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ZusammenfassungDie unter der Kategorie „andere spezifische Diabetesformen“ zusammengefassten Störungen des Glukosestoffwechsels stellen pathophysiologisch und therapeutisch eine sehr heterogene Krankheitsgruppe dar. Umfasst werden Diabetesformen, die im Rahmen von anderen endokrinologischen Erkrankungen auftreten (z. B. Akromegalie, Cushing-Syndrom), medikamentös induzierte Diabetesformen (z. B. Antipsychotikatherapie, Glukokortikoidtherapie, HAART, Checkpoint-Inhibitoren, genetische Formen (z. B. i. R. eines MODY, neonataler Diabetes, Down-Syndrom, Klinefelter-Syndrom, Turner-Syndrom), pankreoprive Formen (z. B. postoperativ, Pankreatitis, Pankreastumoren, Hämochromatose, zystische Fibrose), Infektionen (z. B. kongenitale Rötelninfektion) und seltene autoimmune Formen (z. B. Stiffman-Syndrom). Die Diagnose der spezifischen Diabetesform kann die therapeutischen Erwägungen beeinflussen. Nicht nur pankreoprive Formen, sondern auch Typ 1 oder langjähriger Typ 2 Diabetes mellitus sind häufig mit einer exokrinen Pankreasinsuffizienz assoziiert.

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

Objective: To characterize patients with diabetes treated with a tubeless insulin pump (Omnipod® Insulin Management System; Insulet Corp., Acton, MA), and to evaluate the frequency of acute complications with long-term use of the system. Methods: This retrospective analysis of the German/Austrian Diabetes Patienten Verlaufsdokumentation (DPV) registry included data from 3657 patients with diabetes (n = 3582 type 1, n = 25 type 2, n = 50 latent autoimmune diabetes in adults/other) treated with a tubeless insulin pump. Hemoglobin A1c (HbA1c) levels and frequency of diabetic ketoacidosis (DKA) and severe hypoglycemia (SH) were compared between 1 year pre- and 1 year (n = 2911) or up to 3 years (n = 1311) post-tubeless insulin pump initiation and compared with a contemporary cohort on multiple daily injections (MDI) with 3-year data (n = 1874). Results: Patients using tubeless insulin pump therapy had a median age of 13.7 years [interquartile range 10.8, 17.3], diabetes duration 3.7 years [1.7, 8.0], and HbA1c 7.5% [6.9, 8.2]. In patients with 3 years of follow-up data (n = 1311), the percentage with ≥1 episode of DKA, SH (Level 3, requiring assistance), and SH (coma) event with prior treatment was 6.3%, 5.5%, and 1.7%, respectively. After 3 years of tubeless insulin pump therapy, the frequency of DKA, SH (Level 3), and SH (coma) decreased to 2.2%, 4.1%, and 0.5%, respectively. Both DKA and SH remained significantly lower compared with MDI after adjustment in multiple regression analysis. High treatment retention rates (>90%) were observed. Conclusion: Real-world registry data document that tubeless insulin pump therapy is associated with good glycemic control and a low frequency of DKA and SH in an age group prone to acute complications.

We have deployed a multi-omics approach in large cohorts of patients with existing type 2 diabetes to identify biomarkers for disease progression across three molecular classes, metabolites, lipids and proteins. A Cox regression analysis for association with time to insulin requirement in 2,973 patients in the DCS, ANDIS and GoDARTS cohorts identified homocitrulline, isoleucine and 2-aminoadipic acid, as well as the bile acids glycocholic and taurocholic acids, as predictive of more rapid deterioration. Increased levels of eight triacylglycerol species, and lowered levels of the sphingomyelin SM 42:2;2 were also predictive of disease progression. Of ∼1,300 proteins examined in two cohorts, levels of GDF-15/MIC1, IL-18RA, CRELD1, NogoR, FAS, and ENPP7 were associated with faster progression, whilst SMAC/DIABLO, COTL1, SPOCK1 and HEMK2 predicted lower progression rates. Strikingly, identified proteins and lipids were also associated with diabetes incidence and prevalence in external replication cohorts. Implicating roles in disease compensation, NogoR/RTN4R improved glucose tolerance in high fat-fed mice and tended to improved insulin signalling in liver cells whilst IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. Conversely, high NogoR levels led to islet cell apoptosis. This comprehensive, multi-disciplinary approach thus identifies novel biomarkers with potential prognostic utility, provides evidence for new disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity, investigators of a previous study clustered people with diabetes according to five diabetes subtypes. The aim of the current study is to investigate the etiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic (N = 12,828), metabolomic (N = 2,945), lipidomic (N = 2,593), and proteomic (N = 1,170) data were obtained in plasma. For each data type, each cluster was compared with the other four clusters as the reference. The insulin-resistant cluster showed the most distinct molecular signature, with higher branched-chain amino acid, diacylglycerol, and triacylglycerol levels and aberrant protein levels in plasma were enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher levels of cytokines. The mild diabetes cluster with high HDL showed the most beneficial molecular profile with effects opposite of those seen in the insulin-resistant cluster. This study shows that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.

Aims/hypothesisFive clusters based on clinical characteristics have been suggested as diabetes subtypes: one autoimmune and four subtypes of type 2 diabetes (T2D). In the current study we replicate and cross-validate these T2D clusters in three large cohorts using readily measured variables in the clinic.MethodsIn this cross-sectional study, 15,940 individuals were clustered based on age, BMI, HbA1c, random or fasting C-peptide and HDL in three independent cohorts. Clusters were cross-validated against the original clusters based on HOMA measures. In addition, between cohorts, clusters were cross-validated by re-assigning people based on each cohort’s cluster centres.ResultsFive distinct T2D clusters were identified and mapped back to the original four ANDIS clusters. Using C-peptide and HDL instead of HOMA-B and HOMA-S three of the clusters mapped with high sensitivity (80.6 – 90.7%) to the previously identified Severe Insulin Deficient (SIDD), Severe insulin resistant (SIRD) and Obese (MOD) clusters. The previously described ANDIS MARD cluster could be mapped to the two milder groups in our study – one characterised by high HDL, and the other having not any extreme characteristic (MDH cluster). When these two milder groups were combined they mapped well to the previously labelled MARD cluster (sensitivity 79.4%). In the cross-validation between cohorts, particularly the SIDD and MDH cluster cross-validated well with sensitivities ranging from 73.3% to 97.1%. SIRD and MD showed a lower sensitivity ranging from 36.1% to 92.3% where individuals shifted from SIRD to MD and vice versa.Conclusions/interpretationClusters based on C-peptide instead of HOMA measures result in clusters that resemble those based on HOMA measures, especially for SIDD, SIRD and MOD. By adding HDL, the MARD cluster based upon HOMA measures resulted in the current clustering in two clusters with one cluster having high HDL levels. Cross-validation between cohorts showed generally a good resemblance between cohorts. Together, our results show that the clustering based on clinical variables readily measured in the clinic (age, HbA1c, HDL, BMI and C-peptide) results in informative clusters that are representative of the original ANDIS clusters and stable across cohorts.

Understanding the benefits and risks of treatments to be used by older individuals (≥65 years old) is critical for informed therapeutic decisions. Glucose‐lowering therapy for older patients with diabetes should be tailored to suit their clinical condition, comorbidities and impaired functional status, including varying degrees of frailty. However, despite the rapidly growing population of older adults with diabetes, there are few dedicated clinical trials evaluating glucose‐lowering treatment in older people. Conducting clinical trials in the older population poses multiple significant challenges. Despite the general agreement that individualizing treatment goals and avoiding hypoglycaemia is paramount for the therapy of older people with diabetes, there are conflicting perspectives on specific glycaemic targets that should be adopted and on use of specific drugs and treatment strategies. Assessment of functional status, frailty and comorbidities is not routinely performed in diabetes trials, contributing to insufficient characterization of older study participants. Moreover, significant operational barriers and problems make successful enrolment and completion of such studies difficult. In this review paper, we summarize the current guidelines and literature on conducting such trials, as well as the learnings from our own clinical trial (IMPERIUM) that assessed different glucose‐lowering strategies in older people with type 2 diabetes. We discuss the importance of strategies to improve study design, enrolment and attrition. Apart from summarizing some practical advice to facilitate the successful conduct of studies, we highlight key gaps and needs that warrant further research.

