Key Summary Points
Microangiopathy is a key complication of diabetes. |
Several noninvasive imaging techniques have significantly enhanced our understanding of the myocardial microcirculation. |
A significant area of development is the use of advanced hybrid imaging techniques. |
Introduction
The microcirculation consists of blood vessels less than 150 μm in diameter, including arterioles, capillaries, and venules. This network plays a crucial role in the vascular system, regulating tissue perfusion to ensure optimal gas exchange and the removal of metabolic waste products [1].
Microangiopathy is a key complication of diabetes, marked by structural and functional alterations in the microcirculation. This condition can cause a range of complications, especially impacting the heart, kidneys, eyes, and nerves. The development of microangiopathy in diabetes is complex and not fully understood. It involves various changes, with hyperglycemia and insulin resistance playing central roles, contributing to oxidative stress, inflammatory activation, and impaired endothelial barrier function [2].
Diabetic kidney disease and retinopathy are the most recognized microvascular complications of diabetes. However, in recent years it has become clear that individuals with diabetes frequently develop myocardial microvascular dysfunction. This condition involves a combination of altered vasomotion and long-term structural changes to coronary arterioles, resulting in impaired regulation of blood flow in response to varying oxygen demands of cardiomyocytes [2]. This review focuses on myocardial microvascular dysfunction.
Over the past two decades, numerous studies employing both invasive and noninvasive techniques to assess coronary physiology have significantly enhanced our understanding of the myocardial microcirculation. In particular, positron emission tomography (PET) studies have established normal ranges for myocardial microvascular function in healthy individuals of different ages and sexes [3]. With this expanding knowledge, myocardial microvascular dysfunction has been identified as a significant cause of myocardial ischemia in individuals with angina who do not have obstructive coronary artery disease (CAD). It is also a major factor in various other conditions, including obstructive CAD and heart failure, particularly in the phenotype with preserved ejection fraction [4].
Notably, individuals with diabetes and myocardial microvascular dysfunction face a worse prognosis with higher rates of hospitalization for heart failure, and an increased risk of sudden cardiac death and myocardial infarction compared to those without, even in the absence of obstructive CAD [5, 6]. Studies have shown that the mortality rates for people with diabetes and myocardial microvascular dysfunction are at least as high as those for individuals without diabetes but with known obstructive CAD [7].
Systemic chronic inflammation within the microvasculature is a pathophysiological integral part of microvascular dysfunction and has a central role in the development of vascular complications [2]. This chronic low-grade inflammation contributes to structural and metabolic changes in the heart, such as left ventricular hypertrophy, myocardial fibrosis, calcium-related abnormalities, and impaired myocardial energy utilization [8].
Molecular imaging techniques that target activated macrophages, neovascularization, or increased cellular metabolic activity can effectively detect vascular inflammation noninvasively. These techniques include contrast-enhanced ultrasonography, magnetic resonance imaging (MRI), and PET imaging using radiotracers like [18F]-fluorodeoxyglucose or somatostatin receptor analogues [9].
The primary aim of this review is to provide an overview of both established and emerging noninvasive imaging techniques for assessing myocardial microvascular dysfunction. The secondary aim is to summarize the current understanding of the effects of newer glucose-lowering drugs on the myocardial microcirculation.
This article is based on previously published studies and does not contain any new studies with human participants or animals performed by any of the authors.
Advanced Imaging Techniques for Assessing Microvascular Function
Positron Emission Tomography/Single Photon Emission Computed Tomography
Both PET and single photon emission computed tomography (SPECT) are valuable imaging techniques when assessing microvascular function in diabetes, each with distinct advantages and limitations.
PET has extensive clinical data supporting its use in evaluating microvascular function as prognostic marker [10, 11] in both people with and without diabetes [12]. PET offers high spatial resolution, allowing for regional assessment of myocardial tissue or the epicardial arteries (Fig. 1). It cannot image the microvasculature directly, but it can quantitatively measure myocardial blood flow (MBF) and myocardial flow reserve (MFR, the ratio of MBF during near-maximal coronary vasodilation to resting MBF), which are crucial for assessing microvascular function. Myocardial perfusion can be measured using PET with different radiotracers such as oxygen-15 labelled water (15O), the potassium analogue rubidium-82 (82Rb), 13N-ammonia, and 18F-flurpiridaz [13] by compartmental models describing the kinetics of the contrast concentration after intravenous bolus injection as a function of time (Fig. 2) [14, 15].
