How Protein Can Lower Blood Sugar in Type 2 Diabetes | Dr Nicola Guess | EP#432

Episode Overview

• Host Simon Hill (nutritionist, physiotherapist, author, and co-founder of the gut health company 38TERA) interviews Dr. Nicola Guess (registered dietitian, part-time academic researcher at the University of Oxford, private-practice clinician, and former NHS dietitian circa 2008) on managing and putting type 2 diabetes and prediabetes into remission without weight loss.
• The conversation challenges the conventional paradigm that type 2 diabetes remission requires losing 10 kg of body weight—an approach that is often undesirable or clinically inappropriate for older adults (over 60 or 65 years old, the largest group with type 2 diabetes)—and outlines Dr. Guess's 2022 calorie-independent dietary framework.
• Dr. Guess explains the physiological mechanisms of type 2 diabetes, detailing how intact amino acid sensors on pancreatic beta cells allow a high-protein (30% of calories), low-carbohydrate diet rich in unsaturated fats and viscous fiber to lower blood glucose by more than medications, even while keeping body weight stable.
• The discussion expands into broader metabolic health topics, including liver and pancreatic organ cross-talk, the genetics of fat deposition, why glucose spikes are only directly toxic at diabetic thresholds, and how menopause, Polyendocrine Metabolic Syndrome (formerly PCOS), and night-shift work alter glucose regulation.
• The episode concludes by examining the clinical realities of GLP-1 receptor agonists, addressing misconceptions around lean mass loss, bone density, weight regain upon drug cessation, and how widespread medication use may reshape the commercial food environment.

