# Lipid Sensing in Pancreatic Alpha Cells

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $381,250

## Abstract

Abstract
Sphingolipid Accumulation in the Pancreatic Alpha Cell Links Insulin Resistance to Hyperglycemia
This grant evaluates the contribution of lipid metabolite accumulation in the pancreatic alpha cell to the
aberrant production of the pancreatic peptide glucagon and glucagon’s ensuing hyperglycemic effects.
Pancreatic islets secrete both insulin and glucagon in a manner which is tightly juxtaposed. The hormone
glucagon, which promotes hepatic glucose production, has long been underestimated as a contributor to
metabolic disease. Diabetes mellitus results from insufficient insulin secretion to match insulin demands by
various tissues. This includes a demand by the alpha cell for insulin to diminish glucagon production and
secretion. Our preliminary data suggest that impaired insulin action within the alpha cell can promote
hyperglucagonemia, which drives hyperglycemia, aberrant gluconeogenesis, and excess glucose efflux from
the liver. Sphingolipids, such as ceramides and glucosylceramides, are an important class of bioactive lipids
which may impair insulin signal transduction in the alpha cell. Most recently, we demonstrated that ceramide is
sufficient to impair insulin-induced suppression of glucagon from alpha cells. The levels of these lipids change
as a function of adipose tissue mass and functionality, and are partially driven by cellular availability of
palmitoyl-CoA. Aberrant accumulation of sphingolipids has been implicated in a multitude of metabolic
processes, including atherosclerosis, insulin resistance, lipotoxic heart failure, beta cell apoptosis and beta cell
dysfunction. The adipose-derived secretory factor adiponectin promotes an increase in ceramide catabolism,
which is dependent on adiponectin receptors 1 and 2 (AdipoR1/R2). The associated ceramidase activity
promotes ceramide degradation and correlates with the suppression of hepatic glucose efflux. Fibroblast
growth factor 21 (FGF21, a reported glucagon suppressor), rapidly stimulates adiponectin secretion and
improves glycemia by harnessing adiponectin’s ceramide-lowering potential. Preliminary results suggest that
novel small molecule mimetics of adiponectin (currently in pharmaceutical development) may offer the same
potential therapeutic benefits of adiponectin to improve glucose homeostasis by decreasing ceramide excess
and glucagon secretion. Here, we will test the following 3 questions via 3 interrelated aims: 1)Does the alpha
cell become insulin, leptin, or GABA resistant in a sphingolipid-dependent manner? 2) Does adiponectin act as
a glucagon suppressor via adiponectin receptor-induced ceramidase activity and ceramide-lowering within the
alpha cell? 3) Does FGF21 have a direct effect on the alpha cell or does it rely on adiponectin to blunt
glucagon secretion? We propose that ceramide within the alpha cell is a key link between insulin resistance
and diabetes and serves as a critical physiologic node for regulation of glycemia; this would be a prime target
for ...

## Key facts

- **NIH application ID:** 9964800
- **Project number:** 5R01DK112826-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** WILLIAM L HOLLAND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964800

## Citation

> US National Institutes of Health, RePORTER application 9964800, Lipid Sensing in Pancreatic Alpha Cells (5R01DK112826-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9964800. Licensed CC0.

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