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DavidPerlmutterMD · 2021-11-29 · David Perlmutter (host), Richard Johnson

Uric Acid - The Acid You May Need to Drop - with Dr. Johnson | The Empowering Neurologist EP. 138

48 claims checked against research: 3 needing context 31 supported 2 corroborated online 12 unverified

3

Needs context

0:46:16Richard Johnsonneeds contextlow

Hibernating bears and long-distance migrating birds become insulin resistant during fat storage.

"The hibernating bear and the long-distance migrating bird, they become insulin resistant as well." (said at 0:46:16)

Reversible metabolic adaptations in hibernators and long-distance migratory species are well-documented, but the timing in bears differs from the typical assumption: physiological studies in brown and grizzly bears demonstrate that they remain insulin sensitive during the hyperphagic fat-storage period (spring and autumn) and develop reversible, protective insulin resistance specifically during winter hibernation fasting to preserve glucose for the central nervous system. In migratory birds, extreme pre-migratory fat accumulation and naturally high circulating glucose levels occur without progressing to pathological insulin resistance or diabetes.

0:56:44Richard Johnsonneeds contextmoderate

As fruit ripens and becomes overripe, its sugar content increases while its vitamin C content decreases.

"they'll eat fruit, but they'll wait till it ripens. Even more, they like it when it's almost a little mushy. And what happens is, when that happens, the sugar content goes up and the vitamin C content goes down." (said at 0:56:44)

The statement requires qualification. As fruits ripen, complex carbohydrates and starches are typically converted into simple reducing sugars (such as glucose and fructose) and total soluble solids increase, confirming the rise in sugar content. However, the trajectory of vitamin C (ascorbic acid) varies significantly depending on the fruit species and ripening phase: during standard maturation and ripening, vitamin C often increases alongside sugars (such as in tomatoes, bell peppers, and papayas), while in the late senescence or overripe ('mushy') stages, oxidative degradation can lead to a net decline in ascorbic acid in several fruits.

1:10:39Richard Johnsonneeds contextlow

A study conducted in Japan on lean, healthy individuals without diabetes, hypertension, or elevated triglycerides found that high uric acid alone increased the risk for developing obesity, diabetes, hypertension, and chronic kidney disease over the following years.

"we did do this one study where we took people—this was a study in Japan, but we took all these people who were lean, did not have diabetes, did not have high blood pressure, did not have high triglycerides. Basically, they were healthy, and the only thing they had was a high uric acid. And that group, you know, we didn't have to worry about confounding factors. None of them were overweight. And that group showed that they had an increased risk for developing obesity, diabetes, high blood pressure, chronic kidney disease in the next few years compared to people who did not have a high uric acid." (said at 1:10:39)

A 5-year longitudinal cohort study conducted in Tokyo, Japan (Kuwabara et al., 2017) examined 5,899 healthy adults who were lean (not overweight/obese) and free of hypertension, diabetes, dyslipidemia, and chronic kidney disease (CKD) at baseline. Over 5 years, isolated asymptomatic hyperuricemia was associated with a statistically significant increased risk of developing overweight/obesity (8.9% vs. 3.0%), hypertension (14.9% vs. 6.1%), dyslipidemia (23.1% vs. 15.5%), and CKD (19.0% vs. 10.7%). The incidence of diabetes was also higher in the hyperuricemic group (1.7% vs. 0.9%), but this difference was a trend that did not reach statistical significance (P = 0.087).

31

Supported by research

0:00:00Richard Johnsonsupportedmoderate

Elevated serum uric acid independently predicts the future development of hypertension, obesity, and diabetes.

"We realized that there are many, many studies that show that a high uric acid independently predict hypertension. And it independently predict obesity and diabetes and all these things." (said at 0:00:00)

Extensive prospective observational literature and meta-analyses confirm that elevated serum uric acid (SUA) independently predicts the development of incident hypertension and type 2 diabetes, even after adjusting for traditional metabolic and cardiovascular risk factors. A meta-analysis of 17 prospective cohort studies comprising over 320,000 individuals demonstrated a significant linear increase in incident hypertension risk per 1 mg/dL increase in SUA (RR 1.10, 95% CI: 1.07–1.13). Similarly, a meta-analysis of prospective cohorts showed that higher SUA independently predicts future type 2 diabetes (RR 1.56 comparing highest to lowest categories) after multivariate adjustment for metabolic syndrome components.

0:03:59Richard Johnsonsupportedmoderate

Transplanting a kidney from a hypertensive animal to a normotensive animal transfers susceptibility to hypertension.

"And so uh some studies had been done where they had taken people or animals with hypertension, and they found that if they transplanted the kidney from that animal to another animal, that you could transplant or you could transfer the uh the susceptibility to hypertension." (said at 0:03:59)

Classic renal cross-transplantation studies in multiple animal models—including Dahl salt-sensitive rats, Milan hypertensive rats, spontaneously hypertensive rats (SHR), and stroke-prone SHR—consistently demonstrate that kidney transplantation from a genetically hypertensive donor to a normotensive recipient transfers high blood pressure and hypertension susceptibility. Conversely, transplanting a kidney from a normotensive donor into a hypertensive recipient lowers blood pressure or blunts the development of hypertension. Observational studies in human kidney transplant recipients similarly show that donor genetic predisposition to hypertension significantly influences post-transplant recipient blood pressure.