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Fig. 1
Myocardial uptake of 82Rb. Static positron emission tomography (PET) reconstructions of the myocardial uptake of 82Rb for myocardial perfusion imaging
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Fig. 2
Time–activity curves from myocardial perfusion imaging. Example, positron emission tomography (PET) time–activity curves for the arterial input (red), a coronary segment (white), and global myocardium (yellow) after an intravenous bolus injection of 15O-water. Analyzed using Carimas imaging platform
SPECT is more widely available and less expensive than PET, making it a more accessible option for many. It has been used for decades in myocardial perfusion imaging and has a well-established role in clinical practice. Technological advances, such as new more sensitive cadmium zinc telluride cameras, are improving SPECT’s ability to measure MBF, although it is still less precise than PET in this regard [16].
In both research and clinical practice, the choice between PET and SPECT depends on several factors. For people with diabetes, who often have diffuse and microvascular disease, the precise quantification of blood flow provided by PET can be particularly advantageous.
Long axial field-of-view positron emission tomography (LAFOV-PET) has been developed and introduced clinically in recent years [17]. The scanner equipment is still very expensive and thus only available at a few selected institutions worldwide. LAFOV-PET offers several advantages over conventional PET scanners that makes it an exciting emerging technique for studying the microvasculature.
One of the main benefits for assessing microvascular dysfunction in people with diabetes is that the extended axial field of view allows for simultaneous full body organ coverage, which is particularly beneficial for assessing systemic conditions like cardiometabolic syndrome, where multiple organs and tissues are involved (Fig. 3) [18].
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Fig. 3
15O-water in long axial field-of-view positron emission tomography. Example, maximal intensity projection of whole body 15O-water distribution. 4 min acquisition (courtesy of Dr. P. Cramon)
Additionally, LAFOV-PET enables dynamic imaging with high sensitivity, capturing real-time physiological processes such as organ perfusion, glucose metabolism, and fatty acid uptake [19]. Another advantage of LAFOV-PET is its increased sensitivity allowing for a lower radiopharmaceutical dose and thus a reduced radiation dose to the patient, which is especially important for people with diabetes who are at lifelong risk of multiple cardiovascular complications and thus may require multiple scans over time.
In summary, PET and SPECT are both valuable imaging techniques when assessing microvascular function in diabetes, each with distinct advantages and major clinical use. PET offers high spatial resolution and precise quantification of myocardial blood flow, making it particularly useful for people with diabetes, while SPECT is more widely available and cost-effective. The emerging LAFOV-PET provides full-body coverage and dynamic imaging, offering significant benefits for systemic conditions like cardiometabolic syndrome.
Magnetic Resonance Imaging
In the context of diabetes, MRI can detect and quantify microvascular changes in various organs, including the heart. Like PET and SPECT, MRI can assess myocardial perfusion and detect early signs of myocardial microvascular dysfunction using dynamic contrast-enhanced MRI in people with diabetes. Images are acquired during the first myocardial passage of the gadolinium-based contrast agent during vasodilator stress and repeated at rest. The ratio between the rest and stress perfusion reduces in microvascular dysfunction. In general, however, MRI is not the method of choice for myocardial perfusion imaging in clinical practice [20] primarily because of a more laborious setup.
Still, MRI is a powerful tool for evaluation of the microvasculature. Its noninvasive nature and lack of ionizing radiation further enhance its suitability for clinical studies with the possibility of repeated assessments in people with diabetes.
An emerging very advanced technique to study cellular metabolism in vivo is dual modality hyperpolarized magnetic resonance spectroscopy and PET (hyperPET). This approach has just been shown to be feasible in humans [21]. The key feature is a combination of the functional imaging from PET with the real-time imaging of cellular metabolism from hyperpolarized MRI. However, this very demanding technique will most likely be reserved to very few academic institutions and smaller pathophysiological studies. A more accessible technique is hybrid PET/MRI combining the strength of PET and MRI.
