1545-P: Characterization of Metabolic Defects in Pancreatic Cancer–Related Diabetes and Type 2 Diabetes in the DETECT Study

Abstract

Diabetes due to pancreatic ductal adenocarcinoma (PDAC-D) is often difficult to clinically distinguish from type 2 diabetes (T2D) and both insulin resistance and reduced insulin secretion have been implicated in its pathophysiology. Although these metabolic defects are similar to those seen in T2D, the degree to which they relatively contribute to hyperglycemia in PDAC-D has not been established. Additionally, there is a lack of understanding of alpha cell function in PDAC-D. We sought to address these gaps in the DETECT study (NCT03460769). Adults with PDAC-D (n=28) or T2D (n=99) (diabetes diagnosis <3 years) underwent a standardized liquid mixed-meal tolerance test with serum glucose, insulin, and glucagon measurements. Insulin sensitivity was assessed by the Matsuda index, insulin secretion by the insulinogenic index, and beta cell function by the oral disposition index. The mean duration of diabetes was 10.8 months in PDAC-D and 12.5 months in T2D (P=0.51). HbA1c was higher in PDAC-D (7.27% vs 6.58%, P=0.03). The area under the curve (AUC) of the glucose response was similar in PDAC-D vs T2D (232 vs. 238 mg.min/ml, P=0.08). Insulin sensitivity was 2.5x higher in PDAC-D than in T2D (3.65 vs 1.45, P<0.001). In contrast, insulin secretion was 81% lower in PDAC-D (18 vs 95 μU/mg, P<0.001), and the oral disposition index was 40% lower (0.80 vs. 1.32, P<0.001). Fasting glucagon was similar in PDAC-D and T2D (21.1 vs 17.7 pM, P=0.09). In both groups, glucagon rose after the meal, but the incremental AUC was 57% higher in PDAC-D (581 vs. 370 pM.min, P=0.01). These results suggest that impaired insulin secretion is considerably more important than insulin resistance in the etiology of hyperglycemia of PDAC-D and that post-prandial alpha-cell dysregulation is likely to play a greater role than previously recognized. Collectively, these data also suggest that targeting insulin and glucagon levels, rather than insulin resistance, may be a more effective strategy to treat PDAC-D. Disclosure F.G.S.Toledo: Research Support; Dompé. R.V.Considine: Research Support; Lilly Diabetes. S.T.Chari: Advisory Panel; Nestlé Health Science, Guardant, Bluestar genomics. S.C.Graham: None. D.K.Andersen: None. J.Rinaudo: None. J.Serrano: None. M.O.Goodarzi: Advisory Panel; Nestlé Health Science, Other Relationship; Nestlé Health Science. P.Hart: Consultant; Sagent Pharmaceuticals. On behalf of the cpdpc: n/a. Y.Li: Stock/Shareholder; Agenus, Inc. F.Wang: None. D.Yadav: None. M.Bellin: Consultant; Insulet Corporation, Vertex Pharmaceuticals Incorporated, Research Support; Dexcom, Inc., ViaCyte, Inc. K.Cusi: Consultant; Poxel SA, Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns, Research Support; Echosens, Inventiva, LabCorp, Zydus. W.E.Fisher: None. Y.C.Kudva: Advisory Panel; Novo Nordisk, Research Support; Dexcom, Inc. W.Park: Advisory Panel; AbbVie Inc., Ariel Medicine, Nestlé Health Science, Consultant; Arctx Medical, Craif, Research Support; AbbVie Inc., Stock/Shareholder; Arctx Medical. Funding National Institutes of Health (U01DK108306, U01DK108288, U01DK108320, U01DK108323, U01DK108326, U01DK108327, U01DK108328, U01DK108300, U01DK108314, U01DK126300)