Empagliflozin improves vascular insulin sensitivity and muscle perfusion in persons with type 2 diabetes.

Sodium glucose cotransporter 2 inhibitors (SGLT2is) improved major adverse cardiovascular events (MACE), heart failure, and renal outcomes in large trials; however, a thorough understanding of the vascular physiological changes contributing to these responses is lacking. We hypothesized that SGLT2i therapy would diminish vascular insulin resistance and improve hemodynamic function, which could improve clinical outcomes. To test this, we treated 11 persons with type 2 diabetes for 12 wk with 10 mg/day empagliflozin and measured vascular stiffness, endothelial function, peripheral and central arterial pressures, skeletal and cardiac muscle perfusion, and vascular biomarkers before and at 120 min of a euglycemic hyperinsulinemic clamp at weeks 0 and 12. We found that before empagliflozin treatment, insulin infusion lowered peripheral and central aortic systolic pressure (P < 0.05) and muscle microvascular blood flow (P < 0.01), but showed no effect on other vascular measures. Following empagliflozin, insulin infusion improved endothelial function (P = 0.02), lowered peripheral and aortic systolic (each P < 0.01), diastolic (each P < 0.05), mean arterial (each P < 0.01), and pulse pressures (each P < 0.02), altered endothelial biomarker expression, and decreased radial artery forward and backward pressure amplitude (each P = 0.02). Empagliflozin also improved insulin-mediated skeletal and cardiac muscle microvascular perfusion (each P < 0.05). We conclude that empagliflozin enhances insulin's vascular actions, which could contribute to the improved cardiorenal outcomes seen with SGLT2i therapy.NEW & NOTEWORTHY The physiological underpinnings of the cardiovascular benefits of SGLT2 inhibitors remain uncertain. We tested whether empagliflozin mitigates vascular insulin resistance in patients with type 2 diabetes. Aortic and peripheral systolic, diastolic, mean and pulse pressures, endothelial function, vascular stiffness, and heart and muscle microvascular perfusion were measured before and during an insulin infusion at baseline and after 12 wk of empagliflozin. After empagliflozin, vascular responses to insulin improved dramatically.

Insulin-induced vasoconstriction is prevalent in muscle microvasculature of otherwise healthy persons with type 1 diabetes.

Insulin's microvascular actions and their relationship to insulin's metabolic actions have not been well studied in adults with type 1 diabetes mellitus (T1DM). We compared the metabolic and selected micro- and macrovascular responses to insulin by healthy adult control (n = 16) and subjects with T1DM (n = 15) without clinical microvascular disease. We measured insulin's effect on 1) skeletal muscle microvascular perfusion using contrast-enhanced ultrasound (CEU), 2) arterial stiffness using carotid-femoral pulse-wave velocity (cfPWV) and radial artery pulse wave analysis (PWA), and 3) metabolic insulin sensitivity by the glucose infusion rate (GIR) during a 2-h, 1 mU/min/kg euglycemic-insulin clamp. Subjects with T1DM were metabolically insulin resistant (GIR = 5.2 ± 0.7 vs. 6.6 ± 0.6 mg/min/kg, P < 0.001). Insulin increased muscle microvascular blood volume and flow in control (P < 0.001, for each) but not in subjects with T1DM. Metabolic insulin sensitivity correlated with increases of muscle microvascular perfused volume (P < 0.05). Baseline measures of vascular stiffness did not differ between groups. However, during hyperinsulinemia, cfPWV was greater (P < 0.02) in the T1DM group and the backward pulse wave pressure declined with insulin only in controls (P < 0.03), both indices indicating that insulin-induced vascular relaxation in controls only. Subjects with T1DM have muscle microvascular insulin resistance that may precede clinical microvascular disease.NEW & NOTEWORTHY Using contrast ultrasound and measures of vascular stiffness, we compared vascular and metabolic responses to insulin in patients with type 1 diabetes with age-matched controls. The patients with type 1 diabetes demonstrated both vascular and metabolic insulin resistance with more than half of the patients with diabetes having a paradoxical vasoconstrictive vascular response to insulin.

