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The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia that contributes to over 150,000 deaths each year. Hypertension, ischemic heart disease, and smoking are among the leading risk factors for AF. Historically, it is well-accepted that AF is treated by cardiologists and frequently by specialists of heart electrophysiology. However, an overwhelming majority of patients with AF initially present to their primary care physicians (PCP). Yet, the assessment of PCP skills in the management of AF has not been well studied. We used the Edocate® virtual patient simulation platform and smartphone application to test the skills of physicians in a “virtual” clinic where their decisions in selecting diagnostic and management steps over several encounters were used for analysis of their knowledge and as a learning tool. We applied this application to assess the level of knowledge in managing AF in 25 PCP. The virtual patient was a 68-year-old man (an active smoker) with hypertension, hyperlipidemia, myocardial infarction 5 years ago, presenting with a 30-day history of palpitations and shortness of breath. On presentation, his blood pressure was 145/93 mmHg, ECG showed AF with a ventricular rate of 132 bpm. He was on atorvastatin 40 mg/d, aspirin 100 mg/d, and ramipril 5 mg/d. Total cholesterol was 155 mg/dl and LDL 85 mg/dl. Comprehensive analysis of the PCP choices via the Edocate platform revealed that only 62% of the participants elected to refer this patient to cardiology. While 65% addressed smoking cessation, only 38% achieved LDL levels of

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

As any other aspect of contemporary life, an old and established field of CME undergoes a transformation into a “digital age.” Virtual patient simulation (VPS) has shown to be an interactive and efficient way of engaging healthcare professionals (HCP) in continuing medical education. VPS can identify gaps in knowledge and improve competence, using engaging, online tools. The Edocate VPS Platform has been developed by a group of physicians, education experts, and computer specialists. In this communication, we report the experience of several hundreds of HCP using the Edocate VPS application in the fields of type 2 diabetes (T2DM) and hyperlipidemia. The Edocate VPS application, displaying both simple and complex clinical situations, was presented to an international group of HCPs who had the task to perform physical exams, order lab and imaging tests, update the medical record with the right diagnoses, prescribe medications, and perform long-term follow-up through multiple visits. The HCPs received personalized, guideline-based, feedback on their actions. The analytical capabilities of the Edocate VPS platform run very deep and allow in-depth analysis of learners’ competence in achieving the best outcomes, while teaching to apply a personalized approach, avoiding side effects of medications, and providing instantaneous access to the most current references in the field. The data collected from the program has shown significant gaps in knowledge and adherence to guidelines in the areas of management of T2DM and hyperlipidemia. Only about 50% of all participants achieved guideline-compatible glycemic control – namely HbA1c below 7%. Furthermore, only 41% of practicing physicians and 23% of family medicine residents achieved levels of LDL below 70 mg/dl in their virtual patients. In conclusion, the data presented in this communication strongly suggests that this novel simulation platform can enable medical organizations to create immersive VPS cases for their primary educational and CME efforts.

Management of hyperlipidemia (HL) in patients with Type 2 diabetes (T2DM) has been taught extensively but the real-life competency is difficult to evaluate. Edocate’s proprietary virtual patient simulation smartphone and web-based application (APP) allows an innovative way of learning and objective assessment of the provider’s proficiency in approach to and management of a given medical condition. We utilized this novel educational APP to analyze the real-life knowledge of 894 healthcare providers (HCP) in several projects within multiple geographies in the management of HL in patients with T2DM. The HCP managed 1-3 patients with T2DM and HL in their virtual clinic. HCP chose medications, made diagnostic adjustments, and ordered laboratory tests of their choice. Based on their selections, the APP simulated the course of diabetes and hyperlipidemia throughout multiple virtual visits, requiring diverse management decisions and addressing medications’ side effects, while adhering to guidelines and accepted standards of care. Results: Conclusions: 1. Innovative patient simulation-based learning APP revealed adequate but not perfect HL management skills. 2. NP - DM have the best guideline-recommended approach to therapy, followed by practicing MD/DO. 3. Intensive therapy achieving LDL levels below 50 or even 70 mg/dl remains elusive. 4. Edocate’s patient simulation-based learning application helps identify knowledge gaps, prescription patterns and HCP decision-making processes. 5. This APP accurately assesses the “real-life” knowledge and patterns of practice while offering cutting-edge ways of learning to dramatically improve competency levels.