0:04:30Richard Johnsonsupportedlow

An autopsy study from the 1960s found that over 95% of patients with gout had evidence of kidney disease.

"And so there was a study done in the '60s looking at patients with gout uh and looking at autopsies, and they found that um kidney disease was present in something like 95% or higher." (said at 0:04:30)

A landmark 1960 postmortem study by Talbott and Terplan evaluated renal pathological changes in patients with gout and found that nearly all examined cases (close to 99–100%) had histological evidence of kidney disease, including arteriolosclerosis, glomerulosclerosis, and interstitial fibrosis.

0:05:30Richard Johnsonsupportedhigh

Humans have higher baseline serum uric acid levels than most other mammals because humans lack the liver enzyme uricase.

"And um and so it turns out that humans have higher uric acid than other animals because we lack an enzyme called uricase. And uricase is an enzyme in the liver that degrades uric acid. So, humans have a little bit higher uric acid than most other mammals." (said at 0:05:30)

The speaker's statement is accurate and well-established in comparative biochemistry and evolutionary biology. In most mammals, uricase (urate oxidase) degrades uric acid into allantoin. During hominoid evolution in the Miocene epoch, humans and other great apes acquired loss-of-function mutations (pseudogenization) in the urate oxidase gene (UOX), resulting in the loss of functional hepatic uricase activity and markedly higher baseline serum uric acid concentrations compared to other mammals.

0:06:15Richard Johnsonsupportedvery low

Pharmacologically raising uric acid in laboratory rats using a uricase inhibitor causes hypertension without causing intrarenal crystal deposition.

"So, in order to raise uric acid in a laboratory rat, we actually gave it this uricase inhibitor, thinking that we were going to get low-grade inflammation in the kidney and crystals, and that that might cause high blood pressure. But what we found was that uh we did get high blood pressure. The animals became hypertensive when we raised uric acid, but when we looked in the kidneys, we didn't see any crystals at all." (said at 0:06:15)

The speaker's statement accurately describes findings from experimental animal research (Mazzali et al., 2001). In rats fed the uricase inhibitor oxonic acid to induce mild hyperuricemia, the animals developed systemic hypertension within three weeks, while histological examination of the kidneys revealed no urate crystal deposition. Because this evidence is derived entirely from animal models, the GRADE certainty is very low.

0:08:10Richard Johnsonsupportedvery low

Treating hyperuricemic rats with allopurinol prevents hypertension, and discontinuing uricase inhibition normalizes blood pressure.

"And then we realized that we needed to do controls where we lowered the uric acid, like with drugs like allopurinol or other types of drugs. And so she did those studies, and then the animals didn't get hypertensive. And then we also did the thing where we raised the uric acid, and the blood pressure went up, and then we stopped the uricase inhibitor, so the uric acid levels came down, and then the blood pressure came down." (said at 0:08:10)

The speaker's description matches the experimental findings from rat studies on oxonic acid-induced hyperuricemia. In these experiments, rats given the uricase inhibitor oxonic acid developed elevated blood pressure, which was prevented by concurrent administration of the xanthine oxidase inhibitor allopurinol or a uricosuric drug. Furthermore, blood pressure returned to normal levels when uric acid was lowered, either by allopurinol administration or by withdrawing the uricase inhibitor. Because this evidence is derived entirely from animal models, the GRADE certainty is very low.

0:14:15Richard Johnsonsupportedmoderate

Approximately 90% of adolescents with newly diagnosed primary essential hypertension have elevated serum uric acid, compared to under 5% of normotensive controls.

"And if you had primary hypertension, what we call essential hypertension, the hypertension associated with obesity, the uric acid was elevated. And it was like 90% of these kids had high uric acid versus like less than 5% of the controls." (said at 0:14:15)

The speaker accurately summarizes clinical research examining serum uric acid levels in pediatric and adolescent essential hypertension. In foundational studies led by Feig and colleagues evaluating adolescents with newly diagnosed primary (essential) hypertension, approximately 89–90% of patients with untreated essential hypertension demonstrated elevated serum uric acid levels (hyperuricemia, typically defined as >5.5 mg/dL), compared to fewer than 5% of normotensive healthy controls or secondary hypertension controls. Subsequent randomized clinical trials by the same investigators demonstrated that reducing serum uric acid using allopurinol or uricosuric agents significantly lowered casual and 24-hour ambulatory blood pressure in these hyperuricemic adolescents.

0:15:25Richard Johnsonsupportedmoderate

In a randomized, double-blind, placebo-controlled trial of adolescents with newly diagnosed primary hypertension, lowering uric acid with allopurinol normalized blood pressure in 88% of subjects compared to ~5% on placebo.

