Abstract
Controlling the blood glucose level is of outmost importance for the prevention of the micro- and macrovascular diabetic complications observed in patients with type 1 diabetes (T1D). Although the pathogenesis behind the complex cascade of complications is far from solved, one possible mechanism could be a negative effect of glucose on the arteries resulting in a stiffening of the arteries and ultimately in vascular complications. Intriguingly, patients with T1D have been shown to suffer from premature arterial aging compared to nondiabetic subjects—an association that is even more evident in the presence of diabetic complications such as diabetic nephropathy. Arterial stiffness has in several patient populations been shown to independently predict cardiovascular disease. However, interventional studies aimed at attenuating arterial stiffness to reduce cardiovascular disease in T1D are yet to come. Moreover, most of the data on pharmacological treatments of arterial stiffening are directed toward pathophysiological pathways other than hyperglycemia. Interestingly, the sodium-glucose transport-2 (SGLT2) inhibitor empagliflozin was recently shown to reduce both blood pressure and arterial stiffness in patients with type 2 diabetes. Whether, these effects can also be replicated in patients with T1D is an intriguing question. Tight metabolic and antihypertensive control are still of central importance for the prevention and the treatment of diabetic complications. However, the need for a noninvasive intermediate marker to identify at risk patients for aggressive treatment is evident. One such tool might be arterial stiffness linking diabetes to increased cardiovascular risk. Future research efforts exploring large-scale databases will play a key role in the identification of other clinically useful markers.
Keywords
A particularly strict glycemic control is essential to prevent diabetic complications in patients with type 1 diabetes (T1D). Notably, the pathophysiology lying behind this cascade is not clear. One path may go via glucose toxicity to the blood vessels and result in stiffening of the arteries, vascular complications, and eventually to early death in patients with T1D as discussed in this review article.
Using Large-Scale Databases in T1D Research
The Finnish Diabetic Nephropathy (FinnDiane) study is an ongoing nationwide prospective multicenter study launched in January 1997. 1 It was established to identify risk factors for T1D and its complications with special emphasis on diabetic kidney disease. To date the FinnDiane database comprises more than 8000 well-characterized patients with T1D. A prospective phase including s third patient visit is ongoing.
The patients have been recruited since 1997 from 21 university and central hospitals, 33 district hospitals, and 26 primary health care centers across Finland. All patients visit these centers in person. Data collected during study visits on medication, cardiovascular status, and diabetic complications are registered by standardized questionnaires that are completed by the patient’s attending physician and thus immediately verified from the medical files. Furthermore, blood pressure, height, weight, and waist-to-hip ratio are also recorded. In addition, blood samples are drawn from each patient and stored as whole blood, serum, and plasma, as well as extracted DNA. To characterize the patients with regard to the absence or presence of diabetic nephropathy timed overnight or 24-hour urine samples are collected and stored. The patient visits accumulate an large amount of data which are stored in secure electronic databases for future analyses. The primary aim of the FinnDiane study is to carefully characterize not only the phenotype but also the genetic background and thereby includes a comprehensive battery of variables associated with a multifactorial disease.
It is of note that large-scale medical registries have been collected in Finland for decades. Combining these national registries, such as the hospital discharge registry, and the Finnish National Death Registry, with the FinnDiane database, enables longitudinal analyses with long-term follow-up. Cumulatively, the follow-up time that stretch over 15 years includes a large number of cardiovascular events as well as deaths providing the platform for observational long-term follow-up studies.
At the FinnDiane research center in Helsinki, a neurovascular laboratory has been established and expanded during the last 10 years. The vascular status is extensively assessed with high quality methodology consisting of the following measurements: arterial stiffness by applanation tonometry, carotid intima-media thickness by ultrasound, and endothelial function by peripheral arterial tonometry. Furthermore, testing of autonomic function is performed by measuring finger pressure wave forms with a pletysmograph in response to different maneuvers, such as controlled breathing, the orthostatic test as well as the Valsalva test. Spontaneous baroreflex sensitivity is 1 of the main indexes. In addition, retinal pictures are obtained from each patient to map their retinopathy status. Last, bone morphometry and body fat distribution is measured by dual-energy X-ray absorptiometry. The aim of measuring these subclinical markers is to gain insight into the vascular health, including mechanisms underlying these processes, to learn more about the vascular aging of patients with T1D.
Using this approach we have performed a number of studies to characterize the effect of hyperglycemia on arterial stiffness, a subclinical marker of cardiovascular disease, in this patient population. However, the ultimate goal is to study all diabetic complications in patients with T1D to find individuals at risk and ultimately change their clinical outcome and prognosis.
From Hyperglycemia to Diabetic Complications
The hyperglycemic milieu in patients with T1D contributes to the development of complications 2 via a number of pathological pathways. 3 A common factor seems to be hyperglycemia-induced overproduction of superoxide by the mitochondrial electron-transport chain. 4 Spillover superoxide partially inhibits the glycolytic enzyme GADPH, and hereby diverts upstream metabolites (glucose, fructose-6-phosphate, glyceraldehyde-3 phosphate) from glycolysis.