Overall, MRI is a powerful, noninvasive tool for evaluating microvascular changes in various organs in people with diabetes, though it is primarily used in research because of its complexity, need for highly skilled operators, and cost. Hyperpolarized magnetic resonance spectroscopy is an emerging technique with potential for high specificity in cellular metabolism.
Computed Tomography
Computed tomography (CT) can assess microvascular function in diabetes, particularly through techniques like CT perfusion and coronary CT angiography (CCTA) [22]. CT perfusion can diagnose microvascular dysfunction by evaluating MBF at rest and during stress like PET, SPECT, and MRI [23]. This allows for the detection of areas with impaired perfusion or reduced MFR. CT myocardial perfusion seems to have incremental prognostic value compared to CCTA alone, both in people with and without diabetes [24]. The CT perfusion method is not as clinically validated as myocardial perfusion with PET and therefore does not have the same level of adoption.
CCTA is useful in people with diabetes owing to its ability to visualize CAD and assess the extent of atherosclerotic plaque. However, the spatial resolution of this technique restricts it to the epicardial coronary arteries and not the microcirculation. Therefore, in people with diabetes, who are at higher risk for CAD, CCTA can help in early detection and management of obstructive CAD rather than microvascular dysfunction. From a pathophysiological point of view, coronary CT imaging has a spatial resolution allowing for detailed visualization of the coronary artery plaque composition in addition to the luminal obstruction. The combination of luminal stenosis with high-risk anatomical features of the plaques can potentially predict future major cardiac events in people with diabetes [25]. However, CT imaging does involve exposure to ionizing radiation and the use of iodinated contrast agents, which can pose risks, especially in people with diabetes and kidney impairment.
In summary, CT can assess microvascular function in diabetes through techniques like CT perfusion and CCTA, with CT perfusion providing incremental prognostic value compared to CCTA alone. The techniques have widespread clinical use. However, CT imaging involves ionizing radiation and iodinated contrast agents, posing risks, especially for people with diabetes and kidney impairment.
Echocardiography
Transthoracic echocardiography is noninvasive and widely available, making it an accessible option for many settings. However, it is operator-dependent and can be limited by image quality [26], especially in people with poor acoustic windows. The spatial resolution does not allow for direct visualization of the myocardial microvasculature using echocardiography, but it can assess microvascular dysfunction in people with diabetes indirectly, particularly by transthoracic Doppler echocardiography and contrast echocardiography. Doppler echocardiography can measure the coronary flow velocity reserve (CFVR) by assessing the changes in blood flow velocity in response to stress. The method uses pulsed-wave Doppler of the proximal left anterior descending coronary artery. The method correlates with MFR measurements by intracoronary Doppler flow wire [27], but the reported correlation with MFR measured with PET varies from r = 0.4 to 0.8 [28, 29].
An alternative method is contrast echocardiography that improves the visualization of myocardial perfusion by using microbubble contrast agents that increase the echogenicity of the blood. This technique can detect areas with reduced perfusion in the myocardium and thus assess microvascular dysfunction. Compared with SPECT, this method seems accurate in detecting myocardial perfusion abnormalities [30] and a small study in human volunteers indicated a good correlation with MFR derived from PET [31]. Advancements in image resolution and software algorithms are making echocardiographic methods increasingly more reliable and accessible.
In brief, transthoracic echocardiography is a noninvasive, widely available, and clinically applicable method for assessing microvascular dysfunction in people with diabetes, though it is operator-dependent and can be limited by image quality.
Provocation Tests
The microvasculature is a complex system that cannot be fully assessed with just a single test. Additionally, provoking the cardiovascular system is often necessary to diagnose early subclinical changes. There are various coronary provocation tests available, each targeting different physiological pathways [32].
Acetylcholine is an endothelial-dependent vasodilator [33] and is considered the gold standard for assessing coronary endothelial function. However, because acetylcholine must be injected intracoronarily, the test is not feasible for imaging studies. Additionally, the test carries the risk of severe vasospasm, which can lead to significant chest pain and arrhythmias.
Physiological provocation tests, such as the cold pressor test (CPT), also provide valuable information about myocardial microvascular function and is a simpler and noninvasive alternative to intracoronary acetylcholine. CPT involves immersing the patient’s hand or foot in ice-cold water to induce a powerful sympathetic response, which affects MBF [34, 35]. The acetylcholine test provides specific information about endothelial function, whereas CPT is a more general and complex test, assessing overall myocardial perfusion under stress. CPT has been employed to evaluate myocardial microcirculation changes in various patient groups, including those with diabetes [36]. The main limitation of CPT is the large physiological variation in response to the test as well as discomfort for the participant, making it less applicable in clinical practice.