Key Concepts

• Speaker Disclosures, Funding, and Episode Sponsors: Dr. Guess sees patients in private practice and recently received funding from the UK's National Institute for Health and Care Research (NIHR) to develop a weight-independent dietary program for type 2 diabetes and run a feasibility trial with 150 participants. Simon Hill is the co-founder of 38TERA (which sells in the US, UK, Australia, New Zealand, and soon Canada, using Shopify). Episode sponsors include Function Health (offering 160+ lab tests/year for $1/day; code SIMON25 for a $25 credit at functionhealth.com/simonhill), Shopify (shopify.com/proof), Eight Sleep (Pod 5 smart mattress cover; code THEPROOF for up to $350 off at eightsleep.com/theproof), and IM8 (Daily Ultimate Essentials multinutrient supplement co-founded by David Beckham; code SIMON for 10% off plus a free welcome kit at im8health.com).
• The Evolution of Type 2 Diabetes Remission: Bariatric surgery data originally demonstrated that patients could achieve type 2 diabetes remission, sparking scientific inquiry into whether remission was driven by weight loss or calorie-independent factors. About 7 to 8 years ago, remission became a widely recognized possibility, typically requiring 10 kg of weight loss to strip fat from the liver. While older definitions defined remission as a non-diabetic HbA1c under 48 mmol/mol without medications (with some allowing metformin as "partial remission"), the current official ADA/EASD definition requires an HbA1c less than 48 mmol/mol on two occasions at least 3 months apart without medications.
• Weight-Neutral Remission and the Frailty Trap: Chasing 10 kg of weight loss is often inappropriate for adults over 60 or 65. Dr. Guess has observed 72-year-old clinic patients who lost 10 kg to strip liver fat and ended up looking like "starvation victims," having reduced their weight below a healthy threshold. Building on her 2022 review/framework (and supported by other research groups showing prediabetes remission without weight loss), controlled weight-stable studies show that a high-protein (30% of calories), low-carbohydrate diet lowers postprandial blood glucose by 4 mmol/L (approximately 75 mg/dL), matching or exceeding the effect of medications.
• Pathophysiology, Complications, and Glucose Toxicity Thresholds: Type 2 diabetes may be better understood as a disorder of fat metabolism (fat-derived insulin resistance and organ cross-talk) rather than purely a glucose disorder. While lowering blood glucose in type 2 diabetes 100% reduces microvascular complications (eyes, kidneys, amputations), the data on macrovascular complications (heart attacks and strokes) is much murkier; preventing cardiovascular events requires managing LDL cholesterol and blood pressure. Furthermore, glucose is directly harmful to tissues only at diabetic levels: sustained fasting glucose above 7 mmol/L, HbA1c above 48 mmol/mol, or 2-hour post-meal glucose above 11 mmol/L (with type 2 diabetic spikes reaching 17–18 mmol/L). There is currently no data showing post-meal glucose excursions are directly harmful in people without diabetes.
• Organ Function, Liver Fat, and Genetics: Metabolic health is defined by optimal organ function—specifically an insulin-sensitive skeletal muscular system and a healthy liver, which acts as the primary manager of metabolism. Preclinical studies demonstrate cross-talk between the liver and pancreas, though Dr. Guess hedges that it is very difficult to study the exact extent to which liver fat is causal in type 2 diabetes versus simply linked to calorie excess and obesity. Research by geneticist Hania at the University of Leicester using UK Biobank magnetic resonance (MR) imaging data of pancreatic, liver, intra-abdominal (visceral), and subcutaneous fat shows that genetics dictate fat storage: people genetically able to store fat in subcutaneous tissue are metabolically much healthier than those who deposit it centrally as visceral and liver fat.
• Energy Excess vs. Insulin Resistance First: Addressing whether hyperinsulinemia precedes and causes weight gain, Dr. Guess hedges that determining which comes first in free-living humans is really difficult to study if one happens shortly after the other. However, in controlled overfeeding studies, fasting insulin rises in the short term before any change in body weight occurs, providing direct evidence that calorie excess causes insulin resistance. Conversely, calorie reduction improves metabolism before weight loss occurs, and subsequent weight loss lowers fasting insulin. Additionally, cross-sectional studies of people without diabetes show that defective insulin secretion can be observed before any changes in hepatic or peripheral insulin sensitivity.
• Beta-Cell Amino Acid Sensing: Unlike type 1 diabetes—where beta cells are destroyed by the immune system (and where Dr. Guess declines to comment deeply on stem cell islet infusions because she is "not a type 1 person")—early type 2 diabetes involves a functional defect where beta cells are still present, though restoring beta cells alone without fixing liver fat or muscle insulin resistance would only fix about 10% of the problem. In type 2 diabetes, beta-cell glucose sensors become defective, impairing glucose-stimulated insulin secretion. However, beta-cell amino acid sensors remain functional. Infusing amino acids intravenously or orally in humans, or adding them to in vitro petri dish cultures of beta-cell lines or cadaver beta cells from deceased type 2 diabetes patients, produces a marked insulin response. At Oxford, Dr. Guess's team is studying the 20 amino acids (which act via different mechanisms on beta cells, unlike glucose which uses only one) to identify 3 complementary insulinogenic amino acids for a targeted supplement for older adults who struggle to chew or consume 30% protein—though she notes we will know if this works in about 10 years.
