HoldsUp

DavidPerlmutterMD · 2021-05-03 · David Perlmutter (host), Robert H. Lustig

Take Back Your Health - with Dr. Robert H. Lustig | The Empowering Neurologist EP. 122

49 research-tied claims examined: 7 contradicted 7 overstated 7 context 20 supported 8 unverified

20

Supported by research

0:04:03Robert H. Lustigsupportedhigh

The hormone leptin was discovered in 1994.

"that really started my obesity career, was the discovery of leptin in 1994." (said at 0:04:03)

The hormone leptin (the product of the obese/ob gene) was identified and cloned by Jeffrey Friedman and colleagues in 1994, a landmark discovery that established adipose tissue as an active endocrine organ regulating energy balance.

0:06:35Robert H. Lustigsupportedvery low

In animal studies, lesioning the hypothalamus causes hypothalamic obesity by placing the neural connection between the brain and the pancreas for insulin release into hyperdrive.

"And so lesioning the hypothalamus led to this obesity syndrome in rats called hypothalamic obesity. And what was determined was that the reason that those rats gained so much weight was because the connection between the brain and the pancreas to release insulin was in hyperdrive." (said at 0:06:35)

Classic animal experiments established that lesions to the ventromedial hypothalamus (VMH) in rodents produce rapid hyperinsulinemia and hypothalamic obesity primarily driven by parasympathetic (vagus nerve) overactivity connecting the brain to the pancreatic beta-cells. Studies demonstrated that acute post-lesion hyperinsulinemia is abolished by subdiaphragmatic vagotomy, and that transplanting denervated pancreatic tissue to the kidney capsule prevents the development of hyperinsulinemia and hypothalamic obesity after VMH lesions. Because this evidence is derived entirely from animal models, the certainty of evidence is graded as very low.

0:07:36Robert H. Lustigsupportedmoderate

In pediatric patients with hypothalamic obesity, administering octreotide suppressed insulin release, resulting in weight loss, spontaneous physical activity, and quality-of-life improvements that correlated directly with the degree of insulin suppression.

"So in a clinical research protocol, we gave kids with this disorder this drug, octreotide, to suppress insulin. And lo and behold, not only did they lose weight—which was remarkable enough because these kids only gained weight and fast, so that was remarkable on its own—but they started exercising spontaneously... and it turned out the degree of quality of life improvement correlated with the degree of insulin suppression: the lower we got the insulin, the better these kids felt." (said at 0:07:36)

Published clinical trials led by the speaker directly support this claim. In an open-label pilot study of 8 pediatric patients with hypothalamic obesity (PMID 10431109), octreotide administration suppressed excessive insulin secretion during oral glucose tolerance testing and led to significant weight loss (-4.8 kg vs +6.0 kg pre-study). In a subsequent randomized, double-blind, placebo-controlled trial of 18 children (PMID 12788859), octreotide suppressed insulin response (P = 0.034), significantly reduced weight gain and BMI (+1.6 kg vs +9.1 kg for placebo, P < 0.001; BMI -0.2 vs +2.2 kg/m²), improved physical activity per parent report (P = 0.03), and demonstrated quality-of-life improvements that directly correlated with the degree of insulin suppression (P = 0.041). The certainty is moderate given the randomized controlled design, limited by the small sample size inherent to this rare condition.

0:10:09Robert H. Lustigsupportedmoderate

Excess circulating insulin activates intracellular pathways leading to vascular smooth muscle proliferation, reduced cellular autophagy, and an increased risk of cancer.

"And the problem is if you have too much, you activate a whole set of other pathways in the cell, all of which lead to vascular smooth muscle proliferation, reduced autophagy, and increased risk for cancer." (said at 0:10:09)

The speaker accurately summarizes well-established physiological and molecular actions of elevated insulin signaling. Insulin stimulates vascular smooth muscle cell (VSMC) proliferation and migration primarily through the mitogen-activated protein kinase (MAPK) pathway. Concurrently, activation of the PI3K/Akt/mTOR pathway by insulin suppresses macroautophagy. Chronic hyperinsulinemia is also well recognized in epidemiological and mechanistic literature as a driver of increased risk and progression for several types of cancer through its mitogenic and anti-apoptotic signaling.

0:11:11Robert H. Lustigsupportedhigh

The insulin receptor is coupled to the mitogen-activated protein kinase (MAP kinase) pathway, which stimulates cell growth and division.

