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Background: SGLT2i (sodium-glucose cotransporter 2 inhibitor), a class of anti-diabetic medications, is shown to reduce blood pressure (BP) in hypertensive patients with type 2 diabetes. Mechanisms underlying this action are unknown but SGLT2i-induced sympathoinhibition is thought to play a role. Whether SGLT2i reduces BP and sympathetic nerve activity (SNA) in a nondiabetic prehypertension model is unknown., Methods: Accordingly, we assessed changes in conscious BP using radiotelemetry and alterations in mean arterial pressure and renal SNA during simulated exercise in nondiabetic spontaneously hypertensive rats during chronic administration of a diet containing dapagliflozin (0.5 mg/kg per day) versus a control diet., Results: We found that dapagliflozin had no effect on fasting blood glucose, insulin, or hemoglobin A 1C levels. However, dapagliflozin reduced BP in young (8-week old) spontaneously hypertensive rats as well as attenuated the age-related rise in BP in adult spontaneously hypertensive rat up to 17-weeks of age. The rises in mean arterial pressure and renal SNA during simulated exercise (exercise pressor reflex activation by hindlimb muscle contraction) were significantly reduced after 4 weeks of dapagliflozin (Δmean arterial pressure: 10±7 versus 25±14 mm Hg, Δrenal SNA: 31±17% versus 68±39%, P <0.05). Similarly, rises in mean arterial pressure and renal SNA during mechanoreflex stimulation by passive hindlimb stretching were also attenuated by dapagliflozin. Heart weight was significantly decreased in dapagliflozin compared with the control group., Conclusions: These data demonstrate a novel role for SGLT2i in reducing resting BP as well as the activity of skeletal muscle reflexes, independent of glycemic control. Our study may have important clinical implications for preventing hypertension and hypertensive heart disease in young prehypertensive individuals.

Purpose: To determine the effectiveness of a shared decision-making (SDM) tool versus guideline-informed usual care in translating evidence into primary care, and to explore how use of the tool changed patient perspectives about diabetes medication decision making., Methods: In this mixed methods multicenter cluster randomized trial, we included patients with type 2 diabetes mellitus and their primary care clinicians. We compared usual care with or without a within-encounter SDM conversation aid. We assessed participant-reported decisions made and quality of SDM (knowledge, satisfaction, and decisional conflict), clinical outcomes, adherence, and observer-based patient involvement in decision-making (OPTION12-scale). We used semi-structured interviews with patients to understand their perspectives., Results: We enrolled 350 patients and 99 clinicians from 20 practices and interviewed 26 patients. Use of the conversation aid increased post-encounter patient knowledge (correct answers, 52% vs. 45%, p = 0.02) and clinician involvement of patients (Mean between-arm difference in OPTION12, 7.3 (95% CI 3, 12); p = 0.003). There were no between-arm differences in treatment choice, patient or clinician satisfaction, encounter length, medication adherence, or glycemic control. Qualitative analyses highlighted differences in how clinicians involved patients in decision making, with intervention patients noting how clinicians guided them through conversations using factors important to them., Conclusions: Using an SDM conversation aid improved patient knowledge and involvement in SDM without impacting treatment choice, encounter length, medication adherence or improved diabetes control in patients with type 2 diabetes. Future interventions may need to focus specifically on patients with signs of poor treatment fit., Clinical Trial Registration: ClinicalTrial.gov: NCT01502891., (© 2021. The Author(s).)

Background: The HEALTHY Study was a multicomponent school-based intervention, designed to prevent type 2 diabetes mellitus (T2DM) in middle-school students., Objectives: We examined whether the difference in dietary magnesium intake, BMI percentile, and plasma glucose and insulin concentrations from 6th to 8th grade were related in the intervention schools and in the control schools that participated in the HEALTHY Study., Methods: A total of 2181 ethnically diverse students, from 11.3 to 13.7 y of age, with completed dietary records, BMI percentile, and plasma glucose and insulin concentrations at 6th and 8th grades were included. Dietary magnesium intake was self-reported using the Block Kids FFQ. A hierarchical multiple regression model was used to determine whether the differences in dietary magnesium intake, BMI percentile, and plasma glucose and insulin concentrations from 6th to 8th grades were related, while adjusting for dietary calcium intake and total energy intake., Results: The difference in dietary magnesium intake was significantly related to changes in BMI percentile from 6th to 8th grade in intervention and in control schools [intervention: β: -0.07; 95% CI: -0.58, -0.02; P = 0.03; R2 (regression coefficient effect size): 0.14; 95% CI for R2: 0.10, 0.17; control: β: -0.08; 95% CI: -0.63, -0.09; P = 0.01; R2: 0.12; 95% CI for R2: 0.08, 0.15]. The difference in dietary magnesium intake was not related to plasma glucose and insulin concentrations in intervention and in control schools., Conclusions: We conclude that a multicomponent intervention was associated with reduced risk of T2DM, and that this association may be modulated, in part, by magnesium. The differences in dietary magnesium intake from 6th to 8th grade were negatively related to changes in BMI percentile among middle-school students., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Patients with diabetes display heightened blood pressure response to exercise, but the underlying mechanism remains to be elucidated. There is no direct evidence that insulin resistance (hyperinsulinemia or hyperglycemia) impacts neural cardiovascular control during exercise. We propose a novel paradigm in which hyperinsulinemia or hyperglycemia significantly influences neural regulatory pathways controlling the circulation during exercise in diabetes., (Copyright © 2021 by the American College of Sports Medicine.)

Background: Data on dietary magnesium intake on the risk of type 2 diabetes mellitus (T2DM) among children and adolescents is limited., Aim: We examined whether dietary magnesium intake was related to body mass index (BMI) percentile, and glycemic indices at baseline and at end of the HEALTHY Study for both intervention and control schools. The HEALTHY Study was a multi-component, school-based intervention, to prevent T2DM in children and adolescents from 6th to 8th grades., Methods: A secondary data analyses of 2181 ethnically diverse students with completed dietary records, BMI percentile, and plasma insulin and glucose concentrations at baseline (6th grade) and end of study (8th grade) were included from the HEALTHY Study. Dietary magnesium intake was self-reported using the Block Kids Food Frequency Questionnaire. A hierarchical multiple regression model was used to determine the relationships between dietary magnesium intake, BMI percentile, and glycemic indices at baseline and end of the HEALTHY Study, adjusting for magnesium intake from supplements, total energy intake, and fitness level., Results: Dietary magnesium intake was related to BMI percentile at baseline and at end of the HEATHY Study (β = -0.05, 95% CI = -0.02 to 0, p = 0.04; β = -0.06, 95% CI = -0.02 to -0.003, p = 0.004); R 2 [regression coefficient effect size] = 0.03; R 2 = 0.06). Dietary magnesium intake was not related to plasma insulin and glucose concentrations at baseline and end of the HEALTHY Study., Conclusion: Dietary magnesium intake was inversely related to BMI percentile among middle school students from the HEALTHY Study. Research is required to evaluate the dose-response relationship between fruit and vegetable consumption (good sources of magnesium) and risk of T2DM in children and adolescents. This relationship also needs to be explored among different BMI categories.

