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Objective: A1C measurement has advantages over measures of plasma glucose. Few studies have evaluated the A1C-fasting plasma glucose (FPG) relationship and whether oral antidiabetes drugs (OADs) and ethnic or geographic variations affect the relationship. Baseline A1C and FPG data from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial participants were analyzed to 1) elucidate the relationship between A1C and FPG in people with moderate dysglycemia (A1C 5.6-9.0% [38-75 mmol/mol]) and additional risk factors for cardiovascular disease, 2) determine whether this relationship is altered by use of an OAD, and 3) study whether geographic and ethnic differences exist.Research Design and Methods: Analysis was performed of 12,527 participants with dysglycemia or early type 2 diabetes recruited in North America, South America, Europe, Australia, and Asia who comprised white, Latin American, Asian, black, and other ethnicities. The A1C-FPG relationships were analyzed using cubic B spline curves in all participants and in subgroups not using an OAD or using an OAD and comprising persons of different ethnic or geographic origin.Results: A strong relationship between FPG in the range of 5.6-9.0 mmol/L and the corresponding A1C was seen across different geographic regions and ethnic groups. A smaller increase in A1C per unit increase in FPG occurred for persons taking an OAD versus those not taking an OAD.Conclusions: The strong relationship between A1C and FPG in moderate dysglycemia is not significantly affected by ethnic or geographic differences. Use of an OAD alters the relationship and should be considered when interpreting A1C level. [ABSTRACT FROM AUTHOR]

Objective: Self-management of type 2 diabetes including avoidance of hypoglycemia is complex, but the impact of cognition on safe self-management is not well understood. This study aimed to assess the effect of baseline cognitive function and cognitive decline on subsequent risk of severe hypoglycemia and to assess the effect of different glycemic strategies on these relationships.Research Design and Methods: Prospective cohort analysis of data from the ACCORD trial included 2,956 adults aged ≥55 years with type 2 diabetes and additional cardiovascular risk factors. Cognitive tests (Digit Symbol Substitution Test [DSST], Rey Auditory Verbal Learning Test, Stroop Test, and Mini Mental Status Examination) were conducted at baseline and 20 months. Study outcomes were incident confirmed severe hypoglycemia requiring medical assistance (HMA) and hypoglycemia requiring any assistance (HAA).Results: After a median 3.25-year follow-up, a 5-point-poorer baseline score on the DSST was predictive of a first episode of HMA (hazard ratio 1.13 [95% CI 1.08-1.18]). Analyses of the other cognitive tests and of HAA were consistent with the DSST results. Cognitive decline over 20 months increased the risk of subsequent hypoglycemia to a greater extent in those with lower baseline cognitive function (P(interaction) = 0.037). Randomization to an intensive versus standard glycemic strategy had no impact on the relationship between cognitive function and the risk of severe hypoglycemia.Conclusions: Poor cognitive function increases the risk of severe hypoglycemia in patients with type 2 diabetes. Clinicians should consider cognitive function in assessing and guiding their patients regarding safe diabetes self-management regardless of their glycemic targets. [ABSTRACT FROM AUTHOR]

Objective: Elevated glucose levels are common after an acute myocardial infarction (AMI) and increase the risk of death. Prior trials of glucose control after AMI have been inconsistent in their ability to lower glucose levels and have reported mixed effects on mortality. We developed a paper-based glucose-lowering algorithm and assessed its feasibility and safety in the setting of AMI.Research Design and Methods: A total of 287 participants with an acute ST segment elevation myocardial infarction (STEMI) and a capillary glucose level ≥8.0 mmol/L were randomly allocated to glucose management with intravenous glulisine insulin using this algorithm in the coronary care unit (CCU), followed by once-daily subcutaneous insulin glargine for 30 days versus standard glycemic approaches. The primary outcome was a difference in mean glucose levels at 24 h. Participants were followed for clinical outcomes through 90 days.Results: At 24 