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1

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

Kahn, Steven E. ; Mather, Kieren J. ; Arslanian, Silva A. ; [et al.]

American Diabetes Association ; 2021

In: Diabetes Care Vol. 44, No. 9 ( 2021-09-01), p. 1961-1969

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In: Diabetes Care, American Diabetes Association, Vol. 44, No. 9 ( 2021-09-01), p. 1961-1969

Abstract: To determine whether β-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 & gt;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 & lt; 0.001) and lower insulin sensitivity (youth r = −0.228, P = 0.066; adults r = −0.324, P & lt; 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 β-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 β-cell function and insulin sensitivity in youth versus adults.

Type of Medium: Online Resource

ISSN: 0149-5992 , 1935-5548

URL: Article

DOI: 10.2337/dc21-0460

Language: English

Publisher: American Diabetes Association

Publication Date: 2021

detail.hit.zdb_id: 1490520-6

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2

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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

Sam, Susan ; Edelstein, Sharon L. ; Arslanian, Silva A. ; [et al.]

American Diabetes Association ; 2021

In: Diabetes Care Vol. 44, No. 9 ( 2021-09-01), p. 1938-1947

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In: Diabetes Care, American Diabetes Association, Vol. 44, No. 9 ( 2021-09-01), p. 1938-1947

Abstract: 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 β-cell responses predicted month 12 and month 21 glycemic worsening (P & lt; 0.01). Lower baseline OGTT-derived β-cell responses predicted month 21 worsening (P & lt; 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 & lt; 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening (P & lt; 0.05). CONCLUSIONS Glycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline β-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults.

Type of Medium: Online Resource

ISSN: 0149-5992 , 1935-5548

URL: Article

DOI: 10.2337/dc21-0027

Language: English

Publisher: American Diabetes Association

Publication Date: 2021

detail.hit.zdb_id: 1490520-6

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

Mokhlesi, Babak ; Tjaden, Ashley H. ; Temple, Karla A. ; [et al.]

American Diabetes Association ; 2021

In: Diabetes Care Vol. 44, No. 4 ( 2021-04-01), p. 993-1001

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In: Diabetes Care, American Diabetes Association, Vol. 44, No. 4 ( 2021-04-01), p. 993-1001

Abstract: 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 β-cell function remains unclear. We aimed to investigate the association of OSA and short sleep duration with β-cell function in overweight/obese adults with prediabetes or recently diagnosed, treatment-naive type 2 diabetes. RESEARCH DESIGN AND 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 & lt;6 vs. ≥6 h) were not associated with fasting glucose, 2-h glucose, insulin sensitivity, or β-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 β-cell responses.

Type of Medium: Online Resource

ISSN: 0149-5992 , 1935-5548

URL: Article

DOI: 10.2337/dc20-2127

Language: English

Publisher: American Diabetes Association

Publication Date: 2021

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4

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Association of Self-Reported Sleep and Circadian Measures With Glycemia in Adults With Prediabetes or Recently Diagnosed Untreated Type 2 Diabetes

Mokhlesi, Babak ; Temple, Karla A. ; Tjaden, Ashley H. ; [et al.]

American Diabetes Association ; 2019

In: Diabetes Care Vol. 42, No. 7 ( 2019-07-01), p. 1326-1332

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In: Diabetes Care, American Diabetes Association, Vol. 42, No. 7 ( 2019-07-01), p. 1326-1332

Abstract: Sleep disturbances and circadian misalignment (social jet lag, late chronotype, or shift work) have been associated with worse glycemic control in type 2 diabetes (T2D). Whether these findings apply to adults with prediabetes is yet unexplored. We hypothesized that self-reported short sleep, poor sleep quality, and/or circadian misalignment are associated with higher glycemia, BMI, and blood pressure (BP) in adults with prediabetes or recently diagnosed, untreated T2D. RESEARCH DESIGN AND METHODS Our cohort included 962 overweight/obese adults ages 20–65 years with prediabetes or recently diagnosed, untreated T2D who completed a 2-h oral glucose tolerance test and validated sleep questionnaires. Independent associations of sleep and circadian variables with glycemia, BMI, and BP were evaluated with regression models. RESULTS The multiethnic cohort was 55% men, with mean ± SD age 52.2 ± 9.5 years and BMI 34.7 ± 5.5 kg/m2. Mean sleep duration was 6.6 ± 1.3 h. Poor sleep quality was reported by 54% and high risk for obstructive sleep apnea by 64%. HbA1c was significantly higher in those reporting & lt;5 or & gt;8 h sleep per night. Sleep duration & gt;8 h was also associated with higher fasting glucose and & lt;6 h with higher BMI. Shift work was also associated with higher BMI. Social jet lag and delayed chronotype were associated with higher BP. CONCLUSIONS In our cohort, self-reported short and long sleep were both associated with adverse measures of glycemia, and short sleep and shift work were associated with higher BMI. Further research using objective measures of sleep is needed to better delineate the relationship between sleep and glycemia in adults with prediabetes or T2D.