Accuracy of a Risk Alert Threshold for ICU Hypoglycemia: Retrospective Analysis of Alert Performance and Association With Clinical Deterioration Events.

OBJECTIVES: To quantify the accuracy of and clinical events associated with a risk alert threshold for impending hypoglycemia during ICU admissions. DESIGN: Retrospective electronic health record review of clinical events occurring greater than or equal to 1 and less than or equal to 12 hours after the hypoglycemia risk alert threshold was met. SETTING: Adult ICU admissions from June 2020 through April 2021 at the University of Virginia Medical Center. PATIENTS: Three hundred forty-two critically ill adults that were 63.5% male with median age 60.8 years, median weight 79.1 kg, and median body mass index of 27.5 kg/m2. INTERVENTIONS: Real-world testing of our validated predictive model as a clinical decision support tool for ICU hypoglycemia. MEASUREMENTS AND MAIN RESULTS: We retrospectively reviewed 350 hypothetical alerts that met inclusion criteria for analysis. The alerts correctly predicted 48 cases of level 1 hypoglycemia that occurred greater than or equal to 1 and less than or equal to 12 hours after the alert threshold was met (positive predictive value = 13.7%). Twenty-one of these 48 cases (43.8%) involved level 2 hypoglycemia. Notably, three myocardial infarctions, one medical emergency team call, 19 deaths, and 20 arrhythmias occurred greater than or equal to 1 and less than or equal to 12 hours after an alert threshold was met. CONCLUSIONS: Alerts generated by a validated ICU hypoglycemia prediction model had a positive predictive value of 13.7% for real-world hypoglycemia events. This proof-of-concept result suggests that the predictive model offers clinical value, but further prospective testing is needed to confirm this.

Acute hyperglycaemia enhances both vascular endothelial function and cardiac and skeletal muscle microvascular function in healthy humans.

KEY POINTS: Multiple clinical studies report that acute hyperglycaemia (induced by mixed meal or oral glucose) decreases arterial vascular function in healthy humans. Feeding, however, impacts autonomic output, blood pressure, and insulin and incretin secretion, which may themselves alter vascular function. No prior studies have examined the effect of acute hyperglycaemia on both macro- and microvascular function while controlling plasma insulin concentrations. Macrovascular and microvascular functional responses to euglycaemia and hyperglycaemia were compared. Octreotide was infused throughout both protocols to prevent endogenous insulin release. Acute hyperglycaemia (induced by intravenous glucose) enhanced brachial artery flow-mediated dilatation, increased skeletal muscle microvascular blood volume and flow, and expanded cardiac muscle microvascular blood volume. Compared to other published findings, the results suggest that vascular responses to acute hyperglycaemia differ based on the study population (i.e. normal weight vs. overweight/obese) and/or glucose delivery method (i.e. intravenous vs. oral glucose). ABSTRACT: High glucose concentrations acutely provoke endothelial cell oxidative stress and are suggested to trigger diabetes-related macro- and microvascular injury in humans. Multiple clinical studies report that acute hyperglycaemia (induced by mixed meal or oral glucose) decreases arterial vascular function in healthy humans. Feeding, however, impacts autonomic output, blood pressure, and insulin and incretin secretion, which may each independently alter vascular function and obscure the effect of acute hyperglycaemia per se. Surprisingly, no studies have examined the acute effects of intravenous glucose-induced hyperglycaemia on both macro- and microvascular function while controlling plasma insulin concentrations. In this randomized study of healthy young adults, we compared macrovascular (i.e. brachial artery flow-mediated dilatation, carotid-femoral pulse wave velocity and post-ischaemic brachial artery flow velocity) and microvascular (heart and skeletal muscle perfusion by contrast-enhanced ultrasound) functional responses to euglycaemia and hyperglycaemia. Octreotide was infused throughout both protocols to prevent endogenous insulin release. Acute intravenous glucose-induced hyperglycaemia enhanced brachial artery flow-mediated dilatation (P = 0.004), increased skeletal muscle microvascular blood volume and flow (P = 0.001), and expanded cardiac muscle microvascular blood volume (P = 0.014). No measure of vascular function changed during octreotide-maintained euglycaemia. Our findings suggest that unlike meal-provoked acute hyperglycaemia, 4 h of intravenous glucose-induced hyperglycaemia enhances brachial artery flow-mediated dilatation, provokes cardiac and skeletal muscle microvascular function, and does not impair aortic stiffness. Previous findings of acute large artery vascular dysfunction during oral glucose or mixed meal ingestion may be due to differences in study populations and meal-induced humoral or neural factors beyond hyperglycaemia per se. (ClinicalTrials.gov number NCT03520569.).

