Eight weeks of empagliflozin does not affect pancreatic fat content and insulin secretion in people with prediabetes

Hummel, Julia; Machann, Jürgen; Dannecker, Corinna; Kullmann, Stephanie; Birkenfeld, Andreas L.; Häring, Hans‐Ulrich; Fritsche, Andreas; Wagner, Róbert; Heni, Martin

doi:10.1111/dom.14733

Cited by 5 publications

(4 citation statements)

References 22 publications

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“…Several human interventional studies have demonstrated significant improvements in β-cell glucose sensitivity and secretory function in vivo , as measured by the incremental AUC of plasma C-peptide concentrations during hyperglycemic clamps (the gold-standard assessment of β-cell function in vivo ) and the Disposition Index [33, 63, 64]. However, this is not a universal finding, and a very recent study in humans with pre-diabetes failed to show improvements in insulin secretion following 8-weeks of SGLT2i treatment [66].…”

Section: Discussionmentioning

confidence: 99%

Persistent Inflammatory Lipotoxicity Impedes Pancreatic β-cell Function in Diet-Induced Obese Mice Despite Correction of Glucotoxicity

Valdez

Palavicini

Bakewell

et al. 2022

Preprint

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Insulin resistance is a hallmark feature of Type 2 Diabetes (T2D), but the progression of the disease is closely linked to a deterioration in β-cell mass and function. While the precise mechanisms of β-cell failure are unclear, chronic hyperglycemia (glucotoxicity) and dyslipidemia (lipotoxicity) are considered contributing factors; however, the relative importance of these insults on β-cell function remains controversial. To examine this, we dissociated glucotoxicity from lipotoxicity using a high-fat diet (HFD)-fed mouse model of T2D and the glucose-lowering SGLT2 inhibitor, canagliflozin (CANA). As expected, HFD-feeding impaired glucose tolerance and isolated islet function. However, despite improvements in glucose tolerance and indices of β-cell insulin secretory function in vivo, CANA failed to restore isolated β-cell function. Shotgun lipidomics analysis of isolated islets revealed that HFD-feeding induced glycerophospholipid remodeling with a persistent increase in arachidonic acid (20:4)-enriched molecular species. Further analysis revealed that lysophosphatidylcholine (LPC) was the predominant lipid class elevated in HFD islets following correction of glucotoxicity with CANA. In follow-up experiments, LPC stimulations acutely and dose-dependently impaired glucose-stimulated insulin secretion (GSIS) in isolated wild-type islets, mechanistically linking this lipid class to β-cell dysfunction. Our findings indicate that persistent inflammatory lipotoxicity impedes β-cell function in diet-induced obese (DIO) rodents even after normalization of hyperglycemia. If replicated in humans, these data suggest that interventions targeting lipotoxicity may be beneficial for the long-term protection of pancreatic β-cell function in T2D.

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Section: Discussionmentioning

confidence: 99%

Persistent Inflammatory Lipotoxicity Impedes Pancreatic β-cell Function in Diet-Induced Obese Mice Despite Correction of Glucotoxicity

Valdez

Palavicini

Bakewell

et al. 2022

Preprint

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“…All the four prospective studies used a magnetic resonance system at 3T to determine IPFD and the sample size of these studies ranged from 30 to 78 individuals [ 43 – 46 ]. Three out of four prospective studies were randomised controlled trials, including two placebo-controlled trials [ 43 , 44 ]. A study from India found an absolute reduction in IPFD by 1.5% (a relative reduction of 20%) following 17 weeks of dapagliflozin use [ 45 ], and a study from China showed an absolute reduction in IPFD by 1.2% (a relative reduction of 20%) following 24 weeks of dapagliflozin use [ 46 ].…”

Section: Glucose-lowering Medicationsmentioning

confidence: 99%

“…The IPFD change was independent of weight change in the Chinese study [ 46 ] and dependent of weight change in the Indian study [ 45 ]. The two placebo-controlled trials used empagliflozin as the study intervention and they came from Germany and France [ 43 , 44 ]. The German study found an absolute reduction of 0.9% (a relative reduction of 13%) in IPFD following 8 weeks of SGLT-2 inhibitor use [ 44 ].…”

Section: Glucose-lowering Medicationsmentioning

confidence: 99%

“…The two placebo-controlled trials used empagliflozin as the study intervention and they came from Germany and France [ 43 , 44 ]. The German study found an absolute reduction of 0.9% (a relative reduction of 13%) in IPFD following 8 weeks of SGLT-2 inhibitor use [ 44 ]. The French study found an absolute reduction in IPFD by 2.5% (a relative reduction of 12%) following 12 weeks of SGLT-2 inhibitor use [ 43 ].…”

Section: Glucose-lowering Medicationsmentioning

confidence: 99%

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The Pharmacological Landscape for Fatty Change of the Pancreas

Petrov

2024

Drugs

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The quest for medications to reduce intra-pancreatic fat deposition is now quarter a century old. While no specific medication has been approved for the treatment of fatty change of the pancreas, drug repurposing shows promise in reducing the burden of the most common disorder of the pancreas. This leading article outlines the 12 classes of medications that have been investigated to date with a view to reducing intra-pancreatic fat deposition. Information is presented hierarchically—from preclinical studies to retrospective findings in humans to prospective interventional studies to randomised controlled trials. This lays the grounds for shepherding the most propitious drugs into medical practice through well-designed basic science studies and adequately powered randomised controlled trials.

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Effect of dapagliflozin on liver and pancreatic fat in patients with type 2 diabetes and non-alcoholic fatty liver disease

Shi,

Zhang,

Wang

et al. 2023

Journal of Diabetes and its Complications

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Eight weeks of empagliflozin does not affect pancreatic fat content and insulin secretion in people with prediabetes

Cited by 5 publications

References 22 publications

Persistent Inflammatory Lipotoxicity Impedes Pancreatic β-cell Function in Diet-Induced Obese Mice Despite Correction of Glucotoxicity

Persistent Inflammatory Lipotoxicity Impedes Pancreatic β-cell Function in Diet-Induced Obese Mice Despite Correction of Glucotoxicity

The Pharmacological Landscape for Fatty Change of the Pancreas

Effect of dapagliflozin on liver and pancreatic fat in patients with type 2 diabetes and non-alcoholic fatty liver disease

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