h, the mean glucose level was 1.41 mmol/L (95% CI 0.69-2.13) lower in the insulin (6.53 vs. 7.94 mmol/L). Differences in glucose levels were maintained at 72 h and 30 days. A total of 22.7% of the insulin group versus 4.4% of the standard group had biochemical hypoglycemia (with neither signs nor symptoms) in the CCU because of lower glycemic goals. However, there were no differences in symptomatic hypoglycemia or clinical outcomes between the groups.Conclusions: A paper-based insulin algorithm targeting glucose levels of 5.0-6.5 mmol/L (90-117 mg/dL) can be feasibly implemented in the CCU. A cardiovascular outcomes trial using this approach can determine whether targeted glucose lowering improves patient outcomes. [ABSTRACT FROM AUTHOR]

Objective: To examine the prospective associations of baseline vitamin D [25-hydroxyvitamin D; 25(OH)D] with insulin resistance (IR), β-cell function, and glucose homeostasis in subjects at risk for type 2 diabetes.Research Design and Methods: We followed 489 subjects, aged 50 ± 10 years, for 3 years. At baseline and follow-up, 75-g oral glucose tolerance tests (OGTTs) were administered. IR was measured using the Matsuda index (IS(OGTT)) and the homeostasis model assessment of IR (HOMA-IR), β-cell function was determined using both the insulinogenic index divided by HOMA-IR (IGI/IR) and the insulin secretion sensitivity index-2 (ISSI-2), and glycemia was assessed using the area under the glucose curve (AUC(glucose)). Regression models were adjusted for age, sex, ethnicity, season, and baseline value of the outcome variable, as well as baseline and change in physical activity, vitamin D supplement use, and BMI.Results: Multivariate linear regression analyses indicated no significant association of baseline 25(OH)D with follow-up IS(OGTT) or HOMA-IR. There were, however, significant positive associations of baseline 25(OH)D with follow-up IGI/IR (β = 0.005, P = 0.015) and ISSI-2 (β = 0.002, P = 0.023) and a significant inverse association of baseline 25(OH)D with follow-up AUC(glucose) (β = -0.001, P = 0.007). Progression to dysglycemia (impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes) occurred in 116 subjects. Logistic regression analyses indicated a significant reduced risk of progression with higher baseline 25(OH)D (adjusted odds ratio 0.69 [95% CI 0.53-0.89]), but this association was not significant after additional adjustment for baseline and change in BMI (0.78 [0.59-1.02]).Conclusions: Higher baseline 25(OH)D independently predicted better β-cell function and lower AUC(glucose) at follow-up, supporting a potential role for vitamin D in type 2 diabetes etiology. [ABSTRACT FROM AUTHOR]

Objective: It is unknown whether computer-generated, patient-tailored feedback leads to improvements in glycemic control in people with type 2 diabetes.Research Design and Methods: We recruited people with type 2 diabetes aged ≥ 40 years with a glycated hemoglobin (A1C) ≥ 7%, living in Hamilton, Canada, who were enrolled in a community-based program (Diabetes Hamilton) that provided regular evidence-based information and listings of community resources designed to facilitate diabetes self-management. After completing a questionnaire, participants were randomly allocated to either receive or not receive periodic computer-generated, evidence-based feedback on the basis of their questionnaire responses and designed to facilitate improved glycemic control and diabetes self-management. The primary outcome was a change in A1C after 1 year.Results: A total of 465 participants (50% women, mean age 62 years, and mean A1C 7.83%) were randomly assigned, and 12-month A1C values were available in 96% of all participants, at which time the A1C level had decreased by an absolute amount of 0.24 and 0.15% in the intervention and control groups, respectively. The difference in A1C reduction for the intervention versus control group was 0.09% (95% CI -0.08 to 0.26; P = 0.3). No between-group differences in measures of quality of life, diabetes self-management behaviors, or clinical outcomes were observed.Conclusions: Providing computer-generated tailored feedback to registrants of a generic, community-based program that supports diabetes self-management does not lead to lower A1C levels or a better quality of life than participation in the community-based program (augmented by periodic A1C testing) alone. [ABSTRACT FROM AUTHOR]

