Hyperinsulinemia: The Metabolic Condition We Rarely Diagnose- but Routinely Treat Too Late

David S. Klein, MD FACA FACPM
Feb 13
4 min read

Diagram showing insulin resistance leading to compensatory hyperinsulinemia before diabetes develops — Insulin Resistance vs Hyperinsulinemia

Introduction: When “Normal” Labs Are Misleading

Many patients are told their metabolic health is “fine” because fasting glucose and HbA1c fall within reference ranges. Yet cardiovascular disease, visceral obesity, hypertension, fatty liver disease, and cognitive decline continue to progress.

The missing diagnosis is often hyperinsulinemia—chronically elevated insulin levels that precede diabetes by many years and quietly drive much of modern chronic disease. In clinical practice, we routinely treat the consequences of hyperinsulinemia while failing to identify the condition itself.

What Hyperinsulinemia Is—and Is Not

Hyperinsulinemia is a state of persistently elevated circulating insulin, usually arising as a compensatory response to insulin resistance. Its purpose is initially protective: maintaining normal blood glucose in the face of impaired cellular insulin signaling¹.

This distinction is critical:

Insulin resistance is the cellular defect
Hyperinsulinemia is the hormonal response

Patients may have normal glucose, normal HbA1c, and yet live in a chronically anabolic, pro-inflammatory, pro-atherogenic state driven by excess insulin.

Insulin Is Not a Benign Hormone

This infographic illustrates the systemic effects of hyperinsulinemia, showing how chronically elevated insulin contributes to cardiovascular disease, weight gain, fatty liver disease, hypertension, cognitive decline, and accelerated aging—often years before diabetes is diagnosed. — Systemic Effects of Hyperinsulinemia: Vascular, Cognition, Organ Failure

Insulin is a powerful growth and storage hormone. When chronically elevated, it exerts systemic effects far beyond glucose control:

Suppresses lipolysis and promotes fat storage²
Increases renal sodium retention and blood pressure³
Activates sympathetic nervous system tone⁴
Stimulates vascular smooth muscle proliferation⁵
Inhibits autophagy and cellular repair mechanisms⁶

Over time, these effects accelerate cardiometabolic disease and biological aging—even in the absence of diabetes.

Cardiovascular Disease Begins Here

Hyperinsulinemia directly contributes to atherosclerosis through multiple pathways:

Endothelial dysfunction and impaired nitric oxide signaling
Increased triglyceride-rich lipoprotein production
Promotion of small dense LDL particles
Chronic low-grade inflammation

Prospective studies demonstrate that elevated fasting insulin predicts cardiovascular events independently of glucose levels⁷. In other words, heart disease often begins before diabetes—not after.

Weight Gain That Defies Calories Alone

Patients frequently report gaining weight despite caloric restriction and regular exercise. Hyperinsulinemia provides the explanation.

Chronically elevated insulin:

Locks adipose tissue into storage mode
Prevents effective fat mobilization
Drives visceral and hepatic fat accumulation
Increases hunger signaling through central mechanisms

In this context, weight gain is not a failure of discipline—it is a predictable hormonal outcome⁸.

The Overlooked Link to Hypertension and Fatty Liver

Insulin increases renal sodium reabsorption and plasma volume, contributing directly to hypertension⁹. Simultaneously, hepatic insulin resistance combined with hyperinsulinemia drives de novo lipogenesis, leading to metabolic dysfunction–associated steatotic liver disease (MASLD)¹⁰.

Both conditions frequently emerge years before diabetes is diagnosed, yet share the same upstream driver.

Why Routine Testing Misses Hyperinsulinemia

Standard metabolic panels do not measure insulin. As a result, hyperinsulinemia often remains invisible until pancreatic compensation fails.

More informative markers include:

Fasting insulin
HOMA-IR
Triglyceride-to-HDL ratio
Oral glucose tolerance testing with insulin measurements

Early identification reframes treatment away from glucose suppression and toward metabolic restoration.

Hyperinsulinemia and Accelerated Aging

From a longevity perspective, chronic insulin elevation is particularly concerning.

Hyperinsulinemia:

Activates mTOR signaling
Suppresses AMPK and FOXO pathways
Inhibits autophagy
Accelerates mitochondrial dysfunction

These mechanisms link excess insulin to sarcopenia, vascular stiffness, immune senescence, and neurodegeneration¹¹.

Clinical Takeaway

Hyperinsulinemia is not a benign laboratory curiosity—it is a central driver of cardiometabolic disease, cognitive decline, and accelerated aging. Treating blood sugar alone addresses the final chapter of a long pathophysiologic story. Detecting and correcting hyperinsulinemia earlier allows intervention while disease remains reversible.

Concerned about metabolic health despite “normal” labs?

Advanced metabolic evaluation—including insulin-based testing—is available at Stages of Life Medical Institute. Early detection allows meaningful prevention.

REFERENCES

¹ Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595–1607.https://pubmed.ncbi.nlm.nih.gov/3056758/

² Boden G. Obesity, insulin resistance and free fatty acids. Endocrinol Metab Clin North Am. 2008;37(3):635–646.https://pubmed.ncbi.nlm.nih.gov/18775356/

³ DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14(3):173–194.https://pubmed.ncbi.nlm.nih.gov/2044434/

⁴ Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest. 1991;87(6):2246–2252.https://pubmed.ncbi.nlm.nih.gov/2040704/

⁵ Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011;14(5):575–585.https://pubmed.ncbi.nlm.nih.gov/22055501/

⁶ Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle. 2006;5(18):2087–2102.https://pubmed.ncbi.nlm.nih.gov/17012837/

⁷ Després JP, Lamarche B, Mauriège P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med. 1996;334(15):952–957.https://pubmed.ncbi.nlm.nih.gov/8596596/

⁸ Ludwig DS, Ebbeling CB. The carbohydrate–insulin model of obesity: beyond “calories in, calories out.” JAMA Intern Med. 2018;178(8):1098–1103.https://pubmed.ncbi.nlm.nih.gov/29971320/

⁹ Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Hypertension. 2015;65(6):1005–1011.https://pubmed.ncbi.nlm.nih.gov/25855790/

¹⁰ Smith GI, Shankaran M, Yoshino M, et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest. 2020;130(3):1453–1460.https://pubmed.ncbi.nlm.nih.gov/31917689/

¹¹ Barzilai N, Huffman DM, Muzumdar RH, Bartke A. The critical role of metabolic pathways in aging. Cell Metab. 2012;16(3):326–337.https://pubmed.ncbi.nlm.nih.gov/22958918/

The medical references cited in this article are provided for educational purposes only and are intended to support general scientific discussion. They are not a substitute for individualized medical advice, diagnosis, or treatment. Clinical decisions should always be made in consultation with a qualified healthcare professional who can account for a patient’s unique medical history, medications, and circumstances.

Subscribe to our Blog