Background: We evaluated the feasibility and safety of endoscopic re-cellularization via electroporation therapy (ReCET) (Endogenex. Plymouth, MN) in restoring impaired duodenal signaling adversely impacting glucose control in type 2 diabetes (T2D). Method: We enrolled 30 adults with T2D: duration ≤10 years; HbA1c 7.5-11.0%; BMI of 24-40 kg/m2; C-peptide ≥333pmol/L; 1-4 non-insulin glucose-lowering medications (GLMs) at stable dose. Post-procedure GLMs were unchanged. Primary endpoint: Device or procedure-related serious adverse events (SAEs). Secondary endpoints: Changes in metabolic parameters at 24W. Results: The first 12 participants received single energy (Single Tx) then 18 received double energy application (Double Tx) with no device/procedure-related SAEs. Forty-five adverse events were reported in 23/30 participants (sore throat [17/30]; transient diarrhea [9/30]) and 80% were mild. HbA1c reduction at 24W was greater with double vs. single Tx (p<0.05). For double Tx vs. baseline: FPG was 7.5±1.7 mmol/L vs. 9.8±2.2 mmol/L (p<0.01), HOMA-IR 4.5±3.6 vs. 7.4±3.3 (p<0.01), Time-in-range 79.4±18.8 % vs. 59.0±24.2% (p<0.01), triglyceride 2.0±1.2mmol/L vs. 2.9±1.9mmol/L (P<0.05) and Δweight -5.1%±4.1% (p<0.01). Conclusions: Our data suggest that ReCET is safe and associated with clinically meaningful changes in metabolic control in T2D patients on GLMs. Disclosure C.Yuan: None. A.Sartoretto: Advisory Panel; Bariatek, Research Support; Endogenex, Erbe Electromedizin GMBH, Speaker's Bureau; Pfizer Inc., Stock/Shareholder; Apollo Endosurgery. B.Holt: None. G.Cameron: None. G.Marinos: None. F.E.Napier-flood: None. B.K.Abu dayyeh: Advisory Panel; Endogenex, Consultant; Apollo Endosurgery, Boston Scientific Corporation, Medtronic, Research Support; USGI, Endogastric Solutions. D.N.O'neal: None.