Type of Medium: Online Resource

ISSN: 0149-5992 , 1935-5548

URL: Article

DOI: 10.2337/dc19-0298

Language: English

Publisher: American Diabetes Association

Publication Date: 2019

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5

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

Arslanian, Silva A. ; El ghormli, Laure ; Kim, Joon Young ; [et al.]

American Diabetes Association ; 2021

In: Diabetes Care Vol. 44, No. 3 ( 2021-03-01), p. 817-825

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In: Diabetes Care, American Diabetes Association, Vol. 44, No. 3 ( 2021-03-01), p. 817-825

Abstract: 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 β-cell function (βCF) in youth versus adults with impaired glucose tolerance or recently diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS This 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 βCF at baseline and the change in glucose response curves 12 months after randomization were assessed. RESULTS At 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 & lt; 0.05). βCF was lowest in IIn versus MPh and BPh in youth and adults (P & lt; 0.05), yet compared with adults, youth had higher βCF in BPh and MPh (P & lt; 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. CONCLUSIONS Despite 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 β-cell hypersecretion in youth was not present in the IIn curve, emphasizing the severity of β-cell dysfunction in youth with this least favorable glucose response curve.

Type of Medium: Online Resource

ISSN: 0149-5992 , 1935-5548

URL: Article

DOI: 10.2337/dc20-2134

Language: English

Publisher: American Diabetes Association

Publication Date: 2021

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6

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Association of Habitual Daily Physical Activity With Glucose Tolerance and β-Cell Function in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes From the Restoring Insulin Secretion (RISE) Study

Temple, Karla A. ; Tjaden, Ashley H. ; Atkinson, Karen M. ; [et al.]

American Diabetes Association ; 2019

In: Diabetes Care Vol. 42, No. 8 ( 2019-08-01), p. 1521-1529

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In: Diabetes Care, American Diabetes Association, Vol. 42, No. 8 ( 2019-08-01), p. 1521-1529

Abstract: We examined the relationship between habitual daily physical activity and measures of glucose tolerance, insulin sensitivity, and β-cell responses in adults with impaired glucose tolerance (IGT) or drug-naive, recently diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS Participants included 230 adults (mean ± SD age 54.5 ± 8.5 years, BMI 35 ± 5.5 kg/m2; 42.6% women) who underwent a 3-h oral glucose tolerance test (OGTT) and hyperglycemic clamp. Wrist accelerometers worn for 7 consecutive days measured total physical activity counts (TAC) (daily mean 233,460 [∼50th percentile for age]). We evaluated whether TAC was associated with fasting plasma glucose, OGTT 2-h plasma glucose or glucose incremental area under the curve (G-iAUC), hyperglycemic clamp measures of insulin sensitivity (steady-state glucose infusion rate/insulin [M/I] ) and β-cell responses (acute C-peptide response to glucose, steady-state C-peptide, and maximal β-cell response), and OGTT C-peptide index (ΔC-peptide0–30/Δglucose0–30). RESULTS After adjustments for confounders, there was no association of TAC with fasting plasma glucose, 2-h glucose, or G-iAUC. Higher TAC was associated with higher insulin sensitivity (M/I). After adjusting for M/I, higher TAC was not associated with measures of β-cell response. CONCLUSIONS In adults with IGT or drug-naive, recently diagnosed type 2 diabetes, higher levels of habitual physical activity are associated with higher insulin sensitivity. Further studies are needed to understand why higher levels of physical activity are not associated with better β-cell response.

Type of Medium: Online Resource

ISSN: 0149-5992 , 1935-5548

URL: Article

DOI: 10.2337/dc19-0538

Language: English

Publisher: American Diabetes Association

Publication Date: 2019

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

Kahn, Steven E. ; Edelstein, Sharon L. ; Arslanian, Silva A. ; [et al.]

American Diabetes Association ; 2021

In: Diabetes Care Vol. 44, No. 9 ( 2021-09-01), p. 1948-1960

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In: Diabetes Care, American Diabetes Association, Vol. 44, No. 9 ( 2021-09-01), p. 1948-1960

Abstract: 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 & lt; 0.01). LB in adults also reduced fasting glucagon, steady-state glucagon, and AGR at 12 and 24 months (P & lt; 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.

Type of Medium: Online Resource

ISSN: 0149-5992 , 1935-5548

URL: Article

DOI: 10.2337/dc21-0461

Language: English

Publisher: American Diabetes Association

Publication Date: 2021

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Impact of Insulin and Metformin Versus Metformin Alone on β-Cell Function in Youth With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes

The RISE Consortium ; Nadeau, Kristen J. ; Hannon, Tamara S. ; [et al.]