Background: Few studies have evaluated continuous glucose monitoring (CGM) in older patients with type 2 diabetes mellitus (T2DM) not using injectable therapy. CGM is useful for investigating hypoglycemia and glycemic variability, which is associated with complications in T2DM. Methods: A CGM substudy of Individualized treatMent aPproach for oldER patIents in a randomized trial in type 2 diabetes Mellitus (IMPERIUM)) was conducted. Patients were vulnerable (moderately ill and/or frail) older (≥65 years) individuals with suboptimally controlled T2DM. Strategy A comprised glucose-dependent therapies (n = 26) with a nonsulfonylurea oral antihyperglycemic medication (OAM) and a glucagon-like peptide-1 receptor agonist as the first injectable. Strategy B comprised non-glucose-dependent therapies (n = 21) with sulfonylurea as the preferred OAM and insulin glargine as the first injectable. Primary endpoints were duration and percentage of time spent with blood glucose (BG) ≤70 mg/dL over 24 hours at week 24. Results: Duration and percentage of time spent with hypoglycemia at ≤70 mg/dL were similar for Strategy A and Strategy B; glycemic control improved similarly in both arms (LSM change in HbA1c at week 24; A = −1.2%, B = −1.4%). Duration and percentage time spent with euglycemia and hyperglycemia were also similar in both arms. However, Strategy A was associated with lower within-day (21.1 ± 1.2 vs 25.1 ± 1.4, P = .046) and between-day (5.4 ± 1.0 vs 9.1 ± 1.3, P = .038) BG variability (coefficient of variance [LSM ± SE]) at week 24. Conclusions: This CGM substudy in older patients with T2DM showed lower within- and between-day BG variability with glucose-dependent therapies but similar HbA1c reductions and hypoglycemia duration with glucose-independent strategies.

Recent evidence has documented distinct effects of individual saturated FAs (SFAs) on cardiometabolic outcomes, with potential protective effects from odd- and very long-chain SFAs (VLSFAs). Cross-sectional and prospective associations of individual serum SFAs (12:0, 14:0, 15:0, 16:0, 18:0, 20:0, 22:0, and total SFA) with proinflammatory biomarkers and adiponectin were investigated in 555 adults from the IRAS. Principal component analysis (PCA) of proinflammatory markers yielded three clusters: principal component (PC) 1: fibrinogen, white cell count, C-reactive protein; PC 2: plasminogen activator inhibitor-1 (PAI-1), TNF-α, IL-18; PC 3: IL-6 and IL-8. Cross-sectional analyses on proinflammatory PCs and adiponectin, and prospective analyses on 5 year PAI-1 and fibrinogen concentrations were conducted with multiple regression. Total SFA and 16:0 were positively associated with PC 1 and PC 2, and negatively associated with adiponectin. The 14:0 was positively associated with PC 1 and negatively associated with adiponectin. In contrast, 15:0, 20:0, and 22:0 were negatively associated with PC 2, and 20:0 and 22:0 were positively associated with adiponectin. The 18:0 was negatively associated with PC 3. Prospectively, 15:0, 18:0, 20:0, and 22:0 were negatively associated with 5 year PAI-1 concentrations. The results demonstrate that individual SFAs have distinct roles in subclinical inflammation, highlighting the unique metabolic impacts of individual SFAs.

AIM: To compare the glycaemic outcomes of 2 glucose-lowering treatment strategies in vulnerable (moderately ill and/or frail) patients aged ≥65 years with type 2 diabetes whose individual HbA1c targets were not met with diet/exercise and/or oral antihyperglycaemic medications (OAMs). METHODS: The primary endpoint of this study was a composite of achieving/maintaining individualised HbA1c targets without 'clinically significant' hypoglycaemia (severe hypoglycaemia or repeated hypoglycaemia causing interruption of patients' activities or blood glucose

OBJECTIVE N-acetylglucosamine/galactosamine (GlycA) and sialic acid (GlycB) moieties of glycosylated serum proteins are nonspecific measures of inflammation, but conclusive data on their relationship with insulin resistance or insulin secretion are missing. Therefore, we aimed to examine the relation of GlycA, GlycB, and C-reactive protein (CRP) to direct measures of insulin sensitivity (insulin sensitivity index [SI]) and insulin secretion (acute insulin response [AIR]). RESEARCH DESIGN AND METHODS This study used cross-sectional analyses and included 1,225 participants with and without type 2 diabetes in the Insulin Resistance Atherosclerosis Study (IRAS). SI and AIR were measured using the frequently sampled intravenous glucose tolerance test, and GlycA and GlycB were measured using nuclear magnetic resonance spectroscopy. RESULTS GlycA and GlycB had a strong correlation with CRP (r = 0.60 [P < 0.001] and r = 0.46 [P < 0.001], respectively). In a linear regression model with both GlycA and CRP as independent variables, GlycA (β × 1 SD, −0.04 ± 0.02; P < 0.01) and CRP (−0.06 ± 0.02; P < 0.001) were independently associated with SI even after adjusting for demographics, smoking, physical activity, plasma glucose, and BMI. However, neither CRP nor GlycA had an independent relationship with AIR. CONCLUSIONS GlycA may complement CRP in evaluating the relationship between inflammation, glucose tolerance, and insulin resistance.

The American Diabetes Association consensus statement on the treatment of type 2 diabetes mellitus (T2DM) in older patients highlights the need for treatment pattern and effectiveness data from real-world settings and populations. This retrospective cohort study assessed the relative frequency of use of four commonly prescribed antihyperglycemia treatments for T2DM and quantified their effectiveness up to 2 years post-initiation.Within a large, U.S.-based, electronic health record database, we investigated usage of insulin, sulfonylureas, glucagon-like peptide-1(GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with T2DM, focusing on those ≥65 years old, although younger patients were included for comparative purposes.Inclusion criteria were met by 77,440 patients. Mean baseline glycosylated hemoglobin (HbA1c) levels for patients ≥65 years old varied among treatments: insulin (7.7% [61 mmol/mol]; n=3,311), sulfonylureas (7.0% [53 mmol/mol]; n=5,706), GLP-1 receptor agonists (7.1% [54 mmol/mol]; n=260), and DPP-4 inhibitors (7.1% [54 mmol/mol]; n=1,096). Older patients demonstrated good glycemic control at therapy initiation and were prescribed glucose-lowering agents at lower HbA1c values compared with younger patients. A large proportion of older patients were prescribed sulfonylureas (56%) and insulin (34%) compared with GLP-1 receptor agonists (3.4%) and DPP-4 inhibitors (12%), despite the associated risk of hypoglycemia.Patients initiating insulin and sulfonylureas demonstrated more sustained glycemic control compared with GLP-1 receptor agonists and DPP-4 inhibitors. A majority of older patients with T2DM was initiated on sulfonylureas and insulin at relatively low levels of HbA1c, a practice not entirely consistent with the recommendations of published guidelines.

Primary objective: Identify risk factors associated with severe hypoglycemia (SH) and investigate the association between mild hypoglycemia and SH in people with type 2 diabetes starting insulin. Secondary objectives: Investigate the association of demographics and clinical factors with SH incidence.Integrated trial database data were obtained for 3 randomized controlled trials that included insulin-naïve people with type 2 diabetes initiating basal (insulin glargine) versus biphasic (insulin lispro mixture) insulin. Standard definitions were used for SH; mild hypoglycemia was defined as all non-SH. Cox regression identified risk factors associated with SH and the correlation between SH and mild hypoglycemia.Data were pooled (N=2931). During 24-48weeks' treatment, 2127 (72.6%) participants experienced ≥1 mild hypoglycemic event but no SH (mean mild hypoglycemia rate=2.33/month). 56 participants (1.9%) experienced ≥1 SH event plus mild hypoglycemia (mean mild hypoglycemia rate=3.95/month); 748 participants (25.5%) had no hypoglycemia. Among factors tested, only mild hypoglycemia rate/month was associated with SH. SH risk was higher (HR=4.24; 95%CI=2.57-6.99;p0.0001) for participants experiencing multiple mild hypoglycemic events/month compared with those experiencing ≤1 mild hypoglycemic event/month.Mild hypoglycemia may predict the first SH event, which is important because SH is a strong and consistent risk factor for morbidity/mortality.

Insulin clearance may decline as an early mechanism compensating for deteriorating insulin sensitivity. However, no previous studies have investigated the association between subclinical inflammation or impaired fibrinolysis and insulin clearance. We examined the association between plasminogen activator inhibitor (PAI)-1, C-reactive protein (CRP), TNF-α, leptin and fibrinogen and the progression of metabolic clearance rate of insulin (MCRI) over time.We studied 784 non-diabetic white, Hispanic and African-American individuals in the Insulin Resistance Atherosclerosis Study (IRAS). Insulin sensitivity, acute insulin response and MCRI were determined from frequently sampled intravenous glucose tolerance tests at baseline and at 5-year follow-up. Inflammatory and fibrinolytic proteins were measured in fasting plasma at baseline.MCRI had declined significantly by 29% at the 5-year follow-up. We observed a significant association between higher plasma PAI-1 levels and the decline in MCRI in multivariable-adjusted regression models (β = -0.045 [95% CI -0.081, -0.0091]). Higher plasma CRP and leptin levels were associated with a decline in MCRI in unadjusted models, but these associations were non-significant after adjusting for BMI and waist circumference (β = -0.016 [95% CI -0.041, 0.0083] for CRP; β = -0.044 [95% CI -0.10, 0.011] for leptin). A higher plasma TNF-α concentration was associated with a decline in MCRI in unadjusted (β = -0.071 [95% CI -0.14, -0.00087]) but not in multivariable-adjusted (β = -0.056 [95% CI -0.13, 0.017]) models. Plasma fibrinogen level was not associated with the change in MCRI.We identified that higher plasma PAI-1 (but not CRP, TNF-α, leptin or fibrinogen) levels independently predicted the progressive decline of insulin clearance in the multiethnic cohort of the IRAS.