Nitric oxide-dependent micro- and macrovascular dysfunction occurs early in adolescents with type 1 diabetes.

Arterial stiffness and endothelial dysfunction are both reported in children with type 1 diabetes (DM1) and may predict future cardiovascular events. In health, nitric oxide (NO) relaxes arteries and increases microvascular perfusion. The relationships between NO-dependent macro- and microvascular functional responses and arterial stiffness have not been studied in adolescents with DM1. Here, we assessed macro- and microvascular function in DM1 adolescents and age-matched controls at baseline and during an oral glucose challenge (OGTT). DM1 adolescents (n = 16) and controls (n = 14) were studied before and during an OGTT. At baseline, we measured: 1) large artery stiffness using both aortic augmentation index (AI) and carotid-femoral pulse wave velocity (cfPWV); 2) brachial flow-mediated dilation (FMD) and forearm endothelial function using postischemic flow velocity (PIFV); and 3) forearm muscle microvascular blood volume (MBV) using contrast-enhanced ultrasound. Following OGTT, AI, cfPWV, and MBV were reassessed at 60 min and MBV again at 120 min. Within individual and between-group, comparisons were made by paired and unpaired t tests or repeated measures ANOVA. Baseline FMD was lower (P = 0.02) in DM1. PWV at 0 and 60 min did not differ between groups. Baseline AI did not differ between groups but declined with OGTT only in controls (P = 0.02) and was lower than DM1 at 60 min (P < 0.03). Baseline MBV was comparable in DM1 and control groups, but declined in DM1 at 120 min (P = 0.01) and was lower than the control group (P < 0.03). There was an inverse correlation between plasma glucose and MBV at 120 min (r = -0.523, P < 0.01). No differences were noted between groups for V̇O2max (mL/min/kg), body fat (%), or body mass index (BMI). NO-dependent macro- and microvascular function, including FMD and AI, and microvascular perfusion, respectively, are impaired early in the course of DM1, precede increases of arterial stiffness, and may provide an early indicator of vascular risk.NEW & NOTEWORTHY This is the first study to show that type 1 diabetes impairs multiple nitric oxide-dependent vascular functions.

Pathophysiologic Signature of Impending ICU Hypoglycemia in Bedside Monitoring and Electronic Health Record Data: Model Development and External Validation.

