337- Insulin resistance masterclass: The full body impact of metabolic dysfunction, treatment & more

KEYPOINTS

• 01

  'Insulin resistance' only means something once you name the tissue and the process

  DeFronzo developed the euglycemic insulin clamp. Insulin is raised by about 100 µU/mL and held there for two hours, while glucose is infused to keep blood sugar near 80–90. Under those conditions about 80–90% of glucose goes into muscle, about 10% into fat, and essentially none into the liver. Different tissues switch off at different insulin levels. A rise of only about 10 µU/mL stops fat breakdown, the liver needs about 50 to stop releasing glucose, and muscle uptake still climbs 20–25% between 100 and 200.

• 02

  Type 2 diabetes needs two defects

  Insulin resistance on its own doesn't cause diabetes as long as the beta cells can keep up. Diabetes appears when genetically vulnerable beta cells wear out from constant overwork. DeFronzo says about 10–15% of people already have clinically significant heart disease when diagnosed, and 'virtually 100%' do if you look carefully. The same blocked signaling step (IRS-1/PI3-kinase) that keeps glucose out of muscle also stops nitric oxide production, which ties insulin resistance directly to atherosclerosis.

• 03

  Too much insulin causes insulin resistance

  When his group raised healthy lean young adults' fasting insulin from about 8 to 20 µU/mL, still below a normal meal spike, they became as insulin resistant as people with type 2 diabetes within 48–72 hours, because the signaling pathway turns itself down. Healthy beta cells make about 35 units of insulin a day, while many patients inject 100–150. He thinks that level is atherogenic, so diet, exercise and other drugs should aim to bring doses back toward a normal range. Those who need insulin should still get it.

• 04

  The 'ominous octet': eight organs drive the disease

  He started from a triad of beta cell, muscle and liver, and added five more. Fat cells stop responding to insulin and release free fatty acids. The gut's incretins (GLP-1 and GIP) are released normally, but the beta cell ignores them, even though they drive about 70% of meal-time insulin. Alpha cells overproduce glucagon. The kidneys increase SGLT2 and hold on to more glucose. The brain becomes resistant to GLP-1, amylin and leptin. Eight faults, so one drug can't be enough.

• 05

  Raised fatty acids are toxic

  Infusing a fat emulsion causes severe insulin resistance in muscle and liver and impairs beta cells within 2–4 hours. Lowering fatty acids for 12 days with acipimox (sold in Europe) sharply reduced muscle fat, greatly improved insulin sensitivity, and raised mitochondrial ATP production by about 50%. So much of the mitochondrial problem follows from fat overload.

• 06

  SGLT2 inhibitors came out of DeFronzo's kidney research

  As a kidney fellow he used phlorizin to show glucose and phosphate transport are linked. The kidneys filter about 180 g of glucose a day, with SGLT2 recovering about 90%. In diabetic animals, blocking this improved beta cells and insulin sensitivity. In people, 14 days of dapagliflozin raised insulin sensitivity by about 35%, the first human evidence that high glucose itself is toxic. He never patented it.

• 07

  Pioglitazone is the only true insulin sensitizer and is heavily underused

  It fixes the signaling defect and moves fat out of muscle, liver and beta cells into tissue under the skin. In a 2017 study it improved heart insulin sensitivity by about 75% and muscle by 74%, and ejection fraction rose 5–10%. Weight gain (about 2–2.5 kg at 15–30 mg, partly from appetite effects in the hypothalamus) and fluid retention put people off. Yet in PROactive (5,238 patients), weight gain was the strongest predictor of survival. He calls it the best drug for NASH.

• 08

  Metformin is useful, but it isn't an insulin sensitizer

  DeFronzo brought it to the US in 1995. Clamp studies never showed that it improves insulin sensitivity. Its transporter isn't present in skeletal or heart muscle, and labeled-tracer scans show it only in the liver, kidney and bladder. It works by reducing glucose production in the liver. The sensitizer myth likely came from ~3 kg weight loss driven by GI side effects. It costs about $5 a month and is fine to add, but it ranks fourth on his list.

• 09

  Start with combination therapy built on the biology

  In EDICT (315 patients, six years), metformin plus exenatide plus pioglitazone from the start kept about 70% of patients below an A1c of 6.5% and produced large gains in insulin sensitivity and beta-cell function. The stepwise ADA approach (metformin, then sulfonylurea, then insulin capped at 60 units) failed in about 71%, with no improvement in either. The NIH's GRADE study found that every single drug added to metformin had stopped working by about year five.

• 10

  His ranking of drugs

  If he could use only one: a modern GLP-1 drug. Two: add pioglitazone, since GLP-1 weight loss cancels its weight gain and fluid retention. Three: add an SGLT2 inhibitor, especially with kidney or heart disease, and he expects the same protection in newly diagnosed patients. Heart-event reductions are about 20% across old and new GLP-1 drugs, which he takes as a sign the benefit levels off.

• 11

  Damaged eating circuits in the brain drive the epidemic

  Processed, calorie-dense food and inactivity are the trigger, he says, but they reshape the brain's reward circuitry. Gray matter shrinks in reward areas, and in obese people those areas take up excess glucose during a clamp, in proportion to how resistant their muscle is.