Browse the evidence

Leptin therapy is effective for weight loss only in patients with leptin deficiency (low circulating levels), not in those with leptin resistance (high levels).

Leptin injections are only effective for people with a specific genetic deficiency causing low leptin levels. For most people with obesity, leptin levels are high, and leptin injections do not work.

Patients with severe obesity and Type 2 Diabetes experience a greater reduction in all-cause mortality from bariatric surgery compared to those with severe obesity alone.

If you have severe obesity and Type 2 Diabetes, bariatric surgery offers an even greater survival benefit than for those with obesity alone. This makes it a particularly strong consideration for managing your health and longevity.

Loss of GIP receptor (GIPR) signaling specifically in GABAergic neurons enhances the body weight loss efficacy of GLP-1 receptor agonists (such as semaglutide or tirzepatide) and dual incretin agonists.

Current obesity medications that target both GLP-1 and GIP receptors (like tirzepatide) work partly by engaging specific brain neurons (GABAergic neurons expressing GIPR). Research suggests that the body's natural GIP signaling in these neurons might actually limit how much weight you can lose with GLP-1 drugs alone. This implies that future treatments might be optimized by either stimulating or blocking GIP signaling in these specific brain cells to maximize weight loss while managing side effects like nausea.

Systemic inhibition of the chromatin modifier LSD1 using GSK-LSD1 or SP2509 reduces body weight, improves insulin sensitivity, and reverses nonalcoholic fatty liver disease (NAFLD) in obese mouse models, independent of reduced food intake.

Targeting the enzyme LSD1 appears to fix the underlying metabolic dysfunction in obesity, not just cause weight loss. It reduces fat tissue inflammation and stops fat from flooding the liver, improving insulin sensitivity directly. This suggests that future drugs targeting LSD1 could treat obesity and its complications like fatty liver and diabetes simultaneously, rather than just suppressing appetite.

Semaglutide treatment for type 2 diabetes does not directly cause retinal damage; observed early worsening of diabetic retinopathy is primarily driven by the magnitude and speed of HbA1c reduction rather than the drug itself.

If you have type 2 diabetes and are starting semaglutide, do not avoid it out of fear of blindness. The risk of retinopathy worsening is linked to how fast your blood sugar drops, not the drug itself. To stay safe, your doctor should check your eyes before starting, and may reduce your insulin or sulfonylurea dose to prevent a rapid glucose drop. Regular eye exams are essential.

Infusion of amino acids to maintain near-basal plasma concentrations in overnight-fasted humans induces insulin resistance by decreasing tissue responsiveness to insulin without altering sensitivity, suggesting a postreceptor defect.

If you are receiving intravenous nutrition containing amino acids while your body is producing or receiving high levels of insulin, your body will become less efficient at processing glucose. This is not a failure of your pancreas, but a direct effect of the amino acids on how insulin works at the cellular level (postreceptor). For healthy individuals eating normally, this effect is likely minimal, but for critically ill patients on parenteral nutrition, it is a significant clinical factor.

SGLT2 inhibitors reduce cardiovascular mortality and heart failure hospitalization in insulin-resistant patients by promoting ketone body production and reducing sympathetic overdrive.

If you have Type 2 Diabetes and heart issues, ask your doctor about SGLT2 inhibitors (like Jardiance or Farxiga). They are proven to protect your heart and reduce hospital stays, not just lower blood sugar. The benefit comes from how they change your heart's energy use and stress levels.

GLP-1 receptor agonists reduce major adverse cardiac events and cardiovascular mortality in patients with Type 2 Diabetes, particularly those without pre-existing heart failure.

If you have Type 2 Diabetes, GLP-1 drugs (like Ozempic or Victoza) are highly recommended for heart protection. They significantly lower the risk of heart attacks and death. If you already have heart failure, they still help prevent new cases but may not stop existing failure from worsening as effectively.

SGLT2 inhibitors lower blood glucose by inhibiting renal glucose reabsorption, resulting in glucosuria, with efficacy dependent on maintaining a filtered glucose load above 80g/day.

SGLT2 inhibitors are effective for lowering blood sugar by helping your kidneys excrete excess glucose, but they only work well if your blood sugar is high enough and your kidneys are functioning adequately. They also offer heart and kidney protection. You must take them as prescribed and maintain good hygiene to minimize infection risks.

Bariatric surgery is a highly effective therapeutic option for individuals with severe obesity (BMI ≥40 or ≥35 with comorbidities) that induces T2DM remission through metabolic changes beyond simple restriction.

If you have a BMI of 40 or higher (or 35+ with diabetes/liver disease), consult a specialist about bariatric surgery. It is a proven, durable treatment that can reverse diabetes through hormonal changes, not just weight loss, but requires lifelong medical monitoring.

GLP-1 receptor agonists (e.g., semaglutide, liraglutide) improve MASH resolution but do not significantly improve liver fibrosis in patients with compensated cirrhosis.

Semaglutide (2.4mg weekly) helps resolve MASH but does not reverse fibrosis in patients with cirrhosis. It is effective for weight loss and glucose control but should not be relied upon to fix advanced scarring alone.

Daily urinary C-peptide excretion normalized by energy intake (CPEP/EI) serves as a valid, noninvasive physiological measure of insulin sensitivity in nondiabetic individuals, inversely correlating with the gold-standard euglycemic-hyperinsulinemic clamp.

For clinical or research settings where frequent blood draws are impractical, collecting 24-hour urine samples to measure C-peptide and dividing by total energy intake provides a reasonably accurate, noninvasive estimate of insulin sensitivity in healthy, nondiabetic adults. This method is not suitable for individuals with kidney disease.