OBJECTIVES: We tested the hypothesis that routine monitoring data could describe a detailed and distinct pathophysiologic phenotype of impending hypoglycemia in adult ICU patients. DESIGN: Retrospective analysis leading to model development and validation. SETTING: All ICU admissions wherein patients received insulin therapy during a 4-year period at the University of Virginia Medical Center. Each ICU was equipped with continuous physiologic monitoring systems whose signals were archived in an electronic data warehouse along with the entire medical record. PATIENTS: Eleven thousand eight hundred forty-seven ICU patient admissions. INTERVENTIONS: The primary outcome was hypoglycemia, defined as any episode of blood glucose less than 70 mg/dL where 50% dextrose injection was administered within 1 hour. We used 61 physiologic markers (including vital signs, laboratory values, demographics, and continuous cardiorespiratory monitoring variables) to inform the model. MEASUREMENTS AND MAIN RESULTS: Our dataset consisted of 11,847 ICU patient admissions, 721 (6.1%) of which had one or more hypoglycemic episodes. Multivariable logistic regression analysis revealed a pathophysiologic signature of 41 independent variables that best characterized ICU hypoglycemia. The final model had a cross-validated area under the receiver operating characteristic curve of 0.83 (95% CI, 0.78-0.87) for prediction of impending ICU hypoglycemia. We externally validated the model in the Medical Information Mart for Intensive Care III critical care dataset, where it also demonstrated good performance with an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.77-0.81). CONCLUSIONS: We used data from a large number of critically ill inpatients to develop and externally validate a predictive model of impending ICU hypoglycemia. Future steps include incorporating this model into a clinical decision support system and testing its effects in a multicenter randomized controlled clinical trial.

Hyperglycemia does not Inhibit Insulin's Effects on Microvascular Perfusion in Healthy Humans: A Randomized Crossover Study.

Diabetes mellitus accelerates vascular disease through multiple biochemical pathways driven by hyperglycemia, with insulin resistance and/or hyperinsulinemia also contributing. Persons with diabetes mellitus experience premature large vessel and microvascular disease when compared to normoglycemic controls. Currently there is a paucity of clinical data identifying how acutely the vasculature responds to hyperglycemia and whether other physiologic factors (e.g., vasoactive hormones) contribute. To our knowledge, no prior studies have examined the dynamic effects of acute hyperglycemia on insulin-mediated actions on both micro- and macrovascular function in the same subjects. In this randomized crossover trial, healthy young adults underwent two infusion protocols designed to compare the effects of insulin infusion during euglycemia and hyperglycemia on micro- and macrovascular function. Both euglycemic- and hyperglycemic-hyperinsulinemia increased skeletal (but not cardiac) muscle microvascular blood volume (each p<0.02) and blood flow significantly (each p<0.04), and these increases did not differ between protocols. Hyperglycemic-hyperinsulinemia trended towards increased carotid-femoral pulse wave velocity (indicating increased aortic stiffness; p= 0.065 after Bonferroni adjustment), while euglycemic-hyperinsulinemia did not. There were no changes in post-ischemic flow velocity or brachial artery flow-mediated dilation during either protocol. Plasma endothelin-1 levels significantly decreased during both protocols (each p<0.02). In this study, acute hyperglycemia for 4 hours did not inhibit insulin's ability to increase skeletal muscle microvascular perfusion but did provoke a slight increase in aortic stiffness. Hyperglycemia also did not adversely affect myocardial microvascular perfusion or endothelial function or prevent the decline of endothelin-1 during insulin infusion.

A MULTICENTER STUDY EVALUATING PERCEPTIONS AND KNOWLEDGE OF INPATIENT GLYCEMIC CONTROL AMONG RESIDENT PHYSICIANS: ANALYZING THEMES TO INFORM AND IMPROVE CARE.

Objective: In this descriptive study, we evaluated perceptions and knowledge of inpatient glycemic control among resident physicians. Methods: We performed this study at four academic medical centers: the University of Mississippi Medical Center, University of Virginia Health System, University of Louisville Health Sciences Center, and Emory University. We designed a questionnaire, and Institutional Review Board approval was granted at each institution prior to study initiation. We then administered the questionnaire to Internal Medicine and Medicine-Pediatric resident physicians. Results: A total of 246 of 438 (56.2%) eligible resident physicians completed the Inpatient Glycemic Control Questionnaire (IGCQ). Most respondents (85.4%) reported feeling comfortable treating and managing inpatient hyperglycemia, and a majority (66.3%) agreed they had received adequate education. Despite self-reported comfort with knowledge, only 51.2% of respondents could identify appropriate glycemic targets in critically ill patients. Only 45.5% correctly identified appropriate inpatient random glycemic target values in noncritically ill patients, and only 34.1% of respondents knew appropriate preprandial glycemic targets in noncritically ill patients. A small majority (54.1%) were able to identify the correct fingerstick glucose value that defines hypoglycemia. System issues were the most commonly cited barrier to successful inpatient glycemic control. Conclusion: Most respondents reported feeling comfortable managing inpatient hyperglycemia but had difficulty identifying appropriate inpatient glycemic target values. Future interventions could utilize the IGCQ as a pre- and postassessment tool and focus on early resident education along with improving system environments to aid in successful inpatient glycemic control. Abbreviations: DM = diabetes mellitus; Emory = Emory University Healthcare; IGC = inpatient glycemic control; IGCQ = Inpatient Glycemic Control Questionnaire; IRB = Institutional Review Board; PGY = postgraduate year; UMMC = University of Mississippi Medical Center; UVA = University of Virginia Health System; UL = University of Louisville Health Sciences Center.

