#140 - Gerald Shulman, MD, PhD: Insulin resistance—molecular mechanisms and clinical implications

KEYPOINTS

• 01

  Insulin resistance is the soil the big chronic diseases grow in

  Peter tells patients that heart disease, cancer and Alzheimer's sit on a foundation of insulin resistance. Shulman credits Gerald Reaven's 1988 Banting lecture with getting the field to see insulin resistance as a driver, not a bystander. Shulman himself won the Banting Medal in 2018.

• 02

  Seeing inside living cells with carbon-13 NMR

  About 99% of the body's carbon is C-12, which NMR can't see. The 1% that is C-13 can be tracked. By infusing C-13-labeled glucose, Shulman's group can watch glucose being turned into muscle glycogen in awake humans, without radioactive tracers or biopsies.

• 03

  Muscle is the first site of insulin resistance

  After a meal, about 80–90% of glucose is normally stored as glycogen, mostly in muscle. In lean, healthy, non-smoking Yale students around 20 years old (BMI about 22–23) who were insulin resistant, glucose flow into muscle glycogen was already about 50% lower than in insulin-sensitive peers, before any weight gain or diabetes.

• 04

  The block is glucose transport, not what Randle predicted

  Philip Randle's 1960s model predicted that fat would raise glucose-6-phosphate inside muscle. Shulman's NMR studies found both glucose-6-phosphate and free glucose fell, pointing to a problem moving glucose into the cell through the GLUT4 transporter. That shifted the field's view of where the problem lies.

• 05

  Diacylglycerol and novel PKCs are the culprits

  When fatty acid delivery outpaces oxidation, intermediates such as acyl-CoAs and diacylglycerol (DAG) build up. In muscle this activates PKC-theta, and in liver PKC-epsilon, which blunts insulin-receptor and IRS signaling. Gene knockouts confirm it. Specifically, the sn-1,2 DAG form at the plasma membrane matters, which can be missed if only total DAG is measured.

• 06

  Muscle insulin resistance diverts carbs to the liver and makes fat

  When muscle can't store glucose, more of a carbohydrate meal reaches the liver. There it is turned into fat through de novo lipogenesis, which was more than twofold higher in insulin-resistant young people, with liver fat up about 2.3-fold. That leads to higher triglycerides and lower HDL. Shulman says lab cut-offs (triglycerides under 150) miss this; these young people had about 100–105 versus 60.

• 07

  Exercise bypasses the block

  Six weeks of StairMaster (three 15-minute bouts at about 65% VO2 max) normalized muscle glycogen synthesis, likely via AMPK moving GLUT4 independently of PI3-kinase. A single 45-minute session shifted ingested glucose into muscle and cut de novo lipogenesis and liver triglycerides. Type 1 diabetics walking briskly for hours a day can need far less insulin.

• 08

  Insulin resistance evolved to protect the brain during starvation

  Rats fasted 48 hours develop fatty liver, DAG build-up, PKC-epsilon activation and hepatic insulin resistance. That switches off glycogen storage and preserves glucose for the brain. Cahill showed humans still got about 40% of brain energy from glucose after 40 days of starvation.

• 09

  Fatty liver is becoming the leading reason for liver transplants

  Fatty liver disease is now the most common liver disease in the world. Peter notes that within about 10 years, NASH and cirrhosis may be the top reason for liver transplants in the US, compared with under 2% of transplants when he was in medical school.

• 10

  Metformin likely works through redox, not complex I

  Most studies used millimolar concentrations of metformin. Plasma levels at the usual dose of 1 g twice a day are about 30–50 micromolar, and perhaps about 100 in the portal vein. At those levels, Shulman says metformin inhibits mitochondrial glycerol-3-phosphate dehydrogenase, changing the cell's redox state and reducing glucose production in the liver.