decreased in the laparoscopic gastric banding arm proportional to increases in IS, with no net benefit on ß-cell function. CONCLUSIONS: Reducing demand on the ß-cell by improving IS through weight loss does not reverse ß-cell dysfunction. L + M was the only treatment that enhanced ß-cell function.

Design and methods of a tailored approach for diabetes prevention in women with previous gestational diabetes.

Aim: To describe the design and methods of an intervention that engaged women with previous gestational diabetes mellitus in a tailored approach for diabetes prevention. Methods: Women participated in biometric tests for BMI and hemoglobin A1c, psychosocial questionnaires and an informed decision-making process to select a lifestyle change program for Type 2 diabetes prevention based on their needs and priorities. Measure time points were at baseline, 6 months and 12 months. Results: The authors recruited 116 women. The outcomes of this study will evaluate the effect of this strategy on participant engagement in lifestyle change programs for Type 2 diabetes prevention. Conclusion: This paper describes a variety of lifestyle change programs and an informed decision-making process for tailoring diabetes prevention programs for a high-risk population.

Patient and Parent Well-Being and Satisfaction With Diabetes Care During a Comparative Trial of Mobile Self-Monitoring Blood Glucose Technology and Family-Centered Goal Setting.

Patient engagement in the process of developing a diabetes treatment plan is associated with person-centered care and improved treatment outcomes. The objective of the present study was to evaluate the self-reported patient and parent-centered satisfaction and well-being outcomes associated with the three treatment strategies utilized in a comparative effectiveness trial of technology-enhanced blood glucose monitoring and family-centered goal setting. We evaluated data from 97 adolescent-parent pairs at baseline and 6-months during the randomized intervention. Measures included: Problem Areas in Diabetes (PAID) child and parent scales, pediatric diabetes-related quality of life, sleep quality, and satisfaction with diabetes management. Inclusion criteria were 1) ages 12-18 years, 2) a T1D diagnosis for at least six months and 3) parent/caregiver participation. Longitudinal changes in survey responses were measured at 6 months from baseline. Differences between and within participant groups were evaluated using ANOVA. The average age of youth participants was 14.8 ± 1.6 years with half of the participants being female (49.5%). The predominant ethnicity/race was Non-Hispanic (89.9%) and white (85.9%). We found that youth perceived 1) greater of diabetes-related communication when using a meter capable of transmitting data electronically, 2) increased engagement with diabetes self-management when using family-centered goal setting, and 3) worse sleep quality when using both strategies together (technology-enhanced meter and family-centered goal setting). Throughout the study, scores for self-reported satisfaction with diabetes management were higher in youth than parents. This suggests that patients and parents have different goals and expectations regarding their diabetes care management and care delivery. Our data suggest that youth with diabetes value communication via technology and patient-centered goal setting. Strategies to align youth and parent expectations with the goal of improving satisfaction could be utilized as a strategy to improve partnerships in diabetes care management.

Differential loss of ß-cell function in youth vs. adults following treatment withdrawal in the Restoring Insulin Secretion (RISE) study.

AIMS: To compare OGTT-derived estimates of ß-cell function between youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes after treatment discontinuation in RISE. METHODS: Youth (n = 89) and adults (n = 132) were randomized to 3 months glargine followed by 9 months metformin (G/M) or 12 months metformin (MET). Insulin sensitivity and ß-cell responses were estimated from 3-hour OGTTs over 21 months. Linear mixed models tested for differences by time and age group within each treatment arm. RESULTS: After treatment withdrawal, HbA1c increased in both youth and adults with a larger net increase in G/M youth vs. adults at 21 months. Among youth, ß-cell function decreased starting at 12 months in G/M and 15 months in MET. Among adults, ß-cell function remained relatively stable although insulin secretion rates decreased in G/M at 21 months. At 21 months vs. baseline ß-cell function declined to a greater extent in youth vs. adults in both the G/M and MET treatment arms. CONCLUSIONS: After treatment withdrawal youth demonstrated progressive decline in ß-cell function after stopping treatment with either G/M or MET. In contrast, ß-cell function in adults remained stable despite an increase in HbA1c over time. ClinicalTrials.gov Identifier: NCT01779375 and NCT01779362 at clinical trials.gov.

