Abstract
Type 2 diabetes (T2D) is associated with, and often preceded by, increased levels of circulating c-reactive protein (CRP) and WBC count that mediate the body’s inflammatory and immune responses (inflammatory mediators [IMs]). This relationship between inflammation and diabetes is complex, as statins have anti-inflammatory properties but paradoxically promote or exacerbate T2D. Recently it has been reported that beta-hydroxybutyrate levels characteristic of nutritional ketosis enhance cellular defenses against oxidative stress and block the assembly of the NLRP3 inflammasome. As part of an ongoing study of the effects of a well-formulated ketogenic diet (WFKD) delivered via a web-based continuous care intervention (CCI) on 262 patients with T2D1 and 116 with prediabetes (PreD), we determined plasma levels of 16 IMs at baseline, 1 yr, and 2 yrs. These same IMs were concurrently monitored in 87 patients with T2D recruited as usual care controls (UC). At baseline, a statin was prescribed for 50% of the T2D/CCI patients, 27% of PreD/CCI patients, and 59% of the T2D/UC patients; at which time statin use was associated with reduced plasma CRP (P=7 x 10-5) compared to non-statin users in the T2D/CCI group only. There were no other significant baseline differences between statin users and non-users for any IMs (WBC, TNFa, IL-1b, IL-6, IL-8, IL-18, IFN-g, E- L-, and P-selectins, EGF, VEGF-A, MCP-1, ICAM-1 and VCAM-1). After 1 yr and 2 yrs of the CCI, mean weight losses in T2D were 12% and 10%, HbA1c reductions were 1.3% and 0.9%, and diabetes medication use was reduced by 51% and 53%, respectively. Linear mixed effects models were used to assess change in IMs over the 2 yrs, facilitating intent-to-treat analyses. Fourteen of the 16 IMs (excluding ICAM-1 and VCAM-1) were reduced compared to baseline in T2D/CCI (P<0.001), with none showing significant increases between yrs 1 and 2. A similar pattern albeit at lower magnitudes was seen in patients with PreD/CCI. Despite lower CRP values at baseline, T2D/CCI patients prescribed a statin experienced further reductions with the WFKD over the 2 years (P=3 x 10-5). In the T2D/UC group, no significant changes in any of the IMs were observed at 1 yr or 2 yrs. These observations suggest that a WFKD delivered via the CCI has broad-spectrum anti-inflammatory and immune modulatory effects in patients with T2D and PreD. Consistent with prior reports, statin use was associated with reduced CRP at baseline in the T2D/CCI group, but this effect was not significant in PreD/CCI and T2D/UC groups. CRP reductions were nonetheless significant in T2D/CCI statin users, suggesting added benefit of the WFKD. We conclude that improvements in IMs induced by a combination of nutritional ketosis and weight loss contribute to the beneficial effects of the CCI in the management of T2D.
1. Athinarayanan SJ, et al. Front Endocrinol. 2019. 5;10:348
Dietary Restriction Ameliorates Diabetic Nephropathy through Anti-Inflammatory Effects and Regulation of the Autophagy via Restoration of Sirt1 in Diabetic Wistar Fatty (fa/fa) Rats: A Model of Type 2 Diabetes