"These were pharmacologically naive, they just had high blood pressure recently diagnosed, and 90% of them responded—88% responded to lowering of uric acid. If we lowered the uric acid to five, they became normotensive. And in the placebo arm, only 5% or so responded." (said at 0:15:25)

The statement refers to a randomized, double-blind, placebo-controlled crossover trial by Feig et al. (2008) published in JAMA, which evaluated 30 adolescents with newly diagnosed, previously untreated stage 1 essential hypertension and serum uric acid ≥6 mg/dL. In the trial, allopurinol treatment (200 mg twice daily for 4 weeks) significantly reduced blood pressure compared to placebo, with 20 of 30 (67%) achieving blood pressure normalization across both casual and ambulatory measurements versus 1 of 30 (3.3%, approximately ~5%) on placebo (P < .001), and a higher response rate (~88%) observed among those achieving target serum urate lowering.

0:17:20Richard Johnsonsupportedmoderate

Lowering serum uric acid with allopurinol significantly lowers elevated plasma renin activity in hypertensive adolescents.

"And lowering uric acid worked in part by reducing the renin-angiotensin system, and in this particular study we measured plasma renin activity, which was high in these children—and it's known that new-onset hypertension is often associated with high renin—and it fell quite significantly with treatment." (said at 0:17:20)

A double-blind, randomized, placebo-controlled crossover trial evaluated adolescents (aged 11–17 years) with newly diagnosed, untreated stage 1 essential hypertension and elevated serum uric acid (≥6 mg/dL) treated with allopurinol (PMID: 18728266). Urate-lowering therapy with allopurinol significantly reduced both clinic and 24-hour ambulatory blood pressure compared to placebo. Related pediatric trials and mechanistic evaluations in prehypertensive/hypertensive adolescents demonstrate that lowering uric acid reverses systemic vascular resistance and attenuates renin-angiotensin-aldosterone system pathway activation (PMID: 18728266, PMID: 23006736).

0:20:15Richard Johnsonsupportedvery low

Uric acid directly impairs endothelial nitric oxide levels through arginine transport inhibition, enzyme inhibition, and direct scavenging or binding.

"And when we put uric acid on cells like endothelial cells, we could block nitric oxide. What was fascinating, David, is it does it multiple ways. It does it by working on the transport of arginine. It works on it by blocking the enzyme. It can scavenge nitric oxide itself. We found that it actually binds nitric oxide. I mean, it really has multiple ways of reducing nitric oxide." (said at 0:20:15)

The claim accurately reflects findings from in vitro cell culture and preclinical animal models. Published studies show that uric acid impairs endothelial nitric oxide (NO) bioavailability through several distinct pathways: direct chemical reaction and scavenging of NO (forming 6-aminouracil), attenuation of L-arginine transport (which limits the substrate required for endothelial nitric oxide synthase), and direct inhibition of endothelial NO production. Because this evidence is derived exclusively from in vitro and animal models, the GRADE certainty for these mechanisms is very low.

0:20:00Richard Johnsonsupportedlow

Early morning circadian increases in serum uric acid correlate with drops in nitric oxide levels.

"And there was even a paper in JAMA, I think it was in JAMA, that looked at circadian rhythm, and they found that when uric acid goes up in early morning, nitric oxide levels fall, and you know, there seems to be a circadian rhythm to it as well." (said at 0:20:00)

A correspondence letter published in JAMA (PMID 10807381) and subsequent chronobiology investigations (e.g., PMID 15470965, PMID 14624405) evaluated the 24-hour circadian rhythms of serum nitric oxide (measured as nitrite/nitrate metabolites) and uric acid in healthy humans, reporting an inverse diurnal pattern where morning rises in uric acid correspond to troughs in circulating nitric oxide metabolites. Because the primary evidence describing this specific circadian relationship in JAMA is from preliminary small-cohort chronobiological observations and correspondence, the certainty of evidence is low.

0:22:55Richard Johnsonsupportedlow

In 1890, obesity prevalence in the population was approximately 2% to 3%.

"Obesity was seen in about 2 to 3% of people in 1890, and it was already rising by 1905, 1920, 1940." (said at 0:22:55)

Historical epidemiological data analyzing physical examination records of US Union Army veterans examined between 1890 and 1900 (white men aged 40–69 years) found an obesity prevalence of approximately 3.4%, closely matching the speaker's estimate of roughly 2% to 3% around 1890. Certainty is low due to reliance on historical observational cohort records restricted to specific demographic groups.

0:26:40Richard Johnsonsupportedvery low

In fructose-fed rats, lowering uric acid reduces blood pressure, triglycerides, insulin levels, blood glucose, and hepatic fat.

"But what we found is that when we lowered the the the uric acid, the blood pressure improved, but guess what? The triglycerides were were less in the blood. The insulin levels came down. The glucose levels were less. The the fat in the liver was less. And even the weight gain was was affected too in the first study, not so much, but in subsequent studies, yes." (said at 0:26:40)

The speaker accurately describes published animal findings from their laboratory. In high-fructose-fed Sprague-Dawley rats, lowering uric acid with allopurinol or benzbromarone prevented or reversed hallmark features of metabolic syndrome, including systolic hypertension, hypertriglyceridemia, hyperinsulinemia, and weight gain. Subsequent investigations from the same group demonstrated that blocking uric acid production with allopurinol prevents fructose-induced hepatic steatosis (liver fat accumulation) and de novo lipogenesis. Because the evidence for these specific findings is derived from rodent models, the overall GRADE certainty is very low.

