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Mechanism of Defective Incretin Action in Beta Cells during Type 2 Diabetes Mellitus

Award Number: R01DK130256
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Mechanism of Defective Incretin Action in Beta Cells during Type 2 Diabetes Mellitus - PROJECT SUMMARY/ABSTRACT The incretin-mediated potentiation of glucose-stimulated insulin secretion (GSIS) accounts for 50% of postprandial insulin secretion and is essential for physiologic glycemic regulation. Upon nutrient stimulus, the two principal incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted, respectively, from intestinal endocrine K- and L-cells and reach β-cells via the circulation, where they bind their receptors, GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) to amplify GSIS. While circulating incretin hormone levels are not impacted by T2DM, incretin effects on β-cell GSIS are significantly diminished in T2DM patients. However, the precise mechanisms underlying diabetes-associated blunting of incretin signaling in β-cells remain unclear. In T2DM, pharmacologic means to increase circulating GLP-1 levels improves GSIS and glycemic control. In contrast, the GIP-mediated incretin effect is notably absent in T2DM; and pharmacologic means to increase circulating GIP concentrations is not met with any GSIS improvement. The molecular mechanisms underlying diminished response to GLP-1 and absent response to GIP in T2DM remain poorly understood. T2DM is in part linked to a chronic inflammatory state with increased levels of local and circulating inflammatory cytokines that negatively impact insulin action in peripheral tissues and negatively impact the endocrine pancreas. We have therefore examined the role of pro-inflammatory cytokines that are elevated in T2DM on incretin signaling in islet -cells. Conversely, we have also interrogated the anti-inflammatory cholinergic signaling system through nicotinic acetylcholine receptors (nAchR) in modulating incretin signaling. Based on our preliminary studies, we hypothesize that TNFα - signaling through its receptor TNFR1 on β- cells - activates the Ser/Thr G-protein receptor kinase 2 (GKR2) in a non-canonical manner to suppress Gαs- activation and cAMP synthesis by ligand activated GIPR and by GLP-1R. Thus, our findings establish a mechanistic link between inflammatory cytokines in T2DM with diminished incretin signaling in β-cells. Our preliminary studies also indicate that in a murine model of T2DM, stimulating the α7 nicotinic acetylcholine receptor (α7-nAchR) reactivates GIPR signaling in β-cells to potentiate GSIS and improve glycemia. Our mechanistic studies indicate that α7-nAchR signaling phosphorylates (TNFα-activated) GRK2 at serine 670 to counteract its inhibitory effects on GIPR and GLP-1R-mediated cAMP synthesis. We now seek to expand our novel and exciting findings specifically a) to understand the role of TNFR1- GRK2-mediated signaling on in vivo β-cell function, on GIP and GLP-1R action as well as how TNFR1 signaling modulates α-cell gene expression in the context of obesity and T2DM; b) to specifically understand the role of GRK2 in mediating resistance to β-cell incretin action in T2DM; and c) to understand the beneficial role of anti- inflammatory α7-nAchR signaling in β-cells in the context of T2DM. We will use complementary in vivo and in vitro approaches to elucidate these important signaling pathways in β-cells using newly generated unique mouse models as well as in vitro in human islets and β-cells. The outcomes of our studies will yield important insights into how inflammatory cytokines of T2DM impact incretin signaling and β-cell function. Our proposed studies will also provide new insights into the effects of nicotinic acetylcholine signaling in β-cells. Finally, our studies identify potentially new receptor targets with the potential to ameliorate β-cell dysfunction in T2DM. .


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $460,862 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	5	5/7/2025	NON-COMPETING CONTINUATION	$460,862
2025	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	3/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$555,101
2025	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/19/2025	NON-COMPETING CONTINUATION	-$483,542
2025	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/19/2025	NON-COMPETING CONTINUATION	-$71,559
														Subtotal = $460,862

Issue Date FY: 2024 ( Subtotal = $448,397 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/10/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$448,397
2024	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $448,397

Issue Date FY: 2023 ( Subtotal = $483,542 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/19/2023	NON-COMPETING CONTINUATION	$483,542
														Subtotal = $483,542

Issue Date FY: 2022 ( Subtotal = $483,542 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/9/2022	NON-COMPETING CONTINUATION	$483,542
														Subtotal = $483,542

Issue Date FY: 2021 ( Subtotal = $483,542 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/11/2021	NEW	$483,542
														Subtotal = $483,542

Grand Total All Awards = $2,359,885

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Mechanism of Defective Incretin Action in Beta Cells during Type 2 Diabetes Mellitus

Award Number: R01DK130256

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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