Smoking and consumption of goitrogenic foods (specifically cruciferous vegetables and processed meats) increase urinary levels of thiocyanate and nitrate, which act as competitive inhibitors of iodine uptake, thereby increasing the risk of iodine deficiency.

Smokers and those eating large amounts of cruciferous vegetables (broccoli, cabbage) or processed meats may have higher levels of goitrogens (thiocyanate/nitrate) in their urine. These substances compete with iodine for absorption. If you smoke or eat these foods heavily, ensure your iodine intake is adequate through diet or supplements to counteract this inhibition.

Pharmacological activation of G protein-coupled receptors (GPCRs) in thermogenic brown and beige adipocytes can increase energy expenditure and improve metabolic health, but current adrenergic agonists have a narrow safety window due to cardiovascular side effects.

While cold exposure is a natural way to activate brown fat, scientists are developing drugs that target specific receptors (GPCRs) to do the same thing. Current drugs like mirabegron show promise for boosting metabolism by ~200 kcal/day, but they can affect heart rate. Future treatments aim to target these receptors more selectively to avoid side effects while still improving metabolic health.

Non-adrenergic Gs-coupled receptors (e.g., secretin, glucagon, adenosine) can stimulate brown adipose tissue thermogenesis independently of the sympathetic nervous system, offering a potential pathway to avoid cardiovascular side effects associated with adrenergic agonists.

Scientists are exploring hormones other than adrenaline (like secretin or glucagon) to activate fat-burning cells. These hormones can boost glucose uptake in brown fat by 57%, but they break down quickly. Future drugs may modify these hormones to last longer, potentially offering a way to boost metabolism without the heart risks of current adrenaline-targeting drugs.

Resmetirom, a selective thyroid hormone receptor beta (THR-β) agonist, significantly reduces hepatic fat content and improves fibrosis markers in patients with non-cirrhotic MASH.

If you have MASH (formerly NASH) with significant liver fat, ask your doctor about resmetirom. It is an FDA-approved medication that targets the liver specifically to reduce fat and improve fibrosis. The standard dose is 80mg or 100mg taken once daily. It is not a supplement but a prescription drug with specific eligibility criteria (non-cirrhotic MASH).

Postprandial plasma leucine concentration and ingested leucine dose are poor predictors of muscle protein synthesis (MPS) rates when protein is consumed as whole foods or mixed meals, indicating that leucine is not the sole or primary driver of the anabolic response in complex nutritional contexts.

Stop obsessing over hitting specific leucine targets with isolated powders. When you eat whole protein sources like eggs, meat, or dairy, your body handles the anabolic signaling effectively regardless of minor variations in leucine content. The food matrix and other nutrients play a crucial role that isolated leucine metrics miss.

GLP-1 receptor agonists provide cardiovascular protection through peripheral anti-inflammatory effects, independent of their weight-loss or glucose-lowering actions.

Beyond helping you lose weight, GLP-1 medications like semaglutide have been shown to protect your heart. This protection comes from reducing inflammation in your body's peripheral tissues, offering a dual benefit for metabolic and cardiovascular health.

Pegozafermin (BIO89-100), an FGF-21 analog, demonstrates improvement in liver fibrosis in patients with MASH, as shown in Phase 2b trials, and has entered Phase 3 clinical trials.

Pegozafermin is an experimental drug for MASH that works by mimicking FGF-21. It is given as a subcutaneous injection every two weeks. It is currently in Phase 3 trials and not yet approved.

Pioglitazone, a PPAR-gamma agonist, improves steatosis, inflammation, and liver biomarkers in patients with MAFLD, but its effect on liver fibrosis is not clear.

Pioglitazone is an older diabetes drug that can improve liver fat and inflammation in MAFLD patients. However, it may cause weight gain and other side effects, and its ability to reverse liver scarring is unclear. It is sometimes used in patients with T2DM and MASH.

Chronic administration of GIP receptor agonists (specifically GIP108) causes functional desensitization of the GIP receptor in pancreatic islets, reducing the efficacy of subsequent glucose-lowering challenges.

Long-term use of GIP-based therapies (like tirzepatide) triggers a biological adaptation where the pancreas becomes less responsive to the drug's glucose-lowering signal. This is a known mechanism called desensitization. However, the drug still promotes weight loss, suggesting the benefit comes from multiple pathways, not just pancreatic sensitivity. If glycemic control wanes, dose adjustments may be necessary.

When adipose tissue storage capacity is exceeded, lipids are redirected to the pancreas causing lipotoxicity, beta-cell dysfunction, and type 2 diabetes.

If you have obesity but do not have diabetes, your body may still be successfully storing fat in your adipose tissue. If you have obesity and diabetes, your body may have reached its limit for storing fat safely, causing fat to leak into your pancreas and damage insulin-producing cells. Focus on improving adipose tissue function rather than just weight loss.

Saturated fatty acids induce beta-cell apoptosis and dysfunction through ceramide accumulation and ER stress, whereas minimal levels of fatty acids are required for normal insulin secretion.

Your body needs some fatty acids to function properly, but too much, especially saturated fat, can poison your insulin-producing cells. This happens when your fat storage cells are full, forcing fat into your pancreas. Managing saturated fat intake and supporting fat storage health are key.

In older adults, the muscle protein synthesis response to protein ingestion is blunted (anabolic resistance), and simply increasing protein intake does not overcome this resistance.

As you age, your muscles become less responsive to protein. Simply eating more protein won't build muscle. You must combine adequate protein intake with resistance exercise to overcome this 'anabolic resistance' and stimulate muscle growth.