The goals of Type 2 diabetes (T2DM) management include achievement of glycemic, blood pressure (BP), and lipid control. All three variables must be addressed adequately in order to prevent diabetic complications. Aim: Using a proprietary smartphone-based application (APP) developed by Edocate Ltd, that simulates virtual visits, we assessed how well healthcare providers (HCPs) manage T2DM. Materials & Methods: A total of 461 HCPs (247 MD, MD/PhD, or DO and 214 NPs) downloaded and used the APP to treat their virtual patients over multiple visits. All patients presented with poorly controlled T2DM, hypertension (HTN) and hyperlipidemia. HCPs chose the first, second and third lines of medications, made diagnostic adjustments, initiated appropriate referrals to specialists, and ordered laboratory tests of their choice. Based on their selections, the APP simulated the course of diabetes and its complications, requiring diverse management decisions on the subsequent virtual visits. Results: In the Edocate virtual clinic, only 53% of HCPs achieved good glycemic control (A1c < 7%), 41% achieved BP control ( Conclusions: Despite a worldwide effort in diabetes education, the knowledge of T2DM management remains suboptimal (as assessed by the simulation APP) and underscores the need for better professional education. Innovative patient simulation-based learning applications can dramatically improve the level of competency in HCPs. Disclosure B. Draznin: None. I. Iancu: None.

Objective: The prevalence of diabetes mellitus (DM) is steadily rising in the U.S., both in the general population and among those with cardiovascular disease (CVD). Understanding how to treat a patient with both conditions is becoming increasingly important. With multiple therapeutic options for CVD management, some medications will invariably impact glycemia in this group of patients. The concept of "DM-friendly" management of CVD is based on a treatment approach of selecting medications that do not impair glycemic control and provide equivalent cardioprotective effects. This article reviews the glycemic effects of various classes of medications commonly used to treat CVD. Methods: Data sources were all PubMed- and Google Scholar-referenced articles in English-language peer-reviewed journals from 1980 through April 2016. Studies selected could include observational studies or prospective clinical trials. Prospective clinical trials included in this review focused on investigating the association of the medication of interest with glycemic outcomes. Meta-analyses and systematic reviews were also included. Results: The data on glycemic effects were lacking for many of the medication classes and individual medications examined. However, in our review, certain beta-blockers and renin angiotensin aldosterone system inhibitors, and select calcium channel blockers were consistently shown to have favorable glycometabolic profiles when compared with other commonly used cardiovascular therapies. Conclusion: Several commonly prescribed medications for the treatment of CVD, such as certain beta-blockers and renin angiotensin aldosterone system inhibiting agents, are associated with favorable glycometabolic effects. As clinicians are more often faced with the challenge of treating patients with DM and concomitant CVD, consideration of how common cardiovascular medications may affect glycemia should be incorporated into the clinical decision making process. Abbreviations: A1C = hemoglobin A1C ACE = angiotensin-converting enzyme ARB = angiotensin II receptor blocker CCB = calcium channel blocker CI = confidence interval CVD = cardiovascular disease DM = diabetes mellitus MI = myocardial infarction RR = relative risk

