Six-Month Periodic Fasting in Patients With Type 2 Diabetes and Diabetic Nephropathy: A Proof-of-Concept Study

Abstract

Context Novel fasting interventions have gained scientific and public attention. Periodic fasting has emerged as a dietary modification promoting beneficial effects on metabolic syndrome. Objective Assess whether periodic fasting reduces albuminuria and activates nephropathy-driven pathways. Design/Participants Proof-of-concept study where individuals with type 2 diabetes (n = 40) and increased albumin-to-creatinine ratio (ACR) were randomly assigned to receive a monthly fasting-mimicking diet (FMD) or a Mediterranean diet for 6 months with 3-month follow-up. Main Outcomes Measures Change in ACR was assessed by analysis of covariance adjusted for age, sex, weight loss, and baseline value. Prespecified subgroup analysis for patients with micro- vs macroalbuminuria at baseline was performed. Change in homeostatic model assessment for insulin resistance (HOMA-IR), circulating markers of dicarbonyl detoxification (methylglyoxal-derived hydroimidazolone 1, glyoxalase-1, and hydroxyacetone), DNA-damage/repair (phosphorylated histone H2AX), lipid oxidation (acylcarnitines), and senescence (soluble urokinase plasminogen activator receptor) were assessed as exploratory endpoints. Results FMD was well tolerated with 71% to 95% of the participants reporting no adverse effects. After 6 months, change in ACR was comparable between study groups [110.3 (99.2, 121.5) mg/g; P = 0.45]. FMD led to a reduction of ACR in patients with microalbuminuria levels at baseline [−30.3 (−35.7, −24.9) mg/g; P ≤ 0.05] but not in those with macroalbuminuria [434.0 (404.7, 463.4) mg/g; P = 0.23]. FMD reduced HOMA-IR [−3.8 (−5.6, −2.0); P ≤ 0.05] and soluble urokinase plasminogen activator receptor [−156.6 (−172.9, −140.4) pg/mL; P ≤ 0.05], while no change was observed in markers of dicarbonyl detoxification or DNA-damage/repair. Change in acylcarnitines was related to patient responsiveness to ACR improvement. At follow-up only HOMA-IR reduction [−1.9 (−3.7, −0.1), P ≤ 0.05]) was sustained. Conclusions Improvement of microalbuminuria and of markers of insulin resistance, lipid oxidation, and senescence suggest the potential beneficial effects of periodic fasting in type 2 diabetes.

Elevated markers of DNA damage and senescence are associated with the progression of albuminuria and restrictive lung disease in patients with type 2 diabetes

“…Comet assay was performed with using Reagent Kit for Higher Throughput Single Cell Gel Electrophoresis Assay (4252-040-K, Trevigen; Gaithersburg, MD, USA). 51 , 52 , 53 , 54 , 55 The assay was performed according to the manufacturer's instructions, with the following modification: For each sample, 10 μl of cells in a v-shaped, 96-well plate were resuspended with 100 μl low-melting agarose; 15 μl of the cell-agarose suspension was then applied to an appropriate well of the 96-well glass plate. Electrophoresis was performed in a standard, horizontal electrophoresis chamber (26 × 18.5 × 9.5 cm; 550 ml) using 200 mM sodium hydroxide and 1 mM EDTA as the alkaline unwinding buffer.…”

Fasting: From Physiology to Pathology

“…[ 183,186 ] Clinically, TRF and FMD are associated with better blood pressure and glycemic control in individuals with diabetes. [ 85,103,206,207 ] Other metabolic parameters, such as triglycerides, cholesterol, and low‐density lipoprotein cholesterol (LDL‐C) would be similarly improved in most of these studies. [ 103,206,207 ] The safety of fasting has been tested in two trials in humans.…”

“…Breast cancer [ 222,345] ; lung cancer [ 346] Diurnal gene expression rhythms↑ angiogenic factors↓ IF Worm: 40.4-77.0% [ 245,246] Flies: 10% [ 247] Mouse: 12.6-20.0% [ 250,252] AD [ 165,166,300,302,347] ; HD [ 348] ; MS [ 120,349] Cognitive function↑ neuronal differentiation↑ A𝛽 deposition↓ BDNF↑ Metabolic syndrome [ 110] T2DM [ 121,153,208] NAFLD [ 114,[213][214][215] Steatosis↓ glycemic control↑ 𝛽-cell mass↑ probiotic↑ ALL [350] ; melanoma; colonic cancer [ 227] ; breast cancer [ 230,351] LEPR signaling PP2A-GSK3𝛽-MCL-1 signal↑ serum glucose levels↓ FMD Mouse:11-19% [ 41,193] PD [305] ; MS [ 178,179] BDNF↑ inflammation↓ remyelination in axons↑ T1DM [ 183,186] T2DM [ 183,186,206,207,352]…”

“…[85,103,206,207] Other metabolic parameters, such as triglycerides, cholesterol, and lowdensity lipoprotein cholesterol (LDL-C) would be similarly improved in most of these studies. [103,206,207] The safety of fasting has been tested in two trials in humans. IF does not cause hypoglycemia for most individuals with T2DM on hypoglycaemic medication.…”

“…FMD is also feasible and effective to reduce body weight and improve metabolic homeostasis in T2DM patients. [206,207] Of note, for diabetes patients, it is essential to evaluate the risk of hypoglycemia before starting fasting regimens. [321] For NAFLD patients, ADF is able to significantly reduce weight and improve dyslipidaemia.…”