0:28:25Richard Johnsonsupportedmoderate

Fructose metabolism rapidly consumes ATP, and the resulting degraded ATP metabolites are converted into uric acid.

"What happens is that fructose consumes a little bit of ATP and when it does that that degraded ATP turns into uric acid. So, it's like a completely different pathway." (said at 0:28:25)

The speaker's statement accurately describes a well-established metabolic pathway. Unlike glucose metabolism, fructose is rapidly phosphorylated by fructokinase (ketohexokinase) without negative feedback regulation. This process rapidly consumes intracellular ATP, generating AMP. The accumulation of AMP activates AMP deaminase, leading to the catabolism of adenine nucleotides down the purine degradation pathway to produce uric acid.

0:29:22Richard Johnsonsupportedvery low

Endothelial nitric oxide synthase (eNOS) knockout mice spontaneously develop features of the metabolic syndrome.

"and I was aware that mice that had endothelial nitric oxide knocked out developed features of metabolic syndrome. And so there it's called the eNOS knockout, but basically if a mouse doesn't make enough nitric oxide, they can develop features of metabolic syndrome." (said at 0:29:22)

Animal model studies confirm that mice with targeted deletion of endothelial nitric oxide synthase (eNOS-/-) spontaneously develop key features of the metabolic syndrome. Controlled experiments show that young eNOS knockout mice exhibit hypertension, insulin resistance (demonstrated by hyperinsulinemia and reduced glucose infusion rates during hyperinsulinemic-euglycemic clamps), dyslipidemia (1.5- to 2-fold elevations in plasma triglycerides, cholesterol, and free fatty acids), as well as elevated uric acid and fibrinogen levels compared to wild-type controls.

0:29:48Richard Johnsonsupportedmoderate

Muscle glucose uptake partially depends on nitric oxide-mediated vasodilation to deliver glucose, and inhibiting this mechanism can cause insulin resistance.

"one of the ways that um glucose is taken up in muscle, part of it requires a little bit of vasodilation and the blood vessels have to be um you know, dilated a little bit to help uh deliver the glucose to the muscle. And if you just um uh in- inhibit that component, that can cause a little bit of insulin resistance." (said at 0:29:48)

Clinical physiological studies and mechanistic animal models confirm that insulin-mediated microvascular recruitment and vasodilation, driven by nitric oxide production, are required for full glucose delivery and disposal in skeletal muscle. Pharmacological or genetic inhibition of this endothelial nitric oxide pathway blunts insulin-stimulated skeletal muscle blood flow and reduces glucose uptake by approximately 20% to 30%, inducing insulin resistance.

0:30:23Richard Johnsonsupportedvery low

Treating endothelial cells with uric acid blocks nitric oxide production.

"endothelial cells, but when we treated them with uric acid, it blocked the nitric oxide production." (said at 0:30:23)

In vitro laboratory experiments demonstrate that treating cultured endothelial cells (including bovine aortic endothelial cells and human umbilical vein endothelial cells) with uric acid significantly inhibits endothelial nitric oxide synthase (eNOS) activity and decreases nitric oxide (NO) production.

0:31:38Richard Johnsonsupportedhigh

Acute administration of fructose does not stimulate insulin secretion or immediately elevate blood glucose substantially in animals or humans.

"And fructose actually doesn't stimulate insulin. Uh and it when you give fructose to an animal or to to a human, uh glucose goes up a little bit, but it's it can often be delayed and it's not very much. So, it's actually what we call low-glycemic um carbohydrate." (said at 0:31:38)

Extensive acute feeding trials and reviews in humans and animal models demonstrate that fructose ingestion produces a much smaller postprandial rise in blood glucose and insulin compared with glucose or starch-based carbohydrates. Because fructose does not directly stimulate pancreatic beta-cell insulin secretion to the degree glucose does and is primarily metabolized in the liver, it produces minimal acute glycemic excursion and is classified as a low-glycemic index carbohydrate.

0:32:07Richard Johnsonsupportedvery low

Chronic feeding of fructose to animals induces severe insulin resistance, resulting in elevated glucose and high insulin levels.

"But when you give fructose to animals, over time they become severely insulin resistant. They become resistant to the effects of insulin and the glucose levels go up. And so you end up with a high insulin, high glucose state when you chronically feed an animal fructose" (said at 0:32:07)

The speaker's statement accurately describes a standard and well-characterized preclinical animal model. Chronic high-fructose diets in rodents consistently induce insulin resistance, fasting hyperinsulinemia, and hyperglycemia, along with other features of metabolic syndrome. Because this evidence is derived from animal models, the GRADE certainty is rated as very low.

0:34:55Richard Johnsonsupportedmoderate

A mutation in uricase occurred in ancestral great apes and humans approximately 15 million years ago that eliminated uricase activity.

"So, again, there was a mutation in an enzyme called uricase. Uh it happened around 15 million years ago and that mutation occurred in our ancestors and it was also the ancestors of the great apes and the ancestors of humans." (said at 0:34:55)

Evolutionary genomic and metabolic studies confirm that ancestral hominoids (the common ancestors of humans and other great apes) experienced inactivating mutations (pseudogenization) in the urate oxidase (uricase) gene during the Miocene epoch (~13–17 million years ago, commonly cited as approximately 15 million years ago). This evolutionary event completely eliminated functional uricase activity in humans and great apes, resulting in higher circulating uric acid levels compared to other mammals.

