Tracking the carbons supplying gluconeogenesis

Shah, Ankit; Wondisford, Fredric E.

doi:10.1074/jbc.rev120.012758

Cited by 35 publications

(18 citation statements)

References 110 publications

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“… 35 , 36 Since we hypothesized Alanine's role was due to its potential influence on gluconeogenesis, we chose to evaluate the effects of acute ketosis after fasting for 24 h because the relative contribution of gluconeogenesis to endogenous glucose production is 47 ± 49% after 14 h and 67 ± 41% after 22 h. 37 , 38 However, there is evidence suggesting that, in the context of short‐term fasting, alanine is the most important contributor via liver gluconeogenesis. 5 , 39 , 40 , 41 , 42 …”

Section: Discussionmentioning

confidence: 99%

Exogenous d‐β‐hydroxybutyrate lowers blood glucose in part by decreasing the availability of L‐alanine for gluconeogenesis

Soto-Mota

Norwitz

Evans

et al. 2021

Endocrino Diabet & Metabol

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Background Interventions that induce ketosis simultaneously lower blood glucose and the explanation for this phenomenon is unknown. Additionally, the glucose‐lowering effect of acute ketosis is greater in people with type 2 diabetes (T2D). On the contrary, L‐alanine is a gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D and infusing of ketones lower circulating L‐alanine blood levels. In this study, we sought to determine whether supplementation with L‐alanine would attenuate the glucose‐lowering effect of exogenous ketosis using a ketone ester (KE). Methods This crossover study involved 10 healthy human volunteers who fasted for 24 h prior to the ingestion of 25 g of d‐β‐hydroxybutyrate (βHB) in the form of a KE drink (ΔG®) on two separate visits. During one of the visits, participants additionally ingested 2 g of L‐alanine to see whether L‐alanine supplementation would attenuate the glucose‐lowering effect of the KE drink. Blood L‐alanine, L‐glutamine, glucose, βHB, free fatty acids (FFA), lactate and C‐peptide were measured for 120 min after ingestion of the KE, with or without L‐alanine. Findings The KE drinks elevated blood βHB concentrations from negligible levels to 4.52 ± 1.23 mmol/L, lowered glucose from 4.97 ± SD 0.39 to 3.77 ± SD 0.40 mmol/L, and lowered and L‐alanine from 0.56 ± SD 0.88 to 0.41 ± SD 0.91 mmol/L. L‐alanine in the KE drink elevated blood L‐Alanine by 0.68 ± SD 0.15 mmol/L, but had no significant effect on blood βHB, L‐glutamine, FFA, lactate, nor C‐peptide concentrations. By contrast, L‐alanine supplementation significantly attenuated the ketosis‐induced drop in glucose from 28% ± SD 8% to 16% ± SD 7% (p < .01). Conclusions The glucose‐lowering effect of acutely elevated βHB is partially due to βHB decreasing L‐alanine availability as a substrate for gluconeogenesis.

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Section: Discussionmentioning

confidence: 99%

Exogenous d‐β‐hydroxybutyrate lowers blood glucose in part by decreasing the availability of L‐alanine for gluconeogenesis

Soto-Mota

Norwitz

Evans

et al. 2021

Endocrino Diabet & Metabol

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“…88,89 Novel production of glucose 90 in the liver 91 and other organs like the kidney 92 may also contribute to an increased glucose level in plasma. 93 Coumarin itself significantly reduced the hepatic gluconeogenic enzymes glucose-6-phosphatase and fructose-1,6-bisphosphatase in diabetic rats. 74 Umbelliferone decreased blood glucose and HbA1c, as well as the activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase.…”

Section: Possible Effects Of Coumarins On Glucose Uptakementioning

confidence: 90%

A Review of Coumarins and Coumarin-Related Compounds for Their Potential Antidiabetic Effect