Construction and preliminary evaluation of the inpatient glycemic control questionnaire (IGCQ): a survey tool assessing perceptions and knowledge of resident physicians.

BACKGROUND: Uncontrolled hyperglycemia in hospitalized patients, with or without diabetes mellitus, is associated with many adverse outcomes. Resident physicians are the primary managers of inpatient glycemic control (IGC) in many academic and community medical centers; however, no validated survey tools related to their perceptions and knowledge of IGC are currently available. As identification of common barriers to successful IGC amongst resident physicians may help foster better educational interventions (ultimately leading to improvements in IGC and patient care), we sought to construct and preliminarily evaluate such a survey tool. METHODS: We developed the IGC questionnaire (IGCQ) by using previously published but unvalidated survey tools related to physician perspectives on inpatient glycemic control as a framework. We administered the IGCQ to a cohort of resident physicians from the University of Mississippi Medical Center, University of Louisville, Emory University, and the University of Virginia. We then used classical test theory and Rasch Partial Credit Model analyses to preliminarily evaluate and revise the IGCQ. The final survey tool contains 16 total items and three answer-choice categories for most items. RESULTS: Two hundred forty-six of 438 (56.2%) eligible resident physicians completed the IGCQ during various phases of development. CONCLUSIONS: We constructed and preliminarily evaluated the IGCQ, a survey tool that may be useful for future research into resident physician perceptions and knowledge of IGC. Future studies could seek to externally validate the IGCQ and then utilize the survey tool in pre- and post-intervention assessments.

Diabetes Mellitus and the Skin: Recognition and Management of Cutaneous Manifestations.

Diabetes mellitus (DM) is a heterogeneous condition characterized by hyperglycemia as a consequence of defects in insulin secretion and variable degrees of insulin resistance. DM is the most common endocrine disorder in the United States, affecting 9.3% of the population (29.1 million people) in 2014. Skin disorders are present in 79.2% of patients with DM, and cutaneous disease may appear as the first sign of DM or develop at any time in the course of the disease. Given the increasing incidence and prevalence of DM in the United States, primary care physicians should be aware of the associated cutaneous manifestations. This clinical review provides a brief guide to primary care physicians for recognizing and managing skin conditions that they may encounter when caring for patients with DM.

Recurrent Diabetic Muscle Infarction Affecting Bilateral Thighs: Uncommon Presentation with Grave Prognosis.