0:42:15Richard Johnsonsupportedvery low

Resurrecting ancestral uricase and inserting it into human liver cells suppresses the large fat-accumulation response seen when uricase-deficient human liver cells are exposed to fructose.

"And Eric was what is brilliant molecular biologist who can actually resurrect extinct genes. And he went and he resurrected the extinct uricase uh from these early apes. And then we put that uricase into liver cells, human liver cells that don't have uricase. And then when we exposed them to sugar, exposed them to fructose, what happened was in the normal cell made a little bit of fat. But the uricase was there and the uric acid levels weren't very high. But when we put fructose on liver cells that in which we the uricase enzyme had been knocked out, we got this whopping response with sugar. I mean, with of fat." (said at 0:42:15)

In a 2014 study led by Eric Gaucher, Richard Johnson, and colleagues (PNAS), ancestral sequence reconstruction was used to resurrect extinct primate uricase enzymes. When stably transfected into uricase-deficient human HepG2 liver cells, functional ancestral uricase suppressed the heightened lipogenic (fat-accumulating) response to fructose that occurs in uricase-deficient human cells. Because this evidence comes solely from in vitro cell-culture experiments, the GRADE certainty is very low.

0:56:14David Perlmutter (host)supportedmoderate

Flavonoids like quercetin and luteolin inhibit the enzyme xanthine oxidase and reduce uric acid production.

"And some of these flavonoids act in a similar mechanism as does the actual pharmaceutical allopurinol by inhibiting xanthine oxidase. Things like quercetin, luteolin can can actually help us reduce our production of uric acid." (said at 0:56:14)

Extensive in vitro, animal, and clinical evidence supports the claim that flavonoids such as quercetin and luteolin inhibit xanthine oxidase and lower uric acid levels. In vitro enzymatic assays demonstrate that both quercetin and luteolin act as direct competitive/mixed-type inhibitors of xanthine oxidoreductase (xanthine oxidase), the enzyme responsible for catalyzing the final steps of uric acid synthesis. Animal studies show that both compounds reduce liver xanthine oxidase activity and lower serum urate. Furthermore, a randomized, double-blind, placebo-controlled crossover trial in humans found that daily supplementation with 500 mg of quercetin for 4 weeks significantly reduced plasma uric acid concentrations.

0:57:54Richard Johnsonsupportedmoderate

A clinical study in Mexico showed that a low-added-sugar diet supplemented with whole natural fruits improved metabolic syndrome as well as or slightly better than a low-sugar diet without fruit supplements.

"So we did a study in Mexico where we put people on a diet low in added sugars. It was low in refined sugar, was low in high-fructose corn syrup... And the other group had the mild caloric restriction and also the low refined sugar, low high-fructose corn syrup, but they were given fruit supplements. And what we found is both worked to reduce the metabolic syndrome, and in fact, the one with the fruit supplements tended to do a little bit better." (said at 0:57:54)

A randomized controlled trial conducted by Madero and colleagues in Mexico evaluated 131 overweight or obese adults placed on energy-restricted diets that restricted added sugars and refined fructose, comparing a strict low-fructose diet (<20 g/day) to a moderate-fructose diet supplemented with natural fruits (50–70 g/day) over 6 weeks. Both diets resulted in significant improvements in metabolic syndrome parameters, including blood pressure, lipid profiles, fasting glucose, insulin resistance, and uric acid, with the group supplemented with natural fruits achieving significantly greater weight loss (4.19 kg vs. 2.83 kg, P = 0.0016).

0:59:45Richard Johnsonsupportedmoderate

Epidemiological studies indicate that drinking fruit juice increases the risk for obesity, whereas consuming whole natural fruits does not.

"So the epidemiologic studies suggest that fruit juice can increase the risk for obesity, whereas natural fruits don't." (said at 0:59:45)

Epidemiological evidence from prospective cohort studies supports the claim. Systematic reviews and meta-analyses of prospective cohort studies show that higher consumption of 100% fruit juice is associated with BMI gain in children and increased body weight in adults (particularly in models unadjusted for total energy intake). In contrast, prospective cohort studies consistently show that higher consumption of whole fruits is inversely associated with long-term weight gain and associated with a reduced risk of adiposity.

0:46:25Richard Johnsonsupportedhigh

Most glucose uptake into the brain does not require insulin, whereas glucose uptake into skeletal muscle is insulin-dependent.

"the muscle likes insulin needs insulin to move the glucose into the muscle. And the liver does too to some extent. But, particularly the muscle likes um needs insulin to drive glucose into the muscle. The muscle can use a lot of our glucose. But, the brain can use a lot of glucose, too. But, most of the brain does not require insulin uh to get into the brain." (said at 0:46:25)

The speaker's statement accurately reflects established human physiology. Brain glucose entry across the blood-brain barrier and into neurons is mediated constitutively by GLUT1 (endothelial cells/astrocytes) and GLUT3 (neurons), which are located continuously on the plasma membrane and do not require insulin for baseline transport. In contrast, glucose uptake into skeletal muscle is primarily mediated by GLUT4, an insulin-dependent glucose transporter that remains largely sequestered in intracellular vesicles under basal conditions and translocates to the cell surface in response to insulin stimulation.

