Do Ketone Supplements Regulate Islet Hormone Secretion?

Ketone bodies are produced from free fatty acids by the liver when blood glucose levels are low, such as during starvation or carbohydrate restriction. Endogenously produced ketone bodies can serve as an alternative fuel source for the brain and peripheral tissues during states of extended fasting. Ketosis is a state of elevated blood ketones (typically less than 5-6 mM), and there are 3 types of ketones (β-hydroxybutyrate [βHB], acetoacetate, and acetone), with the most common ketone in the blood being βHB. Ketosis is different from diabetic ketoacidosis, which is a serious medical condition where ketone concentrations in the blood are as high as 20 mM. The higher ketone concentrations in diabetic ketoacidosis exceed the buffering capacity of the blood leading to acidosis. Ketone body production begins in the liver with the breakdown of free fatty acids to acetyl CoA. Acetyl CoA is then converted to acetoacetate, which is metabolized to βHB in the mitochondrial matrix (by mitochondrial βHB dehydrogenase [BDH1]). A small proportion of acetoacetate spontaneously decarboxylates to acetone and CO2. Acetone cannot effectively be used as an energy source and is often exhaled via the lungs, giving our breath a fruity scent. In healthy individuals, overnight fasting levels of serum βHB range from 0.1 to 0.4 mM and, after 2 to 3 days of fasting, can rise to about 2 mM, and ketoacidosis occurs at levels >3.0 mM (1). Ketone supplementation has the therapeutic potential to enhance physical performance and cognitive function and to treat several common chronic diseases, such as inflammation, cardiovascular and neurological diseases, and diabetes (1). Ketone supplements can help get a person into a ketosis state. The first available ketone supplements were ketone salts and ketone monoesters, which had side effects, including gastrointestinal problems and an unpleasant taste, that made adhering to a longer-term supplement regimen challenging. However, more recent novel ketone supplements are now commercially available and have different chemical properties and/or additives to improve flavor. With the new commercial products, there has been an increase in ketone supplement usage; however, whether they are beneficial has yet to be fully characterized. Studies have shown that ketone supplementation has the potential to treat diabetes. For instance, ketones have been shown to lower blood glucose levels in patients without diabetes (2); however, some studies have shown that this may not be an effective option in patients with type 2 diabetes (3). Ketone supplements may reduce blood glucose levels by increasing insulin secretion; however, the mechanism is unknown. Recently, Banerjee et al (4) looked at the mechanism of the effect of acute and chronic βHB on both insulin and glucagon secretion from pancreatic islets. They found that acute βHB exposure increases insulin secretion and decreases glucagon secretion under physiological glucose concentrations in both human and mouse islets. This is similar to what has been found in other studies with βHB, which showed increased insulin release in INS1 cells (5), rat islets (6), and human islets (7). They also found that there was heterogeneity in human islet responses that seemed to be dependent on donor characteristics, where islets from donors with a body mass index greater than 25 (overweight/obese) had a smaller increase in insulin secretion than islets from donors with a body mass index less than 25. Interestingly, this contrasts with ketones elevating insulin release in obese, but not lean, C57BL/6J mice (8). They also found that proteins involved in cell proliferation, amino acid biosynthesis, and metabolism were altered by βHB treatment in islets. Chronic elevation of βHB can be caused by impaired insulin secretion from islets, a prolonged ketogenic diet, or chronic consumption of ketone supplements. In diabetes, impaired insulin secretion will promote elevated plasma free fatty acids which can be converted to ketone bodies. A possible link between chronic elevation of ketones during the early developmental stages of diabetes may be the cause of the compensatory elevated basal islet insulin secretion and may be an indicator of β-cell dysfunction in individuals with type 2 diabetes (1). Banerjee et al (4) found that, unlike acute, chronic treatment of βHB did not affect islet hormone secretion. To understand the molecular mechanism underlying islet response to chronic βHB treatment, proteomic analysis was performed on human islets treated with βHB for 72 hours. The authors showed that several proteins involved in cell death signaling and nutrient response pathways were altered. They saw an increase in SOCS2 (suppressor of cytokine signaling 2), which is a suppressor of cytokine signaling, and a downregulation of CDK4 (cyclin-dependent kinase 4), which is involved in cell cycle regulation at the G1/S checkpoint. These studies suggest chronic βHB treatment may protect islet cells from cytokine-induced cell death. How are ketones affecting cellular function? In extrahepatic tissues, the mitochondrial uptake of acetoacetate and βHB occurs via monocarboxylate transporters. Once in mitochondria, βHB is oxidized back to acetoacetate by mitochondrial BDH1, followed by conversion to acetoacetate-CoA via succinyl-CoA:3-oxoacid-CoA transferase (SCOT). Acetoacetate-CoA is then cleaved by mitochondrial acetoacetyl-CoA thiolase, yielding 2 molecules of acetyl-CoA that can enter the tricarboxylic acid cycle to produce energy for cells (1). However, chronic elevation of ketones can increase mitochondrial stress, and cells adapt by activating cell-protective mechanisms that include Nrf2 (nuclear factor erythroid 2–related factor 2), sirtuin 1,3, and AMPK (5′-adenosine monophosphate–activated protein kinase). It has also been suggested that βHB can bind several G protein–coupled receptors (GPRs), including GPR41 and GPR109A (hydroxycarboxylic acid receptor 2) (1). Interestingly, treatment of type 2 diabetes with sodium–glucose cotransporter 2 (SGLT2) inhibitors to reduce glucose reabsorption in the kidney was also found to increase systemic ketone body levels (1). Determining which of these potential pathways regulates the response of β-cell function to βHB needs further investigation. Some interesting questions arise from these βHB studies. Will physiological changes in βHB levels play any significant role in regulating glucose homeostasis? What would happen when βHB increases during exercise, which would be predicted to increase insulin secretion? What happens to βHB after it enters islet cells? Is it metabolized, or does it bind a receptor that leads to changes in intracellular signaling? Do ketone supplements lead to physiologically relevant changes in vivo? Does βHB affect cells exposed to other stressors instead of endoplasmic reticulum stress? Answering these questions will better define the role of ketone bodies in regulating islet function and whether it may be useful in treating diabetes and other diseases. The author has nothing to disclose. β-hydroxybutyrate βHB dehydrogenase G protein–coupled receptor

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