Association of Baseline Characteristics With Insulin Sensitivity and β-Cell Function in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study Cohort

OBJECTIVEWe investigated sex and racial differences in insulin sensitivity, β-cell function, and glycated hemoglobin (HbA_1c) and the associations with selected phenotypic characteristics.RESEARCH DESIGN AND METHODSThis is a cross-sectional analysis of baseline data from 3,108 GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) participants. All had type 2 diabetes diagnosed <10 years earlier and were on metformin monotherapy. Insulin sensitivity and β-cell function were evaluated using the HOMA of insulin sensitivity and estimates from oral glucose tolerance tests, including the Matsuda Index, insulinogenic index, C-peptide index, and oral disposition index (DI).RESULTSThe cohort was 56.6 ± 10 years of age (mean ± SD), 63.8% male, with BMI 34.2 ± 6.7 kg/m², HbA_1c 7.5 ± 0.5%, and type 2 diabetes duration 4.0 ± 2.8 years. Women had higher DI than men but similar insulin sensitivity. DI was the highest in Black/African Americans, followed by American Indians/Alaska Natives, Asians, and Whites in descending order. Compared with Whites, American Indians/Alaska Natives had significantly higher HbA_1c, but Black/African Americans and Asians had lower HbA_1c. However, when adjusted for glucose levels, Black/African Americans had higher HbA_1c than Whites. Insulin sensitivity correlated inversely with BMI, waist-to-hip ratio, triglyceride-to-HDL-cholesterol ratio (TG/HDL-C), and the presence of metabolic syndrome, whereas DI was associated directly with age and inversely with BMI, HbA_1c, and TG/HDL-C.CONCLUSIONSIn the GRADE cohort, β-cell function differed by sex and race and was associated with the concurrent level of HbA_1c. HbA_1c also differed among the races, but not by sex. Age, BMI, and TG/HDL-C were associated with multiple measures of β-cell function and insulin sensitivity.     

Durability of Triple Combination Therapy Versus Stepwise Addition Therapy in Patients With New-Onset T2DM: 3-Year Follow-up of EDICT

OBJECTIVETo compare the long-term efficacy of initiating therapy with metformin/pioglitazone/exenatide in patients with new-onset type 2 diabetes mellitus (T2DM) versus sequential addition of metformin followed by glipizide and insulin.RESEARCH DESIGN AND METHODSDrug-naive patients (N = 318) with new-onset T2DM were randomly assigned to receive for 3 years either 1) combination therapy with metformin, pioglitazone, and exenatide (triple therapy) or 2) sequential addition of metformin followed by glipizide and insulin (conventional therapy) to maintain HbA_1c at <6.5% (48 mmol/mol). Insulin sensitivity and β-cell function were measured at baseline and 3 years. The primary outcome was the difference in HbA_1c between the groups at 3 years.RESULTSBaseline HbA_1c ± SEM values were 9.0% ± 0.2% and 8.9% ± 0.2% in the triple therapy and conventional therapy groups, respectively. The decrease in HbA_1c resulting from triple therapy was greater at 6 months than that produced by conventional therapy (0.30% [95% CI 0.21–0.39]; P = 0.001), and the HbA_1c reduction was maintained at 3 years in patients receiving triple therapy compared with conventional therapy (6.4% ± 0.1% and 6.9% ± 0.1%, respectively), despite intensification of antihyperglycemic therapy in the latter. Thus, the difference in HbA_1c between the two treatment groups at 3 years was 0.50% (95% CI 0.39–0.61; P < 0.0001). Triple therapy produced a threefold increase in insulin sensitivity and 30-fold increase in β-cell function. In conventional therapy, insulin sensitivity did not change and β-cell function increased by only 34% (both P < 0.0001 vs. triple therapy).CONCLUSIONSTriple therapy with agents that improve insulin sensitivity and β-cell function in patients with new-onset T2DM produces greater, more durable HbA_1c reduction than agents that lower glucose levels without correcting the underlying metabolic defects.     

HbA1c Diagnostic Categories and β-Cell Function Relative to Insulin Sensitivity in Overweight/Obese Adolescents

OBJECTIVE

The recommended HbA_1c diagnostic categories remain controversial and their utility in doubt in pediatrics. We hypothesized that alterations in the pathophysiologic mechanisms of type 2 diabetes may be evident in the American Diabetes Association recommended at-risk/prediabetes category (HbA_1c 5.7 to <6.5%).

