131: GLP-1 Isn’t Enough - Why Glucagon is the Key to Lasting Weight Loss with Dr. Ben Bikman

Dr. Bikman centers his dietary philosophy on the insulin-to-glucagon ratio. He explains that a carb-heavy meal spikes insulin and suppresses glucagon, raising the ratio into storage mode. A low-carb meal does the opposite. He asserts that this ratio matters more than absolute glucagon levels because insulin is dominant: ‘in a head-to-head, insulin will win that battle.’ By keeping carbs low, you naturally lower insulin, allowing glucagon to fully stimulate hepatic fat oxidation and ketogenesis without interference. He also notes that in type 2 diabetes, both hormones can be elevated simultaneously (hyperglucagonemia alongside hyperinsulinemia), leading to metabolic chaos, which low-carb eating can help correct.

Dr. Bikman frames fasting as the most direct way to demonstrate the bihormonal hypothesis: ‘When you fast, even just overnight, the opposite happens. Insulin drops, glucagon rises, and the ratio shifts the other way.’ He contrasts fasting with a carbohydrate-heavy meal. He notes that during total starvation the ratio is lowest, maximizing endogenous fuel liberation. He also references that the drop in insulin may be more important than the glucagon rise for ketogenesis, but the combination is optimal. He sees fasting as a practical, no-cost tool that anyone can use to let glucagon work without pharmaceutical intervention.

Dr. Bikman says that while GLP-1 drugs help people eat less, they don’t maintain or increase metabolic rate, leading to plateaus. He is highly skeptical of their widespread use and states his view clearly: their main utility is helping people learn to control constant carbohydrate cravings. By pairing a low dose with a low-carb diet, patients could theoretically use the drug as a temporary tool to establish new eating patterns, then transition off. He is not endorsing the drugs but describing a safer application if they are used. This nuanced stance contrasts with the prevailing ‘take it for weight loss’ narrative.

Dr. Bikman explains that human white adipose tissue has very low glucagon receptor expression—in some studies ‘essentially undetectable.’ A 2001 microdialysis study showed no glycerol release from abdominal fat even when glucagon was raised 3-4 fold. A 2020 study on human adipocytes found glucagon only increased lipolysis at super-physiological levels, and a 2022 adipocyte-specific glucagon receptor knockout mouse found no effect on fasting-induced lipolysis or body composition. Thus, the direct lipolysis model is a rodent artifact. He emphasizes that this correction matters because many clinicians and laypeople believe glucagon pulls fat from fat cells, leading to misguided expectations.

Dr. Bikman highlights a 2024 Cell Metabolism paper from the same Yale group that found glucagon infusion in people with fatty liver disease increased hepatic mitochondrial oxidation by about 50%. A Nature paper identified a receptor called INSP3R1 (INSPIRE1) that coordinates calcium release to activate ATGL, the rate-limiting enzyme for intracellular fat breakdown. Crucially, this mechanism was confirmed in humans. He notes that while rodent studies questioned glucagon’s necessity for fasting ketogenesis (mice lacking glucagon signaling still produced ketones), this may again be a species-specific finding, and human data are lacking for that particular question. Nevertheless, the hepatic oxidation and intrahepatic lipolysis pathways are now firmly attested in humans.

Dr. Bikman explains that adding glucagon activation increases energy expenditure and enhances liver fat burning. Tirzepatide (dual agonist) produced ~14.7% weight loss at lower doses/shorter duration, and in patients with NASH, 83% showed resolution of steatohepatitis compared to 18% on placebo, with improved fibrosis scores—an effect he attributes to the glucagon component. The triple agonist retatrutide (GLP-1, GIP, glucagon) yielded ~24% weight loss at 48 weeks, approaching bariatric surgery results. He notes this is glucagon keeping CPT1 active, maintaining fat oxidation even as body weight drops, thus countering metabolic adaptation. Despite the impressive data, he reiterates his reservations about these drugs and argues they should be used only at low doses to help control carb cravings, paired with a low-carb diet.