INTRODUCTION: Diabetic muscle infarction is a rare microangiopathic complication of poorly-controlled diabetes mellitus. Here we present the case of a female with a thirteen year history of poorly-controlled diabetes mellitus who presented with severe right leg pain and swelling and was eventually diagnosed with this condition. CASE PRESENTATION: A 24-year-old female with a thirteen year history of poorly-controlled diabetes mellitus presented with intense right thigh pain and swelling. Initial labs revealed elevated hemoglobin A1c, CK, ESR, and CRP. White blood cell count was within normal limits and patient was afebrile with normal vitals at time of presentation. Magnetic resonance imaging of the right lower extremity demonstrated T1 isohypointensity in the vastus medialis and sartorius with diffuse fascial and subcutaneous edema. Bilateral lower extremity dopplers revealed no evidence of deep vein thrombosis and autoimmune workup was negative. The patient was diagnosed with diabetic muscle infarction given the combination of her clinical presentation and imaging findings. She was started on low-dose aspirin and glycemic control was achieved with a rigorous insulin regimen prior to discharge. She returned six weeks after discharge with persistent right thigh pain and swelling. MRI at this time revealed findings consistent with diabetic muscle infarction in left and right thighs. DISCUSSION: Clinicians should include diabetic muscle infarction in the differential of any diabetic patient who presents with lower extremity pain and swelling and history of poor glycemic control. Maintaining a high index of suspicion can help confirm the diagnosis early and avoid unnecessary tests and interventions that can lengthen recovery time.

Analysis of a Guideline-Derived Resident Educational Program on Inpatient Glycemic Control.

OBJECTIVES: To determine the effects of a guideline-derived resident educational program on inpatient glycemic control and length of hospital stay (LOS). METHODS: We compared the following variables before and after resident education: percentage of patients on basal-plus-bolus regimens, mean fingerstick glucose (FSG), LOS, and rates of hypoglycemia (FSG<70 mg/dL) and severe hypoglycemia (FSG<40 mg/dL). A two-tailed t test was used for all continuous data and P<0.05 was considered statistically significant. RESULTS: After education, more patients (23% vs 8%; P=0.024) were placed on basal-plus-bolus regimens. We observed a decrease in mean FSG (158.7 mg/dL vs 165.1 mg/dL; P=0.028) and LOS (5.03 days vs 6.98 days; P=0.042). Rates of hypoglycemia (4.6% vs 1.5%; P<0.001) and severe hypoglycemia (0.71% vs 0.24%; P=0.089) increased. CONCLUSIONS: Our resident educational program significantly increased the number of patients receiving guideline-based inpatient insulin therapy and was associated with a reduction in mean FSG and LOS. Rates of hypoglycemia showed a statistically significant increase, whereas rates of severe hypoglycemia did not. Larger multicenter studies with adjustment for potential confounders are needed to further assess the impact of educational interventions on inpatient glycemic control.

Pheochromocytoma presenting as acute non-ST elevation myocardial infarction following elective hysterectomy.

INTRODUCTION: Studies have shown patients with pheochromocytoma have a 14-fold higher rate of cardiovascular events than patients with essential hypertension. CASE PRESENTATION: A 47-year-old female was found to have elevated troponins and marked ST depression following elective hysterectomy. The patient underwent cardiac catheterization, and labile blood pressures with a narrow-complex tachycardia were noted during the procedure. No evidence of coronary artery disease or wall motion abnormality was found. After catheterization, the patient complained of abdominal pain with difficulty passing gas. CT abdomen/pelvis revealed a 4.3 x 5 cm left adrenal mass. Plasma metanephrines and 24-hour urine catecholamines suggested pheochromocytoma. She underwent left total adrenalectomy, and pathology confirmed pheochromocytoma. At 3-month follow-up, she was asymptomatic and required only one agent for blood pressure control. DISCUSSION: Suspecting pheochromocytoma in patients with an unexpected myocardialevent and labile hypertension can lead to prompt diagnosis and appropriate preoperative management as well as avoidance of unnecessary procedures.

Graves orbitopathy: update on diagnosis and therapy.

