IPN Researchers Investigate Compound to Comprehensively Address "Type 3 Diabetes"

By Claudia Villalobos | Photography: Javier González

Scientists Cecilia Rosales and Elena Mendieta seek to understand the molecular impact of insulin resistance on the brain.

Diabetes may leave a far deeper imprint on human health than a simple blood glucose measurement reveals. A multidisciplinary research project conducted at the Instituto Politécnico Nacional (IPN) aims to uncover how insulin resistance extends its effects to the central nervous system, opening an experimental pathway toward multi-target molecules capable of mitigating cognitive decline linked to metabolic disease.

Led by Dr. Martha Cecilia Rosales Hernández and Dr. Jessica Elena Mendieta Wejebe at the School of Medicine (Escuela Superior de Medicina, ESM), the project proposes an integrated approach to understanding metabolic dysfunction. Their research centers on a critical question: What happens when insulin resistance reaches the brain?

With this in mind, the researchers are studying "Type 3 Diabetes"—a term not yet recognized as a formal medical diagnosis, but widely used in scientific literature to explore the pathophysiological connection between Type 2 diabetes, central insulin resistance, and cognitive impairment associated with Alzheimer's disease.

Their goal is to identify shared molecular targets between diabetes and Alzheimer's, including key proteins involved in insulin signaling pathways, to determine how systemic metabolic alterations contribute to neurodegenerative processes.

Understanding "Type 3 Diabetes"

Mendieta Wejebe, a Level II researcher in Mexico's National System of Researchers and Research Fellows (Sistema Nacional de Investigadoras e Investigadores, SNII), explained that unmanaged diabetes maintains elevated blood glucose levels while causing disruptions in carbohydrate and lipid metabolism, accompanied by systemic inflammation and oxidative stress.

According to Mendieta Wejebe, these factors impair the integrity of the blood-brain barrier, allowing pro-inflammatory cytokines to penetrate the central nervous system and enabling peripheral metabolic dysfunction to directly impact brain tissue.

Both researchers highlighted that the link between diabetes and Alzheimer's involves key shared molecular targets, notably the enzyme glycogen synthase kinase-3 beta (GSK-3β). While GSK-3β normally plays a vital role in cellular homeostasis, factors like obesity and high-calorie diets can overactivate the enzyme, turning it into a driver of metabolic and neurological damage.

Rosales Hernández (SNII Level III) noted that insulin resistance increases GSK-3β activity, disrupting cellular function, impairing glucose uptake in skeletal muscle and the liver, and reducing overall insulin sensitivity. Furthermore, overactivation of GSK-3β accelerates mechanisms that promote the synthesis and accumulation of amyloid-beta (Aβ) peptides—the primary constituent of the amyloid plaques characteristic of Alzheimer's disease.

"Poor glycemic control generates oxidative stress and pro-inflammatory cytokines, which have been shown to compromise the blood-brain barrier," emphasized Rosales Hernández.

Metabolic and Neurological Observations in Experimental Models

To model these dynamics, the team established an experimental "Type 3 diabetes" model using Wistar rats. After 13 weeks on a high-calorie diet, the animals exhibited impaired glucose tolerance, elevated lipid levels, and systemic insulin resistance.

To determine whether these systemic alterations affected brain tissue, the researchers extended the study to 22 weeks. Following this period, they observed altered GSK-3β activity accompanied by elevated levels of specific pro-inflammatory cytokines within the brain.

While overt accumulation of amyloid-beta peptides and hyperphosphorylated Tau protein was not yet evident, the researchers cautioned that metabolic impairment may leave early molecular signatures in brain tissue well before classic neuropathological hallmarks appear.

Multi-Target Action: Molecule 4y

Rather than attempting to treat neurological damage after it manifests, the project focuses on identifying early molecular events and evaluating preventive therapeutic candidates. A central focus of their research is compound 4y, a novel candidate designed to target both metabolic dysfunction and neurodegenerative pathways simultaneously.

Molecule 4y belongs to a series of 2-aminobenzothiazole-derived guanidinobenzothiazoles. It was originally designed and synthesized by Dr. Alejandro Cruz, an organic chemistry specialist at IPN’s Interdisciplinary Professional Unit of Biotechnology (Unidad Profesional Interdisciplinaria de Biotecnología, UPIBI).

Before biological testing, computational docking tools were utilized to simulate 4y's binding interactions with proteins linked to both diabetes and Alzheimer's, identifying it as one of the most promising candidates in the series.

With global population aging, the intersection of diabetes and cognitive decline represents an escalating public health challenge. Preliminary preclinical results with compound 4y have yielded highly encouraging findings:

Metabolic Regulation: Successfully reduced blood glucose levels and improved lipid profiles in experimental models.

Neuroprotective Effects: Favorable alterations in hippocampal biomarkers associated with neurodegeneration, including reduced GSK-3β overactivity, lower amyloid-beta accumulation, and decreased phosphorylated Tau.

Safety Profile: High experimental doses demonstrated no significant systemic or hepatic toxicity under the evaluated conditions.

The researchers emphasize that these findings remain preclinical and require extensive further validation before clinical trials can be considered.

Future Research Horizons

The next phase of research will evaluate compound 4y in mouse models, enabling extended experimental timelines and behavioral testing to assess memory, spatial learning, and cognitive performance alongside molecular changes.

Directly inhibiting GSK-3β presents clinical challenges due to its essential role in multiple physiological pathways. Consequently, the team is also investigating peripheral biomarkers and metabolites that could serve as early diagnostic indicators of central nervous system alterations stemming from metabolic disease.

The project brings together experts across organic chemistry, pharmacology, experimental biology, and computational modeling to address this complex health challenge.

While not all individuals with Type 2 diabetes will develop cognitive impairment—as genetics, diet, physical activity, and environmental factors influence outcomes—the study highlights the imperative of evaluating brain health in comprehensive diabetes management.

Although "Type 3 Diabetes" is not yet a formal clinical classification, IPN's research underscores a crucial insight: if insulin resistance impacts the central nervous system, comprehensive diabetes care must also consider strategies to safeguard long-term brain health.