Objective: Previous reviews of the effect of oral antidiabetic (OAD) agents on A1C levels summarized studies with varying designs and methodological approaches. Using predetermined methodological criteria, we evaluated the effect of OAD agents on A1C levels.Research Design and Methods: The Excerpta Medica (EMBASE), the Medical Literature Analysis and Retrieval System Online (MEDLINE), and the Cochrane Central Register of Controlled Trials databases were searched from 1980 through May 2008. Reference lists from systematic reviews, meta-analyses, and clinical practice guidelines were also reviewed. Two evaluators independently selected and reviewed eligible studies.Results: A total of 61 trials reporting 103 comparisons met the selection criteria, which included 26,367 study participants, 15,760 randomized to an intervention drug(s), and 10,607 randomized to placebo. Most OAD agents lowered A1C levels by 0.5-1.25%, whereas thiazolidinediones and sulfonylureas lowered A1C levels by approximately 1.0-1.25%. By meta-regression, a 1% higher baseline A1C level predicted a 0.5 (95% CI 0.1-0.9) greater reduction in A1C levels after 6 months of OAD agent therapy. No clear effect of diabetes duration on the change in A1C with therapy was noted.Conclusions: The benefit of initiating an OAD agent is most apparent within the first 4 to 6 months, with A1C levels unlikely to fall more than 1.5% on average. Pretreated A1C levels have a modest effect on the fall of A1C levels in response to treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE The objective of this study was to determine the degree to which ramipril and/or rosiglitazone changed beta-cell function over time among individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) who participated in the Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication (DREAM) Trial, which evaluated whether ramipril and/or rosiglitazone could prevent or delay type 2 diabetes in high-risk individuals. RESEARCH DESIGN AND METHODS The present analysis included subjects (n = 982) from DREAM trial centers in Canada who had oral glucose tolerance tests at baseline, after 2 years, and at the end of the study. beta-Cell function was assessed using the fasting proinsulin-to-C-peptide ratio (PI/C) and the insulinogenic index (defined as 30-0 min insulin/30-0 min glucose) divided by homeostasis model assessment of insulin resistance (insulinogenic index [IGI]/insulin resistance [IR]). RESULTS Subjects receiving rosiglitazone had a significant increase in IGI/IR between baseline and end of study compared with the placebo group (25.59 vs. 1.94, P < 0.0001) and a significant decrease in PI/C (-0.010 vs. -0.006, P < 0.0001). In contrast, there were no significant changes in IGI/IR or PI/C in subjects receiving ramipril compared with placebo (11.71 vs. 18.15, P = 0.89, and -0.007 vs. -0.008, P = 0.64, respectively). The impact of rosiglitazone on IGI/IR and PI/C was similar within subgroups of isolated IGT and IFG + IGT (all P < 0.001). Effects were more modest in those with isolated IFG (IGI/IR: 8.95 vs. 2.13, P = 0.03; PI/C: -0.003 vs. -0.001, P = 0.07). CONCLUSIONS Treatment with rosiglitazone, but not ramipril, resulted in significant improvements in measures of beta-cell function over time in pre-diabetic subjects. Although the long-term sustainability of these improvements cannot be determined from the present study, these findings demonstrate that the diabetes preventive effect of rosiglitazone was in part a consequence of improved beta-cell function. [ABSTRACT FROM AUTHOR]

Objective: Diabetes is associated with cognitive decline and dementia. However, the relationship between the degree of hyperglycemia and cognitive status remains unclear. This was explored using baseline cognitive measures collected in the ongoing Memory in Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.Research Design and Methods: The relationship of A1C and fasting plasma glucose (FPG) levels to performance on four cognitive tests was assessed, adjusting for age and other determinants of cognitive status. The tests were the Digit Symbol Substitution Test (DSST), Mini Mental Status Examination (MMSE), Rey Auditory Verbal Learning Test, and Stroop Test.Results: A statistically significant age-adjusted association was observed between the A1C level and the score on all four cognitive tests. Specifically, a 1% higher A1C value was associated with a significant 1.75-point lower DSST score (95% CI -1.22 to -2.28; P < 0.0001), a 0.20-point lower MMSE score (-0.11 to -0.28; P < 0.0001), a 0.11-point lower memory score (-0.02 to -0.19, P = 0.0142), and a worse score (i.e., 0.75 s more) on the Stroop Test (1.31-0.19, P = 0.0094). The association between the DSST score and A1C persisted in all multiple linear regression models. FPG was not associated with test performance.Conclusions: Higher A1C levels are associated with lower cognitive function in individuals with diabetes. The effect of glucose lowering on cognitive function will be determined by the ongoing ACCORD-MIND trial. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are risk factors for diabetes, cardiovascular disease (CVD), and kidney disease. We determined the effects of ramipril and rosiglitazone on combined and individual CVD and renal outcomes in people with IGT and/or IFG in the Diabetes REduction Assessment With ramipril and rosiglitazone Medication (DREAM) trial. RESEARCH DESIGN AND METHODS: A total of 5,269 people aged >or=30 years, with IGT and/or IFG without known CVD or renal insufficiency, were randomized to 15 mg/day ramipril versus placebo and 8 mg/day rosiglitazone versus placebo. A composite cardiorenal outcome and its CVD and renal components were assessed during the 3-year follow-up. RESULTS: Compared with placebo, neither ramipril (15.7% [412 of 2,623] vs. 16.0% [424 of 2,646]; hazard ratio [HR] 0.98 [95% CI 0.84-1.13]; P = 0.75) nor rosiglitazone (15.0% [394 of 2,635] vs. 16.8% [442 of 2,634]; 0.87 [0.75-1.01]; P = 0.07) reduced the risk of the cardiorenal composite outcome. Ramipril had no impact on the CVD and renal components. Rosiglitazone increased heart failure (0.53 vs. 0.08%; HR 7.04 [95% CI 1.60-31.0]; P = 0.01) but reduced the risk of the renal component (0.80 [0.68-0.93]; P = 0.005); prevention of diabetes was independently associated with prevention of the renal component (P < 0.001). CONCLUSIONS: Ramipril did not alter the cardiorenal outcome or its components. Rosiglitazone, which reduced diabetes, also reduced the development of renal disease but not the cardiorenal outcome and increased the risk of heart failure. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Glyburide is the most widely used sulfonylurea but has unique pharmacodynamic properties that may increase harm. We hypothesized that glyburide causes more hypoglycemia and cardiovascular events than other secretagogues or insulin. RESEARCH DESIGN AND METHODS: Data sources were Medline, Embase, Cochrane, and three other web-based clinical trial registers (1966-2005). Parallel, randomized, controlled trials in people with type 2 diabetes comparing glyburide monotherapy with monotherapy using secretagogues or insulin were selected. Outcomes were hypoglycemia, glycemic control, cardiovascular events, body weight, and death. Titles and abstracts of 1,806 publications were reviewed in duplicate and 21 relevant articles identified. Data on patient characteristics, interventions, outcomes, and validity were extracted in duplicate using predefined criteria. RESULTS: Glyburide was associated with a 52% greater risk of experiencing at least one episode of hypoglycemia compared with other secretagogues (relative risk 1.52 [95% CI 1.21-1.92]) and with 83% greater risk compared with other sulfonylureas (1.83 [1.35-2.49]). Glyburide was not associated with an increased risk of cardiovascular events (0.84 [0.56-1.26]), death (0.87 [0.70-1.07]), or end-of-trial weight (weighted mean difference 1.69 kg [95% CI -0.41 to 3.80]) compared with other secretagogues. Limitations included suboptimal reporting of original trials. Loss to follow-up exceeded 20% in some studies, and major hypoglycemia was infrequently reported. CONCLUSIONS: Glyburide caused more hypoglycemia than other secretagogues and other sulfonylureas. Glyburide was not associated with an increased risk of cardiovascular events, death, or weight gain. [ABSTRACT FROM AUTHOR]

Background: Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drug's ability to prevent type 2 diabetes in individuals at high risk of developing the condition.Methods: 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654.Findings: At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11.6%) individuals given rosiglitazone and 686 (26.0%) given placebo developed the composite primary outcome (hazard ratio 0.40, 95% CI 0.35-0.46; p<0.0001); 1330 (50.5%) individuals in the rosiglitazone group and 798 (30.3%) in the placebo group became normoglycaemic (1.71, 1.57-1.87; p<0.0001). Cardiovascular event rates were much the same in both groups, although 14 (0.5%) participants in the rosiglitazone group and two (0.1%) in the placebo group developed heart failure (p=0.01).Interpretation: Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both. [ABSTRACT FROM AUTHOR]