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Patients with type 2 diabetes display an exaggerated pressor response to exercise. However, evidence supporting the association between the magnitude of the pressor response to exercise and insulin resistance-related factors including hemoglobin A1c (HbA1c) or homeostatic model assessment of insulin resistance (HOMA-IR) in nondiabetic subjects has remained sparse and inconclusive. Thus we investigated the relationship between cardiovascular responses to exercise and insulin resistance-related factors in nondiabetic healthy men ( n = 23) and women ( n = 22) above 60 yr old. We measured heart rate (HR) and blood pressure (BP) responses during: isometric handgrip (IHG) exercise of 30% maximal voluntary contraction, a period of skeletal muscle ischemia (SMI) induced by tourniqueting the arm after IHG, and rhythmic dynamic handgrip (DHG) exercise during SMI. Greater diastolic BP (DBP) responses to DHG with SMI was associated with male sex ( r  = 0.44, P = 0.02) and higher HbA1c ( r  = 0.33, P = 0.03), heart-ankle pulse wave velocity (haPWV) ( r  = 0.45, P < 0.01), and resting systolic BP (SBP) ( r  = 0.36, P = 0.02). HbA1c persisted as a significant determinant explaining the variance in the DBP response to DHG with SMI in multivariate models despite adjustment for sex, haPWV, and resting SBP. It was also determined that the DBP response to DHG with SMI in a group in which HOMA-IR was abnormal (Δ33 ± 3 mmHg) was significantly higher than that of groups in which HOMA-IR was at intermediate (Δ20 ± 4 mmHg) and normal (Δ23 ± 2 mmHg) levels. These data suggest that even in nondiabetic older adults, insulin resistance is related to an exaggerated pressor response to exercise especially when performed under ischemic conditions. NEW & NOTEWORTHY The diastolic blood pressure response to rhythmic dynamic handgrip exercise under ischemic conditions was demonstrated to be correlated with insulin resistance-related factors in nondiabetic older adults. This finding provides important insight to the prescription of exercise in this particular patient population as the blood pressure response to exercise, especially under ischemic conditions, could be exaggerated to nonsafe levels.

The cardiovascular responses to exercise are potentiated in patients with type 2 diabetes mellitus (T2DM). However, the underlying mechanisms causing this abnormality remain unknown. Central command (CC) and the exercise pressor reflex (EPR) are known to contribute significantly to cardiovascular control during exercise. Thus these neural signals are viable candidates for the generation of the abnormal circulatory regulation in this disease. We hypothesized that augmentations in CC as well as EPR function contribute to the heightened cardiovascular responses during exercise in T2DM. To test this hypothesis, changes in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in response to electrical stimulation of mesencephalic locomotor region (MLR), a putative component of the central command pathway, and activation of the EPR, evoked by electrically induced hindlimb muscle contraction, were examined in decerebrate animals. Sprague-Dawley rats were given either a normal diet (control) or a high-fat diet (14-16 wk) in combination with two low doses (35 mg/kg week 1 , 25 mg/kg week 2 ) of streptozotocin (T2DM). The changes in MAP and RSNA responses to MLR stimulation were significantly greater in T2DM compared with control (2,739 ± 123 vs. 1,298 ± 371 mmHg/s, 6,326 ± 1,621 vs. 1,390 ± 277%/s, respectively, P < 0.05). Similarly, pressor and sympathetic responses to activation of the EPR in diabetic animals were significantly augmented compared with control animals (436 ± 74 vs. 134 ± 44 mmHg/s, 645 ± 135 vs. 139 ± 65%/s, respectively, P < 0.05). These findings provide the first evidence that CC and the EPR may generate the exaggerated rise in sympathetic activity and blood pressure during exercise in T2DM.

Objective: To develop and validate a model of incident type 2 diabetes based solely on administrative data., Data Sources/study Setting: Optum Labs Data Warehouse (OLDW), a national commercial administrative dataset., Study Design: HealthImpact model was developed and internally validated using nested case-control study design; n = 473,049 in training cohort and n = 303,025 in internal validation cohort. HealthImpact was externally validated in 2,000,000 adults followed prospectively for 3 years. Only adults ≥18 years were included., Data Collection/extraction Methods: Patients with incident diabetes were identified using HEDIS rules. Control subjects were sampled from patients without diabetes. Medical and pharmacy claims data collected over 3 years prior to index date were used to build the model variables., Principal Findings: HealthImpact, scored 0-100, has 48 variables with c-statistic 0.80815. We identified HealthImpact threshold of 90 as identifying patients at high risk of incident diabetes. HealthImpact had excellent discrimination in external validation cohort (c-statistic 0.8171). The sensitivity, specificity, positive predictive value, and negative predictive value of HealthImpact >90 for new diagnosis of diabetes within 3 years were 32.35, 94.92, 22.25, and 96.90 percent, respectively., Conclusions: HealthImpact is an efficient and effective method of risk stratification for incident diabetes that is not predicated on patient-provided information or laboratory tests., (© Health Research and Educational Trust.)

Objectives: Glycemic control can lower the risk of diabetes-related complications, and delayed treatment intensification can impede optimal diabetes care. This study examines trends in hyperglycemia treatment intensification between 2002 and 2010., Study Design: Retrospective secondary data analysis of a large national administrative data set of privately insured individuals across the United States., Methods: Adults 18 years or older with diabetes, initiated on metformin monotherapy between 2002 and 2007, were studied, stratified by date of first metformin prescription (2002-2003, 2004-2005, 2006-2007). Time to treatment intensification between 2002 and 2010, defined by the addition of ≥1 agents to metformin, was estimated using Kaplan-Meier and Cox proportional hazards regression analysis., Results: There were 75,069 treatment-naïve adults with diabetes first initiated on metformin between 2002 and 2007; mean age was 60 years (SD = 11.5), 49.7% were women, and 63.1% were non-Hispanic white. Diabetes therapy was intensified in 26,169 individuals (34.6%).Treatment intensification became increasingly more likely with time for the 2004-2005 cohort (hazard ratio [HR], 1.07; 95% CI, 1.04-1.10) and for the 2006-2007 cohort (HR, 1.11; 95% CI, 1.07-1.14) compared with the 2002-2003 cohort (P < .001), after adjustment for significant confounders including sex, income level, education level, and comorbidity burden. Sulfonylureas were the most commonly used agents, though their use declined over time; thiazolidinedione use decreased; and incretin use increased (all P < .001)., Conclusions: There was a significant increase in diabetes treatment intensification between 2002 and 2010. Choice of secondline agents changed as well, with decreasing prevalence of thiazolidinedione and sulfonylurea use and rising prevalence of incretin use.