With appearance of new insulins on the market, new clinical challenges, much like unintended consequences, came into light in our daily practice. One of the most pressing issues has become an issue of switching patients to and from newer insulins in various clinical situations. A proper switch from 1 medication to another requires understanding of pharmacokinetics (PK) and pharmacodynamics (PD) of both drugs. Unfortunately, there is no research in this area and, as a result, there are no guidelines nor is there even a consensus. We present 5 clinical scenarios in which the patients were transitioned to or from insulin degludec. Because there are no data and no current consensus, we have polled 200 diabetes care providers soliciting their opinion as to how they would handle these clinical situations. Our poll of endocrinologists revealed multiple approaches as well as elements of confusion among providers. Even though all answers, summarized following each case, might be reasonable, and there might not be a single correct answer, we wish to express our opinion that is based on PK and PD of these insulins. Because there is more than 1 correct way of implementing these transitions, we urge our colleagues to institute a very close follow-up of these patients with frequent adjustments of insulin dose to avoid stacking with potential hypoglycemia.

Objective The objective is to formulate clinical practice guidelines for the treatment of diabetes in older adults. Conclusions Diabetes, particularly type 2, is becoming more prevalent in the general population, especially in individuals over the age of 65 years. The underlying pathophysiology of the disease in these patients is exacerbated by the direct effects of aging on metabolic regulation. Similarly, aging effects interact with diabetes to accelerate the progression of many common diabetes complications. Each section in this guideline covers all aspects of the etiology and available evidence, primarily from controlled trials, on therapeutic options and outcomes in this population. The goal is to give guidance to practicing health care providers that will benefit patients with diabetes (both type 1 and type 2), paying particular attention to avoiding unnecessary and/or harmful adverse effects.

Expert clinicians counter some of the recommendations regarding hemoglobin A1c targets for type 2 diabetes that were proposed in a recent American College of Physicians guideline.

Currently patients with diabetes comprise up to 25–30% of the census of adult wards and critical care units in our hospitals. Although evidence suggests that avoidance of hyperglycemia (>180 mg/dL) and hypoglycemia (

“ A man walks into a bar …” These classic words introduce countless humorous situations. “ A man enters a hospital …” Unfortunately, these words introduce distinctly serious situations that occur at the rate of > 35 million per year across the United States.1 These words introduce a story in people's lives that all too often includes mistakes, misadventures, and even preventable deaths. The hospital is a dangerous place. Approximately one-third of all deaths in this country occur in hospitals.2,3 On any given day, up to 30% of all hospitalized patients have diabetes, placing almost one-third of inpatients at greater risk for complications that may adversely affect their hospital stay. The majority of these hospitalized patients with diabetes are treated with insulin, a medication that occupies a prominent place on the list of high-alert medications of the Institute for Safe Medication Practices.4 It is the leading medication implicated in adverse events requiring treatment in a hospital emergency department.5 Moreover, insulin is responsible for more drug errors during acute hospital care than other commonly used hospital medications.6 What is the best approach to using insulin in the hospital setting? What skills and knowledge must providers have to make the most effective use of insulin and yet minimize the danger of hypoglycemia? There are no simple answers for these questions. As depicted in Figure 1, a single hospitalization often involves multiple transitions, each requiring a careful approach to insulin therapy. The transitions begin when patients enter the hospital. Patients may be admitted to a ward or to the intensive care unit (ICU), proceed directly to the operating room, or undergo various invasive procedures. Patients then move within the hospital among different levels of care with overlapping or sequential interventions such as nothing-by-mouth (nil per …

Objective The cellular effects of restricting fat versus carbohydrate during a low-calorie diet are unclear. The aim of this study was to examine acute effects of energy and macronutrient restriction on skeletal muscle insulin signalling in obesity. Materials/Methods Eighteen obese individuals without diabetes underwent euglycemic–hyperinsulinemic clamp and skeletal muscle biopsy after: (a) 5 days of eucaloric diet (30% fat, 50% carbohydrate), and (b) 5 days of a 30% calorie-restricted diet, either low fat/high carbohydrate (LF/HC: 20% fat, 60% carbohydrate) or high-fat/low carbohydrate (HF/LC: 50% fat, 30% carbohydrate). Results Weight, body composition, and insulin sensitivity were similar between groups after eucaloric diet. Weight loss was similar between groups after hypocaloric diet, 1.3 ± 1.3 kg (p