Although several epidemiological studies have investigated associations between TNF-α and insulin resistance, results have been inconsistent. We studied the relationship between TNF-α and glucose tolerance status as part of the Insulin Resistance Atherosclerosis Study.Serum concentrations of TNF-α were measured in 1558 individuals in a triethnic population across a spectrum of glucose tolerance. Insulin sensitivity and insulin secretion were assessed by a frequently sampled iv glucose tolerance test (FSIGT).Compared with those with normal glucose tolerance, circulating levels of TNF-α were elevated in individuals with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2D) after adjusting for age, gender, ethnicity, clinic site, and body mass index (3.3, 3.5, and 3.7 pg/ml in subjects with normal glucose tolerance, IGT, and T2D, respectively; P0.05). Age-, sex-, and body mass index-adjusted levels of TNF-α differed by ethnicity, with Hispanics having the highest levels and African-Americans having the lowest (4.1, 3.6, and 3.0 pg/ml in Hispanics, non-Hispanic whites, and African-Americans, respectively; P0.05). TNF-α was correlated with waist circumference, high-density lipoprotein, triglycerides, plasminogen activator inhibitor-1 and insulin sensitivity index (SI) (r=0.22, -0.30, 0.35, 0.31, and -0.25; P0.0001); however, correlations varied by ethnicity. After adjusting for demographics and adiposity, individuals characterized by increased insulin resistance (lower SI), had higher levels of TNF-α than subjects characterized by high insulin sensitivity (3.8 and 3.3 pg/ml in subjects with an SI below/above the median at baseline; P0.0001). No differences were found for acute insulin response.We confirm that TNF-α is associated with IGT and T2D in a large, multiethnic population, independent of measures of adiposity. Adjusted values of TNF-α, as well as relationships between TNF-α and variables related to T2D, varied by ethnicity. Increased TNF-α levels were predominantly associated with insulin resistance but not with primary defects in β-cell function.

OBJECTIVE—Methods to assess β-cell function in clinical studies are limited. The aim of the current study was to compare a direct measure of insulin secretion with fasting surrogate markers in relation to glucose tolerance status. RESEARCH DESIGN AND METHODS—In 1,380 individuals from the Insulin Resistance Atherosclerosis Study, β-cell function was assessed using a frequently sampled intravenous glucose tolerance test (first-phase insulin secretion; acute insulin response [AIR]), homeostasis model assessment of β-cell function (HOMA-B), proinsulin levels, and the proinsulin-to-insulin ratio. β-Cell function was cross-sectionally analyzed by glucose tolerance categories (normal glucose tolerance [NGT], n = 712; impaired glucose tolerance [IGT], n = 353; newly diagnosed diabetes by 2-h glucose from an oral glucose tolerance test [OGTT] [DM2h], n = 80; newly diagnosed diabetes by fasting glucose [DMf], n = 135; or newly diagnosed diabetes by fasting and 2-h glucose and established diabetes on diet/exercise only [DM], n = 100). RESULTS—In Spearman correlation analyses, proinsulin and the proinsulin-to-insulin ratio were only modestly inversely related to AIR (r values from −0.02 to −0.27), and AIR was strongly related to HOMA-B (r values 0.56 and 0.58). HOMA-B markedly underestimated the magnitude of the β-cell defect across declining glucose tolerance, especially for IGT and new DM by OGTT compared with AIR. Analyses adjusting for insulin sensitivity showed that β-cell function was compromised in IGT, DM2h, DMf, and DM, relative to NGT, by 13, 12, 59, and 62% (HOMA-B) and by as much as 40, 60, 80, and 75%, using AIR. CONCLUSIONS—Subjects with IGT and early-stage, asymptomatic type 2 diabetic patients have more pronounced β-cell defects than previously estimated from epidemiological studies using homeostasis model assessment.

OBJECTIVE— The objective of the present analysis was to evaluate the association of alanine aminotransferase (ALT) with directly measured insulin sensitivity (Si) in a large, multiethnic cohort of U.S. adults and to determine whether ALT adds to existing metabolic risk definitions in identifying subjects with insulin resistance. RESEARCH DESIGN AND METHODS— Si was directly measured from frequently sampled intravenous glucose tolerance tests among 999 nondiabetic African-American, Hispanic, and non-Hispanic white subjects aged 40–69 years who were participating in the Insulin Resistance Atherosclerosis Study. Subjects also received an oral glucose tolerance test, and fasting insulin, ALT, and alcohol intake were determined. RESULTS— ALT was associated with Si after adjustment for age, sex, ethnicity, impaired fasting glucose, triglycerides, HDL, blood pressure, and waist (clinical model) (P < 0.0001). The association remained significant after further adjustment for fasting insulin and impaired glucose tolerance (P = 0.004). In logistic regression analysis, elevated ALT (upper quartile) was associated with insulin resistance (lowest quartile of Si) after adjustment for age, sex, and ethnicity (odds ratio 3.0 [95% CI 2.2–4.1]). Elevated ALT was independently associated with insulin resistance when included in models with waist circumference, National Cholesterol Education Program criteria for metabolic syndrome, hypertriglyceridemic waist, elevated triglyceride-to-HDL ratio, or homeostasis model assessment of insulin resistance (HOMA-IR) (all P < 0.01). Finally, the addition of elevated ALT improved classification of insulin resistance by area under the receiver operating characteristic curve criteria for all models except HOMA-IR. CONCLUSIONS— ALT was associated with insulin resistance independently of conventional and more detailed metabolic measures. These findings suggest that the addition of ALT to existing clinically based metabolic risk definitions is an inexpensive way to improve the identification of subjects with insulin resistance.

The triacylglycerol (TG)-to-HDL-cholesterol ratio has been shown to detect insulin resistance. However, the added predictive value of a more comprehensive assessment of lipoprotein composition is unknown. We analysed cross-sectional data from 882 non-diabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). Lipoproteins were measured by nuclear magnetic resonance (NMR) spectroscopy. Determined by the frequently sampled intravenous glucose tolerance test, insulin resistance was defined as the lowest sex-specific quartile of insulin sensitivity. The AUC of the receiver operating characteristic curve of HDL-cholesterol and TG levels for detecting insulin resistance was similar to that of the TG-to-HDL-cholesterol ratio (0.676 vs 0.673; p = 0.685), but smaller than the AUC of NMR-detected lipoproteins (0.676 vs 0.745; p

Aims To evaluate third-line thiazolidinedione (TZD) or glimepiride therapy in patients inadequately controlled on metformin + exenatide twice daily, and third-line exenatide twice daily in patients inadequately controlled on metformin + glimepiride. Methods In this randomized, open-label, multicentre trial, 144 patients with type 2 diabetes inadequately controlled [glycated haemoglobin (HbA1c) >9% (75 mmol/mol) after 3 months' treatment or >7% (53 mmol/mol) at two consecutive visits 3 months apart, after 6 months' treatment] on metformin + exenatide twice daily were re-randomized to add-on TZD or glimepiride, and 166 patients inadequately controlled on metformin + glimepiride received add-on exenatide twice daily. Changes in HbA1c, body mass index (BMI), lipids, hypoglycaemia and vital signs were evaluated. Results The median duration of triple therapy was ∼2 years. In patients inadequately controlled on metformin + exenatide twice daily, add-on TZD decreased HbA1c levels significantly better than add-on glimepiride: 130-week difference 0.48% [95% confidence interval (CI) 0.19–0.77] or 5.2 mmol/mol (95% CI 2.1–8.4; p = 0.001), but with significantly increased BMI and systolic blood pressure. The ratio of documented symptomatic (blood glucose ≤70 mg/dl [3.9 mmol/l]) hypoglycaemia rates for add-on glimepiride to add-on TZD was 8.48 (p

The aim of this 52-week, open-label, non-inferiority trial was to compare the safety and efficacy of exenatide (an incretin mimetic) with that of biphasic insulin aspart.Patients on metformin and a sulfonylurea were randomised to exenatide (n = 253; 5 microg twice daily for 4 weeks, 10 microg thereafter) or biphasic insulin aspart (n = 248; twice-daily doses titrated for optimal glucose control), while continuing with metformin and sulfonylurea treatment.Glycaemic control achieved with exenatide was non-inferior to that achieved with biphasic insulin aspart (mean+/-SEM, HbA(1c) change: exenatide -1.04 +/- 0.07%, biphasic insulin aspart -0.89 +/- 0.06%; difference -0.15 [95% CI -0.32 to 0.01]%). Exenatide-treated patients lost weight, while patients treated with biphasic insulin aspart gained weight [between-group difference -5.4 (95% CI -5.9 to -5.0) kg]. Both treatments reduced fasting serum glucose (exenatide -1.8 +/- 0.2 mmol/l, p0.001; biphasic insulin aspart -1.7 +/- 0.2 mmol/l, p0.001). Greater reductions in postprandial glucose excursions following morning (p0.001), midday (p = 0.002) and evening meals (p0.001) were observed with exenatide. The withdrawal rate was 21.3% (54/253) for exenatide and 10.1% (25/248) for biphasic insulin aspart. Nausea (33% incidence, 3.5% discontinuation) was the most common adverse event observed with exenatide.Exenatide treatment resulted in HbA(1c) reduction similar to biphasic insulin aspart and provided better postprandial glycaemic control, making it a potential alternative for the treatment of type 2 diabetes. Treatment with biphasic insulin aspart was associated with weight gain and lower risk of adverse gastrointestinal events. Although the availability of glucose-lowering agents associated with weight reduction may be considered a therapeutic advance, the long-term implications of progressive weight reduction observed with exenatide have yet to be defined.

