Author + information
- aDivision of Cardiovascular Medicine, Department of Internal Medicine, and Abboud Cardiovascular Research Center, University of Iowa, Iowa City, Iowa
- bDepartment of Radiology and Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa
- cStead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa
- ↵∗Address for correspondence:
Dr. Ferhaan Ahmad, 100 Newton Road, 1191D ML, Iowa City, Iowa 52242.
There are 2 families of glucose transporters, the facilitative (GLUT) and the sodium-dependent (SGLT) transporters (1). The SGLTs function by secondary active transport using the Na+ gradient. The SGLT1 isoform is present in small intestinal enterocytes and renal proximal tubule cells, where it mediates glucose uptake (2). Homozygous loss-of-function variants in SLC5A1, the gene encoding SGLT1, lead to glucose/galactose malabsorption with life-threatening diarrhea in newborns. In this issue of the Journal, Seidelmann et al. (3) show that heterozygosity for a haplotype of 3 common missense variants in SLC5A1 (N51S/A411T/H615Q) that cause a modest decrease in SGLT1 function and are present at a frequency of 6.7% in the population is associated with a decreased prevalence of impaired glucose tolerance on oral glucose tolerance tests and obesity in subjects of European and African origin. In subjects of European origin, SLC5A1 variants are also associated with a decreased prevalence of hypertension, lower diastolic blood pressure, decreased heart rate, and lower uric acid levels. In addition, the investigators show that the haplotype is associated with a decreased incidence of diabetes mellitus, heart failure, and death over a median follow-up period of 25 years.
The study design by Seidelmann et al. (3) in this issue of the Journal was robust, and its findings have potentially broad implications. A discovery cohort of 8,478 subjects and a replication cohort of 6,784 subjects were analyzed. The discovery cohort included subjects of European origin from 4 U.S. communities. The replication cohorts were subjects of African origin from the same U.S. communities and subjects recruited from at least 6 Finnish communities. The principal associations identified by the investigators were present in both racial groups and in geographically distant communities. The discovery cohort had excellent longitudinal follow-up with a median of 25 years.
The design of this study (3) is appropriate to find associations between gene alleles and disease outcomes. However, alone, it can be used only to infer causation between exposures and outcomes, and it cannot prove the biological mechanisms that drive such causation. The simplest mechanistic pathway to explain the influence of SLC5A1 variants on outcomes would be that decreased intestinal glucose and galactose absorption and possibly decreased renal reuptake of glucose from the ultrafiltrate lead sequentially to lower net caloric balance, decreased obesity, improved insulin sensitivity, improved glucose tolerance, and less heart failure (Figure 1). However, the association of the SLC5A1 haplotype with impaired glucose tolerance remains significant after inclusion of obesity as a covariate, suggesting the presence of other mechanistic pathways in addition to obesity. Indeed, the investigators propose several plausible explanations for the protective effect of the identified haplotype, including increased levels of beneficial hormones such as glucagon-like peptide-1, decreased fibrosis secondary to low glucose levels, and a direct cardioprotective role. Furthermore, previous studies have shown that hyperglycemia is associated with adverse outcomes and increased mortality in patients with acute myocardial infarction, even in the absence of diabetes (4).
Other potential mechanisms may be related to the fact that SGLT1 transports sodium as well as glucose. Sodium levels affect intravascular volume and blood pressure, which can influence heart failure. This potential mechanism is supported by the fact that, at least in the subjects of European origin, the presence of SLC5A1 variants was associated with a decreased prevalence of hypertension and lower diastolic blood pressure (3). Serum uric acid, which is lower in carriers of these variants, has been shown to be a biomarker for sodium intake, endothelial dysfunction, and hypertension (5). Could the lower heart rate in carriers reflect an indirect effect of sodium entry in the sinoatrial node?
SGLT1 messenger ribonucleic acid was first reported to be highly expressed in the heart in 2003 (6). Our laboratory later showed that SGLT1 protein is expressed in cardiomyocytes, largely at the sarcolemma, and its expression is increased in diabetic cardiomyopathy, ischemia, and glycogen storage cardiomyopathy secondary to mutations in PRKAG2 (7,8). Our unpublished studies suggest that cardiomyocyte-specific knock down of SGLT1 in a transgenic murine model (9) protects the heart against injury in both ischemia/reperfusion and type 2 diabetes mellitus by mechanisms that are independent of its glucose transporter function, including attenuation of oxidative stress. Similarly, other investigators have shown that SGLT1 exacerbates neuronal damage during cerebral ischemia, likely by sodium transport (10). Thus, SLC5A1 variants may be acting at the level of target organs such as the heart and the brain to protect them from ischemia, hyperglycemia, and other metabolic insults.
Unpublished human studies from our laboratory (L. Gifford, September 2014) also suggest that SLC5A1 variants may protect against cardiovascular events in not only relatively healthy population cohorts but also in subjects with severe heart failure. In a cohort of 1,829 subjects with left ventricular ejection fractions ≤30% and implantable cardioverter-defibrillators, the N51S variant is associated with a trend toward decreased nonarrhythmic mortality. This protective trend is more pronounced in the 29% of subjects with nonischemic heart failure (p = 0.15). These data are consistent with the hypothesis that the beneficial effects of these variants are not related solely to a long-term decrease in intestinal glucose and galactose uptake but also direct effects in diseased myocardium.
The study by Seidelmann et al. (3) is a reminder that although the null state for some genes may be pathogenic, moderate decreases in their function may in fact confer a survival benefit. Furthermore, this study illustrates the utility of genetic studies, of both Mendelian single gene disorders and complex polygenic disorders, in identifying novel therapeutic targets in acquired disease. This principle has recently been epitomized by the discovery of variants in PCSK9 that ultimately led to the development of proprotein convertase subtilisin/kexin 9 inhibitors for hypercholesterolemia (11).
The SGLT family has become an established therapeutic target for diabetes control, with SGLT2 as the primary target for inhibition to increase glycosuria. One SGLT2 inhibitor, empagliflozin, reduces cardiovascular death and heart failure in patients with type 2 diabetes (12) by mechanisms that seem, in part, to be distinct from its glucose-lowering effect (13). The focus is now shifting to SGLT1 and the role it can play in diabetes control, and dual SGLT1/2 inhibitors and SGLT1-selective inhibitors are being developed. The investigators (3) used a Mendelian randomization strategy to show that pharmacological inhibition of SGLT1 should lead to decreases in the incidence of diabetes, heart failure, and death. Although randomized controlled trials of novel SGLT1 inhibitors will be required, Mendelian randomization offers the advantage of an early evaluation of the potential effectiveness of SGLT1 inhibitors, in a blinded, randomized population that has had prolonged longitudinal exposure to SGLT1 “inhibition” since conception. The findings of Seidelmann et al. (3) should accelerate exploration of SGLT1 inhibition as a target for not only diabetes control but also for other cardiometabolic indications.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
This research was supported by grants from the National Institutes of Health (R01 HL135000) and the American Heart Association (15GRNT25650003, 16POST27770035). Dr. Ahmad has received support from MyoKardia, Inc., for research unrelated to this editorial. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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