Background: The Patient Assessment of Chronic Illness Care (PACIC) survey is a widely used instrument to assess the patient experience with healthcare delivery., Purpose: This study aims to evaluate the factorial structure of PACIC from the patient perspective., Methods: A postal survey was mailed to 4,796 randomly selected adults with diabetes from 34 primary care clinics. Internal consistencies of PACIC subscales were assessed by Cronhach's α. Factorial structure was evaluated by confirmatory and exploratory factor analyses., Results: Based on responses of 2,055 patients (43% response rate), exploratory factor analysis discerned a 4-factor, not 5-factor, model dominated by patient evaluation of healthcare services (explaining 74% of the variance). The other 3 factors addressed patient involvement (goal setting, participating in the healthcare team) and social support for self-management., Conclusions: The underlying factorial structure of PACIC, which reflects the patient perspective, is dynamic, patient-centered, and differs from the original 5-factor model that was more aligned with views of healthcare delivery stakeholders.

Introduction: Many US adults have multiple chronic conditions, and hypertension and diabetes are among the most common dyads. Diabetes and prediabetes prevalence are increasing, and both conditions negatively affect cardiovascular health. Early diagnosis and treatment of diabetes and prediabetes can benefit people with hypertension by preventing cardiovascular complications., Methods: We analyzed 2011 Minnesota Behavioral Risk Factor Surveillance System data to describe the proportion of adults with hypertension screened for diabetes according to US Preventive Services Task Force Recommendations for blood glucose testing. Covariates associated with lower odds of recent screening among adults without diabetes were determined using weighted logistic regression., Results: Of Minnesota adults with self-reported hypertension, 19.6% had a diagnosis of diabetes and 10.7% had a diagnosis of prediabetes. Nearly one-third of adults with hypertension without diabetes had not received blood glucose screening in the past 3 years. Factors associated with greater odds of not being screened in multivariable models included being aged 18 to 44 years (adjusted odds ratio [AOR], 1.77; 95% confidence interval [CI], 1.23-2.55); being nonobese, with stronger effects for normal body mass index; having no check-up in the past 2 years (AOR, 2.49; 95% CI, 1.49-4.17); having hypertension treated with medication (AOR, 2.01; 95% CI, 1.49-2.71); and completing less than a college degree (AOR, 1.45; 95% CI, 1.14-1.84). Excluding respondents with prediabetes or those not receiving a check-up did not change the results., Conclusions: Failure to screen among providers and failure to understand the importance of screening among individuals with hypertension may mean missed opportunities for early detection, clinical management, and prevention of diabetes.

Objective: While metformin is generally accepted as the first-line agent in treatment of type 2 diabetes, there are insufficient evidence and extensive debate about the best second-line agent. We aimed to assess the benefits and harms of four commonly used antihyperglycemia treatment regimens considering clinical effectiveness, quality of life, and cost., Research Design and Methods: We developed and validated a new population-based glycemic control Markov model that simulates natural variation in HbA1c progression. The model was calibrated using a U.S. data set of privately insured individuals diagnosed with type 2 diabetes. We compared treatment intensification of metformin monotherapy with sulfonylurea, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, or insulin. Outcome measures included life-years (LYs), quality-adjusted life-years (QALYs), mean time to insulin dependence, and expected medication cost per QALY from diagnosis to first diabetes complication (ischemic heart disease, myocardial infarction, congestive heart failure, stroke, blindness, renal failure, amputation) or death., Results: According to our model, all regimens resulted in similar LYs and QALYs regardless of glycemic control goal, but the regimen with sulfonylurea incurred significantly lower cost per QALY and resulted in the longest time to insulin dependence. An HbA1c goal of 7% (53 mmol/mol) produced higher QALYs compared with a goal of 8% (64 mmol/mol) for all regimens., Conclusions: Use of sulfonylurea as second-line therapy for type 2 diabetes generated glycemic control and QALYs comparable with those associated with other agents but at lower cost. A model that incorporates HbA1c and diabetes complications can serve as a useful clinical decision tool for selection of treatment options.

Background: The extant literature lacks breadth on psychological variables associated with health outcome for type 2 diabetes mellitus (T2DM). This investigation extends the scope of psychological information by reporting on previously unpublished factors., Objective: To investigate if intolerance of uncertainty, emotion regulation, or purpose in life differentiate T2DM adults with sustained high HbA(1c) (HH) vs. sustained acceptable HbA(1c) (AH)., Subjects and Methods: Cross-sectional observational study. Adult patients with diagnosed T2DM meeting inclusionary criteria for AH, HH, or a nondiabetic reference group (NDR) were randomly selected and invited to participate. Patients who consented and participated resulted in a final sample of 312 subgrouped as follows: HH (n = 108); AH (n = 98); and NDR (n = 106). Data sources included a survey, self-report questionnaires, and electronic medical record (EMR)., Results: HH individuals with T2DM reported lower purpose in life satisfaction (p = 0.005) compared to the NDR group. The effect size for this finding is in the small-to-medium range using Cohen's guidelines for estimating clinical relevance. The HH-AH comparison on purpose in life was nonsignificant. The emotion regulation and intolerance of uncertainty comparisons across the three groups were not significant., Conclusions: The present study determined that lower purpose in life satisfaction is associated with higher HbA(1c). In a T2DM patient with sustained high HbA(1c), the primary care clinician is encouraged to consider screening for purpose in life satisfaction by asking a single question such as "Do the things you do in your life seem important and worthwhile?" The patient's response will assist the clinician in determining if meaning or purpose in life distress may be interferring with diabetes self-care. If this is the case, the clinician can shift the conversation to the value of behavioral and emotional health counseling., (Copyright © 2013 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Objective: To establish the prevalence of self-reported hypoglycemia among ambulatory patients with diabetes and assess its impact on health-related quality of life (HRQoL)., Methods: This study was a cross-sectional analysis of a postal survey disbursed during the first quarter of 2010 to 875 adults with type 1 or 2 diabetes identified on the basis of an index clinical encounter for diabetes management between August 1, 2005 and June 30, 2006. The survey included questions regarding hypoglycemia, self-rating of health, and questions adapted from Confidence in Diabetes Self-Care, Generalized Anxiety Disorder-7, EuroQol5-D, and the Hypoglycemic Fear Survey. Data were analyzed using a two-sample t test for continuous variables and a chi-square test for categorical variables, with multivariate analysis to adjust for age, gender, diabetes duration, and Charlson comorbidity index., Results: The survey was completed by 418 patients (47.8% response rate). Of the respondents, 26 of 92 (28.3%) with type 1 and 55 of 326 (16.9%) with type 2 diabetes reported at least one episode of severe hypoglycemia within the previous 6 months. Fear of hypoglycemia, including engagement in anticipatory avoidance behaviors, was highest in patients with type 2 diabetes reporting severe hypoglycemia and all patients with type 1 diabetes (P<.001). HRQoL was lower in patients with type 2 (but not type 1) diabetes reporting severe hypoglycemia (P<.01)., Conclusion: Clinicians and health systems should incorporate screening for hypoglycemia into the routine health assessment of all patients with diabetes. Fear of hypoglycemia places patients at risk for counterproductive behaviors, impairs HRQoL, and should be considered in individualizing glycemic goals.