  • supports: Intracellular organization of insulin signaling and GLUT4 translocation. (Recent progress in hormone research 2001) · cited 255x in the literature
    "GLUT1 is ubiquitously expressed with particularly high levels in human erythrocytes and in the endothelial cells lining the blood vessels of the brain. GLUT3 is expressed primarily in neurons and, together, GLUT1 and GLUT3 allow glucose to cross the blood-brain barrier and enter neurons... The GLUT4 isoform is the major insulin-responsive transporter that is predominantly restricted to striated muscle and adipose tissue. In contrast to the other GLUT isoforms, which are primarily localized to the cell surface membrane, GLUT4 transporter proteins are sequestered into specialized storage vesicles that remain within the cell's interior under basal conditions. As postprandial glucose levels rise, the subsequent increase in circulating insulin activates intracellular signaling cascades that ultimately result in the translocation of the GLUT4 storage compartments to the plasma membrane." (abstract, description of GLUT isoforms, passage verified)
    pubmedfull study (doi)
  • supports: Molecular biology of mammalian glucose transporters. (Diabetes care 1990) · cited 871x in the literature
    "The GLUT1 (erythrocyte) and GLUT3 (brain) facilitative glucose-transporter isoforms may be responsible for basal or constitutive glucose uptake... The subcellular localization of the GLUT4 (muscle/fat) isoform changes in response to insulin, and this isoform is responsible for most of the insulin-stimulated uptake of glucose that occurs in muscle and adipose tissue." (abstract, summary of transporter functions)
    pubmedfull study (doi)
0:56:28Richard Johnsonsupportedvery low

Flavonoids including luteolin, quercetin, astilbin, and compounds in mangosteen directly block fructose metabolism.

"Also, they block fructose metabolism themselves. We worked with luteolin and quercetin and mangosteen, astilbin." (said at 0:56:28)

Preclinical and mechanistic research supports the finding that specific flavonoids can inhibit or downregulate key enzymes of fructose metabolism, primarily fructokinase (ketohexokinase). For example, luteolin has been identified and investigated as a fructokinase inhibitor that mitigates endogenous fructose-mediated metabolic and renal injury in rodent models. Similarly, quercetin has been demonstrated to downregulate ketohexokinase (Khk) gene expression in rats fed high-fructose diets. Evidence for these compounds is currently limited to in vitro and animal models.

1:00:51Richard Johnsonsupportedmoderate

Among all types of alcohol, beer raises uric acid levels the most and is associated with the development of metabolic syndrome.

"So beer in particular is the Of all the types of alcohol, it raises the uric acid the most, and it's associated with development of metabolic syndrome." (said at 1:00:51)

Epidemiological and clinical studies consistently show that among alcoholic beverages, beer has the strongest effect on increasing serum uric acid concentrations, followed by distilled liquor, whereas moderate wine intake typically has little to no effect. This pronounced effect is attributed to beer's high purine content (notably guanosine) in addition to the uric acid-increasing effects of ethanol metabolism. Furthermore, hyperuricemia and high beer consumption are established risk factors associated with the components and development of metabolic syndrome.

1:04:49Richard Johnsonsupportedmoderate

The relationship between serum uric acid levels and blood pressure is linear across a wide range.

"Well, so in terms of the relationship of uric acid and blood pressure, it's linear for a long ways." (said at 1:04:49)

Systematic reviews and dose-response meta-analyses of prospective cohort studies support the claim that serum uric acid (SUA) levels exhibit a linear relationship with blood pressure and hypertension risk across a wide range of values. A meta-analysis of 17 prospective cohort studies involving 321,716 adults confirmed a positive, linear dose-response relationship between SUA levels and incident hypertension (p for non-linearity = 0.069), with each 1 mg/dL increase in SUA associated with a 10% increase in risk. Similarly, a meta-analysis assessing prehypertension risk across 79,358 participants found a linear dose-response relationship (p for non-linearity = 0.368), with a 12% increase in prehypertension risk per 1 mg/dL increment in SUA.

1:04:59Richard Johnsonsupportedmoderate

A serum uric acid level around 5.2 to 5.5 mg/dL is an inflection point above which the risk for diabetes, obesity, and kidney disease begins to rise significantly.

"But when it comes to things like diabetes and obesity and risk for kidney disease, it does seem to be that around 5.2 to 5.5 is is like an inflection point." (said at 1:04:59)

Epidemiological cohort studies and meta-analyses support the concept that cardiometabolic and diabetes risks begin to rise non-linearly at serum uric acid (SUA) concentrations around 5.2 to 5.6 mg/dL, which is substantially lower than the traditional laboratory threshold for hyperuricemia (6.8–7.0 mg/dL for gout). In a dose-response meta-analysis of prospective cohort studies examining diabetes incidence, a non-linear relationship was observed with relative risks becoming statistically significant around 5.5 mg/dL (RR 1.25, 95% CI 1.16–1.35) compared to non-significant elevations at 4.5 mg/dL (RR 1.10, 95% CI 0.99–1.22). Similarly, large observational cohorts such as the URic acid Right for heArt Health (URRAH) study and the Brisighella Heart Study identify cut-off thresholds around 5.5 to 5.6 mg/dL for metabolic syndrome, although specific thresholds for incident kidney disease progression show wider variation across populations.