Arterial Stiffness
A better understanding of the mechanisms through which hyperglycemia leads to arterial disease and eventually to the development of diabetic complications is integral to prevent these complications. So far the number of fully described mechanisms are very few, but it is likely that together they contribute to endothelial dysfunction and thus indirectly to the increase in arterial stiffness. 5 Arterial stiffness is strongly linked to cardiovascular disease and considered an intermediate marker of the link between hyperglycemia and vascular complications.
The central arterial pressure wave is composed of a forward traveling wave that is generated by the contraction of the left ventricle of the heart, and a later arriving reflection wave from the periphery. The forward wave relies on the mechanical properties of the large central elastic arteries, but is not influenced by the wave reflection. On the contrary, the reflected wave is dependent on the elastic properties of the entire arterial tree (elastic, muscular arteries, and resistance arteries), the velocity of the wave and the distance to the reflecting sites. 6 As arterial stiffness is increased, the reflected wave returns earlier from the periphery to the heart during the systolic phase. This leads to increased aortic pulse pressure, increased left ventricular afterload, increased LV mass and oxygen demand, decreased stroke volume, and consequently potentiates the development of atherosclerosis. 7
Acute Hyperglycemia and Arterial Stiffness
Acute hyperglycemia has been shown to increase the augmentation index (AIx), a measure of wave reflections, in healthy men. 8 As it was not known whether the presence of chronic hyperglycemia affects the acute response to hyperglycemia, we showed in a substudy of the FinnDiane study that both AIx and brachial pulse wave velocity (PWV), a measure of stiffness in the intermediated-sized arteries, increased during a hyperglycemic clamp in patients with T1D and no complications (Figure 1). 9 Notably, this effect was recently shown to be reversed by the sodium-glucose transport-2 (SGLT2) inhibitor empagliflozin also in T1D. 10
Brachial pulse wave velocity (PWV) at baseline (mean blood glucose 7 mmol/l) and during a hyperglycemic clamp at 0-120 minutes (mean blood glucose 18 mmol/l) in patients with T1D and healthy subjects (controls). Diamonds, type 1 diabetic patients; squares, control subjects. Modified with permission from Gordin et al. 9
As to the mechanisms, chronic inflammation relates to cardiovascular disease 11 and low-grade inflammation to arterial stiffening, 12 and therefore we measured inflammatory markers during baseline (normoglycemia) and acute hyperglycemia. 13 We observed an inflammatory response to acute hyperglycemia in patients with T1D. Interestingly, a recent article showed promising results of glucagon-like peptide 1 (GLP-1) analogs to reduce endothelial dysfunction, chronic inflammation, and oxidative stress, induced by both hyperglycemia and hypoglycemia. 14
Acute Hyperglycemia and Cardiac Repolarization
Increased mortality seen in children and adolescents with T1D compared to nondiabetic subjects of the same age cannot solely be explained by ketoacidosis and nocturnal hypoglycemia (dead-in bed syndrome) has therefore been suggested to be involved. 15 Notably, hypoglycemia was shown to prolong the QT interval (cardiac repolarization) with a potentially fatal outcome. 16 Our results demonstrating that acute hyperglycemia also prolongs cardiac repolarization may indicate that not only hypoglycemia but also hyperglycemia, plays a role in the dead-in bed syndrome, although further studies are warranted. 17
Chronic Hyperglycemia, Arterial Stiffness, and Complications
Studies have shown increased arterial stiffness not only in adults but also in adolescents and children with T1D when compared with nondiabetic subjects.18-21 Notably, the stiffening of the arteries seems to be present before any clinically detectable signs of vascular disease. 22 Data from the FinnDiane study further showed that arterial stiffening is associated with diabetic nephropathy, retinopathy (even without signs of nephropathy), and cardiovascular disease. 23 In line with these data we also showed that the pulse pressure, a crude estimate of arterial stiffness, increases 15 years earlier in patients with T1D compared to nondiabetic controls. 24 In a later prospective analysis of these patients, the pulse pressure independently predicted cardiovascular complications but not diabetic nephropathy. 25 This is in line with the observation that diabetic nephropathy is the main contributor to premature death in these patients. 26
Mechanisms of Arterial Stiffening
To gain insight into the potential mechanisms of the arterial stiffening we have explored a selection of arterial biomarkers in our cohort. One key component of the so called traditional risk factors for cardiovascular disease is the calcification of the arterial tree, frequently seen in patients with chronic kidney disease. Indeed, arterial calcification in turn, relates to vascular stiffening and arteriosclerosis. Recent data have shown that some of the mediators of bone mineralization are also regulators of osteogenic transformation of arterial smooth muscle cell and arterial calcification in diabetes. 27 One intriguing biomarker involved in bone mineralization, osteoprotegerin, was shown to be associated with arterial stiffness as well as coronary artery disease. 28 By exploring osteoprotegerin in approximately 2000 patients with T1D, we observed an association not only between this biomarker and arterial stiffness, but also with cardiovascular events. 29 This finding was independent of urinary albumin excretion rate and renal function. The observation suggests that osteoprotegerin may be directly involved in extraosseous calcification, resulting in stiffening of the arteries and subsequent vascular disease in patients with T1D.
