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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. [ABSTRACT FROM AUTHOR]

Objective: 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 >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 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. [ABSTRACT FROM AUTHOR]

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 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 <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. [ABSTRACT FROM AUTHOR]

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 β-cell function (βCF) 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 βCF 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). βCF was lowest in IIn versus MPh and BPh in youth and adults (P < 0.05), yet compared with adults, youth had higher βCF 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 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. [ABSTRACT FROM AUTHOR]

Objective: 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. [ABSTRACT FROM AUTHOR]

Objective: 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 <5 or >8 h sleep per night. Sleep duration >8 h was also associated with higher fasting glucose and <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. [ABSTRACT FROM AUTHOR]

In cross-sectional studies, adolescents with T2D show poorer cognition than normoglycemic youth. In the Restoring Insulin Secretion (RISE) Study, we assessed longitudinal relationships between insulin sensitivity, β-cell function and cognition in 72 youth (mean age 14.3±2.0, 10-18 y) with IGT or recently diagnosed T2D, randomized to 12 months of metformin (MET) or 3 months of glargine followed by 9 months of metformin (G/M). Hyperglycemic clamps were used to measure insulin sensitivity and β-cell responses: acute (0-10 min) C-peptide response to glucose, steady-state C-peptide (SSCP) at glucose of 11.1 mmol/L, and arginine-stimulated maximum C-peptide response (ACPRmax) at glucose >25 mmol/L. A cognitive battery (CogStateTM and story recall) assessed 1) reaction time; 2) visual discrimination; 3) attention and working memory; and 4) learning and episodic memory. A composite measure of cognition was constructed by scaling the sum of the four domain scores. Linear regression models were fit to assess relationships between cognition, treatment and β-cell function. Treatment group models were adjusted for baseline cognitive function, HbA1c and fasting glucose. β-cell models were adjusted for baseline cognitive and β-cell function. Cognitive composite scores improved over the 12-month treatment period (p<0.001), with no differences between treatment arms. Greater baseline ACPRmax predicted greater improvement in composite scores over 12 months in the G/M (p<0.05), but not MET group (p=0.61). Change in SSCP over the 12-month treatment was positively associated with increased composite scores in the G/M (p<0.05) but not MET group (p=0.35). Thus, improved cognition over the 12-month treatment with G/M in adolescents with IGT or early T2D may be related to practice effects with repeated testing, to changes in β-cell function or to other impacts of insulin treatment. Disclosure: S. Craft: Advisory Panel; Self; vTv Therapeutics. M. Tripputi: None. S. Edelstein: None. M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. A. Claxton: Employee; Self; Alkermes plc. S.A. Arslanian: Research Support; Self; National Institutes of Health. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. E. Barengolts: None. T.S. Hannon: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. B. Mokhlesi: None. K.J. Nadeau: None. A. Sanderlin: None. K.A. Temple: None. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly and Company, Merck & Co., Inc. T. Consortium: None. Funding: American Diabetes Association (1-14-RISE-01 to S.E.K.); National Institute of Diabetes and Digestive and Kidney Diseases [ABSTRACT FROM AUTHOR]

We examined the relationship between habitual daily activity and measures of GT, insulin sensitivity and β-cell responses in 230 adults (mean age 55 y; BMI 35 kg/m2) with IGT or drug-naïve, recently diagnosed T2D. Participants underwent a 3-h OGTT and hyperglycemic clamp. Wrist accelerometers worn for 7 days measured total activity counts (TAC; daily mean 233,461 {∼ 50th %ile for age}). We evaluated whether TAC predicted fasting plasma glucose (FPG); OGTT 2-h plasma glucose (2-h G) 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 [ACPRg], steady-state C-peptide, maximal β-cell response [ACPRmax]); and OGTT C-peptide index (CPI, [ΔC-Peptide0-30/ΔGlucose0-30]). There was no association of TAC with FPG, 2-h G, or G-iAUC. Higher TAC was associated with higher insulin sensitivity. After adjusting for M/I, higher TAC was associated with lower CPI, but not with clamp-based β-cell responses. Despite similar post-load glucose values, adults with IGT or T2D who were more active demonstrated a greater than expected reduction in C-peptide response given their higher insulin sensitivity. Further studies are needed to understand this dissociation of activity effects on insulin sensitivity and β-cell function. Disclosure: K.A. Temple: None. A.H. Tjaden: None. K.M. Atkinson: None. E. Barengolts: None. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. K. Utzschneider: Consultant; Self; Novo Nordisk Inc. D.A. Ehrmann: None. B. Mokhlesi: None. R. Consortium: None. Funding: National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases [ABSTRACT FROM AUTHOR]

Insulin resistance and impaired β-cell function are associated with risk of cognitive decline in adults over 65 y of age. Their impact on cognition in youth and adults <65 y is less clear. We assessed the relationship between insulin sensitivity, β-cell function and cognition in never or briefly-treated youth (n=71, mean age 14.2±2.0, 10-18 y) and treatment-naïve adults (n=236, mean age 54.4±8.6, 26-66 y) with IGT or early T2D in the Restoring Insulin Secretion (RISE) Study. Hyperglycemic clamps were used to measure insulin sensitivity (steady state glucose infusion rate/insulin [M/I]) and β-cell responses: acute (0-10 min) C-peptide (ACPRg) response to glucose, steady-state C-peptide (SSCP) at a serum glucose of 11.1 mmol/L, and arginine-stimulated maximum C-peptide (ACPRmax) responses at glucose >25 mmol/L. The cognitive battery (CogStateTM and story recall) assessed 1) psychomotor speed; 2) visual pattern separation; 3) visual attention and working memory; and 4) verbal learning and episodic memory. Linear regression models were fit to assess relationships between cognition and clamp measures by age group, adjusted for age, education (adults only), race, sex, and diabetes status. Models including β-cell responses were also adjusted for M/I to account for the role of insulin sensitivity to modulate β-cell function. M/I was not associated with cognitive outcomes for adults or children. For adults, reaction time was slower for participants with worse β-cell function assessed by ACPRg and ACPRmax (p<0.05). Lower SSCP in adults was associated with worse visual pattern separation (p<0.05), a test sensitive to risk for age-related cognitive decline, whereas in youth higher SSCP associated with trends for lower scores for learning (p=0.065) and memory (p=0.052). These results suggest that the relationships between β-cell function and specific cognitive domains differ in a developmentally-dependent manner. Disclosure: S. Craft: Advisory Panel; Self; vTv Therapeutics. Research Support; Self; Eli Lilly and Company. A. Claxton: Employee; Self; Alkermes. M. Tripputi: None. S. Edelstein: None. S.A. Arslanian: None. K.A. Temple: None. K.J. Nadeau: None. A. Sanderlin: None. M. Espeland: Research Support; Self; National Institutes of Health. Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals, Inc. B. Mokhlesi: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. R. Consortium: None. Funding: National Institute of Diabetes and Digestive and Kidney Diseases [ABSTRACT FROM AUTHOR]

A response by the authors to a commentary on their study on the association between obstructive sleep apnea in rapid eye movement sleep and reduced glycemic control in type 2 diabetes is presented. They disagree with the perception that their study focused on the effect of rapid eye movement (REM) sleep deprivation due to obstructive sleep apnea on glycemic control in type 2 diabetes. They also explain the model they used to simulate the impact of continuous positive airway pressure therapy.