1:08:33David Perlmutter (host)supportedmoderate

Prolonged fasting and intense exercise temporarily increase blood uric acid levels.

"Make sure when you check your uric acid level that you haven't come off a three-day fast, or you just haven't done some overly intense exercise." (said at 1:08:33)

Published human studies demonstrate that prolonged fasting leads to ketosis and transiently elevated serum uric acid levels (hyperuricemia), primarily because circulating ketone bodies (such as beta-hydroxybutyrate) and organic acids compete with uric acid for renal tubular excretion. Similarly, strenuous or exhaustive exercise accelerates purine nucleotide degradation and produces lactic acid, temporarily raising blood uric acid concentrations. Consequently, undergoing multi-day fasting or intense exertion immediately prior to blood testing can artificially elevate measured uric acid levels.

1:11:38David Perlmutter (host)supportedmoderate

There is a feed-forward cycle between insulin and uric acid clearance in the kidneys.

"there is a feed-forward cycle as it relates to insulin in the kidney with respect to uric acid" (said at 1:11:38)

Evidence demonstrates a bidirectional feed-forward cycle (often described as a vicious cycle) linking insulin and renal uric acid clearance. Hyperinsulinemia and insulin resistance reduce the fractional excretion of urate by stimulating renal urate transporters (notably URAT1/SLC22A12 and GLUT9), increasing renal urate reabsorption and elevating serum uric acid levels. In turn, elevated uric acid promotes systemic insulin resistance, endothelial dysfunction, oxidative stress, and impaired pancreatic beta-cell function, further worsening hyperinsulinemia.

2

Corroborated by web sources

0:35:25Richard Johnsoncorroborated (web)

Lesser apes such as gibbons acquired an independent parallel mutation that knocked out uricase around the same time as ancestral great apes.

"it wasn't just the uh the ancestor to humans and great apes, but the ancestors to the lesser apes, like the gibbon, also had the same or it was a different mutation, but it knocked out uricase around the same time." (said at 0:35:25)

No published record matching the specific claim that lesser apes, such as gibbons, acquired an independent parallel mutation knocking out uricase around the same time as great apes was located; this does not prove the claim false.

corroborated by web sources

Genetic and evolutionary studies confirm that the uricase gene was independently inactivated in lesser apes, such as gibbons, through distinct mutations separate from the pseudogenization event in ancestral great apes during the Miocene epoch.

nih.govoup.comgsu.edu

0:51:33Richard Johnsoncorroborated (web)

Around 1920, people living in America and England had average uric acid levels of 3 to 4 mg/dL.

"And around 1920, humans had—people living in America and England had uric acid levels of three or four, and now everybody's got higher levels." (said at 0:51:33)

No published record matching the claim that average serum uric acid levels among people living in America and England around 1920 were 3 to 4 mg/dL was located; this does not prove the claim false.

corroborated by web sources

Historical biomedical studies and reviews report that average uric acid levels in Western populations during the 1920s were approximately 3.5 mg/dL (within the 3 to 4 mg/dL range) before rising significantly in subsequent decades.

nih.gov

12

No source found (not proven false)

0:12:12Richard Johnsonunverifiedvery low

Prolonged hyperuricemia in rats causes kidney-driven hypertension that persists even after uric acid levels are returned to normal.

"But what we found, as I said, was that initially the high blood pressure was associated with high uric acid and was driven by the uric acid, but over time the kidney took over and then you could lower the uric acid and the high blood pressure persisted." (said at 0:12:12)

No published record matching the claim that prolonged hyperuricemia in rats causes kidney-driven hypertension that persists even after uric acid levels are returned to normal was located; this does not prove the claim false.

0:23:15Richard Johnsonunverifiedvery low

In 1890, diabetes prevalence was reported by Sir William Osler as approximately 2 cases per 100,000 people.

"Diabetes was like two cases per 100,000 people in 1890, that's what, you know, Sir William Osler wrote in his textbook, and then it started to increase dramatically into the '20s and the '40s and the '50s." (said at 0:23:15)

No published record matching the claim that Sir William Osler reported a diabetes prevalence of approximately 2 cases per 100,000 people in 1890 was located; this does not prove the claim false.

0:23:35Richard Johnsonunverifiedvery low

A 1905 study by Janeway of 500 individuals found a hypertension prevalence of only 3% to 5%.

"High blood pressure was actually rare back in 1905, and Janeway, who studied this, you know, 500 people, said there was only like 3 to 5% of people had high blood pressure back then." (said at 0:23:35)

No published record matching a 1905 study by Theodore Janeway evaluating hypertension prevalence in 500 individuals and finding a rate of 3% to 5% was located; this does not prove the claim false. Theodore Caldwell Janeway published a foundational monograph, *The Clinical Study of Blood-Pressure*, in 1904 and subsequent clinical series of patients with elevated blood pressure, but no indexed epidemiological study confirming the specific 1905 cohort and prevalence figures mentioned in the claim was identified in the available literature.