Another multifunctional protein of interest is osteopontin that has also been shown to be part of bone formation and calcification. 30 Notably, it has also been related to vascular calcification in diabetic arteries. 31 We therefore explored the association between serum osteopontin on one hand and diabetic complications and mortality on the other hand in the FinnDiane cohort. Osteopontin was analyzed in 2145 patients with T1D who were followed for 11 years. 32 Serum osteopontin turned out to be a strong predictor of incipient diabetic nephropathy and a first-ever cardiovascular-event. Notably, serum osteopontin also predicted all-cause mortality in T1D (Figure 2). Future studies will elucidate whether it is a mere marker of complications or whether it plays a causal role. Thus, an intriguing question is whether blocking osteopontin would slow the development of diabetic complications and decrease early death in patients with T1D.
Kaplan-Meier survival curves with log-rank tests for death (n = 202) by quartiles of serum osteopontin concentrations. Log-rank P < .001. Modified with permission from Gordin et al. 32
How to Decrease Early Vascular Aging in Diabetic Patients
Several clinical trials have assessed whether a number of pharmacological and nonpharmacological treatments can prevent or retard the development of arterial stiffening.33,34 However, most of these pharmacological treatments focus on interfering and blocking pathophysiologic pathways associated with arterial stiffness rather than testing the effect of glucose-lowering on the arteries.
One such important trial, the Conduit Artery Function Evaluation (CAFE) study, showed that ACE inhibitor based treatment in combination with a Calcium channel blocker was more effective than a combination of a beta-blocker and a diuretic to slow down the arterial stiffening independently of the effect on blood pressure. 35 These results suggested that stiffening of the large arteries may precede systemic arterial hypertension. The only compounds that specifically target the arterial wall, are the advanced glycation end-product breakers. While the experimental data were promising, these compounds have not been brought forward, at least partly due to problems with toxicity.36,37
The data on decreasing arterial stiffening by targeting acute or chronic hyperglycemia are scarce. The insulin sensitizer pioglitazone was shown to reduce aortic PWV in type 2 diabetes (T2D). 38 Moreover, supraphysiological doses of insulin decrease arterial stiffness although this effect is reduced in patients with T1D.39-41 In addition, physiological postprandial hyperinsulinemia causes arterial relaxation in patients with T1D, although this effect is impaired in patients with insulin resistance. 42 The GLP-1 receptor agonists in turn seem to modestly decrease the blood pressure and even more importantly to increase the heart rate of yet unknown reasons. 43 Notably, the SGLT2-inhibitor empagliflozin given to patients with T2D was shown to reduce both blood pressure and arterial stiffness.44,45 These data may to some extent explain why empagliflozin is the first compound to conclusively reduce cardiovascular morbidity and mortality as shown by the EMPA-REG Outcome Study. 46
In summary, the ability of antidiabetic and glucose-lowering agents to reduce arterial stiffness and ultimately prevent vascular complications has not been convincing, until the emergence of the SGLT2-inhibitors that not only reduce blood glucose by removal of excess glucose to the urine but also seem to have, in patients with T2D, consistent effects on arterial stiffness, cardiovascular disease and cardiovascular mortality independently of the effect on glucose. 46 Whether, these effects also can be observed in patients with T1D remains an intriguing question.
Conclusions
Multifactorial antihypertensive and metabolic control remains the cornerstone strategy in the prevention and treatment of diabetic complications. The role of tight glucose control is critical. However, a clear need exists for a tool or surrogate marker to identify the patients at risk before the development of clinically detectable complications. One such marker may be the stiffening of the arteries linking diabetes to high cardiovascular risk. Future research that harnesses large-scale databases may provide new measures to aid the early intervention to attenuate the progression of arterial stiffness and thus diabetic complications.
Footnotes
Acknowledgements
Anna Sandelin, Jaana Tuomikangas, Tuula Soppela, Maikki Parkkonen, and Anna-Reetta Salonen (Folkhälsan Research Center) are acknowledged for their excellent technical assistance.
Abbreviations
AIx, augmentation index; FinnDiane Study, Finnish Diabetic Nephropathy Study; PWV, pulse wave velocity; SGLT2, sodium-glucose transport-2; T1D, type 1 diabetes; T2D, type 2 diabetes.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: PHG has received lecture fees from Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Genzyme, MSD, Novartis, Novo Nordisk, and Sanofi. He is an advisory board member of Abbvie, Astra Zeneca, Boehringer Ingelheim, Cebix, Eli Lilly, Janssen, MSD, and Novartis.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: These studies were supported by grants from Folkhälsan Research Foundation, Academy of Finland (134379), Helsinki University Central Hospital Research Funds (EVO), the Wilhelm and Else Stockmann Foundation, the Waldemar von Frenckell Foundation, the Liv och Hälsa Foundation, the Finnish Medical Society (Finska Läkaresällskapet), the Diabetes Research Foundation, the Nylands Nation Foundation, the Paulo Foundation, the Paavo Nurmi Foundation, the Finnish Medical Foundation, and the Biomedicum Helsinki Foundation.