American Diabetes Association ; 2018

In: Diabetes Care Vol. 41, No. 8 ( 2018-08-01), p. 1717-1725

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In: Diabetes Care, American Diabetes Association, Vol. 41, No. 8 ( 2018-08-01), p. 1717-1725

Abstract: Pediatric type 2 diabetes prevalence is increasing, with β-cell dysfunction key in its pathogenesis. The RISE Pediatric Medication Study compared two approaches—glargine followed by metformin and metformin alone—in preserving or improving β-cell function in youth with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes during and after therapy withdrawal. RESEARCH DESIGN AND METHODS Ninety-one pubertal, overweight/obese 10–19-year-old youth with IGT (60%) or type 2 diabetes of & lt;6 months duration (40%) were randomized to either 3 months of insulin glargine with a target glucose of 4.4–5.0 mmol/L followed by 9 months of metformin or to 12 months of metformin alone. β-Cell function (insulin sensitivity paired with β-cell responses) was assessed by hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). RESULTS No significant differences were observed between treatment groups at baseline, 12 months, or 15 months in β-cell function, BMI percentile, HbA1c, fasting glucose, or oral glucose tolerance test 2-h glucose results. In both treatment groups, clamp-measured β-cell function was significantly lower at 12 and 15 months versus baseline. HbA1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated. CONCLUSIONS In youth with IGT or recently diagnosed type 2 diabetes, neither 3 months of glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of β-cell function. Alternate approaches to preserve β-cell function in youth are needed.

Type of Medium: Online Resource

ISSN: 0149-5992 , 1935-5548

URL: Article

DOI: 10.2337/dc18-0787

Language: English

Publisher: American Diabetes Association

Publication Date: 2018

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9

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

Hannon, Tamara S. ; Edelstein, Sharon L. ; Arslanian, Silva A. ; [et al.]

Hindawi Limited ; 2020

In: Pediatric Diabetes Vol. 21, No. 8 ( 2020-12), p. 1437-1446

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In: Pediatric Diabetes, Hindawi Limited, Vol. 21, No. 8 ( 2020-12), p. 1437-1446

Type of Medium: Online Resource

ISSN: 1399-543X , 1399-5448

URL: Issue

URL: Article

DOI: 10.1111/pedi.v21.8

DOI: 10.1111/pedi.13129

Language: English

Publisher: Hindawi Limited

Publication Date: 2020

detail.hit.zdb_id: 2025536-6

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10

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Metabolic Contrasts Between Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes: II. Observations Using the Oral Glucose Tolerance Test

The RISE Consortium ; Ehrmann, David A. ; Temple, Karla A. ; [et al.]

American Diabetes Association ; 2018

In: Diabetes Care Vol. 41, No. 8 ( 2018-08-01), p. 1707-1716

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In: Diabetes Care, American Diabetes Association, Vol. 41, No. 8 ( 2018-08-01), p. 1707-1716

Abstract: To compare oral glucose tolerance test (OGTT) glucose, C-peptide, and insulin responses and insulin sensitivity in youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 66 youth (80.3% with IGT) and 355 adults (70.7% with IGT) underwent a 3-h OGTT to assess 1) insulin sensitivity (1/fasting insulin), 2) C-peptide index (CPI) and insulinogenic index (IGI) over the first 30 min, and 3) glucose, C-peptide, and insulin incremental areas above fasting over the 3-h post-ingestion (incremental glucose [G-iAUC], incremental C-peptide [CP-iAUC] , and incremental insulin area under the curve [I-iAUC] responses, respectively). RESULTS Fasting, 2-h glucose, and G-iAUC were similar in both age-groups, but youth had ∼50% lower 1/fasting insulin (P & lt; 0.001), 75% higher CPI (mean [95% CI] 0.703 [0.226, 2.183] vs. 0.401 [0.136, 1.183] nmol/mmol; P & lt; 0.001), and more than twofold higher IGI (257.3 [54.5, 1,215.8] vs. 114.8 [28.0, 470.8] pmol/mmol; P & lt; 0.001). Two-hour C-peptide and insulin concentrations, CP-iAUC, and I-iAUC were all higher in youth (all P & lt; 0.001). C-peptide and insulin responses remained significantly greater in youth after adjustment for insulin sensitivity. Within each age-group, individuals with type 2 diabetes versus IGT had significantly lower CPI and IGI with no difference in insulin sensitivity. CONCLUSIONS The balance between insulin sensitivity and β-cell responses differs between youth and adults with IGT or recently diagnosed type 2 diabetes. Despite similar postload glucose levels, youth demonstrate greater C-peptide and insulin responses that exceed what is needed to compensate for their lower insulin sensitivity. Longitudinal studies are required to determine whether this feature contributes to a more rapid decline in β-cell function in youth with dysglycemia.

Type of Medium: Online Resource

ISSN: 0149-5992 , 1935-5548

URL: Article

DOI: 10.2337/dc18-0243

Language: English

Publisher: American Diabetes Association

Publication Date: 2018

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