Effect of Medical and Surgical Interventions on α-Cell Function in Dysglycemic Youth and Adults in the RISE Study.

OBJECTIVE: To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols. RESEARCH DESIGN AND METHODS: Glucagon was measured in three randomized, parallel, clinical studies: 1) 91 youth studied at baseline, after 12 months on metformin alone (MET) or glargine followed by metformin (G/M), and 3 months after treatment withdrawal; 2) 267 adults studied at the same time points and treated with MET, G/M, or liraglutide plus metformin (L+M) or given placebo (PLAC); and 3) 88 adults studied at baseline and after 12 and 24 months of LB or MET. Fasting glucagon, glucagon suppression by glucose, and acute glucagon response (AGR) to arginine were assessed during hyperglycemic clamps. Glucagon suppression was also measured during oral glucose tolerance tests (OGTTs). RESULTS: No change in fasting glucagon, steady-state glucagon, or AGR was seen at 12 months following treatment with MET or G/M (in youth and adults) or PLAC (in adults). In contrast, L+M reduced these measures at 12 months (all P ≤ 0.005), which was maintained 3 months after treatment withdrawal (all P < 0.01). LB in adults also reduced fasting glucagon, steady-state glucagon, and AGR at 12 and 24 months (P < 0.05 for all, except AGR at 12 months [P = 0.098]). Similarly, glucagon suppression during OGTTs was greater with L+M and LB. Linear models demonstrated that treatment effects on glucagon with L+M and LB were largely associated with weight loss. CONCLUSIONS: Glucagon concentrations were reduced by L+M and LB in adults with dysglycemia, an effect principally attributable to weight loss in both interventions.

Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study.

OBJECTIVE: To identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study. RESEARCH DESIGN AND METHODS: A total of 91 youth (10-19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA1c increase ≥0.5% from baseline). RESULTS: Glycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 (P = 0.008) and in 36% of youth versus 20% of adults at month 21 (P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05-0.96, P = 0.044). In both age-groups, lower baseline clamp-derived ß-cell responses predicted month 12 and month 21 glycemic worsening (P < 0.01). Lower baseline OGTT-derived ß-cell responses predicted month 21 worsening (P < 0.05). In youth, higher baseline HbA1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening (P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening (P < 0.05). CONCLUSIONS: Glycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline ß-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults.

Hyperglucagonemia Does Not Explain the ß-Cell Hyperresponsiveness and Insulin Resistance in Dysglycemic Youth Compared With Adults: Lessons From the RISE Study.

OBJECTIVE: To determine whether ß-cell hyperresponsiveness and insulin resistance in youth versus adults in the Restoring Insulin Secretion (RISE) Study are related to increased glucagon release. RESEARCH DESIGN AND METHODS: In 66 youth and 350 adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (drug naive), we performed hyperglycemic clamps and oral glucose tolerance tests (OGTTs). From clamps we quantified insulin sensitivity (M/I), plasma fasting glucagon and C-peptide, steady-state glucagon and C-peptide at glucose of 11.1 mmol/L, and arginine-stimulated glucagon (acute glucagon response [AGR]) and C-peptide (ACPRmax) responses at glucose >25 mmol/L. RESULTS: Mean ± SD fasting glucagon (7.63 ± 3.47 vs. 8.55 ± 4.47 pmol/L; P = 0.063) and steady-state glucagon (2.24 ± 1.46 vs. 2.49 ± 1.96 pmol/L, P = 0.234) were not different in youth and adults, respectively, while AGR was lower in youth (14.1 ± 5.2 vs. 16.8 ± 8.8 pmol/L, P = 0.001). Significant age-group differences in insulin sensitivity, fasting C-peptide, steady-state C-peptide, and ACPRmax were not related to glucagon. Fasting glucose and glucagon were positively correlated in adults (r = 0.133, P = 0.012) and negatively correlated in youth (r = -0.143, P = 0.251). In both age-groups, higher fasting glucagon was associated with higher fasting C-peptide (youth r = 0.209, P = 0.091; adults r = 0.335, P < 0.001) and lower insulin sensitivity (youth r = -0.228, P = 0.066; adults r = -0.324, P < 0.001). With comparable fasting glucagon, youth had greater C-peptide and lower insulin sensitivity. OGTT suppression of glucagon was greater in youth. CONCLUSIONS: Youth with IGT or recently diagnosed type 2 diabetes (drug naive) have hyperresponsive ß-cells and lower insulin sensitivity, but their glucagon concentrations are not increased compared with those in adults. Thus, α-cell dysfunction does not appear to explain the difference in ß-cell function and insulin sensitivity in youth versus adults.

