Type Reserve Research Articles

Pancreatic islet reserve in type 1 diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic islet βcellloss and dysfunction resulting in insulin deficiency and hyperglycemia. During a presymptomatic phase of established β cell autoimmunity, βcellloss may first be evident through assessment of βcellsecretory capacity, a measure of functional βcellmass. Reduction in pancreatic islet βcellreserve eventually manifests as impaired first-phase insulin response to glucose and abnormal glucose tolerance, which progresses until the functional capacity for βcellsecretion can no longer meet the demand for insulin to control glycemia. A functional βcellmass of ∼25% of normal may be required to avoid symptomatic T1D but is already associated with dysregulated glucagon secretion. With symptomatic T1D, stimulated C-peptide levels >0.60 ng/mL (0.200 pmol/mL) indicate the presence of clinically meaningful residual βcellfunction for contributing to glycemic control, although even higher residual C-peptide appears necessary for evidencing glucose-dependent islet β and α cell function that may contribute to maintaining (near)normal glycemia. βcellreplacement by islet transplantation can restore a physiologic reserve capacity for insulin secretion, confirming thresholds for functional βcellmass required for independence from insulin therapy.

Reduced Myocardial Perfusion Reserve in Type 2 Diabetes Is Caused by Increased Perfusion at Rest and Decreased Maximal Perfusion During Stress.

To examine differences in myocardial blood flow (MBF) at rest and during stress between patients with type 2 diabetes and control subjects, and to identify potential predictors of changes in MBF at rest and during stress. A cross-sectional study was conducted of 193 patients with type 2 diabetes and 20 age- and sex-matched control subjects. Cardiovascular magnetic resonance was used to evaluate left ventricular structure and function and MBF at rest and during adenosine-induced stress. MBF was derived as the mean of the flow within all segments of a midventricular slice. Patients with type 2 diabetes had higher global MBF at rest (0.81 ± 0.19 mL/min/g) and lower global MBF during stress (2.4 ± 0.9 mL/min/g) than control subjects (0.61 ± 0.11 at rest, 3.2 ± 0.8 mL/min/g under stress; both P < 0.01). Patients with macroalbuminuria had lower MBF during stress (1.6 ± 0.5 mL/min/g) than did patients with microalbuminuria (2.1 ± 0.7 mL/min/g; P = 0.04), who in turn had lower MBF during stress than did normoalbuminuric patients (2.7 ± 0.9 mL/min/g; P < 0.01). Patients with severe retinopathy had lower MBF during stress (1.8 ± 0.6 mL/min/g) than patients with simplex retinopathy (2.3 ± 0.7 mL/min/g; P < 0.05) and those who did not have retinopathy (2.6 ± 1.0 mL/min/g; P < 0.05). Albuminuria and retinopathy were associated with reduced MBF during stress in a multiple regression analysis. Stress-related MBF inversely correlated with myocardial extracellular volume (P < 0.001; R 2 = 0.37), a measure of diffuse myocardial fibrosis. A trend toward lower basal MBF was observed in patients treated with sodium-glucose cotransporter 2 inhibitors (P = 0.07). Patients with type 2 diabetes have higher global MBF at rest and lower maximal MBF during vasodilator-induced stress than control subjects. Reduced MBF during stress is associated with diabetes complications (albuminuria and retinopathy) and is inversely correlated with diffuse myocardial fibrosis.

Evaluation of Skeletal Muscle Microcirculation and Reserve Function of the Type 2 Diabetes with Contrast-Enhanced Ultrasonography.

This study aimed to discuss clinical application value of contrast-enhanced ultrasonography on lesion skeletal muscle microcirculation and arterial perfusion reserve in type 2 diabetes mellitus and complicated microvessels. Patients in the control group, type 2 diabetes mellitus (DM) group, diabetic microangiopathy (DM + MC) group underwent contrast-enhanced ultrasonography before and after temporary arterial occlusion to observe blood perfusion of gastrocnemius muscle; draw the time-intensity curve of arteriole, muscular tissue, and venule, and obtain perfusion parameters such as contrast agent arrival time and contrast agent transit time. Blood glucose, insulin, insulin resistance index, and relevant blood rheology parameters were measured. Contrast agent transit time of the DM + MC group before arterial occlusion was significantly longer than that of the DM group and control group (P < 0.05). Contrast agent transit time of the DM + MC group after temporary arterial occlusion was significantly longer than that of the DM group and control group (P < 0.05). Contrast agent transit time of △artery-muscle, △artery-vein, and △muscle-vein of the DM group and control group and △artery-muscle of the DM + MC group after arterial occlusion was significantly shortened, when compared with that before arterial occlusion (P < 0.05). For △muscle-vein and △artery-vein contrast agent transit time in the DM + MC group, the difference was not statistically significant. By comparing blood glucose, insulin, insulin resistance index, and relevant blood rheology parameters among the DM + MC group, DM group, and control group, the difference was statistically significant, and there was a good correlation. Contrast-enhanced ultrasonography can be used to evaluate skeletal muscle microcirculation disturbance and arterial reserve function of patients who had type 2 diabetic microangiopathy.