Objective: To investigate the pharmacokinetics (PK), pharmacodynamics, and safety of single-dose RM-131 in type 2 diabetic patients with gastrointestinal cardinal symptoms (GCSI) and previously documented delayed gastric emptying (DGE)., Research Design and Methods: In a randomized crossover study, 10 female patients received RM-131 (100 μg s.c.) or placebo and underwent scintigraphic gastric emptying (GE) and colonic filling at 6 h (CF6) of a solid-liquid meal administered 30 min postdosing. Adverse events, plasma glucose, and hormonal levels were assessed. GCSI daily diary (GCSI-DD) was completed during treatments. PK was assessed in this cohort and healthy volunteers (HVs)., Results: At screening, HbA(1c) was 7.2 ± 0.4% (SEM) and total GCSI-DD score was 1.32 ± 0.21. RM-131 accelerated GE t(1/2) of solids (P = 0.011); mean difference (Δ) in solid GE t(1/2) was 68.3 min (95% CI 20-117) or 66.1%. There were numerical differences in GE lag time, CF6 solids, and GE t(1/2) liquids (all P < 0.14). With a significant (P < 0.014) order effect, further analysis of the first treatment period (n = 5 per group) confirmed significant RM-131 effects on GE t(1/2) (solids, P = 0.016; liquids, P = 0.024; CF6, P = 0.013). PK was similar in DGE patients and HVs. There were increases in 120-min blood glucose (P = 0.07) as well as 30-90-min area under the curve (AUC) levels of growth hormone, cortisol, and prolactin (all P < 0.02) with single-dose RM-131. Only light-headedness was reported more on RM-131., Conclusions: RM-131 greatly accelerates the GE of solids in patients with type 2 diabetes and documented DGE. PK is similar in diabetic patients and HVs.

Objective: Hypoglycemia is a cause of significant morbidity among patients with diabetes and may be associated with greater risk of death. We conducted a retrospective study to determine whether patient self-report of severe hypoglycemia is associated with increased mortality., Research Design and Methods: Adult patients (N = 1,020) seen in a specialty diabetes clinic between August 2005 and July 2006 were questioned about frequency of hypoglycemia during a preencounter interview; 7 were lost to follow-up and excluded from analysis. Mild hypoglycemia was defined as symptoms managed without assistance, and severe hypoglycemia was defined as symptoms requiring external assistance. Mortality data, demographics, clinical characteristics, and Charlson comorbidity index (CCI) were obtained from the electronic medical record after 5 years. Patients were stratified by self-report of hypoglycemia at baseline, demographics were compared using the two-sample t test, and risk of death was expressed as odds ratio (95% CI). Associations were controlled for age, sex, diabetes type and duration, CCI, HbA(1c), and report of severe hypoglycemia., Results: In total, 1,013 patients with type 1 (21.3%) and type 2 (78.7%) diabetes were questioned about hypoglycemia. Among these, 625 (61.7%) reported any hypoglycemia, and 76 (7.5%) reported severe hypoglycemia. After 5 years, patients who reported severe hypoglycemia had 3.4-fold higher mortality (95% CI 1.5-7.4; P = 0.005) compared with those who reported mild/no hypoglycemia., Conclusions: Self-report of severe hypoglycemia is associated with 3.4-fold increased risk of death. Patient-reported outcomes, including patient-reported hypoglycemia, may therefore augment risk stratification and disease management of patients with diabetes.

Background: Statins are an important part of the treatment plan for patients with type 2 diabetes. However, patients who are prescribed statins often take less than the prescribed amount or stop taking the drug altogether. This suboptimal adherence may decrease the benefit of statin initiation., Objective: To estimate the influence of adherence on the optimal timing of statin initiation for patients with type 2 diabetes., Method: The authors use a Markov decision process (MDP) model to optimize the treatment decision for patients with type 2 diabetes. Their model incorporates a Markov model linking adherence to treatment effectiveness and long-term health outcomes. They determine the optimal time of statin initiation that minimizes expected costs and maximizes expected quality-adjusted life years (QALYs)., Results: In the long run, approximately 25% of patients remain highly adherent to statins. Based on the MDP model, generic statins lower costs in men and result in a small increase in costs in women relative to no treatment. Patients are able to noticeably increase their expected QALYs by 0.5 to 2 years depending on the level of adherence., Conclusions: Adherence-improving interventions can increase expected QALYs by as much as 1.5 years. Given suboptimal adherence to statins, it is optimal to delay the start time for statins; however, changing the start time alone does not lead to significant changes in costs or QALYs.

Background: Several guidelines to reduce cardiovascular risk in diabetes patients exist in North America, Europe, and Australia. Their ability to achieve this goal efficiently is unclear., Methods and Findings: Decision analysis was used to compare the efficiency and effectiveness of international contemporary guidelines for the management of hypertension and hyperlipidemia for patients aged 40-80 with type 2 diabetes. Measures of comparative effectiveness included the expected probability of a coronary or stroke event, incremental medication costs per event, and number-needed-to-treat (NNT) to prevent an event. All guidelines are equally effective, but they differ significantly in their medication costs. The range of NNT to prevent an event was small across guidelines (6.5-7.6 for males and 6.5-7.5 for females); a larger range of differences were observed for expected cost per event avoided (ranges, $117,269-$157,186 for males and $115,999-$163,775 for females). Australian and U.S. guidelines result in the highest and lowest expected costs, respectively., Conclusions: International guidelines based on the same evidence and seeking the same goal are similar in their effectiveness; however, there are large differences in expected medication costs.