A Complicated Case of COVID-19 and Hyperglycemic Hyperosmolar Syndrome in an Adolescent Male.

Emerging data demonstrate that comorbid conditions and older age are contributing factors to COVID-19 severity in children. Studies involving youth with COVID-19 and diabetes are lacking. We report the case of a critically ill adolescent male with obesity, type 2 diabetes, and COVID-19 who presented with hyperglycemic hyperosmolar syndrome (HHS). This case highlights a challenge for clinicians in distinguishing severe complications of COVID-19 from those seen in HHS. Youth with obesity and type 2 diabetes may represent a high-risk group for severe COVID-19 disease, an entity that to date has been well-recognized in adults but remains rare in children and adolescents.

Diabetes Prevention in Adolescents: Co-design Study Using Human-Centered Design Methodologies.

BACKGROUND: The rise in pediatric obesity and its accompanying condition, type 2 diabetes (T2D), is a serious public health concern. T2D in adolescents is associated with poor health outcomes and decreased life expectancy. Effective diabetes prevention strategies for high-risk adolescents and their families are urgently needed. OBJECTIVE: The aim of this study was to co-design a diabetes prevention program for adolescents by using human-centered design methodologies. METHODS: We partnered with at-risk adolescents, parents, and professionals with expertise in diabetes prevention or those working with adolescents to conduct a series of human-centered design research sessions to co-design a diabetes prevention intervention for youth and their families. In order to do so, we needed to (1) better understand environmental factors that inhibit/promote recommended lifestyle changes to decrease T2D risk, (2) elucidate desired program characteristics, and (3) explore improved activation in diabetes prevention programs. RESULTS: Financial resources, limited access to healthy foods, safe places for physical activity, and competing priorities pose barriers to adopting lifestyle changes. Adolescents and their parents desire interactive, hands-on learning experiences that incorporate a sense of fun, play, and community in diabetes prevention programs. CONCLUSIONS: The findings of this study highlight important insights of 3 specific stakeholder groups regarding diabetes prevention and lifestyle changes. The findings of this study demonstrate that, with appropriate methods and facilitation, adolescents, parents, and professionals can be empowered to co-design diabetes prevention programs.

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

OBJECTIVE: Obstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet ß-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with ß-cell function in overweight/obese adults with prediabetes or recently diagnosed, treatment-naive type 2 diabetes. RESEARCH DESIGN AND METHODS: Two hundred twenty-one adults (57.5% men, age 54.5 ± 8.7 years, BMI 35.1 ± 5.5 kg/m2) completed 1 week of wrist actigraphy and 1 night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA1c, OGTT-derived outcomes, and clamp-derived outcomes were evaluated with adjusted regression models. RESULTS: Mean ± SD objective sleep duration by actigraphy was 6.6 ± 1.0 h/night. OSA, defined as an apnea-hypopnea index (AHI) of five or more events per hour, was present in 89% of the participants (20% mild, 28% moderate, 41% severe). Higher AHI was associated with higher HbA1c (P = 0.007). However, OSA severity, measured either by AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or <6 vs. ≥6 h) were not associated with fasting glucose, 2-h glucose, insulin sensitivity, or ß-cell responses. CONCLUSIONS: In this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA1c, OSA severity and sleep duration were not associated with measures of insulin sensitivity or ß-cell responses.