RESEARCH DESIGN AND METHODS

We compared in vivo hepatic and peripheral insulin sensitivity by [6,6-²H₂] glucose and a 3-h hyperinsulinemic-euglycemic clamp and β-cell function by a 2-h hyperglycemic clamp (∼225 mg/dL) in overweight/obese (BMI ≥85th percentile) adolescents with prediabetes (HbA_1c 5.7 to <6.5%) (n = 160) to those with normal HbA_1c (<5.7%) (n = 44). β-Cell function was expressed relative to insulin sensitivity (i.e., the disposition index = insulin sensitivity × first-phase insulin).

RESULTS

In the prediabetes versus normal HbA_1c category, fasting glucose, insulin, and oral glucose tolerance test (OGTT) area under the curve for glucose and insulin were significantly higher; hepatic and peripheral insulin sensitivity were lower; and β-cell function relative to insulin sensitivity was lower (366 ± 48 vs. 524 ± 25 mg/kg/min; P = 0.005). A total of 27% of youth in the normal HbA_1c category and 41% in the prediabetes HbA_1c category had dysglycemia (impaired fasting glucose and/or impaired glucose tolerance) by a 2-h OGTT.

CONCLUSIONS

Overweight/obese adolescents with HbA_1c in the at-risk/prediabetes category demonstrate impaired β-cell function relative to insulin sensitivity, a metabolic marker for heightened risk of type 2 diabetes. Thus, HbA_1c may be a suitable screening tool in large-scale epidemiological observational and/or interventional studies examining the progression or reversal of type 2 diabetes risk.Glycated hemoglobin (HbA_1c) is used to monitor diabetes control in diagnosed patients (1). In 2009, an international expert committee recommended that HbA_1c also be used for diagnosis of diabetes and risk of diabetes (1). Subsequently, HbA_1c diagnostic cutoffs were incorporated into the 2010 American Diabetes Association (ADA) guidelines for diabetes (HbA_1c ≥6.5%) and prediabetes (HbA_1c 5.7 to <6.5%) (2). Unlike glycemic measures (e.g., fasting glucose, oral glucose tolerance test [OGTT]), the HbA_1c may be performed in the nonfasting state (2). However, adoption of these proposed criteria continues to be debated (3–8). In cross-sectional studies of adults, the HbA_1c criteria had lower sensitivity for diabetes diagnosis compared with OGTT (6) or a single fasting plasma glucose (9). But, the sensitivity of the HbA_1c criteria improved when compared with repeated fasting plasma glucose samples (3 years apart), and the combination of fasting glucose and HbA_1c provided the greatest predictive value for 10-year diabetes risk compared with fasting glucose alone (single or repeated) (9). Furthermore, in a longitudinal study, HbA_1c identified fewer cases of prediabetes at baseline, but had similar predictive value for progression to diabetes as fasting glucose (∼5-year follow-up) (10). Accordingly, recent pediatric studies indicate that HbA_1c identifies fewer adolescents with diabetes/prediabetes compared with glycemic measures (4,5,11). However, similar to adults, HbA_1c improved the predictive value of glycemic measures alone after a 2-year follow-up in adolescents (5). Because glycemic measures of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are linked to impaired insulin secretion relative to insulin sensitivity, conferring an increased risk of type 2 diabetes (12,13), we hypothesized that alterations in the pathophysiologic mechanisms of type 2 diabetes could be detected in the ADA recommended at-risk/prediabetes category (HbA_1c 5.7 to <6.5%). Therefore, we aimed to evaluate in vivo insulin sensitivity and β-cell function in overweight/obese youth categorized according to the 2010 ADA HbA_1c criteria (2) as normal versus prediabetes.     

Not Only Diabetes but Also Prediabetes Leads to Functional Decline and Disability in Older Adults

OBJECTIVEDiabetes is linked to functional decline, but the impact of prediabetes on physical function is unknown. We aimed to examine and compare the impact of prediabetes and diabetes on physical function and disability progression and to explore whether cardiovascular diseases (CVDs) mediate these associations.RESEARCH DESIGN AND METHODSA cohort of 2,013 participants aged ≥60 from the Swedish National Study on Aging and Care in Kungsholmen, an ongoing population-based longitudinal study, was monitored for up to 12 years. Physical function was measured with chair stand (s) and walking speed (m/s) tests, and disability was measured by summing the numbers of impaired basic and instrumental activities of daily living. Diabetes was identified through medical examinations or clinical records, medication use, or glycated hemoglobin (HbA_1c) ≥6.5%. Prediabetes was defined as HbA_1c ≥5.7–6.4% in participants free of diabetes. CVDs were ascertained through clinical examinations and the National Patient Register. Data were analyzed using mixed-effect models and mediation models.RESULTSAt baseline, 650 (32.3%) had prediabetes and 151 had diabetes (7.5%). In multiadjusted mixed-effect models, prediabetes was associated with an increased chair stand time (β 0.33, 95% CI 0.05–0.61), a decreased walking speed (β −0.006, 95% CI −0.010 to −0.002), and an accelerated disability progression (β 0.05, 95% CI 0.01–0.08), even after controlling for the future development of diabetes. Diabetes led to faster functional decline than prediabetes. In mediation analyses, CVDs mediated 7.1%, 7.8%, and 20.9% of the associations between prediabetes and chair stand, walking speed, and disability progression, respectively.CONCLUSIONSPrediabetes, in addition to diabetes, is associated with faster functional decline and disability, independent of the future development of diabetes. This association may be in part mediated by CVDs.     