Objective: Despite the demonstrated benefits of glycemic control, patient acceptance of basal/bolus insulin therapy for type 1 diabetes has been slow. We investigated whether a basal/bolus insulin regimen involving rapid-acting, dry powder, inhaled insulin could provide glycemic control comparable with a basal/bolus subcutaneous regimen.Research Design and Methods: Patients with type 1 diabetes (ages 12-65 years) received twice-daily subcutaneous NPH insulin and were randomized to premeal inhaled insulin (n = 163) or subcutaneous regular insulin (n = 165) for 6 months.Results: Mean glycosylated hemoglobin (A1C) decreased comparably from baseline in the inhaled and subcutaneous insulin groups (-0.3 and -0.1%, respectively; adjusted difference -0.16% [CI -0.34 to 0.01]), with a similar percentage of subjects achieving A1C <7%. Although 2-h postprandial glucose reductions were comparable between the groups, fasting plasma glucose levels declined more in the inhaled than in the subcutaneous insulin group (adjusted difference -39.5 mg/dl [CI -57.5 to -21.6]). Inhaled insulin was associated with a lower overall hypoglycemia rate but higher severe hypoglycemia rate. The overall hypoglycemia rate (episodes/patient-month) was 9.3 (inhaled) vs. 9.9 (subcutaneous) (risk ratio [RR] 0.94 [CI 0.91-0.97]), and the severe hypoglycemia rate (episodes/100 patient-months) was 6.5 vs. 3.3 (RR 2.00 [CI 1.28-3.12]). Increased insulin antibody serum binding without associated clinical manifestations occurred in the inhaled insulin group. Pulmonary function between the groups was comparable, except for a decline in carbon monoxide-diffusing capacity in the inhaled insulin group without any clinical correlates.Conclusions: Inhaled insulin may provide an alternative for the management of type 1 diabetes as part of a basal/bolus strategy in patients who are unwilling or unable to use preprandial insulin injections. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Repaglinide is an oral anti-diabetic agent that has a short duration of action, and is suitable for preventing post-prandial rises in glucose levels. Targeting post-prandial glucose levels may lead to lower HbA(1c) levels and rates of hypoglycaemia than targeting pre-prandial glucose levels. RESEARCH DESIGN AND METHODS: In 42 centres, 193 drug-naive (n = 122) or metformin-treated (n = 71) individuals with Type 2 diabetes were randomly allocated to a 40-day period of repaglinide dose-titration (starting at 0.5 mg three times daily) based on either self-measured pre-prandial or post-prandial glucose levels. They were followed for a further 12 weeks and HbA(1c) and hypoglycaemia rates were recorded. RESULTS: Repaglinide reduced HbA(1c) by 1.25 and 1.07% in the post-prandial and pre-prandial groups, respectively (P for difference = 0.6), and achieved target glucose levels in 80.7 and 66.7%, respectively (P = 0.16). The effect of titration strategy differed by baseline drug therapy, and was more effective in the metformin-treated individuals who experienced a HbA(1c) fall of 0.6 vs. 1.10% with pre-prandial vs. post-prandial titration (P for metformin-allocated group interaction = 0.043). The rate of hypoglycaemia did not differ by group. CONCLUSIONS: In drug-naive individuals with Type 2 diabetes, similar HbA(1c) levels are achieved with repaglinide when dosing is adjusted according to either post-prandial or pre-prandial levels. Conversely, in metformin-treated individuals, repaglinide dosing according to post-prandial levels may lead to better glycaemic control than dosing according to pre-prandial levels. [ABSTRACT FROM AUTHOR]