Background— Several studies have shown that fibrinolytic and coagulation abnormalities as well as low-grade inflammation predict cardiovascular disease and type 2 diabetes. We studied in the Insulin Resistance Atherosclerosis Study the relation of incident diabetes to dynamic changes of plasminogen activator inhibitor-1 (PAI-1) and fibrinogen. Methods and Results— After a follow-up of 5.2 years, diabetes developed in 140 (16.6%) of 843 individuals (57% women; mean age [range], 54.7 [40, 69] years) (converters versus nonconverters). Baseline and follow-up levels of PAI-1 and fibrinogen (demographically and smoking adjusted) were higher in converters versus nonconverters (mean [SE]): at baseline, 23.7 ng/mL (1.5) versus 14.5 (0.4) and 286.2 mg/dL (4.8) versus 273.6 (2.1); at follow-up, 45.3 ng/mL (3.2) versus 25.9 (0.8) and 292.0 mg/dL (5.6) versus 275.2 (2.5); all P P I ) or waist, change in PAI-1 remained significantly related to incident diabetes (OR, 1.66 [1.28, 2.15], and 1.64 [1.28, 2.10]; P Conclusions— Progression of PAI-1 levels over time, in addition to high baseline PAI-1 levels, is associated with incident diabetes. PAI-1 levels (but not fibrinogen) further increase with the rising glucose levels and the development of diabetes. These findings extend the current knowledge on the relation of fibrinolysis and coagulation abnormalities to the development of type 2 diabetes.

Data from the UKPDS (U.K. Prospective Diabetes Study) indicate a continuous decline in β-cell function in patients with type 2 diabetes. We studied longitudinal changes in β-cell function (follow-up of 5.2 years) in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes, using acute insulin response (AIR) and insulin sensitivity index ( S i ) from a frequently sampled intravenous glucose tolerance test among African-American, Hispanic, and non-Hispanic white subjects aged 40–69 years. At baseline, decreasing levels of both S i and AIR (either unadjusted or adjusted for S i ) mirrored deteriorating glucose tolerance status at baseline and at follow-up. A different pattern was found with respect to longitudinal changes; S i declined in each glucose tolerance category, ranging from −0.81 ×10 −4 min −1 · μU −1 · ml −1 in NGT at baseline and NGT at follow-up (NGT/NGT) to −1.06 ×10 −4 in NGT/diabetes, whereas the directional change in AIR principally determined the glucose tolerance status at follow-up. In NGT/NGT S i decreased by 35% and AIR increased by 34%. Results were similar in each of the three ethnic groups. These data shed light on the natural course of β-cell function; over 5.2 years, mean insulin sensitivity declined in each glucose tolerance category. The change in AIR, however, principally determined glucose tolerance status at follow-up; NGT was maintained by a compensatory increase in insulin secretion. Failure to increase insulin secretion led to IGT, and a decrease in insulin secretion led to overt diabetes. This data may have important implications for the prevention and treatment of type 2 diabetes.

Background— In addition to predicting cardiovascular disease (CVD) morbidity and mortality, the metabolic syndrome is strongly associated with the development of type 2 diabetes mellitus (DM), itself an important risk factor for CVD. Our objective was to compare the ability of various metabolic syndrome criteria (including those recently proposed by the International Diabetes Federation), markers of insulin resistance (IR) and inflammation, and impaired glucose tolerance (IGT) in the prediction of DM and to determine whether various proposed modifications to the National Cholesterol Education program (NCEP) metabolic syndrome definition improved predictive ability. Methods and Results— We examined 822 subjects in the Insulin Resistance Atherosclerosis Study aged 40 to 69 years who were nondiabetic at baseline. After 5.2 years, 148 individuals had developed DM. IGT, metabolic syndrome definitions, and IR markers all significantly predicted DM, with odds ratios ranging from 3.4 to 5.4 (all P P >0.05). Similarly, although IR and inflammation variables were significantly associated with incident DM when included in multivariate models with NCEP-defined metabolic syndrome (all P P >0.05). Conclusions— The International Diabetes Federation and NCEP metabolic syndrome definitions predicted DM at least as well as the World Health Organization definition, despite not requiring the use of oral glucose tolerance testing or measures of IR or microalbuminuria. Modifications or additions to the NCEP metabolic syndrome definition had limited impact on the prediction of DM.

Nonalcoholic fatty liver disease (NAFLD) is emerging as a component of the metabolic syndrome, although it is not known whether markers of NAFLD, including elevated concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALK), predict the development of metabolic syndrome. Our objective was to investigate the associations of elevated AST, ALT, and other liver markers, including C-reactive protein (CRP), with incident National Cholesterol Education Program–defined metabolic syndrome among 633 subjects in the Insulin Resistance Atherosclerosis Study who were free of metabolic syndrome at baseline. Insulin sensitivity (Si) and acute insulin response (AIR) were directly measured from the frequently sampled intravenous glucose tolerance test among African-American, Hispanic, and non-Hispanic white subjects aged 40–69 years. After 5.2 years, 127 individuals had developed metabolic syndrome. In separate logistic regression models adjusting for age, sex, ethnicity, clinic, and alcohol consumption, subjects in the upper quartiles of ALT, ALK, and CRP were at significantly increased risk of incident metabolic syndrome compared with those in the lowest quartile: ALT, odds ratio 2.50 (95% CI 1.38–4.51); ALK, 2.28 (1.24–4.20); and CRP, 1.33 (1.09–1.63). Subjects in the upper quartile of the AST-to-ALT ratio were at significantly reduced metabolic syndrome risk (0.40 [0.22–0.74]). After further adjustment for waist circumference, Si, AIR, and impaired glucose tolerance, the associations of ALT and the AST-to-ALT ratio with incident metabolic syndrome remained significant (ALT, 2.12 [1.10–4.09]; the AST-to-ALT ratio, 0.48 [0.25–0.95]). These associations were not modified by ethnicity or sex, and they remained significant after exclusion of former and heavy drinkers. In conclusion, NAFLD markers ALT and the AST-to-ALT ratio predict metabolic syndrome independently of potential confounding variables, including directly measured Si and AIR.

Background— Subjects with type 2 diabetes have smaller LDL and HDL particles in addition to higher levels of triglycerides and lower HDL cholesterol. Elevated insulin resistance, blood pressure, and dyslipidemia (including small dense LDL) predicted incident diabetes. In the Insulin Resistance Atherosclerosis Study (IRAS) we studied nuclear magnetic resonance (NMR) lipoprotein particle measures in prediabetic individuals, considering potentially modifying covariates, including insulin resistance, as directly measured using a frequently sampled intravenous glucose tolerance test. Methods and Results— Of 830 subjects who were nondiabetic at baseline, 130 (15.7%) developed diabetes after a mean follow-up of 5.2 years. Various lipoprotein abnormalities were found in prediabetic subjects compared with subjects who stayed nondiabetic at follow-up. In logistic regression analyses (demographically adjusted), VLDL particles, large VLDL, LDL particles, small LDL, large HDL, small HDL, VLDL size, LDL size, and HDL size were related to incident diabetes. The relation of VLDL size and small HDL to incident diabetes was independent of waist (odds ratio [OR] [95% CI], 1.43 [1.18 to 1.73] and 1.23 [1.01 to 1.51] for VLDL size and small HDL, respectively) and independent of conventionally (chemically) measured triglycerides and HDL cholesterol (OR [95% CI], 1.45 [1.18 to 1.78] and 1.30 [1.06 to 1.60], respectively). Insulin sensitivity attenuated the relation to incident diabetes of VLDL size (OR [95% CI], 1.25 [1.01 to 1.53]) but not of small HDL particles (OR [95% CI], 1.25 [1.02 to 1.54]). Conclusions— We have shown a range of lipoprotein abnormalities in prediabetic individuals, including compositional changes in HDL and VLDL. These findings extend previous work indicating a proatherogenic state in healthy, nondiabetic subjects who subsequently develop diabetes.

