# The effect of the fasting milieu on beta-cell function in vivo

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $478,866

## Abstract

The overall aim of this application is to better understand the role of the fasting milieu in influencing the ability
of the β-cell to respond to subsequent meal challenges. Prediabetes is the transitory state between normal
glucose metabolism and type 2 diabetes. Prediabetes is often categorized using fasting glucose concentrations
as well as glucose concentrations 2 hours after ingestion of 75g of glucose. These sub-groups differ in their
fasting glucose and free fatty acid concentrations, their β-cell function and their risk of progression to type 2
diabetes. Intriguingly, the component of β-cell response to glucose that depends on fasting insulin synthesis
and storage seems to be impaired in subjects with high free fatty acid concentrations and hyperglycemia. This
suggests that elevation of these substrates might directly influence β-cell function by altering fasting insulin
synthesis and, perhaps, drive the progression of prediabetes to diabetes. In addition, there is a unique sub-
group of prediabetes with isolated, impaired fasting glucose. Data available to date suggest that these subjects
behave like patients with a mutation in the glucokinase (GCK) gene. Previously, our group demonstrated that
people with diabetes have hepatic glucokinase dysfunction. In this series of experiments we will ascertain if
this subgroup does indeed exhibit impaired glucose sensing alone or in combination with a global defect in β-
cell function. This will help to determine if defects in fasting and postprandial insulin secretion, in response to
hyperglycemia, develop independently. Since substrate excess increases demand on the synthetic machinery
of the β-cell, it increases the rate of protein misfolding and induces a protective mechanism, known as the
unfolded protein response, intended to restore endoplasmic reticulum homeostasis. The in vivo correlate of this
response is unknown – 1st phase insulin is absent in type 2 diabetes and there is an increase in proinsulin
release implying defects in insulin synthesis. However, concentrations of proinsulin are unlikely to be
informative of prandial β-cell function as its clearance kinetics are unknown. The proposed experiments will
elucidate how changes in fasting FFA and glucose alter insulin and proinsulin secretion. Since elevated
proinsulin has been associated with β-cell dysfunction, we will examine how changes in proinsulin secretion
change over time. The proposed experiments will help elucidate the mechanisms by which fasting substrate
excess contributes to β-cell dysfunction, and to the progression of prediabetes to type 2 diabetes.

## Key facts

- **NIH application ID:** 10166832
- **Project number:** 5R01DK078646-15
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Adrian Vella
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $478,866
- **Award type:** 5
- **Project period:** 2007-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166832

## Citation

> US National Institutes of Health, RePORTER application 10166832, The effect of the fasting milieu on beta-cell function in vivo (5R01DK078646-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10166832. Licensed CC0.

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