Objective: To examine cross-sectional associations of serum vitamin D [25-hydroxyvitamin D, 25(OH)D] concentration with insulin resistance (IR) and beta-cell dysfunction in 712 subjects at risk for type 2 diabetes.Research Design and Methods: Serum 25(OH)D was determined using a chemiluminescence immunoassay. Insulin sensitivity/resistance were measured using the Matsuda insulin sensitivity index for oral glucose tolerance tests (IS(OGTT)) and homeostasis model assessment of insulin resistance HOMA-IR. beta-Cell function was determined using both the insulinogenic index (IGI) divided by HOMA-IR (IGI/IR) and the insulin secretion sensitivity index-2 (ISSI-2). RESULTS Linear regression analyses indicated independent associations of 25(OH)D with IS(OGTT) and HOMA-IR (beta = 0.004, P = 0.0003, and beta = -0.003, P = 0.0072, respectively) and with IGI/IR and ISSI-2 (beta = 0.004, P = 0.0286, and beta = 0.003, P = 0.0011, respectively) after adjusting for sociodemographics, physical activity, supplement use, parathyroid hormone, and BMI.Conclusions: Vitamin D may play a role in the pathogenesis of type 2 diabetes, as 25(OH)D concentration was independently associated with both insulin sensitivity and beta-cell function among individuals at risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We conducted a systematic review of randomized controlled trials (RCTs) of intensive insulin therapy (IIT) in type 1 diabetes to determine the effect on macrovascular complications. RESEARCH DESIGN AND METHODS: MEDLINE (1966-1996), Citation Index, reference lists, and personal files were used to identify RCTs of > 2 years' duration comparing IIT to conventional therapy (CT) in type 1 diabetes. Two independent reviewers applied selection criteria and identified 11 studies; 5 were subsequently excluded because no data were available for macrovascular complications. Data were extracted on macrovascular disease and cardiovascular risk factors. Macrovascular disease was defined as angina, myocardial infarction, angioplasty, coronary artery bypass graft, stroke, claudication, or peripheral bypass. The first event of each type was counted. RESULTS: IIT decreased the number of macrovascular events (odds ratio [OR] 0.55, [95% CI 0.35-0.88], P = 0.015) but had no significant effect on the number of patients developing macrovascular disease (OR 0.72, [95% CI 0.44-1.17], P = 0.22) or on macrovascular mortality (OR 0.91, [95% CI 0.31-2.65], P = 0.93). CONCLUSIONS: IIT decreases the extent of early macrovascular disease in young individuals with type 1 diabetes but has no effect on the number of patients affected or on macrovascular mortality. These data suggest that IIT may stabilize macrovascular disease or prevent progression in those at risk. [ABSTRACT FROM AUTHOR]

Objectives: This study examines the risk of acute myocardial infarction (MI) conferred by the metabolic syndrome (MS) and its individual factors in multiple ethnic populations.Background: The risk of the MS on MI has not been well characterized, especially in multiple ethnic groups.Methods: Participants in the INTERHEART study (n = 26,903) involving 52 countries were classified using the World Health Organization (WHO) and International Diabetes Federation (IDF) criteria for MS, and their odds ratios (ORs) for MI were compared with the individual MS component factors.Results: The MS is associated with an increased risk of MI, both using the WHO (OR: 2.69; 95% confidence interval [CI]: 2.45 to 2.95) and IDF (OR: 2.20; 95% CI: 2.03 to 2.38) definitions, with corresponding population attributable risks of 14.5% (95% CI: 12.7% to 16.3%) and 16.8% (95% CI: 14.8% to 18.8%), respectively. The associations are directionally similar across all regions and ethnic groups. Using the WHO definition, the association with MI by the MS is similar to that of diabetes mellitus (OR: 2.72; 95% CI: 2.53 to 2.92) and hypertension (OR: 2.60; 95% CI: 2.46 to 2.76), and significantly stronger than that of the other component risk factors. The clustering of > or =3 risk factors with subthreshold values is associated with an increased risk of MI (OR: 1.50; 95% CI: 1.24 to 1.81) compared with having component factors with "normal" values. The IDF definition showed similar results.Conclusions: In this large-scale, multi-ethnic, international investigation, the risk of MS on MI is generally comparable to that conferred by some, but not all, of its component risk factors. The characterization of risk factors, especially continuous variables, as dichotomous will underestimate risk and decrease the magnitude of association between MS and MI. [ABSTRACT FROM AUTHOR]

