A silent metabolic imbalance could be influencing the course of this complex neurological disease.
For decades, multiple sclerosis (MS) has been primarily understood as an autoimmune disorder, where the body's immune system mistakenly attacks the protective sheath (myelin) that covers nerve fibers. But emerging research is revealing a surprising player in the MS story—hyperinsulinemia, a condition characterized by excess insulin in the blood.
This isn't about diabetes alone; it's about how metabolic health may directly influence neurological inflammation and degeneration. Studies now suggest that this hidden metabolic imbalance may be present from the earliest stages of MS, potentially shaping the disease's trajectory in ways scientists are just beginning to understand.
To understand the connection between insulin and multiple sclerosis, we first need to clarify what hyperinsulinemia is—and what it isn't.
Hyperinsulinemia refers to having abnormally high levels of insulin circulating in the blood. It's crucial to distinguish this from diabetes or insulin resistance, though they're often related.
Excess insulin in the bloodstream
When cells don't respond properly to insulin's signals
Typically develops when insulin resistance persists and pancreas function declines
Interestingly, hyperinsulinemia often precedes and can even drive insulin resistance. When the body's cells become less responsive to insulin, the pancreas compensates by producing more of it, leading to elevated blood insulin levels. This creates a cycle that can be challenging to break 7 .
The brain is highly sensitive to insulin, which affects thinking, eating behaviors, and other brain functions. Insulin also influences inflammation, which is a significant aspect of MS. Changes in how insulin works in the body could therefore be involved in the disease process 5 .
The notion that insulin issues might affect the brain isn't entirely new. We've long known that insulin plays important roles in the brain, influencing everything from neurotransmitter release to synaptic plasticity. Research from the Joslin Diabetes Center has demonstrated that insulin signaling in brain cells, particularly microglia (the brain's immune cells), helps regulate their ability to clear away damaging proteins and manage inflammation .
Based on 2023 study data 9
Based on 2023 study data 9
When this signaling breaks down, the consequences can be significant. In conditions like Alzheimer's disease, which shares some mechanistic features with MS, impaired insulin signaling in the brain has been linked to increased inflammation and poorer clearance of harmful proteins .
In MS, the connection appears to follow a similar pattern. A 2023 study published in the Journal of Neuroendocrinology found that MS patients with insulin resistance showed greater cognitive impairments, particularly in verbal memory and spatial comprehension, compared to those without insulin resistance 9 .
The statistics from this study were striking: among MS patients, the prevalence of insulin resistance was 37.8%, and cognitive decline affected 67.56% of participants. The correlation suggested that metabolic and neurological health were intertwined in MS 9 .
In 2015, a pivotal study set out to systematically investigate glucose metabolism and insulin response in MS patients. Published in Metabolic Brain Disease, this research broke new ground by focusing specifically on newly diagnosed patients, offering a unique window into the early stages of the disease 1 .
The researchers designed a comparative study with careful controls to ensure meaningful results:
19 newly diagnosed MS patients and 19 healthy controls matched for age, sex, and body mass index (BMI)
All MS patients were untreated and had low disability scores (EDSS 1.1 ± 0.7), minimizing confounding factors
Oral glucose tolerance test (oGTT) measuring plasma glucose, lactate, insulin and GLP-1 at multiple time points
Fasting adipokines, lipid profiles, and inflammatory parameters
Calculated using established indices (ISI Matsuda and ISI Cederholm) 1
This comprehensive approach allowed researchers to paint a detailed picture of metabolic function in early MS.
The results were telling. While both groups had comparable fasting and post-load glucose concentrations, their insulin responses told a different story:
| Metabolic Parameter | MS Patients | Healthy Controls | P-value |
|---|---|---|---|
| Fasting glucose (mmol/L) | 5.2 ± 0.3 | 5.0 ± 0.4 | 0.05 |
| Insulin sensitivity (ISI Matsuda) | 6.95 ± 3.44 | 10.60 ± 4.81 | 0.011 |
| Insulin sensitivity (ISI Cederholm) | 49.9 ± 15.3 | 61.3 ± 16.3 | 0.032 |
| Insulin response to glucose | Significantly increased | Normal range | 0.022 |
The MS patients showed significantly decreased insulin sensitivity and clear postprandial hyperinsulinemia—their bodies were producing more insulin to handle the same glucose load compared to healthy individuals 1 .