The calculated versus the measured glycosylated haemoglobin (HbA1c) levels in patients with type 2 diabetes mellitus

BackgroundDiabetes mellitus (DM) is a chronic metabolic disorder that is increasing globally. It is associated with chronic complications that are more common among patients with poor glycaemic control. Glycosylated haemoglobin (HbA_1c) is the gold standard for monitoring glycaemic control. Measurements of HbA_1c are relatively expensive and not available in some remote areas of developing countries.MethodsWe conducted a cross‐sectional study to evaluate the agreement between the calculated and measured HbA_1c levels. The equation to compute the calculated HbA_1c also incorporated the fasting blood glucose (FBG) level and was as follows: HbA_1c = 2.6 + 0.03 × FBG (mg/dl).ResultWe enrolled 290 patients with type 2 DM in this study. Of these, 204 (70.3%) were females and the mean (SD) age was 54.9 (12.8) years. The mean (SD) diabetes duration was 6.8 (5.5) years. There were 211 (72.8%) patients using oral hypoglycaemic agents, 62 (21.4%) were using insulin and 17 (5.9%) were using both insulin and oral hypoglycaemic agents. There was a borderline difference between the mean (SD) calculated and measured HbA_1c levels (p = 0.054). There was a significant correlation between the calculated and measured HbA_1c (r = 0.595, p < 0.001). However, there was no agreement between the calculated and measured HbA_1c. The bias ±SD (limits of agreement) for calculated versus measured HbA_1c was −1.008 ± 2.02% (−5.05, 2.032).ConclusionDespite the presence of a significant correlation between the calculated and measured HbA_1c, the calculated level has shown an unacceptable agreement with the measured HbA_1c.     

Elevated levels of interleukin‐35 and interleukin‐37 in adult patients with obstructive sleep apnea

BackgroundSystemic inflammation has a critical role in the pathogenesis of obstructive sleep apnea (OSA). Interleukin (IL)‐35 and IL‐37 have been identified as novel immune‐modulating cytokines with anti‐inflammatory activities in numerous types of inflammatory disease. The present study aimed to examine the serum levels of IL‐35 and IL‐37 in patients with OSA, and to investigate their associations with the severity of OSA.MethodsA total of 97 patients, including 67 cases of OSA and 30 age‐ and gender‐matched healthy control subjects, were enrolled in the present study. All subjects were evaluated by overnight polysomnography. Serum IL‐35, IL‐37, and pro‐inflammatory cytokine IL‐1β levels were examined by ELISA.ResultsCompared with those in the control subjects, serum IL‐35, IL‐37, and IL‐1β levels were significantly elevated in patients with mild, moderate, or severe OSA. Furthermore, a severity‐dependent increase in serum IL‐35 and IL‐37 levels was observed in patients with OSA. IL‐35 and IL‐37 levels were positively correlated with the apnea‐hypopnea index (r = 0.742 and 0.578, respectively; both p < 0.001), while they were negatively correlated with the mean oxygen saturation (r = −0.461 and −0.339, respectively; both p < 0.001) and lowest oxyhaemoglobin saturation (r = −0.616 and −0.463, respectively; both p < 0.001) in patients with OSA. In addition, a positive correlation was observed between IL‐35 or IL‐37 and IL‐1β levels (all p < 0.001).ConclusionThe serum levels of IL‐35 and IL‐37 were significantly increased in patients with OSA and associated with the severity of OSA, implying that IL‐35 and IL‐37 may have a protective role in OSA by counteracting inflammatory responses.     