A limited number of studies have reported associations of markers of liver injury, including elevated concentrations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), with prospective risk of type 2 diabetes. However, only one study has adjusted for a detailed measure of insulin sensitivity (insulin sensitivity index [Si]), which is important given associations of obesity and Si with nonalcoholic fatty liver disease (NAFLD). Our objective was to investigate the associations of elevated AST and ALT with incident type 2 diabetes among 906 participants in the Insulin Resistance Atherosclerosis Study who were nondiabetic at baseline. Si and acute insulin response (AIR) were measured directly from the frequently sampled intravenous glucose tolerance test among black, Hispanic, and non-Hispanic white participants aged 40–69 years. After 5.2 years, 148 individuals had developed type 2 diabetes. Baseline AST and ALT were positively correlated with fasting insulin (r = 0.22 and r = 0.35, respectively), waist circumference (r = 0.18 and r = 0.34), and fasting glucose (r = 0.13 and r = 0.29) and inversely with Si (r = −0.18 and r = −0.30; all P < 0.0001). In separate logistic regression models adjusting for age, sex, ethnicity, clinical center, and alcohol consumption, participants in the highest quartiles (Q4) of AST and ALT were at significantly increased risk of incident type 2 diabetes compared with those in the lowest three quartiles (Q1–Q3): AST: odds ratio (OR) 1.73 (95% CI 1.17–2.57); ALT: OR 2.32 (1.36–3.75). After further adjustment for smoking, waist circumference, triglyceride, HDL, impaired glucose tolerance, Si, and AIR, both AST and ALT remained significantly associated with incident type 2 diabetes: AST, Q4 vs. Q1–Q3: OR 1.98 (1.23–3.17); ALT, Q4 vs. Q1–Q3: OR 2.00 (1.22–3.28). There were no interactions of sex, ethnicity, obesity, impaired glucose tolerance, or Si with AST or ALT in the prediction of type 2 diabetes. When entered into the same model with adjustment for demographic variables, both C-reactive protein and ALT independently predicted type 2 diabetes. In addition, AST and ALT were positively associated with incident type 2 diabetes after excluding former and moderate to heavy drinkers. In conclusion, AST and ALT independently predict type 2 diabetes. Baseline elevations of these markers may reflect NAFLD or related pathologies.

Factor analysis, a multivariate correlation technique, has been used to provide insight into the underlying structure of the metabolic syndrome. The majority of previous factor analyses, however, have used only surrogate measures of insulin sensitivity; very few have included nontraditional cardiovascular disease (CVD) risk factors such as plasminogen activator inhibitor (PAI)-1, fibrinogen, and C-reactive protein (CRP); and only a limited number have assessed the ability of factors to predict type 2 diabetes. The objective of this study was to investigate, using factor analysis, the clustering of metabolic and inflammation variables using data from 1,087 nondiabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS) and to determine the association of these clusters with risk of type 2 diabetes at follow-up. This study includes information on directly measured insulin sensitivity (Si) from the frequently sampled intravenous glucose tolerance test among African-American, Hispanic, and non-Hispanic white subjects aged 40–69 years. Principal factor analysis of data from nondiabetic subjects at baseline (1992–1994) identified three factors, which explained 28.4, 7.4, and 6% of the total variance in the dataset, respectively. Based on factor loadings of ≥ 0.40, these factors were interpreted as 1) a “metabolic” factor, with positive loadings of BMI, waist circumference, 2-h glucose, log triglyceride, and log PAI-1 and inverse loadings of log Si + 1 and HDL; 2) an “inflammation” factor, with positive loadings of BMI, waist circumference, fibrinogen, and log CRP and an inverse loading of log Si + 1; and 3) a “blood pressure” factor, with positive loadings of systolic and diastolic blood pressure. The results were similar within strata of ethnicity, and there were only subtle differences in sex-specific analyses. In a prospective analysis, each of the factors was a significant predictor of diabetes after a median follow-up period of 5.2 years, and each factor remained significant in a multivariate model that included all three factors, although this three-factor model was not significantly more predictive than models using either impaired glucose tolerance or conventional CVD risk factors. Factor analysis identified three underlying factors among a group of inflammation and metabolic syndrome variables, with insulin sensitivity loading on both the metabolic and inflammation variable clusters. Each factor significantly predicted diabetes in multivariate analysis. The findings support the emerging hypothesis that chronic subclinical inflammation is associated with insulin resistance and comprises a component of the metabolic syndrome.

OBJECTIVE—Women with prior gestational diabetes mellitus (pGDM) are at increased risk of developing type 2 diabetes and associated vasculopathy. Because increased fat mass and inflammatory processes are angiopathic risk factors, the relationship between insulin sensitivity, parameters of subclinical inflammation, and plasma concentrations of adipocytokines was investigated in pGDM both at 3 months and 12 months after delivery. RESEARCH DESIGN AND METHODS—Insulin sensitivity (through a frequently sampled intravenous glucose tolerance test) and plasma concentrations of ultrasensitive C-reactive protein (CRP), adiponectin, plasminogen activator inhibitor (PAI)-1, tumor necrosis factor-α, leptin, and interleukin-6 were measured in 89 pGDM (BMI 26.9 ± 0.5 kg/m2, age 32 ± 0.5 years) and in 19 women with normal glucose tolerance during pregnancy (NGT) (23.7 ± 0.9 kg/m2, 31 ± 1.3 years). RESULTS—pGDM showed lower (P < 0.0001) plasma adiponectin (6.7 ± 0.2 μg/ml) than NGT (9.8 ± 0.6 μg/ml) and a decreased (P < 0.003) insulin sensitivity index (Si) and disposition index (P < 0.03), but increased plasma leptin (P < 0.003), PAI-1 (P < 0.002), and CRP (P < 0.03). After adjustment for body fat mass, plasma adiponectin remained lower in pGDM (P < 0.004) and correlated positively with Si (P < 0.003) and HDL cholesterol (P < 0.0001) but negatively with plasma glucose (2-h oral glucose tolerance test [OGTT]) (P < 0.0001), leptin (P < 0.01), CRP (P < 0.007), and PAI-1 (P < 0.0001). On regression analysis, only HDL cholesterol, postload (2-h OGTT) plasma glucose, and Si remained significant predictors of plasma adiponectin, explaining 42% of its variability. Of note, adiponectin further decreased (P < 0.05) only in insulin-resistant pGDM despite unchanged body fat content and distribution after a 1-year follow-up. CONCLUSIONS—Lower plasma adiponectin concentrations characterize women with previous GDM independently of the prevailing insulin sensitivity or the degree of obesity and are associated with subclinical inflammation and atherogenic parameters.

Both impaired glucose tolerance (IGT) (as defined by the 1985 World Health Organization criteria) and impaired fasting glucose (IFG) (as defined by the 1997 American Diabetes Association criteria) represent intermediate metabolic states between normal and diabetic glucose homeostasis. Cardiovascular disease may be related to postglucose load rather than fasting glycemia, i.e., IGT rather than IFG. We hypothesized that subjects with IGT may be more insulin resistant and have higher levels of common cardiovascular risk factors than those with isolated IFG. In the Insulin Resistance Atherosclerosis Study (IRAS), we studied S(i) and first-phase insulin secretion (acute insulin response [AIR]), as derived from a frequently sampled intravenous glucose tolerance test, as well as common cardiovascular risk factors in four different glucose tolerance categories (NFG/NGT [n = 654], NFG/IGT [n = 255], IFG/NGT [n = 59], and IFG/IGT [n = 102]) among nondiabetic subjects. Subjects with isolated postchallenge hyperglycemia (NFG/IGT) had lower S(i) (means +/- SE: 2.10 +/- 0.04 vs. 2.59 +/- 0.13 x 10(-4) min(-1). microU(-1). ml(-1); P = 0.005), lower proinsulin levels (34.4 +/- 1.8 vs. 42.0 +/- 4.5 pmol/l; P = 0.03), higher AIR (273.1 +/- 18.1 vs. 215.9 +/- 30.0 pmol/l; P = 0.04), higher C-reactive protein (2.49 +/- 0.3 vs. 1.49 +/- 0.5 mg/l; P = 0.0015), and higher triglyceride levels (137.7 +/- 5.5 vs. 108.4 +/- 8.9 mg/dl; P = 0.0025) than subjects with isolated fasting hyperglycemia (IFG/NGT). The relation of insulin resistance to glucose tolerance category was consistently seen in women and men and across the three ethnic groups of the IRAS (non-Hispanic whites, African Americans, and Hispanics). Nondiabetic individuals with isolated postchallenge hyperglycemia (IGT) are more insulin resistant than individuals with isolated fasting hyperglycemia (IFG). The risk factor pattern (including increased insulin resistance) seen in isolated IGT identifies a subgroup of nondiabetic individuals who are likely to benefit from early intervention.