Based on 2015 study data 1
Perhaps equally important was what the researchers didn't find. There were no significant differences in lactate, GLP-1, cholesterol, triglycerides, or inflammatory markers like interleukin-6 and TNF between the groups. This suggested that the hyperinsulinemia in early MS wasn't simply a byproduct of chronic inflammation or physical inactivity, pointing instead toward a more fundamental metabolic disruption 1 .
Understanding metabolic aspects of MS requires specialized approaches. Here are the key tools and methods researchers use to unravel the insulin-MS connection:
| Tool/Method | Function/Purpose | Application in MS Research |
|---|---|---|
| Oral Glucose Tolerance Test (oGTT) | Measures body's ability to metabolize glucose | Detects hyperinsulinemia by tracking insulin response over time |
| Insulin Sensitivity Indices (ISI) | Mathematical models estimating insulin sensitivity | Quantifies degree of insulin resistance using Matsuda, Cederholm indices |
| Critical Blood Sampling | Multiple parameter analysis during hypoglycemic events | Measures glucose, insulin, C-peptide, fatty acids, ketones simultaneously |
| Magnetic Resonance Spectroscopy (MRS) | Non-invasive measurement of chemical concentrations in tissue | Quantifies ectopic fat in liver/muscle; studies brain metabolism |
| Cognitive Assessment Batteries | Standardized tests evaluating cognitive function | Links metabolic parameters to cognitive performance in MS |
Research in congenital hyperinsulinism has revealed that C-peptide measurements (a marker of insulin production) may sometimes provide more accurate information than insulin levels alone, as C-peptide isn't subject to the same rapid degradation 4 .
Additionally, the suppression of ketones and free fatty acids has been established as an important marker of excess insulin activity, since insulin inhibits hepatic ketogenesis. This understanding comes from diagnostic protocols for hyperinsulinemic hypoglycemia but proves valuable in understanding the metabolic state in MS as well 4 .
The discovery of hyperinsulinemia in newly diagnosed MS patients has far-reaching implications:
The presence of hyperinsulinemia even in early-stage, untreated patients with low disability suggests metabolic dysfunction may be a core feature of MS, not just a secondary consequence.
Given the established link between insulin resistance and cognitive decline in MS, addressing hyperinsulinemia might help protect against the cognitive impairments that significantly impact quality of life for MS patients 9 .
The metabolic dimension opens new possibilities for managing MS through lifestyle interventions (diet, exercise) or medications that improve insulin sensitivity.
These findings highlight the need to study how insulin-sensitizing approaches might influence MS progression, potentially complementing immunomodulatory therapies.
While the 2015 study provided crucial initial evidence, many questions remain. A 2024 meta-analysis that included 18 datasets confirmed the association between insulin resistance and MS, with stronger effects observed in studies that included mixed MS types rather than only relapsing-remitting MS 2 5 .
The researchers behind this meta-analysis noted significant variability between studies and called for more high-quality research with larger patient groups to confirm and refine our understanding of these associations 2 .
The emerging picture suggests that the relationship between metabolism and neurology is bidirectional—each influencing the other in complex ways that may shape disease progression. As Professor James Johnson, who researches insulin signaling, noted: "We know that insulin acts all over the body through the insulin receptors. We have known for a long time that pancreatic beta-cells that make insulin actually have insulin receptors as well" 8 .
This complexity reminds us that simple cause-effect narratives may not capture the full story. Instead, hyperinsulinemia and MS likely engage in a complicated dance—each potentially worsening the other in a cycle that progressive research continues to unravel.
Key research milestones in understanding the MS-hyperinsulinemia connection