Plasma expression of HIF-1α as novel biomarker for the diagnosis of obstructive sleep apnea-hypopnea syndrome

BackgroundObstructive sleep apnea‐hypopnea syndrome (OSAHS) is a common breathing disorder during sleep with potential lethality and multi‐complications. Polysomnography (PSG) is now the golden standard for the diagnosis obstructive sleep apnea‐hypopnea syndrome. However, PSG is expensive and time‐consuming. Therefore, it is important to find inexpensive and convenient biomarkers for the diagnosis of OSAHS.ObjectiveThe present study aimed to explore the potential diagnostic value of HIF‐1α for OSAHS and its clinical significance.MethodsThis study consisted of 368 patients admitted to the sleep laboratory. The patients were classified according to their apnea‐hypopnea index (AHI) scores as OSA negative (AHI < 5), mild‐moderate (AHI:5‐30), and severe OSA (AHI > 30), and severe OSA treated with continuous positive airway pressure (CPAP). qRT‐PCR was used to detect mRNA levels in the plasma; Pearson''s correlation analysis was performed to analyze the correlation of HIF‐1α mRNA level and the clinicopathological factors of OSAHS; ROC curve was constructed to evaluate the diagnostic value of HIF‐1α mRNA.ResultsHIF‐1α mRNA was significantly up‐regulated in the plasma of OSAHS patients, especially patients with severe OSAHS. HIF‐1α mRNA was positively correlated with the AHI and ODI but negatively correlated with the mean oxygen saturation in patients with OSAHS. Results of ROC curve showed that HIF‐1α is a sensitive biomarker for the diagnosis of OSAHS, especially severe OSAHS.ConclusionsHIF‐1α mRNA might be used as s a convenient and inexpensive method for triaging OSAHS patients PSG assessment in the hospital and evaluate the curative effect.     

Pathogenetic Mechanisms and Cardiovascular Risk: Differences between HbA1c and oral glucose tolerance test for the diagnosis of glucose tolerance

OBJECTIVE

To ascertain to which extent the use of HbA_1c and oral glucose tolerance test (OGTT) for diagnosis of glucose tolerance could identify individuals with different pathogenetic mechanisms and cardiovascular risk profile.

RESEARCH DESIGN AND METHODS

A total of 844 subjects (44% men; age 49.5 ± 11 years; BMI 29 ± 5 kg/m²) participated in this study. Parameters of β-cell function were derived from deconvolution of the plasma C-peptide concentration after a 75-g OGTT and insulin sensitivity assessed by homeostasis model assessment of insulin resistance (IR). Cardiovascular risk profile was based on determination of plasma lipids and measurements of body weight, waist circumference, and blood pressure. Glucose regulation categories by OGTT and HbA_1c were compared with respect to insulin action, insulin secretion, and cardiovascular risk profile.

RESULTS

OGTT results showed 42% of the subjects had prediabetes and 15% had type 2 diabetes mellitus (T2DM), whereas the corresponding figures based on HbA_1c were 38 and 11%, with a respective concordance rate of 54 and 44%. Subjects meeting both diagnostic criteria for prediabetes presented greater IR and impairment of insulin secretion and had a worse cardiovascular risk profile than those with normal glucose tolerance at both diagnostic methods. In a logistic regression analyses adjusted for age, sex, and BMI, prediabetic subjects, and even more T2DM subjects by OGTT, had greater chance to have IR and impaired insulin secretion.

CONCLUSIONS

HbA_1c identifies a smaller proportion of prediabetic individuals and even a smaller proportion of T2DM individuals than OGTT, with no difference in IR, insulin secretion, and cardiovascular risk profile. Subjects fulfilling both diagnostic methods for prediabetes or T2DM are characterized by a worse metabolic profile.The early identification of subjects at high risk for type 2 diabetes mellitus (T2DM) or with unknown DM is crucial to implement measures that may prevent or delay progression from prediabetes to T2DM and reduce the incidence of chronic complications. Diagnostic criteria for these categories of impaired glucose tolerance (IGT) have been classically based on glucose measurements, in particular after a glucose loading during an oral glucose tolerance test (OGTT). The OGTT, however, can be cumbersome, time consuming, and expensive, so that alternative diagnostic tools have been sought. The use of HbA_1c has been repeatedly considered for such a purpose, but the American Diabetes Association (ADA) has only recently proposed adoption of cutoff values of 5.7–6.4% and ≥6.5% for identification of individuals with prediabetes and overt diabetes, respectively (1). The World Health Organization has advocated a similar HbA_1c cutoff for the diabetes diagnosis, although no high-risk category has been identified (2).The performance of these criteria have been compared with determination of fasting plasma glucose levels and/or OGTT in various populations (3–9), but few data have explored whether the two criteria identify in the same individuals the prevalent pathogenetic mechanisms (i.e., insulin secretion and insulin action) and cardiovascular (CV) risk profile. Previous studies have shown that impaired β-cell function can be recognized in people at risk for diabetes even at the time they still have normal glucose tolerance (NGT) (10–13). A recent study, however, has reported that the relationship between β-cell function and HbA_1c can be quite different between those with impaired fasting glucose and those with altered 2-h postload glucose concentrations (14). This raises the possibility that individuals with impaired glucose regulation, as identified by HbA_1c or OGTT, also may differ in their pathogenetic mechanisms and, therefore, their CV risk profile. Therefore, the aim of the current study was to assess insulin secretion, insulin action, and CV risk profile based on different diagnostic criteria for abnormal glucose tolerance.     