• Why Dietary Guidelines Omit High-Protein Diets: Major organizations like the ADA do not currently recommend high-protein diets for type 2 diabetes because their guideline criteria only include free-living trials lasting longer than 6 or 12 months, where dietary adherence typically drops by 3 months. Well-controlled feeding trials demonstrating the efficacy of high-protein diets usually last 5 to 6 weeks, with the longest running 10 weeks.
• Protective Roles of Protein, Fiber, and Fat Quality: Controlled overfeeding trials demonstrate that protein and amino acids lower liver fat and protect the liver from fat deposition. Physical activity and viscous fiber also act as independent mediators protecting against liver fat. Viscous fiber (from oats and legumes) lowers fasting glucose by reducing hepatic glucose output and improving liver, adipose, and muscle insulin sensitivity, while psyllium husk forms a stomach gel that slows glucose absorption. Regarding whether adding legume fiber provides extra glucose lowering on top of a 30% protein low-carb diet, Dr. Guess hedges, "maybe it does." For dietary fat, controlled trials show replacing saturated fats (like butter) with polyunsaturated fats (PUFAs) reduces visceral and liver fat, while meta-analyses and ward-based studies show monounsaturated fats (MUFAs) lower fasting and postprandial glucose even without high protein. Similarly, the PREDIMED study showed a Mediterranean diet supplemented with nuts, seeds, or olive oil prevented type 2 diabetes without significant weight loss.
• Sex Differences, Menopause, and Polyendocrine Metabolic Syndrome (PCOS): In prediabetes, men are more likely to exhibit isolated elevated fasting glucose (liver insulin resistance) with normal postprandial glucose, whereas premenopausal women tend to have elevated postprandial glucose with normal fasting glucose. After menopause (around age 50+), women shift toward the male phenotype with creeping fasting glucose, though hormone replacement therapy (HRT) studies show restoring female hormones reverts women to the female pattern. In PCOS—recently renamed Polyendocrine Metabolic Syndrome—excess insulin is thought to drive ovarian androgen production. While weight loss improves symptoms, a weight-neutral high-protein, low-carb diet massively reduces 24-hour basal insulin exposure despite acute post-meal insulin spikes. For women with this syndrome who do not have insulin resistance, Dr. Guess states we do not yet know the dietary answer.
• Fasting Insulin Assays and Night-Shift Work: Although about 60% to 70% of the population has elevated fasting insulin (and 12% to 13% has type 2 diabetes), measuring fasting insulin in routine GP practice is impractical because samples must be frozen quickly and suffer from marked inter-assay variability without standardization. Regarding circadian disruption, a study by Dr. Guess's group on NHS shift workers with type 2 diabetes confirmed that rotating night shifts elevates glucose independently of other factors, compounded by waking days longer than 24 hours and poor hospital food environments (vending machines and no microwaves). While eating refined carbs late at night slightly impairs blood pressure and glucose homeostasis, Dr. Guess admits she does not know if data exists on eating a large meal at 10:00 PM after late-night resistance training, though she would "die of shock" if it were harmful; the primary danger of late eating is disrupting sleep, which impairs next-day appetite and insulin sensitivity. She also repeatedly hedges ("I don't know whether we can," "that sounds mad to me") on whether 3 to 5 bouts of 20-second HIIT "exercise snacks" the day after a night shift can reset circadian metabolism.
• GLP-1 Medications, Muscle Mass, and Weight Regain: Echoing commentary by Samuel Klein at a recent ADA meeting and researcher Stuart Phillips, Dr. Guess explains that fears of GLP-1s destroying muscle are misread. "Lean mass" on scans includes water, glycogen, and connective tissue—not just skeletal muscle—and there are no GLP-1 receptors on muscle or bone cells. While absolute lean mass drops during weight loss (e.g., losing 30 kg), the proportion of total body weight from lean mass increases, and physical functionality improves. A secondary modeling study comparing GLP-1 receptor agonists to DPP-4 inhibitors even suggested fragility is lower with GLP-1s, though Dr. Guess notes it remains an open question whether sustained weight loss over many years on GLP-1s will impact bone density. Finally, a paper from her Oxford group showed that weight regain upon stopping GLP-1s is greater than after behavioral interventions, underscoring the need to resolve drug supply issues for low maintenance doses and pair medications with light-touch digital/behavioral nutrition support. Over the next 5, 10, 15, to 30 years, she believes widespread GLP-1 use is 100% more likely to reshape the commercial food environment toward healthier foods than government policy.

