#87—Rick Johnson, MD: Fructose—the common link in hypertension, insulin resistance, T2D, & obesity?

KEYPOINTS

• 01

  Uric acid led Johnson from blood pressure to fructose

  Johnson, a nephrologist at the University of Colorado with roughly 700–800 publications, first studied uric acid as a cause of high blood pressure. Raising uric acid in animals with a uricase inhibitor raised their blood pressure, and lowering it brought pressure down. Expecting crystals in the kidney, his team instead found inflammatory changes. Uric acid, long thought to be an inert end product or even an antioxidant, was having pro-inflammatory effects. Since fructose raises uric acid, in 2002 they asked whether sugar could drive blood pressure.

• 02

  Fructose plus allopurinol: one intervention, many effects

  Rats fed fructose developed high blood pressure, and allopurinol, which lowers uric acid, brought it back to normal. They also developed insulin resistance, high triglycerides and fatty liver, and lowering uric acid improved all of those. Johnson calls it a big discovery that linked sugar, uric acid and metabolic disease.

• 03

  Fructose drains cellular energy and flips a metabolic switch

  Fructokinase uses ATP without the brakes that govern glucose metabolism. A big fructose load can drop ATP in the cell by 40–50%, which Johnson describes as a 'mayday' signal. Phosphate gets tied up in fructose-1-phosphate. The falling phosphate pushes AMP down the AMP deaminase pathway, which stores fat, generates uric acid and promotes insulin resistance, rather than the AMPK pathway, which burns fat and is what metformin activates.

• 04

  Fructose is nature's fat-storage signal

  Animals use fruit to fatten before winter or before food runs short. Bears and other hibernators gorge on ripe fruit in the autumn, and orangutans eat large amounts at once to gain fat. Johnson notes that most people don't get fat from a few pieces of tart fruit, but large amounts of fruit juice can increase fat.

• 05

  An ape mutation made humans sensitive to sugar

  As the climate cooled, fruit trees (including figs) disappeared from European forests, and by about 12 million years ago European apes were starving. Johnson argues that a mutation that disabled uricase, which raises uric acid, helped them store fat and survive. The surviving ape returned to Africa and Asia and became the ancestor of the great apes and of humans. His team even resurrected the ancestral uricase. Attia notes that evolution wasn't anticipating a world awash in fructose.

• 06

  Salt raises blood pressure through a spike in serum sodium

  A very salty soup can raise serum sodium from 140 to 142–143 mmol/L, which raises blood pressure acutely, by about 6 mmHg for a 2 mmol/L rise, for a couple of hours. In Johnson's study, giving the same salty soup with water so that serum sodium didn't rise prevented the blood pressure rise. He thinks sugar also plays a role in salt-sensitive hypertension.

• 07

  Blood pressure risk climbs from 120/80, then steeply

  Above about 160–180 mmHg, arteries can no longer constrict enough to protect themselves (autoregulation fails), and stroke risk shoots up almost vertically. But epidemiology also shows a stepwise rise in risk from 120/80 to 140/90, which is why 120/80 is treated as the target.

• 08

  Speed and dose determine how harmful fructose is

  The same 25 g of fructose does more harm when it arrives quickly in liquid form on an empty stomach than when it is eaten with fibre. Johnson says a beverage company could make soda look harmless by having people sip it over three hours. About 20% of fructose is handled by the intestine and perhaps 40% by the liver, with at least 10–20% escaping into the circulation, more at higher doses.

• 09

  The body makes its own fructose from glucose

  High glucose reaching the liver induces aldose reductase, which converts glucose into fructose. Mice given glucose in their drinking water became fat and insulin resistant, even though they ate less chow. Johnson uses this to explain why starchy foods such as French fries can be fattening even though they contain no fructose.