The Hormone Nobody Measured Is Starving Your Nerves | The Pained Brain, Chapter 4

Hyperinsulinemia screening · Neuropathic pain

Screening for Hyperinsulinemia in Patients With Neuropathic Pain

Screen patients with neuropathic or chronic pain for hyperinsulinemia by drawing fasting insulin together with fasting glucose so HOMA-IR is available. Glucose and HbA1c stay in range while insulin output rises, so repeat the insulin on the same platform and read it against outcome-derived thresholds as well as the manufacturer interval.

Glucose-based screening finds dysglycemia late by design. In patients with neuropathic or chronic pain, hyperinsulinemia and the small-fiber and endothelial changes that travel with it are often established years before HbA1c crosses the prediabetes line.

Hyperinsulinemia is the compensatory state that glucose-based screening is structurally unable to see. Fasting glucose and HbA1c stay in range precisely because insulin output is rising, so a panel that stops at glycemia reads as normal through the years in which endothelial function, small-fiber density and pain sensitivity are already changing.

Dr. Padda’s video The Hormone Nobody Measured Is Starving Your Nerves summarizes Chapter 4 of The Pained Brain (Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Dr. KrisJay Fucanan, MD). For practices evaluating Measura [Cardiometabolic and Autonomic Health Analysis], the screening questions are specific: which patients with neuropathic or chronic pain warrant an insulin-axis workup, how to interpret an unstandardized assay, and what a positive result changes.

Can you have hyperinsulinemia without diabetes?

In Whitehall II, future diabetes cases carried 34.2% lower HOMA2 insulin sensitivity than controls at the earliest observation, 13 years before diagnosis. Beta-cell output peaked at 92.6% of reference three years out, and fasting glucose rose from 5.47 to 5.79 mmol/L before turning sharply upward late. A Japanese health-examination cohort of 27,392 adults found insulin-sensitivity separation ten years before a prediabetes diagnosis, at fasting glucose of 91.8 against 89.6 mg/dL, placing onset more than 20 years before diagnosis in most patients.

On hyperinsulinemic-euglycemic clamp testing, normoglycemic hyperinsulinemic subjects disposed of glucose at 6.23 mg/kg/min, statistically indistinguishable from impaired glucose tolerance at 6.37 and new type 2 diabetes at 6.19, against 11.88 in normal controls. The control group was only five people, but the conclusion does not rest on that number.

Why isn’t fasting insulin on the standard panel, and how should it be read?

The American Diabetes Association workgroup that compared commercial insulin methods in 2007 found among-assay variation with a median of 24% and a ceiling of 66%. Its 2010 statement concluded that no criteria existed to classify an individual as insulin resistant and proposed a sequence: standardize the assay, let research define cutoffs, then write guidelines. The first step is still unfinished. In 2025, one of twelve immunoassays matched isotope-dilution mass spectrometry, and there is still no listed reference method or certified reference material. The 2025 Standards of Care define prediabetes by glucose and HbA1c and name no fasting insulin or HOMA-IR recommendation.

That argues for disciplined interpretation, not omission. Draw fasting insulin together with fasting glucose so HOMA-IR is available, repeat on the same platform, and read the value against outcome-derived thresholds as well as the manufacturer interval. In the Tehran Lipid and Glucose Study, cut points predicting incident diabetes were 9.16 microU/mL in men and 11.13 in women. A reference interval built from screened-healthy Brazilian adults topped out at 13.14, with medians near 6.6.

Can hyperinsulinemia damage small nerve fibers before diabetes is diagnosed?

The neuropathy literature has pointed at the prediabetic window for 25 years. Of 107 patients with painful sensory neuropathy labeled idiopathic, 34% had impaired glucose tolerance on a two-hour test despite normal fasting glucose and HbA1c. In a population survey of 4,002 adults, neuropathy prevalence ran 3.25%, 6.29% and 15.12% across normoglycemia, prediabetes and diabetes. In the KORA cohort, each 5 cm of waist raised the odds of incident distal sensorimotor polyneuropathy by 22%, with no modification by diabetes status.

Detection is method-dependent. In the Heidelberg cohort, a full quantitative sensory battery identified neuropathy in 71% of prediabetic patients against 11% on the standard deficit score, conduction studies missed 58% of battery-positive cases, and hyperalgesia was present in more than half. The damage also tracks the insulin axis. Among 5,249 Danes with recently diagnosed type 2 diabetes, the adjusted prevalence ratio for questionnaire-defined polyneuropathy was 1.72 with elevated C-peptide versus 1.42 with elevated HbA1c, and in progressing diabetic neuropathy, triglycerides were the only baseline laboratory value that correlated with a 25% one-year loss of myelinated fiber density. The evidence is not unanimous; Olmsted County cohorts found no prediabetic excess of sensory symptoms or change, so this is a majority reading of the literature.

Can pain and steroid treatment raise insulin resistance?

The relationship runs both ways, which matters most in pain practices. Thirty minutes of experimental painful stimulation reduced insulin-stimulated glucose uptake in ten healthy men from 6.37 to 4.97 mg/kg/min, a 22% fall, with cortisol and epinephrine rising twofold to threefold. Total hip replacement reduced whole-body insulin sensitivity 43% in fasted patients and 18% with a preoperative carbohydrate drink. Two weeks of prednisolone lowered insulin sensitivity dose-dependently in healthy young men and cut insulin-stimulated capillary recruitment by 9% and 17%. Dr. Padda’s position is to have the insulin value in hand before a glucocorticoid injection, which is used as a bridge rather than the plan.