P4469Reduced myocardial perfusion reserve in type 2 diabetes is caused by increased rest perfusion as well as decreased maximal perfusion during stress

Abstract Background Reduced myocardial perfusion reserve is a well-known complication in patients with type 2 diabetes mellitus (T2DM). Furthermore, reduced myocardial perfusion reserve has been linked to the development of diastolic dysfunction, a key characteristic in diabetic cardiomyopathy. However, it is not fully explored whether a decrease in perfusion during stress or an increase in perfusion during rest is responsible for this reduction in myocardial perfusion reserve, nor is it clear what causes these changes. Purpose The purpose of this study was to examine differences in myocardial perfusion in rest and during stress in patients with T2DM compared to healthy control subjects, and to identify potential predictors for changes in perfusion during rest and stress among patients with T2DM. Methods 200 patients with T2DM and 25 healthy volunteers matched for age and sex underwent a comprehensive cardiac MRI protocol including gadolinium first-pass perfusion during rest and stress (adenosine infusion 140 mg/min–1/kg–1). Perfusion was measured on a per-segment basis based on the AHA model and averaged to calculate global perfusion index both during rest and stress. Any areas with infarctions and/or significant perfusion defects were excluded from the analysis. Backwards stepwise multiple linear regression was performed to identify predictors for perfusion changes during rest and stress in patients with T2DM. Variables with P&lt;0.1 in a univariate analysis were included into the models. Results Patients with T2DM had significantly higher rest perfusion index (0.135±0.024 vs. 0.120±0.016; P=0.001) and significantly lower stress perfusion index (0.174±0.041 vs. 0.225±0.027; P&lt;0.001) compared to healthy volunteers. In a multiple linear regression model among patients with T2DM female sex (P&lt;0.001) was associated with increased rest perfusion. In a similar analysis for stress perfusion, diabetes duration (P=0.01), albuminuria (P&lt;0.001) and the presence of ischaemic heart disease (P&lt;0.001) were associated with reduced myocardial stress perfusion index in patients with T2DM. Conclusion In patients with T2DM reductions in myocardial perfusion reserve is caused by a combination of increased basal myocardial blood flow and a decrease in maximal blood flow during stress. Decreased stress perfusion is associated with coronary vascular disease and the diabetic complication albuminuria related to renal microvascular disease. Stress perfusion also decreased with increasing duration of T2DM. This suggest that the coronary microcirculation is gradually damaged in patients with T2DM and that the mechanism responsible is similar to that causing renal microvascular damage. Acknowledgement/Funding Local science committee of Region Zealand, Regional science committee of Region Zealand, The Danish Heart Association

Cardiac Autonomic Function Is Associated With Myocardial Flow Reserve in Type 1 Diabetes.

The link between cardiac autonomic neuropathy and risk of cardiovascular disease is highlighted as an area in which research is needed. This study was undertaken to evaluate the association between measures of cardiac autonomic function and cardiac vascular function in type 1 diabetes using new and sensitive methods. This was a cross-sectional study in patients with type 1 diabetes, stratified by normoalbuminuria (n = 30) and macroalbuminuria (n = 30), and in healthy control subjects (n = 30). Cardiac autonomic function was evaluated using heart rate variability (HRV) indices, cardiovascular autonomic reflex tests (CARTs), and cardiac 123I-metaiodobenzylguanidine (MIBG) imaging. Cardiac vascular function was assessed as myocardial flow reserve (MFR) measured by cardiac 82Rb-positron emission tomography/computed tomography. The measures of cardiac autonomic function (except low frequency-to-high frequency ratio and the Valsalva test ratio) were positively correlated to MFR in unadjusted analysis. All the HRV indices lost significance after adjustment for age and heart rate. After further adjustment for relevant cardiovascular risk factors, the late heart-to-mediastinum ratio directly measuring the function of adrenergic receptors and sympathetic integrity (from the MIBG scintigraphy) and the 30-to-15 ratio (a CART), remained positively associated with MFR (P ≤ 0.04). Cardiac autonomic dysfunction, including loss of cardiac sympathetic integrity in type 1 diabetes, is associated with and may contribute to impaired myocardial blood flow regulation.

Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes.

In type 1 diabetes, cytotoxic CD8+ T cells with specificity for β cell autoantigens are found in the pancreatic islets, where they are implicated in the destruction of insulin-secreting β cells. In contrast, the disease relevance of β cell-reactive CD8+ T cells that are detectable in the circulation, and their relationship to β cell function, are not known. Here, we tracked multiple, circulating β cell-reactive CD8+ T cell subsets and measured β cell function longitudinally for 2 years, starting immediately after diagnosis of type 1 diabetes. We found that change in β cell-specific effector memory CD8+ T cells expressing CD57 was positively correlated with C-peptide change in subjects below 12 years of age. Autoreactive CD57+ effector memory CD8+ T cells bore the signature of enhanced effector function (higher expression of granzyme B, killer-specific protein of 37 kDa, and CD16, and reduced expression of CD28) compared with their CD57- counterparts, and network association modeling indicated that the dynamics of β cell-reactive CD57+ effector memory CD8+ T cell subsets were strongly linked. Thus, coordinated changes in circulating β cell-specific CD8+ T cells within the CD57+ effector memory subset calibrate to functional insulin reserve in type 1 diabetes, providing a tool for immune monitoring and a mechanism-based target for immunotherapy.

Does Autonomic Dysregulation Reduce Cardiac Reserve In Type 2 Diabetes?

Cardiac autonomic dysfunction reduces cardiac reserve in neuropathic patients with diabetes. People with uncomplicated diabetes also have reduced cardiac reserve, but the influence of cardiac autonomic (dys) function has not been identified in these people. PURPOSE: To determine whether people with uncomplicated type 2 diabetes have reduced chronotropic and inotropic responses to β-adrenergic stimulation. METHODS: 8 people with uncomplicated type 2 diabetes (T2D) and 7 matched controls (CON) performed a V[Combining Dot Above]O2max test (with ECG) and DEXA scan. On a second visit, heart rate (HR), left ventricular end-diastolic (EDV), end-systolic (ESV), stroke volume (SV) and cardiac output (Q[Combining Dot Above]) were measured with echocardiography during supine rest, parasympathetic blockade (atropine), and during incremental β-adrenergic stimulation (dobutamine). All volumes were indexed to fat free mass (FFM). Data were analysed with linear mixed models and students t-tests. RESULTS: V[Combining Dot Above]O2max and heart rate (HR) reserve were lower in T2D (P < 0.05) as expected. At rest, HR was higher (P < 0.01) and stroke volume (SVFFM) was smaller (P < 0.05) in T2D but cardiac output (Q[Combining Dot Above]FFM) and ejection fraction (EF) were not different between the groups. After parasympathetic blockade, HR (112 ± 8 vs. 105 ± 8 beats.min−1; P = 0.08) and the increase in HR (ΔHR) were not different (39 ± 8 vs. 45 ± 9; P = 0.22) between the groups. HR was greater in T2D during dobutamine infusion (P < 0.05), but ΔHR (interaction) was not different between groups.T2D achieved 85% maximal HR at a lower dobutamine dose than CON (11 ± 4 vs. 20 ± 10 μkg−1 min−1; P < 0.05). EDVFFM was lower (P < 0.05) during β-adrenergic stimulation in T2D but ESVFFM was not different between groups. Ejection fraction increased (P < 0.05) equally in both groups during β-adrenergic stimulation and SVFFM decreased in T2D but increased in CON (P < 0.05). Q[Combining Dot Above]FFM increased in CON but did not change in T2D during β-adrenergic stimulation (P < 0.05). CONCLUSIONS: HR is increased and SVFFM is reduced in T2D at rest and during β-adrenergic stimulation. EF and ESVFFM were not different during β-adrenergic stimulation, but EDVFFM and SVFFM were smaller in T2D. These data indicate that reduced β-adrenergic responsiveness does not contribute to reduced cardiac reserve in uncomplicated type 2 diabetes during submaximal stress.