"There is—the insulin receptor is coupled to a pathway in the cell that basically makes cells grow and divide. It's called MAP kinase, mitogen-activated protein kinase, and that pathway is very important when you are growing, like for instance a fetus." (said at 0:11:11)

The speaker accurately described the canonical signaling pathway downstream of the insulin receptor. Insulin binding leads to phosphorylation of insulin receptor substrates (such as IRS-1), which couples to the mitogen-activated protein kinase (MAPK/ERK) cascade to stimulate cellular growth, division, and mitogenesis. This signaling mechanism plays a key role in cellular proliferation and developmental processes, including fetal growth.

0:22:56Robert H. Lustigsupportedhigh

Fructose is phosphorylated to fructose-1-phosphate in the liver, depleting ATP to ADP and AMP, which is subsequently converted into uric acid.

"So first of all, fructose is phosphorylated in the liver to fructose-1-phosphate. That reduces ATP to ADP, and then that goes to AMP, that goes to uric acid. And that's the reason why sugar causes gout, is because it raises uric acid." (said at 0:22:56)

The biochemical mechanism described by the speaker is well established in metabolic research. In the liver, fructose is rapidly phosphorylated to fructose-1-phosphate by fructokinase (ketohexokinase). Unlike glucose phosphorylation, this step is not tightly regulated by intracellular energy status, leading to transient depletion of intracellular adenosine triphosphate (ATP) and accumulation of adenosine diphosphate (ADP) and adenosine monophosphate (AMP). The excess AMP enters the purine catabolic pathway, resulting in increased production and systemic accumulation of uric acid, which directly links high fructose and sugar intake to hyperuricemia and gout.

0:23:36Robert H. Lustigsupportedvery low

A 2019 study led by Softic and C. Ronald Kahn showed that glucose stimulates mitochondrial fatty acid oxidation via AMP kinase and hydroxyacyl-CoA dehydrogenase (HADH), whereas fructose inhibits AMP kinase and long-chain acyl-CoA dehydrogenase (ACADL).

"Ron Kahn, the head of the—CEO of Joslin Diabetes Center at Harvard—published a paper, the first author was Softic, S-O-F-T-I-C, in 2019 where he showed that glucose stimulates mitochondrial function through activation of both AMP kinase and HADH, which is hydroxyacyl-CoA dehydrogenase, which is the third step on fatty acid oxidation... Fructose, not only does it inhibit AMP kinase, but it also inhibits another enzyme called ACADL, acyl-CoA dehydrogenase long-chain. And so what happens is the fats build up, and so now you got fatty liver." (said at 0:23:36)

A 2019 mouse study by Softic et al. and C. Ronald Kahn published in Cell Metabolism demonstrated that dietary fructose and glucose exert divergent effects on hepatic mitochondrial function and fatty acid oxidation. Fructose supplementation on a high-fat diet impaired fatty acid oxidation through mechanisms including acetylation and reduced activity of long-chain acyl-CoA dehydrogenase (ACADL) and CPT1a, while glucose supplementation did not impair mitochondrial fat oxidation. Because these findings are derived from preclinical rodent models, the GRADE certainty regarding direct human clinical outcomes is very low, but the speaker's summary accurately reflects the published study's findings and mechanisms.

0:28:32Robert H. Lustigsupportedmoderate

Beta-hydroxybutyrate functions as a signaling molecule that activates sirtuins, stimulating mitochondrial oxidative burning.

"and you're also getting the benefit of the beta-hydroxybutyrate, which is in itself a signaling molecule. It signals sirtuins, which signal mitochondrial function, which signal burning, which is good." (said at 0:28:32)

Preclinical evidence demonstrates that beta-hydroxybutyrate (BHB) acts as a signaling metabolite that upregulates and activates sirtuin enzymes (such as SIRT1 and SIRT3). Activation of these mitochondrial and nuclear sirtuins downstream promotes mitochondrial biogenesis, enhances mitochondrial membrane potential, and stimulates mitochondrial oxidative respiration and metabolic function.

0:29:40Robert H. Lustigsupportedhigh

Wheat is a hexaploid organism rather than a diploid organism.

"Turns out wheat is a very complex organism. It's a hexaploid, not diploid, and there" (said at 0:29:40)

Common bread wheat (Triticum aestivum) is an allohexaploid organism (2n = 6x = 42 chromosomes) composed of three distinct subgenomes (A, B, and D), rather than a diploid organism (which possesses only two sets of chromosomes). It arose through natural hybridization between a tetraploid wheat progenitor (AABB) and the diploid wild grass Aegilops tauschii (DD).