Background: Patient involvement in the choice of antihyperglycemic agents could improve adherence and optimize glycemic control in patients with type 2 diabetes mellitus., Methods: We conducted a pilot, cluster randomized trial of Diabetes Medication Choice, a decision aid that describes 5 antihyperglycemic drugs, their treatment burden (adverse effects, administration, and self-monitoring demands), and impact on hemoglobin A(1c) (HbA(1c)) levels. Twenty-one clinicians were randomized to use the decision aid during the clinical encounter and 19 to dispense usual care and an educational pamphlet. We used surveys and video analysis to assess postvisit decisional outcomes, and medical and pharmacy records to assess 6-month medication adherence and HbA(1c) levels., Results: Compared with usual care patients (n = 37), patients receiving the decision aid (n = 48) found the tool more helpful (clustered-adjusted mean difference [AMD] in a 7-point scale, 0.38; 95% confidence interval [CI], 0.04-0.72); had improved knowledge (AMD, 1.10 of 10 questions; 95% CI, 0.11-2.09); and had more involvement in making decisions about diabetes medications (AMD, 21.8 of 100; 95% CI, 13.0-30.5). At 6-month follow-up, both groups had nearly perfect medication use (median, 100% of days covered), with better adherence (AMD, 9% more days covered; 95% CI, 4%-14%) and persistence (AMD, 12 more days covered; 95% CI, 3-21 days) in the usual care group, and no significant impact on HbA(1c) levels (AMD, 0.01; 95% CI, -0.49 to 0.50)., Conclusion: An innovative decision aid effectively involved patients with type 2 diabetes mellitus in decisions about their medications but did not improve adherence or HbA(1c) levels. Trial Registration clinicaltrials.gov Identifier: NCT00388050.

Background: The net economic value of increased health care spending remains unclear, especially for chronic diseases., Objective: To assess the net value of health care for patients with type 2 diabetes., Design: Economic analysis of observational cohort data., Setting: Mayo Clinic, Rochester, Minnesota, a not-for-profit integrated health care delivery system., Patients: 613 patients with type 2 diabetes., Measurements: Changes in inflation-adjusted annual health care spending and in health status between 1997 and 2005 (with health status defined as 10-year cardiovascular risk), holding age and diabetes duration constant across the observation period ("modifiable risk"), and simulated outcomes for all diabetes complications based on the UKPDS (United Kingdom Perspective Diabetes Study) Outcomes Model. Net value was estimated as the present discounted monetary value of improved survival and avoided treatment spending for coronary heart disease minus the increase in annual spending per patient., Results: Assuming that 1 life-year is worth $200,000 and accounting for changes in modifiable cardiovascular risk, the net value of changes in health care for patients with type 2 diabetes was $10,911 per patient (95% CI, -$8480 to $33,402) between 1997 and 2005, a positive dollar value that suggests the value of health care has improved despite increased spending. A second approach based on diabetes complications yielded a net value of $6931 per patient (CI, -$186,901 to $211,980)., Limitation: The patient population was homogeneous and small, and the wide CIs of the estimates are compatible with a decrease as well as an increase in value., Conclusion: The economic value of improvements in health status for patients with type 2 diabetes seems to exceed or equal increases in health care spending, suggesting that those increases were worth the extra cost. However, the possibility that society is getting less value for its money could not be statistically excluded, and there is opportunity to improve the value of diabetes-related health care., Primary Funding Source: None.

Background: Clinicians often use validated risk models to guide treatment decisions for cardiovascular risk reduction. The most common risk models for predicting cardiovascular risk are the UKPDS, Framingham, and Archimedes models. In this article, the authors propose a model to optimize the selection of patients for statin therapy of hypercholesterolemia, for patients with type 2 diabetes, using each of the risk models. For each model,they evaluate the role of age, gender, and metabolic state on the optimal start time for statins., Method: Using clinical data from the Mayo Clinic electronic medical record, the authors construct a Markov decision process model with health states composed of cardiovascular events and metabolic factors such as total cholesterol and high-density lipoproteins. They use it to evaluate the optimal start time of statin treatment for different combinations of cardiovascular risk models and patient attributes., Results: The authors find that treatment decisions depend on the cardiovascular risk model used and the age, gender, and metabolic state of the patient. Using the UKPDS risk model to estimate the probability of coronary heart disease and stroke events, they find that all white male patients should eventually start statin therapy; however, using Framingham and Archimedes models in place of UKPDS, they find that for male patients at lower risk, it is never optimal to initiate statins. For white female patients, the authors also find some patients for whom it is never optimal to initiate statins. Assuming that age 40 is the earliest possible start time, the authors find that the earliest optimal start times for UKPDS, Framingham, and Archimedes are 50, 46, and 40, respectively, for women. For men, the earliest optimal start times are 40, 40, and 40, respectively., Conclusions: In addition to age, gender, and metabolic state, the choice of cardiovascular risk model influences the apparent optimal time for starting statins in patients with diabetes.

Aims: Decision aids in practice may affect patient trust in the clinician, a requirement for optimal diabetes care. We sought to determine the impact of a decision aid to help patients with diabetes decide about statins (Statin Choice) on patients' trust in the clinician., Methods: We randomized 16 diabetologists and 98 patients with type 2 diabetes referred to a subspecialty diabetes clinic to use the Statin Choice decision aid or a patient pamphlet about dyslipidaemia, and then to receive these materials from either the clinician during the visit or a researcher prior to the visit. Providers and patients were blinded to the study hypothesis. Immediately after the clinical encounter, patients completed a survey including questions on trust (range 0 to total trust = 100), knowledge, and decisional conflict. Researchers reviewed videotaped encounters and assessed patient participation (using the OPTION scale) and visit length., Results: Overall mean trust score was 91 (median 97.2, IQR 86, 100). After adjustment for patient characteristics, results suggested greater total trust (trust = 100) with the decision aid [odds ratio (OR) 1.77, 95% CI 0.94, 3.35]. Total trust was associated with knowledge (for each additional knowledge point, OR 1.3, 95% CI 1.1, 1.6), patient participation (for each additional point in the OPTION scale, OR 1.1, 95% CI 1.1, 1.2), and decisional conflict (for every 5-point decrease in conflict, OR 1.5, 95% CI 1.2, 1.9). Total trust was not associated with visit length, which the decision aid did not significantly affect. There was no significant effect interaction across the trial factors., Conclusions: Preliminary evidence suggests that decision aids do not have a large negative impact on trust in the physician and may increase trust through improvements in the decision-making process.

