SGLT1/2 inhibition improves glycemic control and multi-organ protection in type 1 diabetes

Herat, Lakshini Y.; Matthews, Jennifer; Hibbs, Moira; Rakoczy, Elizabeth; Schlaich, Markus; Matthews, Vance B.

doi:10.1016/j.isci.2023.107260

Cited by 5 publications

(4 citation statements)

References 67 publications

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“…A question that remains is whether the dual SGLT1/2 inhibitor, SOTA, may be beneficial for T1D and even surpass the benefits conferred by sole SGLT2 inhibitors. In our recent study utilizing our T1D Akimba mice [ 90 ], we concluded that SOTA not only significantly decreased fasting blood glucose levels but also promoted healthy weight gain compared with vehicle counterparts. Aside from this, SOTA also improved diabetes-associated polydipsia.…”

Section: Discussionmentioning

confidence: 99%

“… Cardiorenal benefits of Sodium–Glucose Cotransporter 2 (SGLT2) inhibitors and proposed effects on SGLT1 activity: Sodium–Glucose Cotransporter 2, SGLT2; Sodium–Glucose Cotransporter 1, SGLT1; Empagliflozin, EMPA; Dapagliflozin, DAPA; Canagliflozin, CANA; CV, cardiovascular; HF, heart failure and MI, myocardial infarction. SGLT1/2 Inhibition: [ 83 , 97 ], SGLT1 Activity: [ 85 , 90 ], Cardio-Renal Protection: [ 25 , 27 , 51 , 54 , 96 ]. Red arrows indicate an increase in the parameter.…”

Section: Figurementioning

confidence: 99%

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The Impact of SGLT2 Inhibitors in the Heart and Kidneys Regardless of Diabetes Status

Matthews,

Herat,

Schlaich

et al. 2023

IJMS

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Chronic Kidney Disease (CKD) and Cardiovascular Disease (CVD) are two devastating diseases that may occur in nondiabetics or individuals with diabetes and, when combined, it is referred to as cardiorenal disease. The impact of cardiorenal disease on society, the economy and the healthcare system is enormous. Although there are numerous therapies for cardiorenal disease, one therapy showing a great deal of promise is sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors. The SGLT family member, SGLT2, is often implicated in the pathogenesis of a range of diseases, and the dysregulation of the activity of SGLT2 markedly effects the transport of glucose and sodium across the luminal membrane of renal cells. Inhibitors of SGLT2 were developed based on the antidiabetic action initiated by inhibiting renal glucose reabsorption, thereby increasing glucosuria. Of great medical significance, large-scale clinical trials utilizing a range of SGLT2 inhibitors have demonstrated both metabolic and biochemical benefits via numerous novel mechanisms, such as sympathoinhibition, which will be discussed in this review. In summary, SGLT2 inhibitors clearly exert cardio-renal protection in people with and without diabetes in both preclinical and clinical settings. This exciting class of inhibitors improve hyperglycemia, high blood pressure, hyperlipidemia and diabetic retinopathy via multiple mechanisms, of which many are yet to be elucidated.

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

The Impact of SGLT2 Inhibitors in the Heart and Kidneys Regardless of Diabetes Status

Matthews,

Herat,

Schlaich

et al. 2023

IJMS

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show abstract

“…In previous studies, we have shown that SGLT2i produces a compensatory increase in SGLT1 expression in the eye and kidney [4,25]. Therefore, we wanted to ascertain if SGLT2i promotes the same phenomenon in skeletal muscle.…”

Section: Sglt2 Inhibition (Sglt2i) Promotes Sglt1 Expression In Diffe...mentioning

confidence: 97%

“…Sections were then incubated overnight with primary anti-SGLT1 antibodies at 4°C in a humidified chamber. SGLT1 immunohistochemical detection was done in a novel way using a combination of primary antibodies from both Abcam (Rabbit anti-SGLT1, 14685, IgG, Polyclonal, 1:180) and Novus (Rabbit anti-SGLT1, NBP2.20338, IgG, Polyclonal, 1:100) antibodies [25]. Following overnight incubation, sections were washed three times with PBS/0.1% Tween for 5 mins and incubated with anti-rabbit (1:100, Santa Cruz Biotechnology, Sydney, Australia) secondary antibody conjugated with HRP in PBS/0.1% Tween for 1 hr.…”