Background— Elevated levels of proinflammatory proteins are predictive of both cardiovascular (CV) disease and type 2 diabetes. Previously, atherogenic changes in traditional CV risk factors in the prediabetic state were mainly seen in insulin-resistant subjects rather than in those with a predominant defect in insulin secretion. Methods and Results— We studied in prediabetic individuals from the Insulin Resistance Atherosclerosis Study (IRAS) the relation of C-reactive protein (CRP), plasminogen activator inhibitor (PAI)-1, and fibrinogen to defects in insulin sensitivity (S I ) and first-phase insulin secretion, respectively, as assessed using a frequently sampled intravenous glucose tolerance test. One hundred forty-eight of 906 (16.3%) nondiabetic individuals developed diabetes after a mean follow-up of 5.2 years. Prediabetic individuals who were insulin resistant had higher levels of PAI-1 (mean [95% CI], 25.83 ng/mL [22.42 to 29.77] versus 16.31 ng/mL [12.56 to 21.18]; P =0.003) and CRP (mean [95% CI], 2.88 mg/L [2.33 to 3.56] versus 1.68 mg/L [1.13 to 2.49]; P =0.018) than insulin-sensitive individuals, but individuals with decreased acute insulin response tended to have lower rather than higher levels of inflammatory proteins compared with those with high insulin secretion. Prediabetic subjects who were predominantly insulin resistant had higher levels of inflammatory proteins compared with both prediabetic subjects with decreased insulin secretion as well as nonconverters. By contrast, prediabetic subjects with a predominant defect in first-phase insulin secretion had levels of inflammatory proteins indistinguishable from those in nonconverters. Conclusions— We have shown an increased proinflammatory state in prediabetic individuals who are predominantly insulin resistant but not in those with a primary defect in β-cell function. These results provide additional evidence that prediabetic subjects may be at an increased risk of heart disease, and this risk seems to be restricted to subjects with high insulin resistance.

OBJECTIVE—To determine the meaning of Si = 0 derived from the frequently sampled intravenous glucose tolerance test. RESEARCH DESIGN AND METHODS—The issue of assessing insulin resistance in large studies is important because the most definitive method (“gold standard”), the hyperinsulinemic-euglycemic clamp, is expensive and invasive. The frequently sampled intravenous glucose tolerance test (FSIGTT) has been widely used, but in insulin-resistant subjects (especially diabetic subjects), it yields considerable numbers of subjects whose Si is zero. The interpretation of an Si equaling zero is unknown. RESULTS—To address this issue, we examined 1,482 subjects from the Insulin Resistance Atherosclerosis Study (IRAS) using an insulin-modified FSIGTT and minimal model calculation of Si. The proportion of insulin-resistant subjects (Si < 1.61 × 10−4 [min−1 · μU−1 · ml−1] based on the median of the nondiabetic population) was 38.6% in subjects with normal glucose tolerance (NGT), 74% in subjects with impaired glucose tolerance (IGT), and 92% in subjects with type 2 diabetes. The proportion of subjects with Si = 0 was 2.2% in subjects with NGT, 13.2% in subjects with IGT, and 35.7% in subjects with type 2 diabetes. In subjects with IGT, those with Si = 0 had significantly lower HDL cholesterol levels and higher BMI, waist circumference, fibrinogen, plasminogen-activator inhibitor 1 (PAI-1), C-reactive protein (CRP), and 2-h insulin levels than insulin-resistant subjects with Si > 0. In type 2 diabetes, subjects with Si = 0 had significantly greater BMI and waist circumference and higher triglyceride, PAI-1, CRP, fibrinogen, and fasting and 2-h insulin levels than insulin-resistant subjects with Si > 0. In addition, diabetic subjects with Si = 0 had more metabolic disorders related to the insulin resistance syndrome than diabetic insulin-resistant subjects with Si > 0. CONCLUSIONS—We found very few subjects with Si = 0 among subjects with NGT and few subjects with Si = 0 among subjects with IGT. In contrast, Si = 0 was common in subjects with diabetes. Subjects with Si = 0 tended to have more features of the insulin resistance syndrome than other insulin-resistant subjects with Si > 0, as would be expected of subjects with almost no insulin-mediated glucose disposal, thus suggesting that subjects with Si = 0 are correctly classified as being very insulin resistant rather than having failed the minimal model program.

Objective— Obesity is closely linked to the insulin resistance syndrome (IRS), type 2 diabetes, and cardiovascular disease, the primary cause of morbidity and mortality in these patients. Elevated levels of C-reactive protein (CRP) and interleukin-6 (IL-6), indicating chronic subclinical inflammation, have been associated with features of the IRS and incident cardiovascular disease. Methods and Results— We studied the cross-sectional and longitudinal relation of CRP, IL-6, and tumor necrosis factor-α (TNF-α) with features of the IRS in 37 morbidly obese patients with different stages of glucose tolerance before and 14 months after gastric surgery. Weight loss after gastric surgery induced a significant shift from diabetes (37% vs 3%) to impaired glucose tolerance (40% vs 33%) and normal glucose tolerance (23% vs 64%). The baseline concentration of IL-6 was correlated with TNF-α ( r =0.59, P r =0.44, P r =0.48, P r =0.56, P r =0.35, P P P P P Conclusions— Weight loss in morbidly obese patients induces a significant decrease of CRP and IL-6 concentrations in association with an improvement of the IRS.

Background— The 4G/5G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene has been related to cardiovascular disease. Methods and Results— Insulin resistance was measured with a frequently sampled intravenous glucose tolerance test in the Insulin Resistance Atherosclerosis Study (IRAS), and PAI-1 4G/5G promoter genotype was established by allele-specific polymerase chain reaction amplification of genomic DNA. There were 287 subjects with the 4G/4G genotype (18.4%), 691 heterozygote subjects (44.2%), and 586 carriers of the 5G/5G genotype (37.5%). The genotype distribution was different across the 3 ethnic groups ( P =0.001). PAI-1 levels were lower in blacks than in non-Hispanic whites and Hispanics and lower in non-Hispanic whites than in Hispanics (all P =0.0001). Subjects homozygous for the 4G allele had the highest plasma PAI-1, heterozygote subjects were intermediate, and 5G homozygotes had the lowest levels of PAI-1. These patterns remained unaffected by adjustments for age, gender, clinical center, glucose tolerance status, body mass index, waist, triglycerides, and insulin resistance. Multiple linear regression analyses showed that the 4G/5G genotype explained very little of the variation in PAI-1 levels (0.63% in non-Hispanic whites, 0.99% in Hispanics, and 2.37% in blacks), and interaction analyses revealed no significant differences in the relation of circulating PAI-1 levels to the 4G/5G genotype by ethnicity ( P =0.4). Conclusions— We have shown ethnic differences in the PAI-1 4G/5G polymorphism along with corresponding differences in circulating PAI-1 levels. The association of the genotype with PAI-1 levels was seen consistently among all 3 ethnic groups and was unaffected by metabolic covariates, including insulin resistance.

Previous studies in diabetic patients suggested a relationship between delayed gastric emptying and increased ingesta retention in either proximal or distal stomach, but the determinants underlying these abnormalities remained obscure. We aimed at assessing the impact of cardiovascular autonomic neuropathy, blood glucose concentration, long-term glycemic control, and other factors in 34 type I and 43 type II diabetic patients (ages 21–67 and 34–81 years, respectively). Emptying was slower (P < 0.04) in type I diabetic patients than in 20 healthy control subjects (ages 23–63 years). Patients with autonomic neuropathy (N = 45) had slower gastric emptying (P < 0.02) and retained more in the distal stomach (P < 0.0001) than patients without neuropathy (N = 32). Multiple regression analyses revealed that slow emptying and increased distal retention were significantly associated with autonomic neuropathy (P < 0.043, P < 0.0002), whereas blood glucose, glycemic control, diabetes duration, age, and other factors had no discernible influence. Thus, both slow emptying and increased distal ingesta retention seem primarily referable to autonomic neuropathy.

Factor analysis, a multivariate correlation technique, has been used to provide insight into the underlying structure of metabolic syndrome, which is characterized by physiological complexity and strong statistical intercorrelation among its key variables. The majority of previous factor analyses, however, have used only surrogate measures of insulin sensitivity. In addition, few have included members of multiple ethnic groups, and only one has presented results separately for subjects with impaired glucose tolerance. The objective of this study was to investigate, using factor analysis, the clustering of physiologic variables using data from 1,087 nondiabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). This study includes information on the directly measured insulin sensitivity index (SI) from intravenous glucose tolerance testing among African-American, Hispanic, and non-Hispanic white subjects aged 40–69 years at various stages of glucose tolerance. Principal factor analysis identified two factors that explained 28 and 9% of the variance in the dataset, respectively. These factors were interpreted as 1) a “ metabolic” factor, with positive loadings of BMI, waist, fasting and 2-h glucose, and triglyceride and inverse loadings of log(SI+1) and HDL; and 2) a “blood pressure” factor, with positive loadings of systolic and diastolic blood pressure. The results were unchanged when surrogate measures of insulin resistance were used in place of log(SI+1). In addition, the results were similar within strata of sex, glucose tolerance status, and ethnicity. In conclusion, factor analysis identified two underlying factors among a group of metabolic syndrome variables in this dataset. Analyses using surrogate measures of insulin resistance suggested that these variables provide adequate information to explore the underlying intercorrelational structure of metabolic syndrome. Additional clarification of the physiologic characteristics of metabolic syndrome is required as individuals with this condition are increasingly being considered candidates for behavioral and pharmacologic intervention.