Objective: The purpose of this study was to determine whether implementation of a multicomponent organizational intervention can produce significant change in diabetes care and outcomes in community primary care practices., Research Design and Methods: This was a group-randomized, controlled clinical trial evaluating the practical effectiveness of a multicomponent intervention (TRANSLATE) in 24 practices. The intervention included implementation of an electronic diabetes registry, visit reminders, and patient-specific physician alerts. A site coordinator facilitated previsit planning and a monthly review of performance with a local physician champion. The principle outcomes were the percentage of patients achieving target values for the composite of systolic blood pressure (SBP) <130 mmHg, LDL cholesterol <100 mg/dl, and A1C <7.0% at baseline and 12 months. Six process measures were also followed., Results: Over 24 months, 69,965 visits from 8,405 adult patients with type 2 diabetes were recorded from 238 health care providers in 24 practices from 17 health systems. Diabetes process measures increased significantly more in intervention than in control practices, giving net increases as follows: foot examinations 35.0% (P < 0.0.001); annual eye examinations 25.9% (P < 0.001); renal testing 28.5% (P < 0.001); A1C testing 8.1%(P < 0.001); blood pressure monitoring 3.5% (P = 0.05); and LDL testing 8.6% (P < 0.001). Mean A1C adjusted for age, sex, and comorbidity decreased significantly in intervention practices (P < 0.02). At 12 months, intervention practices had significantly greater improvement in achieving recommended clinical values for SBP, A1C, and LDL than control clinics (P = 0.002)., Conclusions: Introduction of a multicomponent organizational intervention in the primary care setting significantly increases the percentage of type 2 diabetic patients achieving recommended clinical outcomes.

Background: Poor quality of information transfer about the benefits and risks of statin drug use may result in patients not making informed decisions that they can act on in a timely fashion., Methods: The effect of a decision aid about statin drugs on treatment decision making in 98 patients with diabetes was determined in a cluster randomized trial of decision aid vs control pamphlet, with concealed allocation, blinding of participants to study goals, and adherence to the intention-to-treat principle. Twenty-one endocrinologists conducted specialty outpatient metabolic consultations. Patients in the intervention group received Statin Choice, a tailored decision aid that presents the estimated 10-year cardiovascular risk, the absolute risk reduction with use of statin drugs, and the disadvantages of using statin drugs. Patients in the control group received the institution's pamphlet about cholesterol management. We measured acceptability, knowledge about options and cardiovascular risk, and decisional conflict immediately after the visit, and adherence to pill taking was measured 3 months later., Results: Patients favored using the decision aid (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.2-6.9); patients who received the decision aid (n = 52) knew more (difference, 2.4 of 9 points; 95% CI, 1.5-3.3), had better estimated cardiovascular risk (OR, 22.4; 95% CI, 5.9-85.6) and potential absolute risk reduction with statin drugs (OR, 6.7; 95% CI, 2.2-19.7), and had less decisional conflict (difference, -10.6; 95% CI, -15.4 to -5.9 on a 100-point scale) than did patients in the control group (n = 46). Of 33 patients in the intervention group taking statin drugs at 3 months, 2 reported missing 1 dose or more in the last week compared with 6 of 29 patients in the control group taking statin drugs (OR, 3.4; 95% CI, 1.5-7.5)., Conclusions: A decision aid enhanced decision making about statin drugs and may have favorably affected drug adherence.

Objective: To examine the association between depressive symptoms and exercise-related variables among patients with type 2 diabetes., Methods: Surveys were completed by 207 primary care patients diagnosed with type 2 diabetes (52% female; 95% white; mean age = 63 years). Multiple linear regression analyses were conducted., Results: Lower use of relapse prevention behavior was significantly associated with higher depression scores in a multivariate model., Conclusions: Patients with diabetes and depression have barriers to exercise (eg, fewer skills for relapse prevention) and may require additional support for exercise initiation and maintenance.

Objective: To develop a pen-and-paper coronary heart disease (CHD) 10-year risk estimator for patients with type 2 diabetes based on the United Kingdom Prospective Diabetes Study (UKPDS) risk equation (based on 4000 patients with diabetes but only available electronically)., Patients and Methods: We used data collected from adults with type 2 diabetes from 6 primary care practices that participated in a randomized trial in Rochester, Minn; patients were enrolled in the study from July 2001 to December 2003, with follow-up through June 2004. We used multivariable linear regression of the CHD risk estimate to formulate prediction equations to estimate average (<15%), elevated, or high (>30%) 10-year CHD risk according to sex, age, diabetes duration, smoking, hemoglobin A1c level, systolic blood pressure, ratio of total cholesterol to high-density lipoprotein cholesterol, and microalbuminuria categories. We selected cut points for the predicted score, seeking to (1) maximize the number of patients with total agreement between our estimator and the UKPDS risk equation, (2) avoid any patient's risk being either overestimated or underestimated by 2 risk categories, and (3) overestimate rather than underestimate coronary risk., Results: A total of 535 patients with type 2 diabetes participated in this study, 400 in the generation cohort and 135 in the validation cohort. Of the 400 patients in the generation cohort, our estimator had an 82% total agreement with the UKPDS calculation, 11% overestimated risk, and 7% underestimated UKPDS coronary risk (weighted kappa=0.77). Results were similar in the 135 patients in the validation cohort (kappa=0.79) and in an independent validation cohort of 52 patients attending a referral diabetes clinic (kappa=0.68)., Conclusion: The pen-and-paper estimator facilitates the point-of-care estimation of coronary risk in situations in which use of a desktop or handheld version of the electronic UKPDS risk engine is not practical or feasible. In our experience, estimation of risk using this tool, when done with patients, can further patients' insight into their risk of coronary events, often leading to enlightened discussions about modification of Individual risk factors.

An elevation in the ratio of proinsulin (PI) to immunoreactive insulin (IRI) is inversely related to beta-cell function in type 2 diabetes, and increased PI is an independent risk factor for coronary heart disease. An objective of the present studies was to assess the effects of the thiazolidinedione insulin sensitizer, rosiglitazone, on indirect markers of beta-cell function and cardiovascular risk in people with type 2 diabetes by measuring plasma PI and the PI:IRI ratio. Parameters of insulin processing, including plasma PI and PI:IRI ratios, were determined in type 2 diabetes patients enrolled in two randomized double-blind studies comparing the effects of rosiglitazone (4 or 8 mg/d) with placebo (study 1, 26-wk treatment) or the sulfonylurea glyburide (study 2, 52-wk treatment). Treatment with rosiglitazone for 26 wk (study 1) produced significant dose-dependent decreases in both plasma PI concentrations (18-29%) and the PI:IRI ratio compared with baseline (7-14%) and placebo (19-29%) (P < 0.001). A significant increase in the PI:IRI ratio in placebo-treated patients occurred (P < 0.001). In study 2, rosiglitazone also significantly reduced both plasma PI and the PI:IRI ratio compared with baseline (P < 0.001). In contrast, glyburide significantly increased both plasma PI (45%; P < 0.001) and the PI:IRI ratio (10%) (P < 0.05 vs. baseline). These results show that rosiglitazone and glyburide have differential effects on absolute PI levels and the PI:IRI ratio in people with type 2 diabetes.