Restoring Insulin Secretion (RISE): Design of Studies of β-Cell Preservation in Prediabetes and Early Type 2 Diabetes Across the Life Span

OBJECTIVE

The Restoring Insulin Secretion (RISE) Consortium is testing interventions designed to preserve or improve β-cell function in prediabetes or early type 2 diabetes.

RESEARCH DESIGN AND METHODS

β-Cell function is measured using hyperglycemic clamps and oral glucose tolerance tests (OGTTs). The adult medication protocol randomizes participants to 12 months of placebo, metformin alone, liraglutide plus metformin, or insulin (3 months) followed by metformin (9 months). The pediatric medication protocol randomizes participants to metformin or insulin followed by metformin. The adult surgical protocol randomizes participants to gastric banding or metformin (24 months). Adult medication protocol inclusion criteria include fasting plasma glucose 95–125 mg/dL (5.3–6.9 mmol/L), OGTT 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA_1c 5.8–7.0% (40–53 mmol/mol), and BMI 25–40 kg/m². Adult surgical protocol criteria are similar, except for fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), BMI 30–40 kg/m², HbA_1c <7.0% (<53 mmol/mol), and diabetes duration <12 months. Pediatric inclusion criteria include fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA_1c ≤8.0% (≤64 mmol/mol), BMI >85th percentile and ≤50 kg/m², 10–19 years of age, and diabetes <6 months.

RESULTS

Primary outcomes are clamp-derived glucose-stimulated C-peptide secretion and maximal C-peptide response to arginine during hyperglycemia. Measurements are made at baseline, after 12 months on treatment, and 3 months after treatment withdrawal (medication protocols) or 24 months postintervention (surgery protocol). OGTT-derived measures are also obtained at these time points.

CONCLUSIONS

RISE is determining whether medication or surgical intervention strategies can mitigate progressive β-cell dysfunction in adults and youth with prediabetes or early type 2 diabetes.     

Allogeneic Mesenchymal Precursor Cells in Type 2 Diabetes: A Randomized,Placebo-Controlled,Dose-Escalation Safety and Tolerability Pilot Study

OBJECTIVE

To assess the safety, tolerability, and feasibility of adult allogeneic bone marrow–derived mesenchymal precursor cells (MPCs) in type 2 diabetes inadequately controlled with metformin either alone or with one additional oral antidiabetic agent.

RESEARCH DESIGN AND METHODS

The study was a dose-escalating randomized placebo-controlled trial assessing one intravenous (IV) infusion of MPCs (rexlemestrocel-L; Mesoblast Inc.) 0.3 × 10⁶/kg (n = 15), 1.0 × 10⁶/kg (n = 15), or 2.0 × 10⁶/kg (n = 15) or placebo (n = 16). Study duration was 12 weeks.

RESULTS

Subjects (21 women, 40 men) with a mean ± SD baseline HbA_1c 8.3 ± 1.0% (67 ± 10.9 mmol/mol), BMI 33.5 ± 5.5 kg/m², and diabetes duration 10.1 ± 6.0 years were enrolled at 18 U.S. sites. No acute adverse events (AEs) were associated with infusion. No serious AEs, serious hypoglycemia AEs, or discontinuations due to AEs over 12 weeks were found. No subjects developed donor-specific anti-HLA antibodies or became sensitized. The safety profile was comparable among treatment groups. Compared with placebo, a single IV infusion of rexlemestrocel-L reduced HbA_1c at all time points after week 1. The adjusted least squares mean ± SE dose-related differences in HbA_1c from placebo in the rexlemestrocel-L groups ranged from −0.1 ± 0.2% (−1.1 ± 2.2 mmol/mol) to −0.4 ± 0.2% (4.4 ± 2.2 mmol/mol) at 8 weeks and from 0.0 ± 0.25% to −0.3 ± 0.25% (−3.3 ± −2.7 mmol/mol) at 12 weeks (P < 0.05 for 2.0 × 10⁶/kg dose at 8 weeks). The clinical target HbA_1c <7% (53 mmol/mol) was achieved by 33% (5 of 15) of the subjects who received the 2.0 × 10⁶/kg dose vs. 0% of those who received placebo (P < 0.05).