Section: Sglt1 Immunohistochemistry Of Quadricep Skeletal Musclementioning

confidence: 99%

Sympathetic Activation Promotes Sodium Glucose Co-Transporter-1 Protein Expression in Rodent Skeletal Muscle

Matthews,

Herat,

Schlaich

et al. 2024

Preprint

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The hyperactivation of the sympathetic nervous system (SNS) is linked to obesity, hypertension, and type 2 diabetes, with elevated norepinephrine (NE) levels being a key feature. Previous research has shown increased sodium-glucose cotransporter 1 (SGLT1) protein in kidneys of hypertensive rodents, prompting investigation into SGLT1 expression in other tissues such as skeletal muscle. This study aimed to assess: i) whether skeletal muscle cells and tissue express SGLT1 and SGLT2 protein; ii) if NE increases SGLT1 in skeletal muscle cells and iii) whether skeletal muscle of neurogenically hypertensive mice exhibits increased SGLT1 expression. We found that i) skeletal muscle cells and tissue are a novel source of SGLT2 protein and ii) NE significantly elevated SGLT1 in skeletal muscle cells. As SGLT2 inhibition (SGLT2i) with Empagliflozin increased SGLT1, in vivo studies with the dual SGLT1/2i, Sotagliflozin were warranted. Treatment of neurogenically hypertensive mice with Sotagliflozin significantly reduced blood pressure. Our findings suggest that SNS activity upregulates the therapeutic target, SGLT1 in skeletal muscle, potentially worsening cardiometabolic control. As clinical trial data suggests cardiorenal benefits with SGLT2i, future studies should aim to utilize sole SGLT1i which may offer a therapeutic strategy for conditions with heightened SNS activity, such as hypertension, diabetes and obesity.

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Hypothalamic sex-specific metabolic shift by canagliflozin during aging

Jayarathne,

Sullivan,

Stilgenbauer

et al. 2024

GeroScience

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The hypothalamus undergoes significant changes with aging and plays crucial roles in age-related metabolic alterations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are anti-diabetic agents that promote glucose excretion, and metabolic homeostasis. Recent studies have shown that a SGLT2i, Canagliflozin (Cana), can extend the median survival of genetically heterogeneous UM-HET3 male mice and improve central metabolic control via increases in hypothalamic insulin responsiveness in aged males, as well as reduced age-associated hypothalamic inflammation. We studied the long- and short-term effects of Cana on hypothalamic metabolic control in UM-HET3 mice. Starting the treatment from 7 months of age, we show that 4 weeks of Cana treatment significantly reduced body weight and fat mass in male but not female mice that was associated with enhanced glucose tolerance and insulin sensitivity observed by 12 months. Indirect calorimetry showed that Cana treatment increased energy expenditure in male, but not female mice, at 12 months of age. Long-term Cana treatment increased metabolic rates in both sexes, and markedly increasing formation of both orexigenic and anorexigenic projections to the paraventricular nucleus of the hypothalamus (PVH) mostly in females by 25 months. Hypothalamic RNA-sequencing analysis revealed increased sex-specific genes and signaling pathways related to insulin signaling, glycogen catabolic pathway, neuropeptide signaling, and mitochondrial function upregulated by Cana, with males showing a more pronounced and sustained effect on metabolic pathways at both age groups. Overall, our data provide critical evidence for sex-specific mechanisms that are affected by Cana during aging suggesting key targets of hypothalamic Cana-induced neuroprotection for metabolic control.

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SGLT1/2 inhibition improves glycemic control and multi-organ protection in type 1 diabetes

Cited by 5 publications

References 67 publications

The Impact of SGLT2 Inhibitors in the Heart and Kidneys Regardless of Diabetes Status

The Impact of SGLT2 Inhibitors in the Heart and Kidneys Regardless of Diabetes Status

Sympathetic Activation Promotes Sodium Glucose Co-Transporter-1 Protein Expression in Rodent Skeletal Muscle

Hypothalamic sex-specific metabolic shift by canagliflozin during aging

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