OGTT Glucose Response Curves, Insulin Sensitivity, and ß-Cell Function in RISE: Comparison Between Youth and Adults at Randomization and in Response to Interventions to Preserve ß-Cell Function.

OBJECTIVE: We examined the glucose response curves (biphasic [BPh], monophasic [MPh], incessant increase [IIn]) during an oral glucose tolerance test (OGTT) and their relationship to insulin sensitivity (IS) and ß-cell function (ßCF) in youth versus adults with impaired glucose tolerance or recently diagnosed type 2 diabetes.RESEARCH DESIGN AND METHODSThis was both a cross-sectional and a longitudinal evaluation of participants in the RISE study randomized to metformin alone for 12 months or glargine for 3 months followed by metformin for 9 months. At baseline/randomization, OGTTs (85 youth, 353 adults) were categorized as BPh, MPh, or IIn. The relationship of the glucose response curves to hyperglycemic clamp-measured IS and ßCF at baseline and the change in glucose response curves 12 months after randomization were assessed.RESULTSAt randomization, the prevalence of the BPh curve was significantly higher in youth than adults (18.8% vs. 8.2%), with no differences in MPh or IIn. IS did not differ across glucose response curves in youth or adults. However, irrespective of curve type, youth had lower IS than adults (P < 0.05). ßCF was lowest in IIn versus MPh and BPh in youth and adults (P < 0.05), yet compared with adults, youth had higher ßCF in BPh and MPh (P < 0.005) but not IIn. At month 12, the change in glucose response curves did not differ between youth and adults, and there was no treatment effect.CONCLUSIONSDespite a twofold higher prevalence of the more favorable BPh curve in youth at randomization, RISE interventions did not result in beneficial changes in glucose response curves in youth compared with adults. Moreover, the typical ß-cell hypersecretion in youth was not present in the IIn curve, emphasizing the severity of ß-cell dysfunction in youth with this least favorable glucose response curve.

The linearized disposition index augments understanding of treatment effects in diabetes.

The disposition index, calculated by multiplying measures of insulin secretion and insulin sensitivity, is widely applied as a sensitivity-adjusted measure of insulin secretion. We have recently shown that linearizing the underlying relationship uniquely permits identification of terms relating to maximal insulin secretion capacity and the secretion-coupling relationship, with both terms separately contributing to differences in the secretion-sensitivity relationship across gradations of glycemia. Here, we demonstrate the application of this linearized equation to the evaluation of treatment-induced changes in the insulin secretion-sensitivity relationship. We applied a combination of repeated-measures multivariate linear regression (evaluating treatment-induced changes in the joint relationship of insulin sensitivity and secretion) plus mixed-model repeated measures (evaluating treatment effects on maximal secretion capacity and on the secretion-sensitivity coupling slope) and compared against a usual application of the disposition index calculated from the same measurements. This novel approach allows a more informative description of treatment-induced changes compared with the usual disposition index, including isolating the source of change within the mutually adjusted relationship and identifying treatment-induced changes in the secretion-sensitivity coupling slope and in maximal insulin secretion. Application of this linearized approach provides an expanded understanding of treatment-induced changes in the insulin sensitivity-secretion relationship.NEW & NOTEWORTHY The linearized insulin secretion-sensitivity relationship allows separate evaluation of the secretion-sensitivity slope and of maximal insulin secretion. Here, we demonstrate the application of this methodology to the evaluation of clinical trial data, showing that it provides an expanded understanding of treatment-induced changes compared with the disposition index.

ß-cells in youth with impaired glucose tolerance or early type 2 diabetes secrete more insulin and are more responsive than in adults.