Resistin, an adipocyte secreted factor, has been suggested to link obesity with type 2 diabetes in rodent models, but its relevance to human diabetes remains uncertain. Although previous studies have suggested a role for this adipocytokine as a pathogenic factor, its functional effects, regulation by insulin, and alteration of serum resistin concentration by diabetes status remain to be elucidated. Therefore, the aims of this study were to analyze serum resistin concentrations in type 2 diabetic subjects; to determine the in vitro effects of insulin and rosiglitazone (RSG) on the regulation of resistin, and to examine the functional effects of recombinant human resistin on glucose and lipid metabolism in vitro. Serum concentrations of resistin were analyzed in 45 type 2 diabetic subjects and 34 nondiabetic subjects. Subcutaneous human adipocytes were incubated in vitro with insulin, RSG, and insulin in combination with RSG to examine effects on resistin secretion. Serum resistin was increased by approximately 20% in type 2 diabetic subjects compared with nondiabetic subjects (P = 0.004) correlating with C-reactive protein. No other parameters, including adiposity and fasting insulin levels, correlated with serum resistin in this cohort. However, in vitro, insulin stimulated resistin protein secretion in a concentration-dependent manner in adipocytes [control, 1215 +/- 87 pg/ml (mean +/- SEM); 1 nM insulin, 1414.0 +/- 89 pg/ml; 1 microM insulin, 1797 +/- 107 pg/ml (P < 0.001)]. RSG (10 nM) reduced the insulin-mediated rise in resistin protein secretion (1 nM insulin plus RSG, 971 +/- 35 pg/ml; insulin, 1 microM insulin plus RSG, 1019 +/- 28 pg/ml; P < 0.01 vs. insulin alone). Glucose uptake was reduced after treatment with 10 ng/ml recombinant resistin and higher concentrations (P < 0.05). Our in vitro studies demonstrated a small, but significant, reduction in glucose uptake with human recombinant resistin in differentiated preadipocytes. In human abdominal sc adipocytes, RSG blocks the insulin-mediated release of resistin secretion in vitro. In conclusion, elevated serum resistin in human diabetes reflects the subclinical inflammation prevalent in type 2 diabetes. Our in vitro studies suggest a modest effect of resistin in reducing glucose uptake, and suppression of resistin expression may contribute to the insulin-sensitizing and glucose-lowering actions of the thiazolidinediones.

Type 2 diabetes is reaching epidemic proportions worldwide, fueled by the increasing prevalence of obesity as many populations adopt a western lifestyle. Secondary complications affecting both the microvascular and macrovascular systems are responsible for premature mortality in Type 2 diabetes, with two thirds or more dying of cardiovascular disease. Two interacting metabolic defects, insulin resistance and beta-cell dysfunction are present in Type 2 diabetes. It is now recognised that insulin resistance is central to a cluster of metabolic abnormalities--called the insulin resistance syndrome--that are responsible for the excess of cardiovascular disease. Older antidiabetic agents such as the sulfonylureas, metformin and insulin are more effective than lifestyle modification in reducing microvascular complications of Type 2 diabetes, but overall do not reduce cardiovascular risk. Metformin, although no more effective as a glucose-lowering agent than sulfonylureas or insulin, does significantly reduce cardiovascular disease, probably as a result of its weak insulin-sensitising action. The newly-marketed thiazolidinedione insulin-sensitising antidiabetic agents also improve multiple biomarkers of cardiovascular risk, suggesting that novel approaches to insulin sensitisation will not only provide effective long-term glycaemic control but improve cardiovascular outcomes in Type 2 diabetes. Multiple therapeutic targets within the insulin signalling cascade are being explored, together with follow-up compounds to the first generation thiazolidinediones. These initiatives, together with developments in beta(3)-adrenoceptor agonists, 11 beta-hydroxysteroid dehydrogenase Type 1 inhibitors and modulators of the glucagon-like peptide 1 axis, all of which also potentially enhance insulin sensitivity, are critically evaluated.

The precise mechanism by which PPARgamma activation by thiazolidinediones (TZDs) improves insulin sensitivity is still unclear. Recent studies have focused on the role of adipocytokines in metabolic control and their regulation by TZDs. In this study, we compared the chronic effects of antihyperglycemic doses of the TZD rosiglitazone, the beta3-adrenoceptor agonist BRL-35135, and the PPARalpha agonist Wy-14,643 on the mRNA expression of adipocytokines in WAT of db/db mice. Rosiglitazone treatment decreased adiponectin and resistin mRNA levels by 57 and 72%, respectively (P < 0.001), with no effect on the level of TNFalpha or RELMalpha transcripts. In comparison, Wy-14,643 reduced adiponectin transcript levels by 31% (P = 0.015) while BRL-35135 increased RELMalpha mRNA expression by 245% (P < 0.001) without effect on the other transcripts. Our results indicate that although a reduction in adiponectin and resistin mRNA levels in WAT by rosiglitazone treatment of diabetic mice may contribute to the antidiabetic effects, an alteration in TNFalpha, adiponectin, resistin, or RELMalpha mRNA expression is not absolutely required for the regulation of blood glucose concentration in the db/db mouse., (Copyright 2001 Academic Press.)