CONCLUSIONS

This short-term study demonstrates the safety and feasibility of up to 246 million MPCs in subjects with type 2 diabetes.     

Glucose Regulation Beyond HbA1c in Type 2 Diabetes Treated With Insulin: Real-World Evidence From the DIALECT-2 Cohort

OBJECTIVETo investigate glucose variations associated with glycated hemoglobin (HbA_1c) in insulin-treated patients with type 2 diabetes.RESEARCH DESIGN AND METHODSPatients included in Diabetes and Lifestyle Cohort Twente (DIALECT)-2 (n = 79) were grouped into three HbA_1c categories: low, intermediate, and high (≤53, 54–62, and ≥63 mmol/mol or ≤7, 7.1–7.8, and ≥7.9%, respectively). Blood glucose time in range (TIR), time below range (TBR), time above range (TAR), glucose variability parameters, day and night duration, and frequency of TBR and TAR episodes were determined by continuous glucose monitoring (CGM) using the FreeStyle Libre sensor and compared between HbA_1c categories.RESULTSCGM was performed for a median (interquartile range) of 10 (7–12) days/patient. TIR was not different for low and intermediate HbA_1c categories (76.8% [68.3–88.2] vs. 76.0% [72.5.0–80.1]), whereas in the low category, TBR was higher and TAR lower (7.7% [2.4–19.1] vs. 0.7% [0.3–6.1] and 8.2% [5.7–17.6] vs. 20.4% [11.6–27.0], respectively; P < 0.05). Patients in the highest HbA_1c category had lower TIR (52.7% [40.9–67.3]) and higher TAR (44.1% [27.8–57.0]) than the other HbA_1c categories (P < 0.05), but did not have less TBR during the night. All patients had more (0.06 ± 0.06/h vs. 0.03 ± 0.03/h; P = 0.002) and longer (88.0 [45.0–195.5] vs. 53.4 [34.4–82.8] minutes; P < 0.001) TBR episodes during the night than during the day.CONCLUSIONSIn this study, a high HbA_1c did not reduce the occurrence of nocturnal hypoglycemia, and low HbA_1c was not associated with the highest TIR. Optimal personalization of glycemic control requires the use of newer tools, including CGM-derived parameters.     

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

OBJECTIVETo 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 METHODSA 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 (HbA_1c increase ≥0.5% from baseline).RESULTSGlycemic 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 < 0.01). Lower baseline OGTT-derived β-cell responses predicted month 21 worsening (P < 0.05). In youth, higher baseline HbA_1c 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).CONCLUSIONSGlycemic 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.     

Postintervention Effects of Varying Treatment Arms on Glycemic Failure and β-Cell Function in the TODAY Trial

OBJECTIVEThe Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that glycemic failure rates were significantly lower in youth randomized to metformin plus rosiglitazone treatment than in youth randomized to metformin alone or metformin plus intensive lifestyle intervention. At the end of the study, rosiglitazone was permanently discontinued, and routine diabetes care resumed. Herein, we report postintervention glycemic failure rates in TODAY participants over an additional 36 months of follow-up for the three original treatment arms and describe insulin sensitivity and β-cell function outcomes.RESEARCH DESIGN AND METHODSA total of 699 participants were randomized during TODAY, of whom 572 enrolled in the TODAY2 observational follow-up. Glycemic failure was defined as HbA_1c ≥8% over a 6-month period, inability to wean from temporary insulin therapy within 3 months after acute metabolic decompensation during TODAY, or sustained HbA_1c ≥8% over two consecutive visits during TODAY2. Oral glucose tolerance tests were conducted, and insulin sensitivity, insulinogenic index, and oral disposition index were calculated.RESULTSDuring the 36 months of TODAY2, glycemic failure rates did not differ among participants by original treatment group assignment. Insulin sensitivity and β-cell function deteriorated rapidly during the 36 months of TODAY2 routine diabetes care but did not differ by treatment group assignment.CONCLUSIONSThe added benefit of preventing glycemic failure by using rosiglitazone as a second agent in youth-onset type 2 diabetes did not persist after its discontinuation. More work is needed to address this rapid progression to avoid long-term diabetes complications.     