A novel battery system for using in extremely low temperature conditions

Abstract A module with 11 thin film battery (TFB) stacks was fabricated to investigate its internal resistance and charging characteristics to a real capacitor with 150 μF. Each cell consisted of thin layers of LiCoO 2 , LiPON and Li on a ceramic substrate, and each layer was deposited by radio frequency (RF) + direct current (DC) hybrid magnetron sputtering, RF reactive sputtering, and thermal evaporation, respectively. In order to increase the effective surface area of the TFB in a limited small volume, 11 cells were stacked and connected in parallel. By designing the thermal switch with a heating source, its capacitor charging performance was well maintained, even at temperatures below −30 °C, as well as at room temperature. Charging to greater than 4 V was completed within 0.06 sec at room temperature and within 0.13 s at −30 °C due to the heat-up process. A novel battery system consisting of the TFB module with a thermal switch and a heating source proved to be a promising substitute for the ampoule type reserve battery in small sized electrical fuses, even at very low temperatures.

Glycemic improvement normalizes myocardial microvascular reserve in type 2 diabetes

Glycemic improvement normalizes myocardial microvascular reserve in type 2 diabetes

Impaired cardiac functional reserve in type 2 diabetic db/db mice is associated with metabolic, but not structural, remodelling

To identify the initial alterations in myocardial tissue associated with the early signs of diabetic cardiac haemodynamic dysfunction, we monitored changes in cardiac function, structural remodelling and gene expression in hearts of type 2 diabetic db/db mice. Cardiac dimensions and function were determined echocardiographically at 8, 12, 16 and 18 weeks of age. Left ventricular pressure characteristics were measured at 18 weeks under baseline conditions and upon dobutamine infusion. The db/db mice were severely diabetic already at 8 weeks after birth, showing elevated fasting blood glucose levels and albuminuria. Nevertheless, echocardiography revealed no significant changes in cardiac function up to 18 weeks of age. At 18 weeks of age, left ventricular pressure characteristics were not significantly different at baseline between diabetic and control mice. However, dobutamine stress test revealed significantly attenuated cardiac inotropic and lusitropic responses in db/db mice. Post-mortem cardiac tissue analyses showed minor structural remodelling and no significant changes in gene expression levels of the sarcoplasmic reticulum calcium ATPase (SERCA2a) or beta1-adrenoceptor (beta1-AR). Moreover, the phosphorylation state of known contractile protein targets of protein kinase A (PKA) was not altered, indicating unaffected cardiac beta-adrenergic signalling activity in diabetic animals. By contrast, the substantially increased expression of uncoupling protein-3 (UCP3) and angiopoietin-like-4 (Angptl4), along with decreased phosphorylation of AMP-activated protein kinase (AMPK) in the diabetic heart, is indicative of marked changes in cardiac metabolism. db/db mice show impaired cardiac functional reserve capacity during maximal beta-adrenergic stimulation which is associated with unfavourable changes in cardiac energy metabolism.

Reduced End-Systolic Pressure-Volume Ratio Response to Exercise

Background— Limitations in the predictive value of negative exercise echocardiography in type 2 diabetes mellitus has been linked to a reduced end-systolic pressure-volume response (ESPVR). We sought whether abnormal ESPVR reflected subclinical diabetic heart disease by examining the association between the ESPVR and markers of myocardial dysfunction and to establish if the change (Δ) or peak systolic blood pressure/end-systolic left ventricular volume ratio (SP/ESV) is a better marker of contractile reserve in type 2 diabetes mellitus. Methods and Results— Resting and exercise echocardiography was performed in 167 apparently healthy patients with type 2 diabetes mellitus (97 men; age, 55±10 years) without ischemia, other cardiac disease, or noncardiac complications of diabetes. Standard echocardiographic and color tissue Doppler measures (early diastolic tissue velocity, strain, and strain rate) were acquired at baseline and peak stress in apical long-axis views. Calibrated integrated backscatter was calculated from a resting parasternal long-axis view. ΔSP/ESV was calculated as [(peak stress SP/ESV)−(rest SP/ESV)]. The 83 subjects who demonstrated a ΔSP/ESV ≤12 mm Hg/mL/m 2 after exercise were older and had lower peak heart rate, resting diastolic and stress systolic tissue velocity, stress ejection fraction, and exercise capacity than the remainder. There was no significant association between ΔSP/ESV and metabolic derangement or echocardiographic measures of deformation or backscatter. Change in Sm and stress ejection fraction were independent correlates of ΔSP/ESV. Conclusions— ΔSP/ESV ratio is associated with established features of subclinical diabetic heart disease as well as determinants of contractile reserve (peak hemodynamic response and stress systolic function). Peak ESPVR is poorly associated with markers of myocardial dysfunction.