To improve glycemic control of hospitalized patients with diabetes and hyperglycemia, many medical centers have established dedicated glucose management teams (GMTs). However, the impact of these specialized teams on clinical outcomes has not been evaluated.We conducted a retrospective study of 440 patients with type 2 diabetes admitted to the medical service for cardiac or infection-related diagnosis. The primary endpoint was a composite outcome of several well-recognized markers of morbidity, consisting of: death during hospitalization, transfer to intensive care unit, initiation of enteral or parenteral nutrition, line infection, new in-hospital infection or infection lasting more than 20 days of hospitalization, deep venous thrombosis or pulmonary embolism, rise in plasma creatinine, and hospital re-admissions.Medical housestaff managed the glycemia in 79% of patients (usual care group), while the GMT managed the glycemia in 21% of patients (GMT group). The primary outcome was similar between cohorts (0.95 events per patient versus 0.99 events per patient in the GMT and usual care cohorts, respectively). For subanalysis, the subjects in both groups were stratified into those with average glycemia of180 mg/dL versus those with glycemia180 mg/dL. We found a significant beneficial impact of glycemic management by the GMT on the composite outcome in patients with average glycemia180 mg/dL during their hospital stay. The number of patients who met primary outcome was significantly higher in the usual care group (40 of 83 patients, 48%) than in the GMT-treated cohort (8 of 33 patients, 25.7%) (P.02).Our data suggest that GMTs may have an important role in managing difficult-to-control hyperglycemia in the inpatient setting.BG = blood glucose GMT = glucose management team HbA1c = hemoglobin A1c ICU = intensive care unit POC = point of care T2D = type 2 diabetes.

Transition of diabetic patients from iv insulin infusion to s.c. insulin frequently results in rebound hyperglycemia.We hypothesized that initiation of a long-acting insulin therapy concurrently with i.v. insulin infusion would decrease the rate of rebound hyperglycemia after discontinuation of the insulin infusion.Sixty-one diabetic patients receiving i.v. insulin therapy participated in this prospective randomized study. Subjects in the intervention group received daily injections of glargine s.c. (0.25 U/kg body weight) starting within 12 h of initiation of i.v. insulin infusion. Capillary blood glucose measurements were obtained up to 12 h after discontinuation of insulin infusion. Rebound hyperglycemia was defined as a blood glucose level greater than 180 mg/dl.The study was conducted at the University of Colorado Hospital.Sixty-one hospitalized patients with known type 1 or type 2 diabetes receiving i.v. insulin infusion participated in the study.The primary outcome of this study was to compare the rates of rebound hyperglycemia between the control and the intervention groups after i.v. insulin infusion is discontinued.Overall, 29 subjects in the control group (93.5%) had at least one glucose value above 180 mg/dl during the 12-h follow-up period. This was significantly greater than the rate of rebound hyperglycemia in the intervention group (10 subjects or 33.3%, P0.001). The effect of the intervention was apparent in subjects who presented with diabetic ketoacidosis, after solid organ transplantation, and in patients with other surgical and medical diagnoses. There were three hypoglycemic measurements in two control subjects (68, 62, and 58 mg/dl) and none in the intervention group.Once-daily s.c. insulin glargine administered during i.v. insulin infusion is a safe method for preventing future rebound hyperglycemia, without increased risk of hypoglycemia.

