# Targeting galectin-3 to overcome insulin resistance in type 2 diabetes

> **NIH NIH R43** · GLYCOMANTRA, INC. · 2020 · $300,000

## Abstract

Project Summary/Abstract
Obesity-associated insulin resistance is a hallmark of type 2 diabetes (T2D) and plays a central role in
metabolic syndrome. Numerous studies suggest a firm connection between obesity-induced inflammation and
insulin resistance mediated by macrophages and other immune cells. A recent elegant study by Olefsky and
his team [Cell publication PMID: 27814523 ] shows that galectin-3 (Gal3), a beta-galactoside-binding lectin, is a
macrophage-derived instigator of “insulin resistance and impaired glucose tolerance”, associated with obesity-
induced T2D. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas
inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese
mice. The study shows that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR
signaling. These fundamental observations elucidate a novel role of Gal3 that promotes obesity-mediated
inflammation (macrophage-derived Gal3) and insulin resistance and suggest that specific inhibition of Gal3
may represent a promising therapeutic strategy to restore insulin sensitivity. Our scientific premise is that we
have developed a very potent Gal3 antagonist, named TFD100, from a natural dietary source [PNAS
publication, PMID 23479624]. TFD100 specifically targets Gal3 with picomolar affinity – the affinity is so high
(10-100-fold more) to counteract Gal3’s natural affinity to its intrinsic ligands such as IR. In our preliminary
studies, Gal3 inhibited IR activation of the engineered CHO/IR/IRS-1 cells, which was reversed by TFD100. Our
research team has extensive expertise in a relevant mouse model of T2D – a high fat diet (HFD)-induced
model in C57BL/6 (B6) . We demonstrated increased expression of Gal3 in liver of HFD fed mice compared to
that of low fat diet (LFD) fed mice. Gal3 is also high in obese mice. Moreover, Gal3 levels in sera of T2D
patients are found significantly linked with indices of insulin resistance. Based on the preliminary data we
hypothesize that that specific inhibition of Gal3 with TFD100 will interfere with Gal3-IR interactions on
myocytes, adipocytes and hepatocytes and thereby restore insulin sensitivity. We will test this
hypothesis in the following specific aim: Investigate the therapeutic utility of TFD100 for treating T2D in a
relevant mouse model. First we will determine TFD100’s ability to impede Gal3-mediated cellular insulin
resistance. Various cells such as adipocytes, myocytes, hepatocytes, and engineered CHO/IR/IRS-1 cells will
be treated with TFD100 and determine its effect on IR activation, signaling, and glucose uptake. Next, we will
determine TFD100’s ability to treat HFD-induced obesity, insulin resistance, and T2D in both male and female
mice. After drug (TFD100) treatment, glucose and insulin tolerance (primary endpoint) will be measured. For
other endpoints, resolution of inflammation and restoration of insulin signaling...

## Key facts

- **NIH application ID:** 10007279
- **Project number:** 1R43DK125126-01
- **Recipient organization:** GLYCOMANTRA, INC.
- **Principal Investigator:** HAFIZ AHMED
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $300,000
- **Award type:** 1
- **Project period:** 2020-05-22 → 2022-05-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007279

## Citation

> US National Institutes of Health, RePORTER application 10007279, Targeting galectin-3 to overcome insulin resistance in type 2 diabetes (1R43DK125126-01). Retrieved via AI Analytics 2026-07-19 from https://api.ai-analytics.org/grant/nih/10007279. Licensed CC0.

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