0:25:28David Perlmutter (host)supportedhigh

The diabetes drug metformin acts to stimulate AMP kinase.

"The drug metformin, which is given—used for diabetes—acts to stimulate this AMP kinase." (said at 0:25:28)

Metformin is a standard first-line medication for type 2 diabetes mellitus. Extensive pharmacological and biochemical research confirms that metformin stimulates/activates AMP-activated protein kinase (AMPK), primarily secondary to its mild inhibition of mitochondrial complex I, which alters cellular energy charge (increasing AMP/ATP ratios). While research indicates metformin also exerts some AMPK-independent metabolic effects, stimulation of AMPK is a well-established component of its molecular mechanism.

0:37:48Robert H. Lustigsupportedvery low

Starving gut bacteria causes them to consume the intestinal epithelial mucin layer, reducing tight junction integrity and allowing lipopolysaccharides and bacteria to enter the bloodstream.

"And if you eat that mucin layer off your intestinal epithelial cells, now the bacteria are opposed right on your intestinal epithelial cells, and that has been shown to reduce the integrity of the tight junctions that basically keep your intestinal barrier. And so now you've got lipopolysaccharides and cytokines and bacteria themselves making their way through to your bloodstream" (said at 0:37:48)

The speaker accurately describes a mechanism demonstrated in gnotobiotic and murine models. Landmark research showed that when gut microbiota are deprived of dietary fiber, commensal bacteria switch to utilizing host-secreted mucin glycoproteins as an energy source. This degrades the protective colonic mucus layer, places bacteria in direct contact with the intestinal epithelium, disrupts mucosal barrier integrity, and facilitates bacterial translocation and inflammation. Because the complete causal chain is demonstrated primarily in animal models, the certainty of evidence for humans is very low.

0:39:11Robert H. Lustigsupportedmoderate

Colonic bacteria ferment soluble fiber into short-chain fatty acids, specifically propionate and butyrate, which exert anti-inflammatory and insulin-sensitizing effects.

"The colonic bacteria love soluble fiber, and they do you a favor because not only do they chew it up, but the waste product of their chewing up that fiber is short-chain fatty acids, propionate and butyrate, which turn out to be anti-inflammatory and anti-insulin for you." (said at 0:39:11)

Colonic bacterial fermentation of soluble dietary fiber produces short-chain fatty acids (SCFAs), principally acetate, propionate, and butyrate. A substantial body of preclinical research and human interventional trials demonstrates that these metabolites promote anti-inflammatory pathways, support intestinal barrier integrity, and improve insulin sensitivity and glycemic control.

0:41:11David Perlmutter (host)supportedhigh

Chronic non-communicable degenerative diseases are the number one cause of death globally according to the World Health Organization.

"these chronic degenerative conditions are, according to the World Health Organization, the number one cause of death on the planet." (said at 0:41:11)

Epidemiological data from the World Health Organization and global health surveillance establish that non-communicable diseases (NCDs)—including cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes—are the leading cause of death globally, accounting for nearly three-quarters of all deaths worldwide.

0:47:47Robert H. Lustigsupportedhigh

Prohormone convertase 1 is the enzyme responsible for cleaving C-peptide from the proinsulin molecule to form mature insulin.

"prohormone convertase 1, which is the enzyme that cleaves the C-peptide out of the proinsulin molecule to make a mature, functional insulin." (said at 0:47:47)

Prohormone convertase 1 (also known as PC1 or PC1/3, encoded by PCSK1) is the primary endoprotease responsible for endoproteolytic cleavage of proinsulin to excise C-peptide and yield mature insulin. While classical models in rodents involved both PC1/3 and PC2 followed by carboxypeptidase E trimming, human beta-cell studies demonstrate that PC1/3 is the primary convertase required for proinsulin processing to mature insulin.

0:54:43Robert H. Lustigsupportedhigh

Hepatic fructose metabolism consumes ATP without a phosphate-scavenging pathway to return it, driving conversion of AMP into uric acid.

"when fructose enters the liver, ATP has to donate a phosphate. So ATP becomes ADP, and then it goes into AMP into uric acid. There's no scavenger mechanism to return that, so it goes to uric acid." (said at 0:54:43)

Published biochemical and clinical research confirms that hepatic fructose metabolism is initiated by ketohexokinase (fructokinase), which rapidly phosphorylates fructose to fructose-1-phosphate using ATP. Because ketohexokinase lacks negative feedback control and traps phosphate in fructose-1-phosphate, rapid ATP depletion occurs alongside intracellular phosphate depletion. This triggers adenylate kinase (converting ADP to AMP) and activates AMP deaminase (normally inhibited by inorganic phosphate), driving purine nucleotide degradation of AMP down the catabolic pathway into uric acid.

