Evidence that High Insulin Levels Lead to Weight Gain

Jason Fung’s book The Obesity Code undergirds the core of my approach to diet and health. I featured The Obesity Code in “Five Books That Have Changed My Life” and tried to distill the essential ideas of The Obesity Code in my post “Obesity Is Always and Everywhere an Insulin Phenomenon.” Insulin is central to Jason Fung’s views. But can insulin really be that important? Here is some of the evidence behind the conclusion that insulin raises body weight, as detailed in Chapter 7 of The Obesity Code, entitled simply “Insulin.”

Correlational evidence:

High insulin secretion has long been associated with obesity: obese people secrete much higher levels of insulin than do those of normal weight. Also, in lean subjects, insulin levels quickly return to baseline after a meal, but in the obese, these levels remain elevated.

Insulin levels are almost 20 percent higher in obese subjects, and these elevated levels are strongly correlated to important indices such as waist circumference and waist/hip ratio. The close association between insulin levels and obesity certainly suggests—but does not prove—the causal nature of this relationship.

Experimental evidence with exogenously varied insulin:

In the landmark 1993 Diabetes Control and Complications Trial, researchers compared a standard dose of insulin to a high dose designed to tightly control blood sugars in type 1 diabetic patients.5 At the end of six years, the study proved that intensive control of blood sugars resulted in fewer complications for those patients.

However, what happened to their weight? Participants in the high-dose group gained, on average, approximately 9.8 pounds (4.5 kilograms) more than participants in the standard group. Yowzers! More than 30 percent of patients experienced “major” weight gain! Prior to the study, both groups were more or less equal in weight, with little obesity. The only difference between the groups was the amount of insulin administered. Were these patients suddenly lacking in willpower? Were they lazier than they had been before the study? Were they more gluttonous? No, no and no. Insulin levels were increased. Patients gained weight.

Effects of a disease that dramatically increases the body’s insulin secretion:

Insulin also causes weight gain in non-diabetics. Consider what happens to patients with insulinomas—very rare insulin-secreting tumors, usually found in non-diabetics. The estimated incidence is only four cases per million per year. This tumor constantly secretes very large amounts of insulin, causing recurrent episodes of hypoglycemia (low blood sugar). But what happens to body weight? A prospective case series showed that weight gain occurs in 72 percent of patients.9 Removal of the tumor resulted in cure in twenty-four out of twenty-five cases. Removal of malignant insulinoma led to rapid and sustained weight loss.

Effects of a disease that dramatically reduces the body’s insulin secretion:

Type 1 diabetes is an autoimmune disease that destroys the insulin-producing beta cells of the pancreas. Insulin falls to extremely low levels. Blood sugar increases, but the hallmark of this condition is severe weight loss. Type 1 diabetes has been described since ancient times. Aretaeus of Cappadocia, a renowned ancient Greek physician, wrote the classic description: “Diabetes is... a melting down of flesh and limbs into urine.” No matter how many calories the patient ingests, he or she cannot gain any weight. Until the discovery of insulin, this disease was almost universally fatal. Insulin levels go waaayyy down. Patients lose a lot of weight.

Effects of psychiatric drugs that raise insulin production:

The drug olanzapine, used to treat psychiatric disorders, is commonly associated with weight gain—5.2 pounds (2.4 kilograms) on average. Does olanzapine raise insulin levels? Absolutely—prospective studies confirm that it does.25 As insulin rises, so does weight.

Gabapentin, a drug commonly used to treat nerve pain is also associated with weight gain, averaging 4.8 pounds (2.2 kilograms). Does it magnify insulin’s effect? Absolutely. There are numerous reports of severe low blood sugars with this drug. It appears that gabapentin increases the body’s own insulin production. Quetiapine is another antipsychotic medication associated with a smaller 2.4-pound (1.1-kilogram) average weight gain. Does it raise insulin levels? Absolutely. Insulin secretion as well as insulin resistance is increased after starting quetiapine.28 In all these cases, we increased insulin levels. People gained weight.

A drug that lowers insulin production by lowering blood sugar in another way:

The newest class of medication for type 2 diabetes is the SGLT-2 (sodium-glucose linked transporter) inhibitors. These drugs block the reabsorption of glucose by the kidney, so that it spills out in the urine. This lowers blood sugars, resulting in less insulin production. SGLT-2 inhibitors can lower glucose and insulin levels after a meal by as much as 35 percent and 43 percent respectively.

But what effect do SGLT-2 inhibitors have on weight? Studies consistently show a sustained and significant weight loss in patients taking these drugs. Unlike virtually all dietary studies that show an initial weight loss followed by weight regain, this study found that the weight loss experienced by patients on SGLT-2 inhibitors continued for one year and longer. Furthermore, their weight loss was predominantly loss of fat rather than lean muscle, although it was generally modest: around 2.5 percent of body weight. (We lowered insulin. Patients lost weight.)

The effects of an insulin enhancer:

The Thiazolidinedione Class of medications works by increasing insulin sensitivity. Thiazolidinediones do not raise insulin levels; instead, they magnify the effect of insulin, and as a result, blood sugars are lowered. Thiazolidinediones enjoyed tremendous popularity after their launch, but because of safety concerns about two of these drugs, rosiglitazone and pioglitazone, they are now rarely used. These drugs showed a major effect other than their blood sugar–lowering ability. By amplifying insulin’s effect, this insulin sensitizer caused weight gain.

Comparing the effects of drugs that all lower blood sugar, some of which raise insulin and one that does not:

There are, however, other medications, called oral hypoglycemic agents, that are taken by mouth and cause the body to produce more insulin. If these drugs also cause obesity, then that is extremely strong evidence of the causal link between insulin and weight gain. …

Insulin, the sulfonylureas and metformin all have different effects on insulin levels. Insulin raises blood insulin levels the most. The sulfonylurea drug class also raises insulin levels, but not as much as insulin, and metformin does not increase insulin at all. These three treatments were compared against each other in another study.

There was no difference in blood sugar control between the metformin group and the sulfonylurea group. But what are the effects of the different treatments on weight? Participants in the insulin group experienced the most weight gain—more than ten pounds (4.5 kilograms) on average. (We raised insulin. Patients gained weight.) Participants in the sulfonylurea group also gained weight—about 6 pounds (2.5 kilograms) on average. (We raised insulin a little. Patients gained a little weight.) Patients in the metformin group did not gain any more weight than those on diet alone. (We didn’t raise insulin. Patients didn’t gain weight.) Insulin causes weight gain.

Put together, this is a lot more evidence than we are used to having for economic propositions. Insulin seems to be big player in an important causal network for weight gain and weight loss. For more on the insulin theory of weight gain and weight loss, see “Obesity Is Always and Everywhere an Insulin Phenomenon,” “Forget Calorie Counting; It's the Insulin Index, Stupid” and “A Conversation with David Brazel on Obesity Research.”

Don’t miss my other posts on diet and health:

I. The Basics

II. Sugar as a Slow Poison

III. Anti-Cancer Eating

IV. Eating Tips

V. Calories In/Calories Out

VI. Wonkish

VIII. Debates about Particular Foods and about Exercise

IX. Gary Taubes

X. Twitter Discussions

XI. On My Interest in Diet and Health

See the last section of "Five Books That Have Changed My Life" and the podcast "Miles Kimball Explains to Tracy Alloway and Joe Weisenthal Why Losing Weight Is Like Defeating Inflation." If you want to know how I got interested in diet and health and fighting obesity and a little more about my own experience with weight gain and weight loss, see “Diana Kimball: Listening Creates Possibilities and my post "A Barycentric Autobiography.