Elevated serum levels of acute-phase proteins, indicating chronic subclinical inflammation, have been associated with cardiovascular disease as well as the insulin resistance syndrome. Chronic inflammation may also be a risk factor for developing type 2 diabetes. We studied the concentrations of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in 1,047 nondiabetic subjects in relation to incident diabetes within 5 years in the Insulin Resistance Atherosclerosis Study. Subjects with diabetes at follow-up (n = 144) had higher baseline levels of fibrinogen (mean ± SD; 287.8 ± 58.8 vs. 275.1 ± 56.0 mg/dl; P = 0.013) as well as of CRP (median [interquartile range]; 2.40 [1.29, 5.87] vs. 1.67 mg/l [0.75, 3.41]; P = 0.0001) and PAI-1 (24 [15, 37.5] vs. 16 ng/ml [9, 27]; P = 0.0001) than nonconverters. The odds ratio (OR) of converting to diabetes was significantly increased with increasing baseline concentrations of the inflammatory markers. In contrast to PAI-1, the association of CRP and fibrinogen with incident diabetes was significantly attenuated after adjustment for body fat (BMI or waist circumference) or insulin sensitivity (SI), as assessed by a frequently sampled intravenous glucose tolerance test. In a logistic regression model that included age, sex, ethnicity, clinical center, smoking, BMI, SI, physical activity, and family history of diabetes, PAI-1 still remained significantly related to incident type 2 diabetes (OR [95% CI] for 1 SD increase: 1.61 [1.20–2.16]; P = 0.002). Chronic inflammation emerges as a new risk factor for the development of type 2 diabetes; PAI-1 predicts type 2 diabetes independent of insulin resistance and other known risk factors for diabetes.

Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: The Insulin Resistance Atherosclerosis Study.BackgroundMicroalbuminuria is a risk factor for cardiovascular disease, but the underlying pathomechanisms are still poorly understood. A relationship between C-reactive protein (CRP), a sensitive marker of inflammation, and atherosclerotic disease has been reported recently.MethodsWe hypothesized that microalbuminuria might be associated with chronic inflammation and investigated the relationship of urinary albumin excretion, as assessed from the albumin-to-creatinine ratio (ACR), in an untimed morning urine specimen, and two inflammatory markers (CRP and fibrinogen) in the large, triethnic population of the Insulin Resistance Atherosclerosis Study (IRAS). After exclusion of subjects with macroalbuminuria, 1481 subjects were studied.ResultsBoth inflammatory markers were related to urinary ACR (r = 0.17 for CRP and r = 0.14 for fibrinogen, both P = 0.0001), an association that remained significant after adjustment for demographic variables, diabetic status, smoking, and use of angiotensin-converting enzyme inhibitors (P < 0.01). Mean levels of CRP and fibrinogen were elevated in microalbuminuric (N = 262) versus normoalbuminuric (N = 1219) subjects (5.37 ± 0.47 vs. 3.80 ± 0.15 mg/L and 295.7 ± 4.0 vs. 278.2 ± 1.6 mg/dL, both P < 0.0001). The associations were consistent among nondiabetic and type 2 diabetic subjects and among the three ethnic groups of the IRAS (non-Hispanic whites, blacks, Hispanics). In a logistic regression model, fibrinogen was independently associated with microalbuminuria (P = 0.047), along with hypertension, female gender, waist circumference, and fasting blood glucose, while CRP was not independently related to microalbuminuria in this model (P = 0.26).ConclusionWe have shown an association of CRP and fibrinogen with urinary albumin excretion in the microalbuminuric range in type 2 diabetic and nondiabetic individuals. Chronic inflammation therefore emerges as a potential mediator between microalbuminuria and macrovascular disease.

OBJECTIVE: Elevated heart rate has been predictive of cardiovascular disease and has been proposed as a global index of the autonomic nervous system influence on the heart. Hyperinsulinism has been shown to trigger sympathetic activity experimentally; however, the clinical and epidemiological data on the association of heart rate with hyperinsulinism and insulin resistance are conflicting. RESEARCH DESIGN AND METHODS: Insulin sensitivity (S(I)) and the acute insulin response (AIR) to glucose were assessed by a frequently sampled intravenous glucose tolerance test and related to resting heart rate in the tri-ethnic nondiabetic population (n = 1,000) of the Insulin Resistance Atherosclerosis Study. RESULTS: Heart rate was related to fasting insulin (r = 0.20), intact proinsulin (r = 0.15), split proinsulin (r = 0.17), and AIR (r = 0.18), and an inverse relation was found between heart rate and S(I) (r = -0.19) (all P values

Background —Subjects who convert to type 2 diabetes mellitus have increased cardiovascular risk factors relative to nonconverters. However, it is not known whether these atherogenic changes in the prediabetic state are predominantly due to insulin resistance, decreased insulin secretion, or both. Methods and Results —We examined this issue in the 7-year follow-up of the San Antonio Heart Study, in which 195 of 1734 subjects converted to type 2 diabetes. At baseline, converters had significantly higher body mass index, waist circumference, triglyceride concentration, and blood pressure and lower HDL cholesterol than nonconverters. Atherogenic changes in converters were markedly attenuated (and no longer significant) after adjustment for the homeostasis model assessment of insulin resistance (HOMA IR, a surrogate for insulin resistance); in contrast, the differences in risk factors between converters and nonconverters increased after adjustment for the ratio of early insulin increment to early glucose increment (ΔI 30-0 /ΔG 30-0 ) during an oral glucose tolerance test (a surrogate for insulin secretion). We also compared converters who had a predominant insulin resistance (high HOMA IR and high ΔI 30-0 /ΔG 30-0 ) (n=56) and converters who had a predominant decrease in insulin secretion (low HOMA IR and low ΔI 30-0 /ΔG 30-0 ) (n=31) with nonconverters (n=1539). Only the converters who were insulin resistant had higher blood pressure and triglyceride levels and lower HDL cholesterol levels than nonconverters. Conclusions —Our data suggest that atherogenic changes in the prediabetic state are mainly seen in insulin-resistant subjects and that strategies to prevent type 2 diabetes might focus on insulin-sensitizing interventions rather than interventions that increase insulin secretion because of potential effects on cardiovascular risk.

OBJECTIVE: LDL particles are heterogeneous in terms of size and density; small dense LDL particles are considered more atherogenic than larger LDL particles. The aim of this study was to investigate the interrelationships among LDL size, insulin, proinsulin (intact and split), and insulin sensitivity in a tri-ethnic population with varying degrees of glucose tolerance (n = 1,549) in the Insulin Resistance Atherosclerosis Study. RESEARCH DESIGN AND METHODS: Insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test with minimal model analysis. Proinsulin levels were measured using highly sensitive assays without detectable cross-reactivity with insulin, and LDL size was determined by gradient-gel electrophoresis. RESULTS: In univariate analyses, LDL size was related to various features of the insulin resistance syndrome, including fasting insulin (r = -0.18), intact proinsulin (r = -0.24), split proinsulin (r = -0.24), the proinsulin-to-insulin ratio (r = -0.14), and insulin sensitivity (r = 0.21; all P < 0.0001). In a multivariate regression model (adjusted for age, BMI, ethnicity, and clinic), triglyceride levels (P = 0.0001), HDL cholesterol (P = 0.0001), sex (P = 0.002), and proinsulin (P = 0.01) were significantly related to LDL size. In the same model stratified by sex, LDL size was significantly inversely related to proinsulin in men (P = 0.005 and P = 0.04 after further adjustment for the glucose tolerance status), but not in women (P > 0.15). CONCLUSIONS: We found an inverse relation of proinsulin to LDL particle size in a large tri-ethnic population with varying degrees of glucose tolerance. This relation was independent of age, BMI, and triglyceride and HDL cholesterol concentrations, and was more pronounced in men than in women.

Abstract —The prevalence of cardiovascular disease (CVD) and atherosclerosis varies among several minority ethnic groups in the United States. Recently, small, dense low density lipoprotein (LDL) particle size has been recognized as a risk factor for CVD. We examined LDL size as a possible explanation for differences in CVD rates in 1571 subjects from the Insulin Resistance Atherosclerosis Study (IRAS), a multiethnic study of insulin resistance and cardiovascular risk factors. LDL size (Å) was significantly different by ethnic group (African Americans 262.1±0.6, Hispanics 257.6±0.6, and non-Hispanic whites 259.2±0.4, P