0:55:17Robert H. Lustigsupportedmoderate

Uric acid is an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), which contributes to elevated blood pressure.

"uric acid is the endogenous inhibitor of the enzyme in your blood vessels, endothelial nitric oxide synthase, or eNOS, which is your endogenous blood pressure lowerer. And so when your uric acid is high, your blood pressure goes up" (said at 0:55:17)

Preclinical in vitro and animal studies demonstrate that elevated uric acid directly impairs endothelial nitric oxide synthase (eNOS) phosphorylation and activity via the Akt pathway, reducing nitric oxide (NO) bioavailability and contributing to endothelial dysfunction and elevated blood pressure. In animal models, hyperuricemia raises arterial blood pressure, an effect reversible by lowering uric acid (e.g., with allopurinol) or enhancing the nitric oxide pathway (such as with L-arginine). Observational human studies also correlate higher serum uric acid with impaired endothelial function.

0:56:30Robert H. Lustigsupportedhigh

Insulin promotes the reabsorption of sodium at the level of the kidney.

"Insulin helps resorb sodium, and so in the face of a high insulin, that 6.9 grams ends up being enormous." (said at 0:56:30)

The claim is supported. Insulin acts directly on multiple segments of the renal tubule (including the proximal tubule and collecting duct via channels such as ENaC) to facilitate renal sodium reabsorption, acutely decreasing urinary sodium excretion independently of the renin-angiotensin-aldosterone system.

0:58:11David Perlmutter (host)supportedmoderate

Primate ancestors developed uricase gene mutations 14 to 18 million years ago that resulted in elevated uric acid levels.

"Dr. Richard Johnson characterized as being a survival mechanism for our primate ancestors 14 to 18 million years ago when we developed the mutation—the uricase mutation, actually there were several—that led to humans, our ancestors rather, having higher levels of uric acid" (said at 0:58:11)

Evolutionary genomic and biochemical studies led by Dr. Richard Johnson and colleagues confirm that ancestral hominoids underwent pseudogenizing mutations in the urate oxidase (uricase) gene during the mid-Miocene epoch (approximately 14 to 18 million years ago). These mutations led to the loss of functional uricase, resulting in higher circulating uric acid levels. Published work demonstrates that higher uric acid functioned as an evolutionary survival mechanism to stimulate fat accumulation, support gluconeogenesis, and maintain blood pressure during periods of global cooling and nutritional famine.

1:07:55Robert H. Lustigsupportedhigh

SARS-CoV-2 uses ACE2 as its entry point to infect cells.

"Because that COVID virus is so freaking goddamn smart, it uses ACE2 as its entry point. And so the more molecules of ACE2 you have on the surface of your cell, the more chance that that virus is going to infect you." (said at 1:07:55)

Extensive in vitro and molecular studies established early in the COVID-19 pandemic that SARS-CoV-2 utilizes angiotensin-converting enzyme 2 (ACE2) as its primary functional host cell entry receptor. Binding of the viral spike glycoprotein to cell-surface ACE2 enables viral attachment and subsequent host cell entry (often facilitated by host proteases such as TMPRSS2).

1:09:00Robert H. Lustigsupportedmoderate

Studies at UCSF showed that eating real food reduces insulin, fatty liver, uric acid, and ALT in nine days.

"We have shown in our studies at UCSF that you can get your insulin down, and you can get your fatty liver down, and you can get your uric acid and your ALT down in nine days—nine days—by eating real food." (said at 1:09:00)

Studies conducted by Dr. Robert Lustig and colleagues at UCSF (such as the 2016 Obesity trial and 2017 Gastroenterology publication) tested a 9-day dietary intervention in children with obesity and metabolic syndrome. In these studies, dietary sugar/fructose was restricted and substituted isocalorically with starch. The trials demonstrated rapid, statistically significant reductions in hyperinsulinemia and insulin kinetics, liver fat (hepatic steatosis measured via magnetic resonance spectroscopy decreased from a median of 7.2% to 3.8%), visceral fat, and circulating metabolic biomarkers over the 9-day period. Describing this intervention as 'eating real food' refers to the study's design of removing processed/added sugars from the children's diets.

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.