The most used test is intravenous infusion of adenosine or dipyridamole to cause vasodilatation partially though endothelial effects [37]. This increases the MBF allowing for the calculation of MFR. The main limitation of vasodilator stress is the fact that it is not a distinct endothelial test, and it cannot distinguish between macro- and microvascular disease.
Inflammation
A pathophysiological integral part of microvascular dysfunction is inflammation within the microvasculature [2]. Using several radioactive molecular imaging tracers for PET, it is possible to visualize and quantify vascular inflammation in vivo. The uptake of tracers is usually quantified in larger vessels like epicardial coronary arteries or carotid arteries, but this mean tracer uptake is used to assess the global vascular inflammation [38] and thus acts as a surrogate marker of microvascular inflammation.
The best studied PET tracer for inflammation is 18F-fluorodeoxyglucose (18F-FDG). This tracer is a glucose analogue that accumulates in areas of high metabolic activity, such as inflammation, because inflammatory cells, particularly macrophages, have high glucose metabolism. PET imaging can thus provide quantification of vascular inflammation and help in monitoring the effectiveness of therapeutic interventions aimed at reducing inflammation [39].
It is important to note that optimal glycemic control is necessary before the scan to minimize interference from high blood glucose concentrations, which can potentially affect the accuracy of 18F-FDG uptake quantification. This limitation is of special importance in people with diabetes. Another limitation of 18F-FDG is the low specificity for inflammation.
These limitations highlight the need for molecular tracers with higher specificity for inflammation and minimal uptake in background tissue. Promising candidates are the somatostatin receptor tracers 64Cu-DOTATATE and 68Ga-DOTATATE (Fig. 4) [40]. These emerging PET tracers are used to image vascular inflammation, especially in cases of endothelial dysfunction and atherosclerosis. DOTATATE binds to somatostatin receptor subtype 2, which is expressed on activated macrophages within inflamed atherosclerotic plaques [41]. By targeting these receptors, DOTATATE serves as a marker of macrophage activity, providing a more specific assessment of vascular inflammation compared to 18F-FDG [42].
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Fig. 4
Hybrid positron emission tomography/computed tomography (PET/CT). Uptake of 64Cu-DOTATATE (in color) in the left coronary artery with calcifications on CT
Another promising PET tracer for use in people with diabetes is 18F-sodium fluoride (18F-NaF), which targets microcalcifications within atherosclerotic plaques, indicating active calcification processes and plaque instability. NaF-PET’s sensitivity for microcalcification may allow for the assessment of early, subclinical atherosclerosis, a diagnosis with special importance in people with diabetes [43].
The integration of novel and specific radioactive tracers with advanced imaging technologies, such as LAFOV PET/CT, is also being investigated [44]. This approach aims to provide comprehensive assessments of systemic inflammation and its impact on cardiovascular health with low radiation dose. The combination of new molecular imaging tracers and advanced imaging systems holds promise for improving personalized diagnosis, monitoring, and treatment of people with diabetes.
Artificial Intelligence
Artificial intelligence (AI) is playing an increasing role in research and development of noninvasive testing of the myocardial microcirculation, also in the context of diabetes. AI techniques can be exploited in several key ways. One notable application is the optimization of all phases of the diagnostic process. For PET, AI is being investigated for use in the reconstruction of images acquired with less radioactivity, potentially leading to lower radiation dose to the patient with the same diagnostic accuracy. Another fascinating possibility is generating a “synthetic CT” from a PET or SPECT scan [45]. Currently, a PET examination requires an attenuation map, typically obtained from a CT scan, to correct for in-body photon attenuation. Replacing this CT scan with a synthetic CT could reduce the radiation exposure. AI can automate the quantification of MBF and MFR, reducing the variability and subjectivity associated with manual image processing. This can potentially ensure more consistent and reproducible results and conclusions, which are essential for treatment evaluation and disease monitoring. AI algorithms can analyze complex imaging datasets from modalities like PET and MRI with high accuracy and speed. Traditional way of analyzing data might miss complex or subtle associations that these algorithms can detect [46].
