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The role of the alpha-cell in the effects of obesity and weight loss on glucose regulation

Award Number: R01DK148505
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: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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The role of the alpha-cell in the effects of obesity and weight loss on glucose regulation - PROJECT SUMMARY The α-cell overproduces glucagon in obesity and insulin resistance, stimulating hepatic glucose production in fasting and postprandial states and promoting the development of Type 2 Diabetes Mellitus (T2DM). In contrast to their role in stimulating hepatic glucose production, it is increasingly evident that α-cells also play an important role in the potentiation of glucose-stimulated insulin secretion (GSIS) through paracrine crosstalk with β-cells. It remains unknown how the balance between these hyper- vs. hypoglycemic roles of the α-cell are altered by obesity and weight loss, two conditions with a major impact on the β-cell. Bariatric surgery is highly effective at weight loss and improving glycemic regulation. Data from human and mouse studies, including our preliminary data, demonstrate that both obesity and bariatric surgery increase circulating glucagon concentrations. While our data demonstrate that pancreatic preproglucagon is necessary for the improvement in glucose tolerance induced by bariatric surgery, we also find that bariatric surgery lowers the glucagon response to insulin-induced hypoglycemia in mice. Further, these two different energy states, obesity and weight loss through bariatric surgery, raise postprandial plasma glucagon levels but exert opposing effects on glycemic regulation. Obesity therapeutics in the pipeline include glucagon agonism to promote weight loss, but these beneficial effects on body weight are only achieved when combined with drugs that lower plasma glucose. Thus, to optimize the benefits of novel glucagon agonists, there is a critical need to understand the hyper- and hypoglycemic roles of glucagon under different metabolic conditions. Guided by our preliminary data, and that the balance of insulin to glucagon is critical for both hepatic and islet function, our overarching hypothesis is that obesity and bariatric surgery shift the primary target of α-cells from the liver (promoting hepatic glucose production) in obesity to the islet (promoting insulin secretion) after bariatric surgery. Aim 1 will determine the impact of obesity and weight loss on hepatic and islet responses to glucagon. We will compare the hepatic and islet responses to exogenous glucagon administration in obesity and with dietary or surgical weight loss. Further, we will use genetic and pharmaceutical approaches to determine the contribution of the α-cell to the impact of obesity and dietary or surgical weight loss on insulin secretion. Aim 2 will determine the mechanisms driving the impact of obesity and weight loss on α-cell function. We will use a combination of in vivo and ex vivo tools with single-cell resolution to determine the regulatory factors that drive the increase in glucagon with obesity and weight loss. Given the number of drugs in the pipeline that target GLP-1R and/or glucagon receptor signaling for treatment of obesity, it is critical to understand the impact of obesity and weight loss on α-cell function and glucagon action. By using this combination of in vivo and ex vivo strategies, these studies will define the mechanisms by which differing metabolic conditions influence α-cell function and glucagon action on β-cells and hepatocytes. This information could drive the generation of future combined therapeutics that utilize glucagon to treat obesity.


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: 2026 ( Subtotal = $782,890 )
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/7/2026	NEW	$782,890
														Subtotal = $782,890

Grand Total All Awards = $782,890

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The role of the alpha-cell in the effects of obesity and weight loss on glucose regulation

Award Number: R01DK148505

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: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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