# PRESERVATION OF BETA CELL FUNCTION IN PREDIABETES: IGT AND IFG

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $663,044

## Abstract

ABSTRACT/PROJECT SUMMARY
Type 2 diabetes mellitus (T2DM) affects ~29.1 million individuals in the US and is associated with
significant morbidity and mortality from both microvascular and macrovascular complications. The
microvascular, and to a lesser extent macrovascular, complications primarily are related to
hyperglycemia. Therefore, it is logical to initiate therapy early in the natural history of T2DM, at the
“prediabetic” stage, with interventions that reverse specific pathophysiologic defects present in IGT and
IFG. In both IGT and IFG, the progression to T2DM is characterized by progressive beta cell failure.
Although both IGT and IFG represent high risk states for future T2DM, we have shown that they are
characterized by distinct pathophysiologic defects. Individuals with IFG have impaired 1st phase insulin
secretion and hepatic insulin resistance and both of these defects strongly are correlated with the
increase in fasting plasma glucose concentration. In contrast, IGT subjects have decreased 2nd phase
insulin secretion and severe muscle insulin resistance. Therefore, one would expect patients with IGT
and IFG to respond differently to different pharmacologic interventions. Thus, dapagliflozin, an SGLT2
inhibitor that induces glucosuria, reduces the FPG, and reverses glucotoxicity might be expected to be
effective in IFG, while pioglitazone, a thiazolidinedione that activates PPAR, reverses lipotoxicity,
augments 2nd phase insulin secretion and improves muscle insulin sensitivity, would be expected to be
most effective in IGT. Saxagliptin, a DPP4 inhibitor, that augments both 1st and 2nd phase insulin
secretion, would be expected to work well in both IGT and IFG. We will test this hypothesis by treating
individuals with isolated IGT and isolated IFG with the following interventions: (1) metformin; (2)
dapagliflozin; (3) pioglitazone; (4) saxagliptin; (5) placebo for 30 months. After 30 months, all medications
will be discontinued for 6 months to examine whether the beneficial effects on beta cell function (insulin
secretion/insulin resistance [disposition] index) persist. At baseline, 30, and 36 months subjects will
receive: (i) euglycemic insulin clamp, (ii) 2-step hyperglycemic clamp with GLP-1 infusion, (iii) OGTT
with measurement of GLP-1 and GIP. This will provide state-of-the-art quantitation of beta cell function
and insulin resistance and define the effect of the various pharmacologic interventions on these key
pathophysiologic parameters.

## Key facts

- **NIH application ID:** 9999563
- **Project number:** 5R01DK024092-37
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** RALPH A DEFRONZO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $663,044
- **Award type:** 5
- **Project period:** 1998-06-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999563

## Citation

> US National Institutes of Health, RePORTER application 9999563, PRESERVATION OF BETA CELL FUNCTION IN PREDIABETES: IGT AND IFG (5R01DK024092-37). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999563. Licensed CC0.

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