Aim: To investigate the potential of rosiglitazone, a highly potent agonist at the nuclear peroxisome proliferator activated receptor-gamma (PPAR-gamma), to prevent the development of diabetes in the Zucker diabetic fatty (ZDF) rat or to ameliorate the condition at a later stage of the disease., Methods: Rosiglitazone (10 micromol/kg body weight daily) was given via the diet to ZDF rats from aged 6 weeks, before the onset of hyperglycaemia (Prevention group), or from aged 21 weeks after hyperglycaemia and proteinuria were established (Intervention group). Untreated ZDF rats and age-matched Zucker lean rats (ZL) served as controls and the experiment was terminated when the animals were aged 28 weeks., Results: Whilst the combined ZDF control and Intervention groups were already hyperglycaemic (14.6 +/- 1.6 vs. ZL 5.7 +/- 0.1 mmol/l, mean +/- s.e.m.; p < 0.05), glycosuric and polydipsic at aged 11 weeks, and thereafter had a declining plasma insulin concentration, rosiglitazone Prevention treatment maintained normoglycaemia even at aged 27 weeks (3.7 +/- 0.3 mmol/l vs. ZL 3.0 +/- 0.3 mmol/l; NS). Intervention treatment at aged 21 weeks, however, failed to ameliorate the diabetes. These functional data were supported by determinations of pancreatic insulin content (microg/mg tissue as follows: ZL, 43.1 +/- 3.9; ZDF control (28 weeks) + ZDF Intervention control (21 weeks), 6.0 +/- 0.8; Prevention, 63.6 +/- 15.8; Intervention, 6.2 +/- 0.9) and by morphological, immunohistochemical and electron microscopical examination of pancreata at the end of the study. Thus, islets from rosiglitazone Prevention rats were similar to ZL rats, whereas ZDF controls and Intervention rats exhibited islets depleted of insulin, with a disorganized architecture and an ultrastructure indicative of work hypertrophy. ZDF control rats and Intervention rats, though not rosiglitazone Prevention rats, also exhibited marked proteinuria, indicative of renal glomerular damage., Conclusions: Our results demonstrate that in ZDF rats, rosiglitazone prevents the progression from insulin resistance to overt diabetes. These data provide a rationale for investigating whether treatment with rosiglitazone of patients with early signs of perturbed glucose metabolism (e.g. impaired fasting glucose (IGT)) may prevent the progression to type 2 diabetes and its associated complications.

Context: Compliance with recommendations from the American Diabetes Association for management of patients with diabetes is not optimal. Changing physician practice patterns with provider-focused interventions can be difficult. We report results after implementation of a type 2 diabetes mellitus guideline., Objective: To increase the annual rate of microalbumin/urine protein testing, dilated eye examinations, and foot examinations for patients with diabetes and to reduce overall levels of hemoglobin A1c (Hb A1c)., Design: Before-after study., Intervention: From April 1996 to June 1998, a guideline on type 2 diabetes mellitus was implemented with multicomponent interventions. These included small group educational sessions led by opinion leaders, an electronic version of the guideline, audit with feedback, and enhanced clinical orders support. Medical records of random samples of patients with diabetes were audited for specific diabetes performance measures on a monthly basis. Baseline data were compared with results at the end of the implementation effort., Setting: Southeastern Minnesota, excluding Olmsted County., Participants: Adult patients seen at one practice of 18 general internists., Outcome Measures: Outcome measures included Hb A1c values and annual performance of a urine protein test, foot examination, and dilated eye examination., Results: Gradual, sustained; and statistically significant improvements in the three annual performance measures were observed. Urine protein testing increased from 24% to 66% (P = 0.001), dilated eye examinations increased from 63% to 84% (P = 0.001), and foot examinations increased from 86% to 97% (P = 0.001). Mean Hb A1c values +/- SD also improved from 7.8% +/- 1.0% to 7.1% +/- 0.7% (P < 0.001) in patients who received continuing care for diabetes., Conclusions: Statistically significant improvements were observed after continuous improvement efforts were focused on providers in an individual group practice. When used to implement a diabetes guideline, such interventions may improve delivery of services and reduce Hb A1c levels in patients with diabetes.

High resolution 1H nuclear magnetic resonance (NMR) spectroscopic analysis of biofluids is a recently established tool for evaluating inherited and acquired errors in metabolic control. In the present study 1H NMR analysis of urine was used to monitor efficacy of BRL 49653, a potent and selective antihyperglycaemic agent, following oral administration for up to 36 weeks to the genetically diabetic C57BL/KsJ db/db mouse. The effects of BRL 49653 on carbohydrate and fatty acid metabolism were monitored by determination of changes in concentrations of low molecular weight urinary metabolites. A qualitative comparison of the NMR spectra of urine from untreated diabetic mice with those of lean littermates and literature examples revealed several abnormalities, the majority of which could be explained in terms of the non-insulin dependent diabetes syndrome exhibited by these animals. Quantitatively the most prominent was the extreme glycosuria of both young (8-12 weeks; 0.9 g glucose kg-1 h-1) and older (42 weeks; 2 g glucose kg-1 h-1) diabetic mice. This was accompanied by the excretion of a number of unassigned sugar derivatives and by ketone bodies. Administration of BRL 49653 (3 mumol kg-1) to db/db mice for 24 days reduced blood glucose concentrations to values comparable with non-diabetic lean littermates and reduced glycosuria by > 90%. BRL 49653 significantly reduced excretion of unassigned sugars, acetate, lactate, and the ketone bodies, acetoacetate, 3-D-hydroxybutyrate and acetone. The anti-diabetic efficacy of BRL 49653, assessed from the pattern of urinary metabolites, was maintained over a 36-week treatment period. These results demonstrate the value of 1H NMR to evaluate non-invasively the efficacy of novel therapeutic agents.

BRL 26830A, (R*, R*)-(+/-)-methyl 4-[2-[(2-hydroxy-2-phenylethyl) amino] propyl]-benzoate, (E)-2-butenedioate (2:1) salt, is a new antihyperglycemic agent orally active in obese-hyperglycemic animal models. In C57Bl/6 ob/ob mice, BRL 26830A (1 mg/kg) given daily for periods of 14 d-6 weeks produced a marked improvement in glucose tolerance and a reduction in the fasting plasma insulin concentration. Adipocytes prepared from treated mice showed improved insulin responsiveness. In Zucker fa/fa rats, treatment with BRL 26830A (2.9 mg/kg/d for 23 d) produced improvements in both glucose tolerance and whole animal insulin sensitivity, as assessed by rate of fall of blood glucose in response to an intravenous dose of insulin. In C57Bl/KSJ db/db mice, BRL 26830A (admixed with food at 50 mg/kg diet) decreased blood glucose to values similar to those in lean mice. At the end of a 10-week treatment, BRL 26830A-treated mice had a higher plasma and pancreatic insulin content than the untreated db/db mice. In normoglycaemic rats and mice, BRL 26830A increases the plasma insulin concentration and increases glucose disposal. However, in most circumstances, there is a counteracting increase in endogenous glucose synthesis and, therefore, no change in blood glucose occurs. Improvements in glucose tolerance occur in 24-h fasted rats and mice. BRL 26830A has thermogenic activity and it is suggested that this might be linked to increased glucose utilization. Brown adipose tissue (BAT) of C57Bl/KSJ db/db mice has a reduced maximum glycolytic capacity relative to lean littermates. Treatment with BRL 26830A increased the glycolytic capacity 10-fold.