Graves orbitopathy (GO) is an autoimmune disorder representing the most frequent extrathyroidal manifestation of Graves disease. It is rare, with an age-adjusted incidence of approximately 16.0 cases per 100,000 population per year in women and 2.9 cases per 100,000 population per year in men. GO is an inflammatory process characterized by edema and inflammation of the extraocular muscles and an increase in orbital connective tissue and fat. Despite recent progress in the understanding of its pathogenesis, GO often remains a major diagnostic and therapeutic challenge. It has become increasingly important to classify patients into categories based on disease activity at initial presentation. A Hertel exophthalmometer measurement of >2 mm above normal for race usually categorizes a patient as having moderate-to-severe GO. Encouraging smoking cessation and achieving euthyroidism in the individual patient are important. Simple treatment measures such as lubricants for lid retraction, nocturnal ointments for incomplete eye closure, prisms in diplopia, or botulinum toxin injections for upper-lid retraction can be effective in mild cases of GO. Glucocorticoids, orbital radiotherapy, and decompression/rehabilitative surgery are generally indicated for moderate-to-severe GO and for sight-threatening optic neuropathy. Future therapies, including rituximab aimed at treating the molecular and immunological basis of GO, are under investigation and hold promise for the future.

Hemoglobin A1c Variability Metrics Predict Coronary Artery Calcium and Cardiovascular Events in Type 1 Diabetes: The CACTI Study.

CONTEXT: Interventions that decrease mean glucose have reduced rates of micro- and macrovascular complications in type 1 diabetes (T1D). However, the difference in cardiovascular risk between people with T1D and the general population endures, suggesting that factors beyond hemoglobin A1C (HbA1c) normalization drive cardiovascular outcomes. OBJECTIVE: To determine whether various HbA1c metrics predict anatomic cardiovascular disease (CVD) risk factors and/or CVD events in people with T1D. METHODS: We used linear regression to analyze the relationship of several HbA1c metrics to anatomic CVD risk factors and then used Cox regression to model their relationship to incident CVD events in the CACTI Study (ClinicalTrials.gov Identifier: NCT00005754). RESULTS: In linear regression models adjusted for age, sex, and T1D duration, baseline Hba1c (b = 0.3998, P = 0.0236), mean HbA1c (b = 0.5385, P = 0.0109), and HbA1c SD (b = 1.1521, P = 0.0068) were each positively associated with square root transformed coronary artery calcium volume. Conversely, only mean HbA1c (b = 1.659, P = 0.0048) positively associated with pericardial adipose tissue volume. In survival models adjusted for age, sex, and T1D duration, baseline HbA1c [hazard ratio (HR): 1.471, 95% CI: 1.257-1.721], mean HbA1c (HR: 1.850, 95% CI: 1.511-2.264), time-varying HbA1c (HR: 1.500, 95% CI: 1.236-1.821), and HbA1c SD (HR: 1.665, 95% CI: 1.022-2.711) each independently predicted CVD events over 14.3 ± 5.2 person-years of follow-up. CONCLUSIONS/INTERPRETATION: We found that various HbA1c metrics positively correlated with CAC volume and independently predicted incident CVD events in the CACTI T1D cohort. These associations with CVD events persisted for baseline HbA1c, mean HbA1c, and time-varying HbA1c even after adjustment for numerous CVD risk factors.

Metformin's Impact on the Microvascular Response to Insulin.

Metformin improves insulin's action on whole-body glucose metabolism in various insulin-resistant populations. The detailed cellular mechanism(s) for its metabolic actions are multiple and still incompletely understood. Beyond metabolic actions, metformin also impacts microvascular function. However, the effects of metformin on microvascular function and microvascular insulin action specifically are poorly defined. In this mini-review, we summarize what is currently known about metformin's beneficial impact on both microvascular function and the microvascular response to insulin while highlighting methodologic issues in the literature that limit straightforward mechanistic understanding of these effects. We examine potential mechanisms for these effects based on pharmacologically dosed studies and propose that metformin may improve human microvascular insulin resistance by attenuating oxidative stress, inflammation, and endothelial dysfunction. Finally, we explore several important evidence gaps and discuss avenues for future investigation that may clarify whether metformin's ability to improve microvascular insulin sensitivity is linked to its positive impact on vascular outcomes.

Predictors of arterial stiffness in adolescents and adults with type 1 diabetes: a cross-sectional study.