Aims/hypothesis. Proinsulin concentrations are increased relative to insulin concentrations in subjects with Type II (non-insulin-dependent) diabetes mellitus. This could be secondary to hyperglycaemia or insulin resistance or due to a defect in insulin secretion. Methods. We investigated the association between fasting insulin, intact proinsulin and the intact proinsulin: insulin ratio with insulin sensitivity, estimated by a frequently sampled intravenous glucose tolerance test and the minimal model and with acute insulin response (AIR) in 182 newly diagnosed Type II diabetic subjects aged 40 to 69 years. None of the subjects was receiving hypoglycaemic medication. Results. Insulin sensitivity correlated inversely with fasting insulin (r s = –0.42) and intact proinsulin (r s = –0.32) (p < 0.001). The intact proinsulin:insulin ratio was not correlated with insulin sensitivity. AIR correlated positively with intact proinsulin (r s = 0.23) and inversely with the intact proinsulin:insulin ratio (r s = –0.29, p < 0.001). Fasting glucose correlated positively with intact proinsulin (r s = 0.34) and the intact proinsulin:insulin ratio (r s = 0.24, p < 0.001). The intact proinsulin:insulin ratio increased by decreasing AIR (quartiles of AIR from high to low: 7.8, 8.2, 9.7 and 12.1 %, p < 0.001). This association was independent of age, sex, ethnicity, body mass index, fasting glucose, and insulin sensitivity. Conclusion/interpretation. Insulin resistance (low insulin sensitivity) was not related to the intact proinsulin:insulin ratio in subjects with Type II diabetes. In contrast, both low AIR and high fasting glucose concentrations were associated with a disproportionate increase in proinsulin concentration. These results suggest that increased intact proinsulin:insulin ratio is a marker of a defect in insulin secretion in Type II diabetic subjects. [Diabetologia (1999) 42: 1060–1066]

Summary Aims There is increasing evidence suggesting that leptin plays a major role in the regulation of energy homeostasis, as well as in the neuroendocrine and reproductive systems. Leptin is synthesized in the human placenta. The aim of this study was to relate serum leptin levels during pregnancy to glucose tolerance, body mass index (BMI) and specific metabolic variables, such as specific insulin and proinsulin. Methods A 2-h 75 g oral glucose tolerance test was performed in 221 pregnant women at 22–29 weeks of gestation (median 25th week). Serum leptin was measured using a radioimmunoassay. In 49 women, sequential leptin measurements were performed (during pregnancy and post partum (median 5 months)). Results During pregnancy serum leptin was significantly related to body weight (r = 0.49), BMI (r = 0.51), fasting immunoreactive insulin (r = 0.46), specific insulin (r = 0.43) and proinsulin (r = 0.29) (all P-values

OBJECTIVE To investigate whether autonomic neuropathy or hyperglycemia plays a crucial etiological role in gastric retention of ingesta frequently found in type I diabetic patients. RESEARCH DESIGN AND METHODS We investigated the gastric emptying of a radiolabeled semisolid 1,168 kJ meal in 38 female and 45 male patients (age 18–75 years; illness duration 3–46 years). None took drugs affecting gastrointestinal motility. Fasted patients underwent tests of cardiovascular autonomic and peripheral nerve function. Blood glucose levels were determined before and after the scintigraphic recording of gastric emptying. RESULTS The percentage of meal remaining in the stomach at the end of the 50-min recording time was related significantly to the patients' degree of cardiovascular autonomic neuropathy [r (81) = 0.235, P < 0.028] but not to their degree of peripheral neuropathy, preprandial blood glucose level, HbA1c indicative of glycemic control, diabetes duration, and age. The patients' mean residual percentage of meal was significantly > that of 48 healthy subjects, that is, 71.1 ± 15.1 vs. 53.5 ± 13.1% [means ± SD; t (129) = 6.48, P < 0.0001]. The healthy individuals' mean residual percentage + 2 SD was exceeded in 22 patients. CONCLUSIONS Slow gastric emptying in patients with type I diabetes seems related to the degree of autonomic neuropathy but not to peripheral neuropathy, actual blood glucose, and glycemic control.

Glycaemic control deteriorates progressively over time in patients with type 2 diabetes. Options for treatment escalation remain controversial after failure of first-line treatment with metformin. We compared add-on exenatide with glimepiride for durability of glycaemic control in patients with type 2 diabetes inadequately controlled by metformin alone.We did an open-label, randomised controlled trial at 128 centres in 14 countries between Sept 5, 2006, and March 29, 2011. Patients aged 18-85 years with type 2 diabetes inadequately treated by metformin were randomly assigned via a computer-generated randomisation sequence to receive exenatide twice daily or glimepiride once daily as add-on to metformin. Randomisation was stratified by predetermined categories of glycated haemoglobin (HbA(1C)) concentration. The primary outcome was time to inadequate glycaemic control and need for alternative treatment, defined as an HbA(1c) concentration of more than 9% after the first 3 months of treatment, or more than 7% at two consecutive visits after the first 6 months. Analysis was by intention to treat. This trial is registered with EudraCT, number 2005-005448-21, and ClinicalTrials.gov, number NCT00359762.We randomly assigned 515 patients to the exenatide group and 514 to the glimepiride group, of whom 490 versus 487 were the intention-to-treat population. 203 (41%) patients had treatment failure in the exenatide group compared with 262 (54%) in the glimepiride group (risk difference 12·4 [95% CI 6·2-18·6], hazard ratio 0·748 [0·623-0·899]; p=0·002). 218 (44%) of 490 patients in the exenatide group, and 150 (31%) of 487 in the glimepiride group achieved an HbA(1c) concentration of less than 7% (p0·0001), and 140 (29%) versus 87 (18%) achieved concentrations of 6·5% and less (p=0·0001). We noted a significantly greater decrease in bodyweight in patients given exenatide than in those given glimepiride (p0·0001). Five patients in each treatment group died from causes unrelated to treatment. Significantly fewer patients in the exenatide group than in the glimepiride group reported documented symptomatic (p0·0001), nocturnal (p=0·007), and non-nocturnal (p0·0001) hypoglycaemia. Discontinuation because of adverse events (mainly gastrointestinal) was significantly higher (p=0·0005) in the exenatide group than in the glimepiride group in the first 6 months of treatment, but not thereafter.These findings provide evidence for the benefits of exenatide versus glimepiride for control of glycaemic deterioration in patients with type-2 diabetes inadequately controlled by metformin alone.Eli Lilly and Company; Amylin Pharmaceuticals.

Methods to assess beta-cell function in clinical studies are limited. The aim of the current study was to compare a direct measure of insulin secretion with fasting surrogate markers in relation to glucose tolerance status.In 1,380 individuals from the Insulin Resistance Atherosclerosis Study, beta-cell function was assessed using a frequently sampled intravenous glucose tolerance test (first-phase insulin secretion; acute insulin response [AIR]), homeostasis model assessment of beta-cell function (HOMA-B), proinsulin levels, and the proinsulin-to-insulin ratio. Beta-cell function was cross-sectionally analyzed by glucose tolerance categories (normal glucose tolerance [NGT], n = 712; impaired glucose tolerance [IGT], n = 353; newly diagnosed diabetes by 2-h glucose from an oral glucose tolerance test [OGTT] [DM2h], n = 80; newly diagnosed diabetes by fasting glucose [DMf], n = 135; or newly diagnosed diabetes by fasting and 2-h glucose and established diabetes on diet/exercise only [DM], n = 100).In Spearman correlation analyses, proinsulin and the proinsulin-to-insulin ratio were only modestly inversely related to AIR (r values from -0.02 to -0.27), and AIR was strongly related to HOMA-B (r values 0.56 and 0.58). HOMA-B markedly underestimated the magnitude of the beta-cell defect across declining glucose tolerance, especially for IGT and new DM by OGTT compared with AIR. Analyses adjusting for insulin sensitivity showed that beta-cell function was compromised in IGT, DM2h, DMf, and DM, relative to NGT, by 13, 12, 59, and 62% (HOMA-B) and by as much as 40, 60, 80, and 75%, using AIR.Subjects with IGT and early-stage, asymptomatic type 2 diabetic patients have more pronounced beta-cell defects than previously estimated from epidemiological studies using homeostasis model assessment.

The objective of the present analysis was to evaluate the association of alanine aminotransferase (ALT) with directly measured insulin sensitivity (S(i)) in a large, multiethnic cohort of U.S. adults and to determine whether ALT adds to existing metabolic risk definitions in identifying subjects with insulin resistance.S(i) was directly measured from frequently sampled intravenous glucose tolerance tests among 999 nondiabetic African-American, Hispanic, and non-Hispanic white subjects aged 40-69 years who were participating in the Insulin Resistance Atherosclerosis Study. Subjects also received an oral glucose tolerance test, and fasting insulin, ALT, and alcohol intake were determined.ALT was associated with S(i) after adjustment for age, sex, ethnicity, impaired fasting glucose, triglycerides, HDL, blood pressure, and waist (clinical model) (P0.0001). The association remained significant after further adjustment for fasting insulin and impaired glucose tolerance (P = 0.004). In logistic regression analysis, elevated ALT (upper quartile) was associated with insulin resistance (lowest quartile of S(i)) after adjustment for age, sex, and ethnicity (odds ratio 3.0 [95% CI 2.2-4.1]). Elevated ALT was independently associated with insulin resistance when included in models with waist circumference, National Cholesterol Education Program criteria for metabolic syndrome, hypertriglyceridemic waist, elevated triglyceride-to-HDL ratio, or homeostasis model assessment of insulin resistance (HOMA-IR) (all P0.01). Finally, the addition of elevated ALT improved classification of insulin resistance by area under the receiver operating characteristic curve criteria for all models except HOMA-IR.ALT was associated with insulin resistance independently of conventional and more detailed metabolic measures. These findings suggest that the addition of ALT to existing clinically based metabolic risk definitions is an inexpensive way to improve the identification of subjects with insulin resistance.