Overall, integration of AI into imaging techniques for assessing microcirculation holds great promise for improving the early detection and management of microvascular complications in diabetes.
Treatment of Myocardial Microvascular Dysfunction
The primary goal in treating individuals with myocardial microvascular dysfunction has traditionally focused on aggressive management of cardiovascular risk factors. This approach is driven by the high risk of CAD among those with myocardial microvascular dysfunction [47].
Research on the impact of glycemic control and treatment with renin-angiotensin system blockers on myocardial microvascular function is quite limited. A cross-sectional study investigating glycemic control in individuals with type 2 diabetes found that optimal glycemic control did not correlate with improved myocardial microcirculatory function [48]. A study in rats demonstrated that treatment with an angiotensin-converting enzyme inhibitor enhanced myocardial microcirculation following induced ischemia [49]; however, this has not been confirmed in humans.
The use of newer glucose-lowering drugs such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide receptor agonists (GLP-1RA) represents a new advancement in reducing risk of cardiovascular and kidney diseases [50, 51, 52–53]. The mechanisms behind these beneficial effects cannot be solely attributed to the modification of traditional risk factors. It has been suggested that improvements in myocardial microvascular function may play a role. Preclinical studies have demonstrated positive effects of SGLT2i and GLP-1RA therapies on myocardial microcirculation. However, these benefits still need to be confirmed by the limited number of clinical trials conducted to date [2].
Studies with SGLT2i-Based Therapy
The SIMPLE trial included 90 individuals with type 2 diabetes randomly assigned to receive either empagliflozin (an SGLT2i) or placebo for 13 weeks. MFR was measured using 82Rb-PET/CT at start of treatment and at week 13. The study showed no significant treatment effect or change in MFR within the groups [54]. This could be due to the high prevalence of concurrent treatments, which may have diminished the impact of empagliflozin on MFR, and the relatively high baseline MFR (mean of 2.21).
Lauritsen et al. investigated the impact of empagliflozin on MFR and MBF in a crossover study including 13 individuals with type 2 diabetes. Participants were randomly assigned to receive either empagliflozin or placebo. Each study period was 4 weeks. MFR and MBF were assessed using 15O-H2O PET/CT. The study showed that empagliflozin reduced resting MBF by 13% (P < 0.01) but did not significantly affect MBF at stress or MFR [55].
Suhrs et al. conducted a crossover study to examine the effect of empagliflozin on CFVR in 26 individuals with type 2 diabetes. The study utilized transthoracic Doppler echocardiography to assess CFVR. Participants were randomized to receive either empagliflozin or placebo for 12 weeks, with a 2-week washout period between treatments. No significant effect of empagliflozin on CFVR was demonstrated [56].
The DAPAHEART trial included 16 individuals with type 2 diabetes and stable CAD, who were equally randomized to receive either dapagliflozin (an SGLT2i) or placebo for 4 weeks. The study demonstrated a significant improvement in MFR, assessed using 13N-ammonia PET/CT, in the dapagliflozin group compared to the placebo group [57]. Furthermore, a 4-year follow-up revealed that the 30% increase in MFR observed after 4 weeks of treatment was maintained over 4 years [58].
Table 1 summarizes the studies evaluating the effect of SGLT2i-based therapy on the myocardial function in people with type 2 diabetes. Overall, the evidence is limited, and further studies are warranted.
Table 1. Studies evaluating the effect of SGLT2i-based therapy on the myocardial function in people with type 2 diabetes
Study | Numbers of participants | Treatment duration (weeks) | Assessment method | Key findings |
|---|---|---|---|---|
SIMPLE Trial | 90 | 13 | 82Rb-PET/CT | No significant effect of empagliflozin on MFR |
Lauritsen et al. | 13 | 4 | 15O-H2O PET/CT | Empagliflozin reduced resting MBF by 13% (P < 0.01) but did not affect stress MBF or MFR |
Suhrs et al. | 26 | 12 | Transthoracic Doppler echo | No significant effect of empagliflozin on CFVR |
DAPAHEART Trial | 16 | 4 | 13N-ammonia PET/CT | Significant improvement in MFR with dapagliflozin compared to placebo. 30% increase in MFR sustained over 4 years |
CFVR coronary flow velocity reserve, MBF myocardial blood flow, MFR myocardial flow reserve, PET/CT positron emission tomography/computed tomography
Studies with GLP-1RA-Based Therapy
A randomized, single-blind, crossover study including 20 individuals with type 2 diabetes but no history of cardiovascular disease found no changes in CFVR, as assessed by Doppler-flow echocardiography, after 10 weeks of treatment with liraglutide (a GLP-1RA) compared to no treatment [59].