Prediabetes,Diabetes, and the Risk of All-Cause and Cause-Specific Mortality in a Japanese Working Population: Japan Epidemiology Collaboration on Occupational Health Study

OBJECTIVEPrediabetes has been suggested to increase risk for death; however, the definitions of prediabetes that can predict death remain elusive. We prospectively investigated the association of multiple definitions of prediabetes with the risk of death from all causes, cardiovascular disease (CVD), and cancer in Japanese workers.RESEARCH DESIGN AND METHODSThe study included 62,785 workers who underwent a health checkup in 2010 or 2011 and were followed up for death from 2012 to March 2019. Prediabetes was defined according to fasting plasma glucose (FPG) or glycated hemoglobin (HbA_1c) values or a combination of both using the American Diabetes Association (ADA) or World Health Organization (WHO)/International Expert Committee (IEC) criteria. The Cox proportional hazards regression model was used to investigate the associations.RESULTSOver a 7-year follow-up, 229 deaths were documented. Compared with normoglycemia, prediabetes defined according to ADA criteria was associated with a higher risk of all-cause mortality (hazard ratio [HR] 1.53; 95% CI 1.12–2.09) and death due to cancer (HR 2.37; 95% CI 1.45–3.89) but not with death due to CVD. The results were materially unchanged when prediabetes was defined according to ADA FPG, ADA HbA_1c, WHO FPG, or combined WHO/IEC criteria. Diabetes was associated with the risk of all-cause, CVD, and cancer deaths.CONCLUSIONSIn a cohort of Japanese workers, FPG- and HbA_1c-defined prediabetes, according to ADA or WHO/IEC, were associated with a significantly increased risk of death from all causes and cancer but not CVD.     

Plasma Levels of Alpha and Gamma Synucleins in Autism Spectrum Disorder: An Indicator of Severity

ObjectivesThe aim of this study was to correlate plasma levels of the synaptic proteins α-synuclein and γ-synuclein in autism spectrum disorder (ASD) children in order to elucidate their possible contribution to the pathogenesis of ASD and to study their association with the severity of the disorder.Subjects and MethodsPlasma levels of α-synuclein and γ-synuclein were measured in 38 male children diagnosed with ASD and 40 healthy age-matched male children by ELISA.ResultsOur results showed that plasma levels of α-synuclein (18.02 ± 5.3 pg/mL) were significantly higher in ASD children than in control children (14.39 ± 2 pg/mL), and plasma levels of γ-synuclein were decreased in the ASD group (23.74 ± 7.7 pg/mL) compared to the control group (32.40 ± 6.8 pg/mL) (p < 0.0001). Our data also indicate that plasma levels of both α-synuclein and γ-synuclein are significantly associated with the severity of ASD.ConclusionsOur study showed that alteration in α-synuclein and γ-synuclein might be associated with ASD pathogenesis and could be an indicator of the severity of the disorder.     

High Calorie Intake Is Associated With Worsening Insulin Resistance and β-Cell Function in Hispanic Women After Gestational Diabetes Mellitus

OBJECTIVETo assess associations between dietary intake and rates of change in insulin resistance and β-cell function in Hispanic women with prior gestational diabetes mellitus (GDM).RESULTSThe median length of follow-up from the first postpartum evaluation was 8.0 years (interquartile range 4.5–10.8 years). At baseline, women were 32 ± 5.7 years old and had a median calorie intake of 2,091 kcal/day. Over the course of follow-up, dietary intake did not change significantly. Higher baseline calorie intake was associated with a faster decline in insulin sensitivity, measured by the insulin sensitivity index (S_I) (P = 0.029), and β-cell compensation, measured by the disposition index (DI) (P = 0.027), over time. These associations remained after adjustment for baseline characteristics; changes in BMI, calorie intake, levels of physical activity; and additional pregnancies during the follow-up period. The median rates were −0.06 vs. −0.02 units/year for S_I and −810 vs. −692 units/year for DI for women with baseline calorie intake above versus below the cohort median.CONCLUSIONSHigh calorie intake is associated with a faster decline in insulin sensitivity and β-cell compensation in Hispanic women who are at high risk for type 2 diabetes, independent of adiposity.     