INTRODUCTION: Individuals with type 1 diabetes have increased arterial stiffness compared with age-matched healthy controls. Our aim was to determine which hemodynamic and demographic factors predict arterial stiffness in this population. RESEARCH DESIGN AND METHODS: Carotid-femoral pulse wave velocity (cfPWV) was examined in 41 young adults and adolescents with type 1 diabetes without microvascular complications. Two ordinary least squares regression analyses were performed to determine multivariate relationships between cfPWV (loge) and (1) age, duration of diabetes, sex, and hemoglobin A1c and (2) augmentation index (AIx), mean arterial pressure, flow-mediated dilation (FMD), and heart rate. We also examined differences in macrovascular outcome measures between sexes. RESULTS: Age, sex, and FMD provided unique predictive information about cfPWV in these participants with type 1 diabetes. Despite having similar cardiovascular risk factors, men had higher cfPWV compared with women but no differences were observed in other macrovascular outcomes (including FMD and AIx). CONCLUSIONS: Only age, sex, and FMD were uniquely associated with arterial stiffness in adolescents and adults with uncomplicated type 1 diabetes. Women had less arterial stiffness and similar nitric oxide-dependent endothelial function compared with men. Larger, prospective investigation is warranted to determine the temporal order of and sex differences in arterial dysfunction in type 1 diabetes.

Heart Failure: An Underappreciated Complication of Diabetes. A Consensus Report of the American Diabetes Association.

Heart failure (HF) has been recognized as a common complication of diabetes, with a prevalence of up to 22% in individuals with diabetes and increasing incidence rates. Data also suggest that HF may develop in individuals with diabetes even in the absence of hypertension, coronary heart disease, or valvular heart disease and, as such, represents a major cardiovascular complication in this vulnerable population; HF may also be the first presentation of cardiovascular disease in many individuals with diabetes. Given that during the past decade, the prevalence of diabetes (particularly type 2 diabetes) has risen by 30% globally (with prevalence expected to increase further), the burden of HF on the health care system will continue to rise. The scope of this American Diabetes Association consensus report with designated representation from the American College of Cardiology is to provide clear guidance to practitioners on the best approaches for screening and diagnosing HF in individuals with diabetes or prediabetes, with the goal to ensure access to optimal, evidence-based management for all and to mitigate the risks of serious complications, leveraging prior policy statements by the American College of Cardiology and American Heart Association.

Microvascular Dysfunction in Diabetes Mellitus and Cardiometabolic Disease.

This review takes an inclusive approach to microvascular dysfunction in diabetes mellitus and cardiometabolic disease. In virtually every organ, dynamic interactions between the microvasculature and resident tissue elements normally modulate vascular and tissue function in a homeostatic fashion. This regulation is disordered by diabetes mellitus, by hypertension, by obesity, and by dyslipidemia individually (or combined in cardiometabolic disease), with dysfunction serving as an early marker of change. In particular, we suggest that the familiar retinal, renal, and neural complications of diabetes mellitus are late-stage manifestations of microvascular injury that begins years earlier and is often abetted by other cardiometabolic disease elements (eg, hypertension, obesity, dyslipidemia). We focus on evidence that microvascular dysfunction precedes anatomic microvascular disease in these organs as well as in heart, muscle, and brain. We suggest that early on, diabetes mellitus and/or cardiometabolic disease can each cause reversible microvascular injury with accompanying dysfunction, which in time may or may not become irreversible and anatomically identifiable disease (eg, vascular basement membrane thickening, capillary rarefaction, pericyte loss, etc.). Consequences can include the familiar vision loss, renal insufficiency, and neuropathy, but also heart failure, sarcopenia, cognitive impairment, and escalating metabolic dysfunction. Our understanding of normal microvascular function and early dysfunction is rapidly evolving, aided by innovative genetic and imaging tools. This is leading, in tissues like the retina, to testing novel preventive interventions at early, reversible stages of microvascular injury. Great hope lies in the possibility that some of these interventions may develop into effective therapies.