In a double-blind trial, 36 individuals without diabetes but with clinically stable heart failure with reduced ejection fraction were randomized to receive either liraglutide or placebo. After 24 weeks, no improvements were observed in myocardial glucose uptake, MBF, or MFR [60].
Overall, the potential of therapies based on SGLT2is and GLP-1RAs to improve myocardial microvascular dysfunction has not been established. However, the human studies face limitations such as small sample sizes and a low prevalence of baseline microvascular dysfunction.
Research into novel treatments for myocardial microvascular dysfunction remains an unmet clinical need.
Conclusion
Noninvasive testing of microcirculation in people with diabetes is promising and multifaceted, focusing on enhancing early detection, reducing radiation with high diagnostic accuracy and comfort. A significant area of development is the use of advanced hybrid imaging techniques such as PET/CT or PET/MRI. These methods allow for detailed visualization and quantification of blood flow, endothelial function, and inflammation in the microvasculature, providing critical insights into the early stages of microvascular disease in diabetes.
The integration of advanced imaging technologies with AI is also a key future direction. These algorithms can analyze large image datasets to identify patterns and predict the progression of microvascular complications in diabetes, potentially leading to earlier and more personalized interventions.
Overall, these advancements aim to improve the early detection and management of microvascular complications in diabetes, ultimately enhancing outcomes and quality of life.
Author Contributions
Tine W. Hansen and Rasmus S. Ripa contributed to the concept of the review, as well as to the drafting and revision of the manuscript.
Funding
No funding or sponsorship was received for this study or publication of this article.
Declarations
Conflict of Interest
Tine W. Hansen and Rasmus S. Ripa hold shares in Novo Nordisk A/S. Rasmus S. Ripa has received consultancy fees from Novo Nordisk A/S and Minerva Imaging. Tine W. Hansen is an Editorial Board member of Diabetes Therapy. Tine W. Hansen was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.
Ethical Approval
This article is based on previously published studies and does not contain any new studies with human participants or animals performed by any of the authors.
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Abstract
Microangiopathy is a key complication of diabetes, adversely effecting several organs including the heart, kidneys, eyes, and nerves. This review focuses on myocardial microvascular dysfunction, a condition characterized by altered vasomotion and long-term structural changes to coronary arterioles, resulting in impaired regulation of blood flow in response to varying oxygen demands of cardiomyocytes. Presence of myocardial microvascular dysfunction is associated with increased risk of cardiovascular disease, even in the absence of obstructive coronary artery disease. Several noninvasive imaging techniques to assess coronary physiology have significantly enhanced our understanding of the myocardial microcirculation. These methods allow for detailed visualization and quantification of blood flow, endothelial function, and inflammation in the microvasculature, providing critical insights into the early stages of microvascular disease in diabetes. A significant area of development is the use of advanced hybrid imaging techniques such as positron emission tomography/computed tomography (PET/CT) and positron emission tomography/magnetic resonance imaging (PET/MRI). The integration of advanced imaging technologies with artificial intelligence is also a key future direction. Overall, these advancements aim to improve the early detection and management of microvascular complications in diabetes, ultimately enhancing outcomes and quality of life. The aim of this review is to provide an overview of both established and emerging noninvasive imaging techniques for assessing myocardial microvascular dysfunction.
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Details
; Ripa, Rasmus S. 2
1 Steno Diabetes Center Copenhagen, Herlev, Denmark; University of Copenhagen, Department of Clinical Medicine, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X)
2 Copenhagen University Hospital - Bispebjerg, Department of Clinical Physiology and Nuclear Medicine, Copenhagen, Denmark (GRID:grid.4973.9) (ISNI:0000 0004 0646 7373); University of Copenhagen, Department of Clinical Medicine, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X)