Quotes

• At 0:03:02 - "If you have type 2 diabetes and you follow a high protein, low carbohydrate diet—by high protein I'm talking 30% of calories from protein, so it's quite a lot—you can lower your glucose by more than medications." - Dr. Guess explaining the core clinical finding behind calorie-independent dietary management of type 2 diabetes.
• At 0:03:18 - "Postprandial glucose in some of the studies come down by 4 mmol/L. That's—I can't do the maths in my head—but it's about 75 mg/dL. Huge, without weight loss." - Quantifying the magnitude of blood glucose reduction achieved in weight-stable feeding trials.
• At 0:06:33 - "Type 2 diabetes possibly could be better thought of as a disorder of fat metabolism. It's probably fat-derived insulin resistance and organ cross-talk that's causing it." - Reframing the underlying pathophysiology of type 2 diabetes beyond simple blood sugar elevation.
• At 0:06:57 - "Even if you lower glucose, it doesn't necessarily prevent heart attacks or strokes. So now let's think about this from the context of remission: just normalizing your glucose alone is not a guarantee that you're not going to get any of the complications of type 2." - Highlighting why managing LDL cholesterol and blood pressure remains essential for preventing macrovascular complications even when glucose is normalized.
• At 0:09:55 - "It's the dose and the duration of exposure to that dose that matters here. And right now, there's no data that glucose is directly harmful if you don't have diabetes." - Clarifying that transient post-meal glucose excursions are not toxic in normoglycemic individuals.
• At 0:14:32 - "There is really good trial data that protein and amino acids lowers liver fat, but also protects the liver from fat deposition in overfeeding trials." - Explaining how dietary protein directly defends the primary metabolic organ against ectopic fat accumulation.
• At 0:18:32 - "If you overfeed calories, you overwhelm the body very, very quickly. So you see in the short term a rise in fasting insulin before you see any change in weight." - Citing controlled overfeeding evidence to show that energy excess drives hyperinsulinemia rather than insulin resistance preceding calorie excess.
• At 0:22:01 - "If you've got type 2 diabetes and you have a bowl of cereal, your glucose goes up, but your pancreas has no idea because the sensor's not working. But there are amino acid sensors, and they still work in type 2 diabetes." - Illustrating the beta-cell mechanism that allows dietary protein to stimulate insulin secretion when glucose sensing fails.
• At 0:26:18 - "I remember some patients in my clinic who were like 72 years old, and because they'd heard this thing about, 'Oh, you've got to lose 10 kilograms, remove the fat from your liver, that's how you get remission,' they'd done that. And I'm not kidding when I say some of them looked like starvation victims afterwards." - Describing the clinical harm of applying aggressive weight-loss remission protocols to older adults.
• At 0:43:23 - "I never, ever care about whole fruit. Unless someone has an allergy, the idea that anyone needs to be worried or avoiding whole fruit is just madness." - Dismissing fears that fructose in whole fruit contributes to liver fat or insulin resistance.
• At 0:57:21 - "What we see with that high protein, low carb type of diet, the data clearly shows that 24-hour insulin exposure reduces massively, because you're just getting that nice peak after a meal, that's normalizing glucose, and insulin comes straight back down." - Explaining why acute protein-induced insulin spikes actually lower total daily insulin exposure in conditions like Polyendocrine Metabolic Syndrome (PCOS).
• At 1:06:06 - "Well, we know the answer to using GLP-1s on metabolic health: they overwhelmingly improve metabolic health. Like, they prevent heart attacks, they get rid of diabetes, normalize glucose, lower liver fat." - Summarizing the comprehensive cardiometabolic benefits of GLP-1 receptor agonists.

Takeaways

• Adopt a 30% protein, low-carbohydrate diet for weight-neutral glucose control: If you have type 2 diabetes or prediabetes and cannot or should not lose weight (especially if you are over age 60–65), aim for 30% of your calories from protein while reducing carbohydrates to stimulate intact beta-cell amino acid sensors, which can lower post-meal glucose by ~4 mmol/L (75 mg/dL) and help reduce medication burden (such as coming off insulin or dropping from 3 medications down to 1, often keeping metformin).
• Combine lean animal or plant proteins with legumes: Because vegan and meat-based amino acid profiles have only marginal differences in insulin secretory response, pair lean proteins (like fish, chicken breast, or plant-based meat alternatives—which Dr. Guess used to reverse elevated liver fat on MR imaging in a vegan patient eating under 10 g of protein/day) with lentils or chickpeas to gain ~8 g of extra protein plus viscous fiber.
• Skip protein preloading and eat protein with your meal: Do not worry about eating protein 15 to 30 minutes before carbohydrates or following a strict meal order; while preloading works in studies, it is an annoying way to eat, and consuming protein alongside your meal is sufficient to trigger an insulin response.
• Prioritize viscous fiber and unsaturated fats to protect your liver and heart: Incorporate oats, legumes, or a psyllium husk supplement (which forms a gel in the stomach to slow glucose absorption) and replace saturated fats like butter with PUFAs and MUFAs (nuts, seeds, olive oil) to strip liver fat, lower fasting glucose, and manage LDL cholesterol and blood pressure to prevent heart attacks and strokes.
• Keep whole fruit in your diet: Do not avoid whole fruit out of fear of fructose or liver fat; if you are on a strict low-carbohydrate diet for type 2 diabetes, simply choose lower-sugar fruits or eat fruit at the end of a meal so glucose absorption remains slow and minimal.
• Track routine clinical markers rather than fasting insulin: Assess your metabolic health using waist circumference (the single most important indicator of harmful internal fat), blood pressure, LDL cholesterol, HbA1c, physical activity history, and resting heart rate, rather than requesting routine GP fasting insulin tests that suffer from inter-assay variability.
• Protect sleep and plan nutrition around late workouts and GLP-1 therapy: Feel free to eat a nutritious post-workout meal at 10:00 PM as long as it does not disrupt your sleep, and if using GLP-1 medications, pair them with behavioral nutrition support and maintenance dosing strategies to prevent post-cessation weight regain.