Ranđelović

Bipat

2021

Clin Med Insights Endocrinol Diabetes

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Background and aims: Worldwide, type 2 diabetes mellitus accounts for a considerable burden of disease, with an estimated global cost of >800 billion USD annually. For this reason, the search for more effective and efficient therapeutic anti-diabetic agents is continuing. Coumarins are naturally derived and synthetic molecules with a wide variety of biological actions. The most common application of these molecules in medicine is for their thrombostatic activity. This study aims to give an overview of the current knowledge about the applicability of these chemical products in the therapeutic strategy against diabetes and its complications. Methods: For this purpose, we searched internet databases for publications and abstracts in English that investigated the effects of coumarins or coumarin-like agents with potential anti-diabetic activity. Results: The result is that a variety of these agents have proven in in vitro, in silico, and simple animal models to possess properties that may reduce the glucose absorption rate in the intestines, increase the level of insulin, increase the cellular uptake of glucose or reduce the gluconeogenesis. In addition, some of these agents also reduced the level of glycation of peptides in diabetic animal models and showed antioxidant properties. Conclusion: In conclusion, we can summarize that coumarins and their related derivatives may be potential antidiabetic agents. Useful formulations with appropriate pharmacokinetic and pharmacodynamic properties must be developed and tested for their efficacy and toxicity in comprehensive animal models before they can enter clinical trials.

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“…First, the relative contribution of the different gluconeogenic organs (liver, kidneys, and intestine) and of the different gluconeogenic substrates (lactate, glycerol, alanine, and glutamine), varies depending on whether a person is in the fed or fasted state 30,31 . However, there is evidence suggesting that, in the context of short-term fasting, alanine is the most important contributor via liver gluconeogenesis [32][33][34][35][36] .…”

Section: Limitations Of This Studymentioning

confidence: 99%

Exogenous D-β-Hydroxybutyrate Lowers Blood Glucose by Decreasing the Availability of L-Alaninefor Gluconeogenesis

Soto-Mota

Norwitz

Evans

et al. 2021

Preprint

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BackgroundInterventions that acutely increase blood ketone concentrations simultaneously lower blood glucose levels, although the explanation for this phenomenon is unknown. The hypoglycaemic effect of acute ketosis is greater in people with type 2 diabetes (T2D) in whom gluconeogenesis contributes significantly to hyperglycaemia. L-alanine is a gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D. As infusion of ketones lower circulating L-alanine blood levels, we sought to determine whether supplementation with L-alanine would attenuate the hypoglycaemic effect of an exogenous ketone ester (KE) supplement.MethodsThis crossover study involved 10 healthy human volunteers who fasted for 24 hours prior to the ingestion of 25 g of D-β-hydroxybutyrate (βHB) in the form of a KE drink (ΔG®) on two separate visits. During one of the visits participants additionally ingested 2 g of L-alanine to see if L-alanine supplementation would attenuate the hypoglycaemic effect of the KE drink. Blood L-alanine, L-glutamine, glucose, βHB, free fatty acids (FFA), lactate, and C-peptide were measured every fifteen minutes for 120 minutes after ingestion of the KE, with or without L-alanine.FindingsThe KE drinks elevated blood βHB concentrations from negligible levels to 4.5 ± 1.24 mmol/L, lowered glucose from 4.97 to 3.77 ± 0.4 mmol/L, and lowered and L-alanine from 0.56 to 0.41 ± 0.9 mmol/L. L-alanine in the KE drink elevated blood L-Alanine to 0.68 ± mmol/L, but had no significant effect on blood βHB, L-glutamine, FFA, lactate, nor C-peptide concentrations. By contrast, L-alanine supplementation significantly attenuated the ketosis-induced drop in glucose from 28% to 16% (p<0.001).ConclusionsThe hypoglycaemic effect of acutely elevated βHB is partially due to βHB decreasing L-alanine availability as a substrate for gluconeogenesis.

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Tracking the carbons supplying gluconeogenesis

Cited by 35 publications

References 110 publications

Exogenous d‐β‐hydroxybutyrate lowers blood glucose in part by decreasing the availability of L‐alanine for gluconeogenesis

Exogenous d‐β‐hydroxybutyrate lowers blood glucose in part by decreasing the availability of L‐alanine for gluconeogenesis

A Review of Coumarins and Coumarin-Related Compounds for Their Potential Antidiabetic Effect

Exogenous D-β-Hydroxybutyrate Lowers Blood Glucose by Decreasing the Availability of L-Alaninefor Gluconeogenesis

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