Impaired cardiac functional reserve in type 2 diabetic db/db mice is associated with metabolic, but not structural, remodeling

To identify the nature of myocardial alterations associated with diabetes, cardiac function, structural remodeling, and gene expression in hearts of type 2 diabetic db/db mice were studied.Db/db mice showed typical characteristics of type 2 diabetes and preserved cardiac function up to 18 wks of age under non‐challenging conditions. However, β‐adrenergic stimulation with dobutamine revealed impaired contractile and relaxation reserve capacity. Tissue analyses showed no signs of structural remodeling. Neither β1‐adrenoceptor (β1AR) expression nor phosphorylation state of contractile protein targets of β1AR – protein kinase A (PKA) signaling were altered. In contrast, the substantially increased expression of uncoupling protein‐3 (UCP3) and angiopoietin‐like‐4 (Angptl4), along with decreased phosphorylation of AMP‐activated protein‐kinase (AMPK) in the heart of diabetic animals, are indicative of altered mitochondrial efficiency, decline in plasma triacylglycerol consumption and changes in intermediary substrate metabolism, respectively, which together may compromise ATP synthesis, required for maintenance of cardiac function at increased work load.We conclude that impaired cardiac functional reserve capacity during maximal β‐adrenergic stimulation, is an early sign of cardiac dysfunction in db/db mice which is primarily associated with unfavorable changes in cardiac metabolism.

Reduced coronary reserve in response to short‐term ischaemia and vasoactive drugs in ex vivo hearts from diabetic mice

The aim of the present study was to compare the coronary flow (CF) reserve of ex vivo perfused hearts from type 2 diabetic (db/db) and non-diabetic (db/+) mice. The hearts were perfused in the Langendorff mode with Krebs-Henseleit bicarbonate buffer (37 degrees C, pH 7.4) containing 11 mmol L(-1) glucose as energy substrate. The coronary reserve was measured in response to three different interventions: (1) administration of nitroprusside (a nitric oxide donor), (2) administration of adenosine and (3) production of reactive hyperaemia by short-term ischaemia. Basal CF was approximately 15% lower in diabetic when compared with non-diabetic hearts (2.1 +/- 0.1 vs. 2.6 +/- 0.2 mL min(-1)). The maximum increase in CF rate in response to sodium nitroprusside and adenosine was significantly lower in diabetic (0.6 +/- 0.1 and 0.9 +/- 0.1 mL min(-1) respectively) than in non-diabetic hearts (1.2 +/- 0.1 and 1.4 +/- 0.1 mL min(-1) respectively). Also, there was a clear difference in the rate of return to basal CF following short-term ischaemia between diabetic and non-diabetic hearts. Thus, basal tone was restored 1-2 min after the peak hyperaemic response in non-diabetic hearts, whereas it took approximately 5 min in diabetic hearts. These results show that basal CF, as well as the CF reserve, is impaired in hearts from type 2 diabetic mice. As diabetic and non-diabetic hearts were exposed to the same (maximum) concentrations of NO or adenosine, it is suggested that the lower coronary reserve in type 2 diabetic hearts is, in part, because of a defect in the intracellular pathways mediating smooth muscle relaxation.

Angiotensin converting enzyme inhibition improves impaired coronary flow reserve in type 2 diabetes mellitus

Angiotensin converting enzyme inhibition improves impaired coronary flow reserve in type 2 diabetes mellitus

Proliferative Retinopathy Predicts Impairment in Brain Vasomotor Reserve in Type II Diabetes

Ninety-four diabetic patients, asymptomatic for cerebrovascular disease, stratified according to the presence of proliferative retinopathy (PDR), background retinopathy (BDR) and no diabetic retinopat

Effect of captopril on renal functional reserve in Type 1 (insulin-dependent) diabetes mellitus

Effect of captopril on renal functional reserve in Type 1 (insulin-dependent) diabetes mellitus