0:24:25Richard Johnsonunverifiedvery low

Average population serum uric acid levels increased from around 3.0 mg/dL in the 1920s to approximately 5.5 to 6.0 mg/dL in modern times.

"And it's very easy to show that uric acid levels went from about three milligrams percent in 1920 to an average of like five and a half or six milligrams percent like now." (said at 0:24:25)

No published record matching the claim that average population serum uric acid levels increased from approximately 3.0 mg/dL in the 1920s to 5.5 to 6.0 mg/dL in modern times was located; this does not prove the claim false.

0:09:17Richard Johnsonunverifiedvery low

Approximately 25% to 30% of people with high blood pressure have elevated serum uric acid, and in severe hypertension the prevalence rises to 50% to 75%.

"it was known that 25% of people, 30% of people with high blood pressure have a high uric acid, and if you have bad hypertension, it's like 50 or even 75%." (said at 0:09:17)

No published record matching the specific prevalence estimates (that 25% to 30% of individuals with hypertension and 50% to 75% of those with severe hypertension have hyperuricemia) was located; this does not prove the claim false.

0:41:30Richard Johnsonunverifiedvery low

Rats administered a uricase inhibitor along with fructose show more severe metabolic syndrome, more liver fat, higher blood pressure, and worse insulin resistance than rats given the same dose of fructose alone.

"And lo and behold, the animals that got the uricase inhibitor plus fructose, even though they got the same amount of fructose, they they showed a lot worse metabolic syndrome. They had more fat in their liver. They had higher blood pressures. They had worse insulin resistance." (said at 0:41:30)

No published record matching the claim that rats administered a uricase inhibitor along with fructose show more severe metabolic syndrome, higher liver fat, increased blood pressure, and worse insulin resistance compared to rats given fructose alone was located; this does not prove the claim false.

0:48:53Richard Johnsonunverifiedvery low

Gorillas have serum uric acid levels around 3 to 4 mg/dL, whereas monkeys with functional uricase have levels around 1 to 2 mg/dL.

"their uric acid levels were like three. Uh they weren't seven or eight. They were like three or four milligrams percent. And the uh monkeys and stuff that had the uricase, they had uric acid levels of one or two." (said at 0:48:53)

No published record matching the claim that gorillas have serum uric acid levels around 3 to 4 mg/dL while monkeys with functional uricase have levels around 1 to 2 mg/dL was located; this does not prove the claim false.

0:51:03Richard Johnsonunverifiedvery low

Yanomami Indians living in southern Venezuela have serum uric acid levels around 3 mg/dL, compared to 5.5 to 6 mg/dL in Western researchers.

"And their uric acid levels were like three, just like the gorilla. Whereas the members of the party that had gone down there, like Jim Neel and Bill Oliver's blood, their uric acids were like five and a half, six." (said at 0:51:03)

No published record matching the claim that Yanomami individuals had serum uric acid levels around 3 mg/dL compared to 5.5 to 6 mg/dL in visiting researchers (such as James Neel or William Oliver) was located; this does not prove the claim false.

1:00:24David Perlmutter (host)unverifiedvery low

Close to 70% of processed foods on grocery store shelves in the United States contain added sweeteners.

"close to 70% of the processed foods on the grocery store shelves in America now with added sweetener, much of that derived from high-fructose corn syrup." (said at 1:00:24)

No published record matching the claim that close to 70% of processed foods on grocery store shelves in the United States contain added sweeteners was located; this does not prove the claim false.

1:00:36David Perlmutter (host)unverifiedvery low

Alcohol metabolism consumes ATP to produce AMP, which leads to uric acid creation.

"And the third player would be alcohol, which also enters into the similar metabolic pathway, utilizing ATP to AMP and creating uric acid." (said at 1:00:36)

No published record matching the claim that alcohol metabolism utilizes ATP to AMP to create uric acid was located; this does not prove the claim false.

1:01:41Richard Johnsonunverifiedvery low

Non-alcoholic beer increases the risk of raising uric acid levels due to brewer's yeast purines.

"Right, it's the brewer's yeast. In fact, non-alcoholic beer also increases the risk for raising uric acid in a" (said at 1:01:41)

No published record matching the claim that non-alcoholic beer increases the risk of raising uric acid levels due to brewer's yeast purines was located; this does not prove the claim false. While studies have evaluated the purine content of beer and the impact of alcoholic beer on serum uric acid, direct published clinical trials assessing the isolated uric-acid-raising effect of non-alcoholic beer due specifically to yeast purines were not identified.

1:02:27Richard Johnsonunverifiedvery low

Drinking beer raises uric acid levels within two hours, whereas consuming sugar raises uric acid levels within 15 to 30 minutes.

"So if you drink beer, for example, your uric acid levels will go up within two hours. If you drink sugar, your uric acid levels go up in 15 to 30 minutes." (said at 1:02:27)

No published record matching the claim that drinking beer raises uric acid levels within two hours whereas consuming sugar raises uric acid levels within 15 to 30 minutes was located; this does not prove the claim false.

Unverified means no publication matching the claim was located; it does not prove the claim false. Spotted an error? See the corrections policy - disputes from the people quoted are prioritized.