How do you test for hyperinsulinemia, and what does a positive result change?

Candidates include patients with painful neuropathy labeled idiopathic; chronic pain with central adiposity, elevated triglycerides or low HDL at normal glucose; fibromyalgia and migraine patients, in whom insulin resistance has been reported in some cohorts and not others; and patients facing repeated glucocorticoid exposure. Measurements matched to the mechanism:

Laboratory panels with fasting glucose, HbA1c and lipids, with fasting insulin requested so HOMA-IR can be calculated, and C-peptide where the insulin axis is in question.
Sudomotor testing, which assesses sweat-gland function mediated by distal small fibers, the fibers conduction studies do not sample.
Arterial stiffness and endothelial function, because selective insulin resistance impairs the nitric oxide arm; among 40 obese nondiabetic adults, flow-mediated dilation was 9.2% in the most resistant HOMA-IR tertile against 18.0% in the least.
Bioimpedance body composition, since central adiposity carries neuropathy risk independent of glycemic category.

A positive finding reframes part of the pain problem as metabolic and establishes a baseline. The intervention evidence favors reducing insulin demand over lowering glucose by any route: a year of supervised exercise raised distal leg intraepidermal nerve fiber density by 1.5 fibers/mm in type 2 diabetes with no HbA1c change, while the intensive glycemic arm of ACCORD showed a hazard ratio of 0.95 for the composite including neuropathy, with weight gain, severe hypoglycemia and excess mortality. That reading is inference across trials not designed to test insulin, and it should be charted as such. Pace matters too: reported nerve injuries during rapid weight loss on newer agents clustered at a median of 3.7 kg per month.

Documentation, fall risk and workflow

Put the insulin-axis panel on a standing order triggered by neuropathic symptoms or a pain diagnosis with metabolic features, so the order does not depend on who sees the patient. In older patients, a small-fiber deficit is also a fall-risk data point, so pair it with the balance and memory workup described in cognitive assessment and fall prevention. Annual wellness visits and MIPS or HEDIS cardiometabolic measures can carry the documentation, as outlined in MIPS and quality reporting.

In Dr. Padda’s practice every new patient has a fasting insulin drawn before any procedure. The share of US adults who are metabolically healthy is under 12.2% on NHANES 2009 to 2016 and under 7% on the tighter post-2021 criteria; in that clinic population it is under 3% overall and under 1% of chronic pain patients. Read the clinic numbers honestly, as practice-reported figures from our own population, not trial outcomes, and individual results vary, which is why the study-level detail sits in the book companion for Chapter 4.

Frequently asked questions

Is fasting insulin reliable enough to act on?

Reliable within a platform, variable between platforms. Repeatability on a single assay is high, yet cross-platform agreement with mass spectrometry remains poor. Order it with fasting glucose, repeat it on the same laboratory platform, and interpret trends and HOMA-IR rather than one value set against another laboratory’s interval. Interpreting the report.

Which patients with neuropathy should be screened for hyperinsulinemia?

Those with painful neuropathy labeled idiopathic, symptoms despite normal fasting glucose and HbA1c, central adiposity or elevated triglycerides. A third of one idiopathic painful neuropathy series had impaired glucose tolerance detectable only on a two-hour challenge, and waist circumference predicted incident neuropathy regardless of diabetes status in a prospective German cohort. Selection criteria.

Does a normal nerve conduction study rule out metabolic neuropathy?

No. Conduction studies sample large fibers, while metabolic injury typically begins in small fibers. In prediabetic patients studied at Heidelberg, conduction missed 58% of the neuropathy found by a full sensory battery. Small-fiber measures such as sudomotor testing sample a different fiber population and should be read alongside the examination rather than in place of it. Specialty applications.

How do these results get into the chart?

Results return to the ordering physician as a report for interpretation. Laboratory values and sudomotor and vascular findings can be filed as discrete results linked to the problem list, which is what makes serial comparison and quality documentation practical over time. Getting diagnostic results into the chart.

Should the insulin finding be discussed before a steroid injection?

It belongs in the informed discussion. Two weeks of prednisolone reduced insulin sensitivity and capillary recruitment dose-dependently in healthy men, and pain itself induces acute insulin resistance. A documented baseline lets the patient see why terrain repair accompanies the injection rather than following it. High insulin with normal blood sugar.

How do you know you have hyperinsulinemia?

Only by measuring insulin. Fasting glucose and HbA1c stay in range precisely because insulin output is rising, so a glucose-only panel reads as normal. Draw fasting insulin together with fasting glucose so HOMA-IR can be calculated, add C-peptide where the insulin axis is in question, and repeat on the same laboratory platform, because commercial insulin assays disagree by a median of 24%.

How do you treat hyperinsulinemia?

By lowering the demand for insulin, not just the glucose number. A year of supervised exercise raised leg nerve fiber density by 1.5 fibers per millimeter in type 2 diabetes with no change in HbA1c, while intensive glucose lowering in ACCORD barely moved the composite that included neuropathy and brought weight gain and severe hypoglycemia. Pace matters: reported nerve injuries during rapid weight loss clustered at a median of 3.7 kg per month.

Build the insulin-axis workup into your practice

Learn how the Measura protocol fits a pain, primary care or endocrine workflow, from standing orders to report interpretation.

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References

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