# Ectopic Lipids in the Pancreatic Alpha Cell Link Insulin Resistance to Hyperglycemia

> **NIH VA I01** · VA NORTH TEXAS HEALTH CARE SYSTEM · 2020 · —

## Abstract

Ectopic Lipids in the Pancreatic Alpha Cells Link Insulin Resistance to Hyperglycemia
 Just as insulin insufficiency can lead to elevated glucagon secretion, preliminary data suggest that
impaired insulin action within the -cell can also promote hyperglucagonemia, hyperglycemia,
aberrant gluconeogenesis, and excess glucose efflux from the liver. Pancreatic perfusion with anti-insulin
serum causes marked hyperglucagonemia, and ablation of insulin receptor from -cells prompts fed
hyperglucagonemia and glucose intolerance. Sphingolipids, such as ceramides and glucosylceramides, are
an important class of bioactive lipids which may impair insulin signal transduction in the -cell. Most
recently, it has been demonstrated that ceramide is sufficient to impair insulin-induced suppression of glucagon
from -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, -cell apoptosis and -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.
 We hypothesize that: 1) Preventing ceramide excess within -cells enhances suppression of glucagon by 3
of its endogenous attenuating signals (insulin, leptin, and GABA-all repress glucagon via Akt/FoxO1) A
portion of adiponectin’s glucose-lowering effects are mediated by inhibiting glucagon secretion which is directly
triggered by adiponectin receptor-driven lowering of sphingolipids in -cells; 3) The glucagon-suppressive
effects of FGF21 are mediated by ceramide-lowering within the -cell in an adiponectin-dependent manner;
and 4) Limiting glucagon secretion or glucagon receptor activation improves insulin signal transduction by
preventing glucagon-induced activation of PP2A. In essence, we believe that the insulin-desensitizing
effects heavily studied in muscle, liver and adipose can also occur in the -cell, triggering
hyperglucagonemia, hyperglycemia, and metabolic sequelae of diabetes. As such, many potential
therapeutic agents currently under development (including FGF21 analogs, adiponectin mimetics, and
ceramide synthesis inhibitors) may ...

## Key facts

- **NIH application ID:** 9864015
- **Project number:** 5I01BX003747-04
- **Recipient organization:** VA NORTH TEXAS HEALTH CARE SYSTEM
- **Principal Investigator:** Roger Harold Unger
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864015

## Citation

> US National Institutes of Health, RePORTER application 9864015, Ectopic Lipids in the Pancreatic Alpha Cell Link Insulin Resistance to Hyperglycemia (5I01BX003747-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9864015. Licensed CC0.

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