Adenosine monophosphate-activated protein kinase (AMPK), silent mating type information regulation 2 homologue 1 (SIRT 1), and peroxisome proliferator-activated receptor γ co-activator α (PGC1α) constitute an energy sensing cellular network that controls mitochondrial biogenesis. Caloric restriction activates both AMPK and SIRT-1 to increase ATP production from fat oxidation. We characterized AMPK and SIRT 1 expression and activity in human skeletal muscle in response to dietary fat or carbohydrate intake on the background of either overfeeding or caloric restriction. AMPK phosphorylation and acetylation of PGC1α (as a measure of SIRT activity) were determined. Euglycemic-hyperinsulinemic clamp and muscle biopsies were performed in human subjects participating in 2 separate studies. In study 1, 21 lean healthy individuals were overfed for 5 days, while in study 2, 18 obese otherwise healthy individuals consumed a calorie-restricted diet for 5 days. Under both conditions - overfeeding and caloric restriction - high fat/low carbohydrate (HF/LC) diet significantly increased phosphorylation of AMPK and deacetylation of PGC1α in skeletal muscle without affecting total amounts of AMPK, PGC1α, or SIRT 1. In contrast, low fat/high carbohydrate (LF/HC) hypocaloric diet reduced phosphorylation of AMPK and deacetylation of PGC1α. Our data indicate that a relative deficiency in carbohydrate intake or, albeit less likely, a relative excess of fat intake even in the absence of caloric deprivation is sufficient to activate the AMPK-SIRT 1-PGC1α energy-sensing cellular network in human skeletal muscle.

Despite significant advances in inpatient diabetes management, it is still a challenge to choose the safest and most efficacious subcutaneous insulin regimen for diabetic patients on continuous enteral nutrition (EN) therapy. The authors conducted a retrospective analysis of glycemic control in 22 non-critically ill diabetic patients, receiving at least 3 days of continuous EN. Patients received different insulin regimens while on continuous EN, including a basal/bolus glargine/lispro regimen (group 1, n = 8), 70/30 biphasic insulin twice daily (group 2, n = 8), and 70/30 biphasic insulin 3 times a day (group 3, n = 6). The glucose data from 72 hours from the initiation of EN were analyzed (12 point-of-contact glucose measurements per patient). Overall, the degree of control was comparable in all groups, with target range maintained more consistently in group 3 (70/30 insulin administered 3 times daily). In this group, 69% of values were in the target range (140-180 mg/dL) as compared with 24% in glargine/lispro group and 22% in the 70/30 insulin bid group. Eight hypoglycemic episodes occurred among the 3 groups: 5 episodes in group 1 (5.4%), 2 episodes in group 2 (2.1%), and 1 episode in group 3 (1.4%) (P = .05, groups 2 and 3 vs group 1). Administration of 70/30 biphasic insulin 3 times daily is a safe therapeutic regimen in diabetic patients on continuous EN as it maintains glycemia in the target range and might produce fewer episodes of hypoglycemia.

Context: Cardiovascular disease is the major cause of death in adults with diabetes, yet little is specifically known about the effects of type 1 diabetes (T1D) on cardiovascular outcomes in youth. Although insulin resistance (IR) likely contributes to exercise and cardiovascular dysfunction in T2D, IR is not typically considered a contributor in T1D. Objective: We hypothesized that cardiopulmonary fitness would be reduced in T1D youth in association with IR and cardiovascular dysfunction. Design and Participants: This cross-sectional study at an academic hospital included 12 T1D adolescents compared with 12 nondiabetic controls, similar in age, pubertal stage, activity level, and body mass index. Outcome Measures: Cardiopulmonary fitness was measured by peak oxygen consumption (VO2peak) and oxygen uptake kinetics (VO2kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, intramyocellular lipid by magnetic resonance spectroscopy, and body composition by dual-energy x-ray absorptiometry. Results: T1D adolescents had significantly decreased VO2peak, peak work rate, and insulin sensitivity compared with nondiabetic adolescents. T1D youth also had reduced vascular reactivity and evidence of diastolic dysfunction and left ventricular hypertrophy. Despite their IR and reduced cardiovascular fitness, T1D youth had paradoxically normal intramyocellular lipid, waist to hip ratio, and serum lipids and high adiponectin levels. In multivariate analysis, IR primarily, and forearm blood flow secondarily, independently predicted VO2peak. Conclusions: T1D youth demonstrated IR, impaired functional exercise capacity and cardiovascular dysfunction. The phenotype of IR in T1D youth was unique, suggesting a pathophysiology that is different from T2D, yet may adversely affect long-term cardiovascular outcomes.