Background: Morbidities related to obesity are usually associated with its severity and duration. Yet, the onset of serious morbidities in early adulthood among otherwise healthy adolescents with obesity is understudied. We aimed to investigate the association between adolescent BMI and serious morbidities before age 25 years., Methods: In this nationwide, retrospective cohort study, we included Israeli conscripts aged 17-21 years who underwent pre-recruitment medical evaluation between Jan 1, 1996, and Dec 31, 2017, were deemed medically eligible for military service, and were recruited to the Israeli Defense Forces between 1998 and 2018. Exclusion criteria were missing height or weight or service ineligibility for non-medical or medical reasons. Baseline BMI was converted into age-specific and sex-specific percentiles and classified using the US Centers for Disease Control and Prevention categories. The primary outcome was incidence of serious morbidity disqualifying individuals from completing mandatory service. Participants were followed from enlistment until end of service (3 years for males and 2 years for females), onset of serious morbidity, or Dec 31, 2021. Cox models with adjustment to various socio-economic confounders were applied to calculate the hazard ratio (HR) and 95% CI for serious morbidity for the BMI categories., Findings: A total of 1 264 355 adolescents aged 16-20 years were assessed for military service. 145 702 were excluded; 144 705 were considered ineligible for service (133 112 for non-medical reasons and 11 593 for medical reasons), and 2867 had missing height or weight data. The study included 1 118 653 individuals (622 989 [55·7%] males and 495 664 [44·3%] females), with 23 347 cases of serious morbidity recorded over 2 534 873 person-years. Incidence of serious morbidity increased across BMI groups in both sexes. Among males, compared with those with normal BMI, the adjusted HRs were 0·89 (95% CI 0·83-0·95) for underweight, 1·21 (1·16-1·27) for overweight, 1·39 (1·32-1·47) for obesity class 1, 2·82 (2·60-3·06) for obesity class 2, and 5·14 (4·37-6·04) for obesity class 3. For females, the respective ratios were HR 0·95 (95% CI 0·84-1·09) for underweight, 1·27 (1·17-1·37) for overweight, 1·63 (1·45-1·82) for obesity class 1, 4·00 (3·46-4·61) for obesity class 2, and 7·30 (5·65-9·43) for obesity class 3. Results persisted in sensitivity analyses restricted to those with unimpaired health at baseline or those in civilian-equivalent office employments., Interpretation: Obesity in otherwise healthy adolescents was linked with increased risk of serious morbidity before age 25 years. Reducing adolescent obesity will have substantial short-term and long-term health benefits in young adults., Funding: Sheba Medical Center., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: Alleviation of unrecognized glucotoxicity, with resultant recovery of β-cell function, could amplify the glucose-lowering effect of pharmacotherapy and contribute to the variable therapeutic response observed among patients with type 2 diabetes (T2D). However, clinical evidence supporting this concept is lacking. Short-term intensive insulin therapy (IIT) can ameliorate glucotoxicity and improve β-cell function in early T2D. Thus, for evidence of recovery of glucotoxicity-associated β-cell dysfunction, we sought to determine whether there exists a baseline fasting glucose threshold above which the post-IIT improvement in both β-cell function and glycemia is amplified., Research Design and Methods: IIT (glargine, lispro) was administered for 3 weeks to 108 adults with T2D (mean duration 1.8 ± 1.4 years). Oral glucose tolerance tests before and after IIT enabled assessment of β-cell function by Insulin Secretion-Sensitivity Index-2 and insulinogenic index/HOMA-insulin resistance. For each level of baseline fasting glycemia from 6.0 to 10.5 mmol/L, we modeled the difference in IIT-induced percentage change in β-cell function between those at/above the indicated glucose level and those below it., Results: The relationship between baseline fasting glucose and the differential change in β-cell function was nonlinear. Instead, this relationship was best fit by a cubic regression model with inflection (amplification) at fasting glucose at 9.3 mmol/L. Moreover, baseline fasting glucose at 9.3 mmol/L also identified the inflection point at which nonlinear reductions in fasting glucose and 2-h glucose, respectively, were both amplified., Conclusions: The respective improvements in β-cell function and glycemia in response to short-term IIT are amplified in those in whom baseline fasting glucose exceeds a defined threshold, consistent with reversal of glucotoxicity., (© 2024 by the American Diabetes Association.)