The Paradoxical Role of Circulating Ketone Bodies in Glycemic Control of Individuals with Type 2 Diabetes: High Risk, High Reward?

Abstract

Introduction: Fasting plasma ketone bodies (KB) are elevated in individuals with type 2 diabetes (T2D) and could affect glycemic control and disease progression. Prolonged KB exposure may result in adaptive beneficial responses, counteracting glycemic dysregulation. In the current proof-of-concept study in adults with T2D, we hypothesized that fasting plasma KB are cross-sectionally associated with poorer glycemic control but prospectively with better glycemic control. Materials and Methods: Fasting plasma KB were measured via nuclear magnetic resonance spectroscopy in patients with T2D treated in primary care (Zodiac cohort; The Netherlands). We analyzed the associations between KB and HbA1c at baseline using linear regression analyses and HbA1c changes over time using linear mixed models. We adjusted for potential confounders, including risk factors for poor glycemic control. Individuals with T2D participating in the general population-based PREVEND study were used as a replication cohort. Results: We included 271 individuals with T2D with a total of 859 HbA1c measurements during a follow-up period of 3.0 (2.0–3.2) years. At baseline, the total amount of fasting plasma KB was independently and positively associated with HbA1c levels (regression coefficient in the fully adjusted analysis = 0.31; 95% CI 0.06–0.57, per doubling of KB; p = 0.02). In contrast, in the longitudinal analyses, fasting plasma KB were associated with a yearly HbA1c (%) decrease of −0.10 (95% CI −0.19 to −0.00 per doubling baseline KB; p = 0.05). Results were replicated in 387 individuals with T2D from a general population cohort with a total of 1115 glucose measurements during a follow-up period of 7.5 (7.2–8.0) years. A yearly decrease in fasting plasma glucose (mmol/L) of 0.09 was found per doubling of baseline KB. Conclusions: This study is the first to suggest a paradoxical role of circulating KB on glycemic control in T2D: elevated KB are associated with cross-sectionally poorer glycemic control but longitudinally with better long-term glycemic control.

Fasting Plasma Ketone Bodies Are Associated with NT-proBNP: A Potential Mechanism to Provide Fuel for the Failing Heart

“…In that study, the impact of (suspected) NAFLD on mortality was in part mediated by ketone body levels [ 33 ], a relevant finding because obesity is a strong risk factor for both NAFLD and HF [ 47 , 48 , 49 ]. Moreover, plasma ketone bodies are associated with new-onset diabetes in individuals with normal fasting glucose initially [ 50 ], whereas higher ketone bodies relate to worse glycemic control among patients with established T2D [ 51 ].…”

Exploring the differences in serum metabolite profiles after intake of red meat in women with rheumatoid arthritis and a matched control group

“…The higher concentration of acetoacetic acid in the current study could perhaps be explained by the fact that the women without RA had higher HbA1c, indicating less glycemic control. Ketone bodies have been reported to be positively associated with HbA1c levels in patients with type 2 diabetes in fasting samples [ 39 ]. However, all patients in our study had less than 42 mmol/mol HbA1c in fasting samples and were regarded as non-diabetic or even non-pre-diabetic.…”

“…However, all patients in our study had less than 42 mmol/mol HbA1c in fasting samples and were regarded as non-diabetic or even non-pre-diabetic. Ketone bodies have been reported to both initially induce inflammation, and to also have beneficial effects in the long term [ 39 ]. Due to this, in combination with the fact that the difference in AUC min could be a chance finding, we do not want to further speculate as to what caused these results.…”

On the Need to Distinguish between Insulin-Normal and Insulin-Resistant Patients in Testosterone Therapy

“…This must be taken into account before the administration of TRT to IR hypogonadal patients. Recently, circulating ketone bodies have been recorded in individuals with type 2 diabetes [ 77 ].…”

“…Regarding the ketosis observed in IR after TRT, this could be managed by the utilization of remedies previously proposed for “keto flu” [ 77 ]: increasing sodium supplements with electrolytes, drinking broth (including bone broth and stock cubes) and increasing magnesium, potassium and dietary fat intake (including avocadoes, MCT, olives, butter, nuts and fat bombs), as well as increasing water intake.…”