The incidence of pediatric type 2 diabetes (T2D) is rising, with unclear effects on the cardiovascular system. Cardiopulmonary fitness, a marker of morbidity and mortality, is abnormal in adults with T2D, yet the mechanisms are incompletely understood.We hypothesized that cardiopulmonary fitness would be reduced in youth with T2D in association with insulin resistance (IR) and cardiovascular dysfunction.We conducted a cross-sectional study at an academic hospital that included 14 adolescents (age range, 12-19 yr) with T2D, 13 equally obese adolescents and 12 lean adolescents similar in age, pubertal stage, and activity level.Cardiopulmonary fitness was measured by peak oxygen consumption (VO(2)peak) and oxygen uptake kinetics (VO(2)kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, body composition by dual-energy x-ray absorptiometry, intramyocellular lipid by magnetic resonance spectroscopy, and inflammation by serum markers.Adolescents with T2D had significantly decreased VO(2)peak and insulin sensitivity, and increased soleus intramyocellular lipid, C-reactive protein, and IL-6 compared to obese or lean adolescents. Adolescents with T2D also had significantly prolonged VO(2)kinetics, decreased work rate, vascular reactivity, and adiponectin, and increased left ventricular mass and fatty acids compared to lean adolescents. In multivariate linear regression analysis, IR primarily, and fasting free fatty acids and forearm blood flow secondarily, were significant independent predictors of VO(2)peak.Given the strong relationship between decreased cardiopulmonary fitness and increased mortality, these findings in children are especially concerning and represent early signs of impaired cardiac function.

Mitochondrial dysfunction has been linked to etiology of insulin resistance, however the mechanism remains unknown. In this study we investigated whether mitochondrial dysfunction induced by cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP) alters insulin sensitivity in 3T3-L1 adipocytes and which cellular signaling molecules might be involved. Fully differentiated 3T3-L1 adipocytes were treated with 10 microM FCCP for 1h, resulting in increased serine-307 phosphorylation of IRS-1 and decreased insulin-stimulated tyrosine phosphorylation, association of p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase) with IRS-1, decreased insulin-stimulated PI 3-kinase activity and H(3)-2-deoxyglucose (2DOG) uptake. A partial (46%) knockdown of JNK1 blocked FCCP-induced serine phosphorylation of IRS-1 and restored insulin-stimulated tyrosine phosphorylation of IRS-1, association of p85alpha subunit of PI 3-kinase with IRS-1, activation of PI 3-kinase, and stimulation of 2DOG uptake. Thus, FCCP-induced mitochondrial dysfunction may cause insulin resistance that is ameliorated by reduction of JNK1 expression.

Medial artery vascular smooth muscle cell (VSMC) calcification increases the risk of cardiovascular mortality in type 2 diabetes. However, the influence of insulin on VSMC calcification is unclear. We explored the effects of insulin on rat VSMC calcification in vitro and found that in a dose-dependent fashion, insulin attenuates VSMC calcification induced by high phosphate conditions as quantified by the o-cresolphthalein calcium (OCPC) method. In an in vitro model of insulin resistance in which cells are exposed to elevated insulin concentrations and the PI 3-kinase pathway is selectively inhibited, increased VSMC calcification was observed, suggesting that the PI 3-kinase pathway is involved in this attenuating effect of insulin. We postulated that insulin may also have an effect on phosphate or calcium transport in VSMC. We found that insulin increases phosphate transport at 3 and 24 h. This effect was mediated by increased Vmax for phosphate transport but not Km. Because type III sodium-phosphate co-transporters Pit-1 and Pit-2 are found in VSMC, we examined their expression by Western blot and real-time RT-PCR. Insulin stimulates Pit-1 mRNA modestly (*p