The Effectiveness of a Proactive,Three-Level Strategy to Identify People With Prediabetes in a Large Workforce With Employer-Sponsored Health Insurance

OBJECTIVERates of diagnosis of prediabetes and uptake of the National Diabetes Prevention Program (NDPP) are low. We evaluated a proactive three-level strategy to identify individuals with prediabetes in a population with employer-sponsored health insurance.RESEARCH DESIGN AND METHODSWe studied 64,131 insured employees, dependents, and retirees ≥18 years of age without diagnosed diabetes, 19,397 (30%) of whom were estimated to have prediabetes. Individuals with prediabetes were identified by 1) searching claims diagnoses and previously performed HbA_1c test results, 2) risk stratifying people 40–64 years of age without diabetes, prediabetes, or documented normal HbA_1c to identify individuals at higher risk and encourage them to be tested, and 3) using a media campaign to encourage employees not otherwise targeted to self-screen and, if at higher risk, to be tested.RESULTSUsing claims and laboratory data, 11% of the population was identified as having prediabetes. Of those 40–64 years of age, 25% were identified as being at higher risk, and 27% of them were tested or diagnosed within 1 year. Of employees exposed to the media campaign, 14% were tested or diagnosed within 1 year. Individuals with prediabetes were older, heavier, and more likely to have hypertension and dyslipidemia. Testing and diagnosis were associated with receiving medical care and provider outreach. A total of 8,129 individuals, or 42% of those with prediabetes, were identified.CONCLUSIONSAnalysis of existing health insurance data facilitated the identification of individuals with prediabetes. Better identification of people with prediabetes is a first step in increasing uptake of the NDPP.     

Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas

OBJECTIVESulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA_1c reduction.RESEARCH DESIGN AND METHODSAs an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA_1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions.RESULTSAfter establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA_1c reduction at a genome-wide scale (P < 5 × 10⁻⁸). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10⁻⁸), lower reduction in HbA_1c. Similarly, the C allele was associated with higher glucose trough levels (β = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (β = 0.21, P = 2.04 × 10⁻⁵⁸). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA_1c (P = 4.80 × 10⁻⁸). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10⁻⁷), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA_1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor.CONCLUSIONSWe have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs.     

Association Between Cardiorespiratory Fitness and the Determinants of Glycemic Control Across the Entire Glucose Tolerance Continuum

OBJECTIVECardiorespiratory fitness (VO_2max) is associated with glycemic control, yet the relationship between VO_2max and the underlying determinants of glycemic control is less clear. Our aim was to determine whether VO_2max is associated with insulin sensitivity, insulin secretion, and the disposition index, a measure of compensatory pancreatic β-cell insulin secretion relative to insulin sensitivity, in subjects representing the entire range of the glucose tolerance continuum.RESULTSA low VO_2max was associated with high HbA_1c (r = −0.33), high fasting glucose (r = −0.34), high 2-h OGTT glucose (r = −0.33), low Si_OGTT (r = 0.73), and high early-phase (r = −0.34) and late-phase (r = −0.36) GSIS_OGTT. Furthermore, a low VO_2max was associated with low early- and late-phase DI_OGTT (both r = 0.41). Interestingly, relationships between VO_2max and either glycemic control or late-phase GSIS_OGTT deteriorated across the glucose tolerance continuum.CONCLUSIONSThe association between poor cardiorespiratory fitness and compromised pancreatic β-cell compensation across the entire glucose tolerance continuum provides additional evidence highlighting the importance of fitness in protection against the onset of a fundamental pathophysiological event that leads to type 2 diabetes.     

Obstructive Sleep Apnea Among Obese Patients With Type 2 Diabetes

OBJECTIVE

To assess the risk factors for the presence and severity of obstructive sleep apnea (OSA) among obese patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Unattended polysomnography was performed in 306 participants.

RESULTS

Over 86% of participants had OSA with an apnea-hypopnea index (AHI) ≥5 events/h. The mean AHI was 20.5 ± 16.8 events/h. A total of 30.5% of the participants had moderate OSA (15 ≤ AHI <30), and 22.6% had severe OSA (AHI ≥30). Waist circumference (odds ratio 1.1; 95% CI 1.0–1.1; P = 0.03) was significantly related to the presence of OSA. Severe OSA was most likely in individuals with a higher BMI (odds ratio 1.1; 95% CI 1.0–1.2; P = 0.03).

CONCLUSIONS

Physicians should be particularly cognizant of the likelihood of OSA in obese patients with type 2 diabetes, especially among individuals with higher waist circumference and BMI.We report the prevalence of obstructive sleep apnea (OSA) and the factors that increase the risk and severity of OSA among 306 obese patients with type 2 diabetes enrolled in Sleep AHEAD, a four-site ancillary study of the Look AHEAD Trial (Action for Health in Diabetes).