OBJECTIVE: Glycemic control deteriorates more rapidly in youth vs adults. We compared model-derived measures of ß-cell function between youth and adults with either impaired glucose tolerance (IGT) or type 2 diabetes to determine if a ß-cell defect differentiates these age groups. METHODS: This is a cross-sectional analysis of baseline data from the Restoring Insulin Secretion (RISE) Study. Youth (54 Y-IGT, 33 Y-D) and adults (250 A-IGT, 104 A-D) underwent 3-hour oral glucose tolerance tests for modeling of insulin secretion rates (ISRs), glucose sensitivity, and rate sensitivity. Insulin sensitivity was quantified as the glucose infusion rate/insulin (M/I) from a hyperglycemic clamp. RESULTS: Youth had lower insulin sensitivity despite similar body mass index. Analyses were adjusted for insulin sensitivity. Youth had higher basal ISRs (Y-IGT 200 ± 161 vs A-IGT 152 ± 74, P < .001; Y-D 245 ± 2.5 vs A-D 168 ± 115 pmol/min/m2 , P = .007) and total ISRs (Y-IGT 124 ± 86 vs A-IGT 98 ± 39, P < .001; Y-D 116 ± 110 vs A-D 97 ± 62 nmol/m2 , P = .002). Within IGT, glucose sensitivity (Y-IGT 140 ± 153 vs A-IGT 112 ± 70 pmol/min/m2 /mM, P = .004) and rate sensitivity (median[interquartile range]:Y-IGT 2271[1611, 3222] vs A-IGT 1164[685, 1565] pmol/m2 /mM, P < .001) were higher in youth, but not different by age group within diabetes. CONCLUSIONS: Model-derived measures of ß-cell function provide additional insight into the pathophysiology of type 2 diabetes in youth with higher ISRs and ß-cell secretion more responsive to glucose in youth relative to adults even after adjusting for differences in insulin sensitivity. It is unknown whether these findings in youth reflect ß-cells that are healthier or whether this is a defect that contributes to more rapid loss of function.

Withdrawal of medications leads to worsening of OGTT parameters in youth with impaired glucose tolerance or recently-diagnosed type 2 diabetes.

BACKGROUND: The RISE Pediatric Medication Study compared strategies for preserving ß-cell function, including a 9-month follow-up after treatment withdrawal to test treatment effect durability. OBJECTIVE: Evaluate OGTT measures of glucose and ß-cell response through 12 months of intervention and 9 months of medication washout. PARTICIPANTS: Youth (n = 91) aged 10 to 19 years with BMI ≥85th percentile and impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (T2D). METHODS: A multicenter randomized clinical trial comparing insulin glargine for 3 months followed by metformin for 9 months (G→Met) or metformin alone (Met) for 12 months. We report within-group changes from baseline to end of medication intervention (M12), baseline to 9 months post-medication withdrawal (M21), and end of medication (M12) to M21. OGTT C-peptide index [CPI] paired with 1/fasting insulin evaluated ß-cell response. RESULTS: At M12, both treatments were associated with stable fasting glucose (G→Met baseline 6.0 ± 0.1 vs M12 5.9 ± 0.2 mmol/L, P = .62; Met baseline 6.1 ± 0.2 vs M12 6.0 ± 0.2 mmol/L, P = .73) and 2-hour glucose (G→Met baseline 10.2 ± 0.4 vs M12 9.3 ± 0.5 mmol/L, P = .03; Met baseline 10.2 ± 0.4 vs M12 10.6 ± 0.6 mmol/L, P = .88). Following medication withdrawal, fasting glucose worsened (G→Met M21 8.6 ± 1.8, P = .004; Met M21 7.8 ± 0.7 mmol/L, P = .003), as did 2-hour glucose (G→Met M21 13.2 ± 1.4, P = .002; Met M21 13.1 ± 1.2 mmol/L, P = .006), associated with declines in ß-cell response. CONCLUSIONS: G→Met and Met were associated with stable glucose measures during 12 months of treatment in youth with IGT or recently diagnosed T2D. Glucose and ß-cell response worsened post-medication withdrawal, suggesting treatment must be long-term or alternative treatments pursued.