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INSULIN
I CAN MAKE YOU FAT
ACTUALLY, I CAN make anybody fat. How? By prescribing insulin. It won’t matter that you have willpower, or that you exercise. It won’t matter what you choose to eat. You will get fat. It’s simply a matter of enough insulin and enough time.
High insulin secretion has long been associated with obesity: 1 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,2 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.
Insulin levels can be difficult to measure since levels fluctuate widely throughout the day in response to food. It is possible to measure an “average” level, but doing so requires multiple measurements throughout the day.
Fasting insulin levels (measured after an overnight fast) are a simpler, one- step measurement. Sure enough, research reveals a close association between high fasting insulin levels and obesity, and this relationship becomes even stronger when we consider only a person’s fat mass rather than his or her total weight. In the San Antonio Heart Study,3 high fasting insulin was tightly correlated to weight gain over eight years of follow up. As we shall see in chapter 10, an insulin-resistant state leads also to high fasting insulin. This relationship is not coincidental, as insulin resistance itself plays a key role in causing obesity.
So, we know that the association between elevated insulin and obesity has already been clearly established. The question now is whether this association is, in fact, a causal relationship. Does high insulin cause obesity?
PUTTING IT TO THE TEST
THE “INSULIN CAUSES obesity” hypothesis is easily tested. We can prove a causal relationship by experimentally giving insulin to a group of people and then measuring their weight gain. Therefore, for our experiment, here’s our fundamental question: If you take insulin, will you get fat?
The short answer is an emphatic “Yes!” Patients who use insulin regularly and physicians who prescribe it already know the awful truth: 4 the more insulin you give, the more obesity you get. Insulin causes obesity. Numerous studies, conducted mostly on diabetic patients, have already demonstrated this fact. Insulin causes weight gain.
Insulin is commonly used to treat both types of diabetes. In type 1 diabetes, there is destruction of the insulin-producing cells of the pancreas, resulting in very low levels of insulin. Patients require insulin injections to survive. In type 2 diabetes, cells are resistant to insulin and insulin levels are high. Patients do not always require insulin and are often treated first with oral medications.
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.
Long-term studies in type 2 diabetes show the same weight-gaining effect of insulin. 6 The United Kingdom Prospective Diabetes Study Group, organized in the 1970s, was, at that time, the largest and longest study ever done for type 2 diabetes. Its primary purpose was to determine if intensive blood glucose management was beneficial in treating type 2 diabetes, but there were many separate sub-studies within this study. Once again, two similar groups received standard versus intensive treatment. Within the intensive group, patients were given one of two treatments—either insulin injections or a sulfonylurea drug, which increases the body’s own insulin secretion. Both treatments will increase insulin levels, although by different mechanisms. Insulin injections will raise serum levels higher than the sulfonylurea.
What happened to the participants’ weight? The intensive group gained an average of about 6.8 pounds (3.1 kilograms). Those that were treated with insulin gained even more—about 9 pounds (4 kilograms) on average. Increased insulin levels, whether by direct insulin injection or the use of sulfonylurea, caused significant weight gain. Once again, insulin levels were increased. Patients gained weight.
Newer types of long-acting insulin produce weight gain, too.7 A 2007 study compared three different insulin protocols. What happened to the participants’ weight? The study noted, “Patients generally gained weight on all regimens.” Participants in the basal insulin group, which received the lowest average insulin dose, gained the least average amount of weight—4.2 pounds (1.9 kilograms). Those in the prandial insulin group, which received the most insulin, gained the most weight—12.5 pounds (5.7 kilograms) on average. The intermediate group gained on average 10.3 pounds (4.7 kilograms). The more insulin doctors gave, the more weight participants gained.
And reducing caloric intake proved useless. In a fascinating 1993 study,8 high-dose insulin allowed virtual normalization of blood sugars in a group of type 2 diabetic patients. Starting from zero, the dose was increased to an average of 100 units per day over a period of six months. At the same time, patients decreased their caloric intake by more than 300 calories per day.
The patients’ blood sugar levels were great. But what happened to their weight? It increased by an average of 19 pounds (8.7 kilograms)! Despite eating less than ever, patients gained weight like crazy. It wasn’t calories that drove their weight gain. It was insulin.
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.10
A 2005 case study11 describes a twenty-year-old woman diagnosed with an insulinoma. She had gained 25 pounds over the year prior to her diagnosis. Increased caloric intake did not account for the weight gain.
Reduced caloric intake did not account for the weight loss. The defining element was insulin: its rise and fall corresponded to the rise and fall in weight.
ORAL HYPOGLYCEMIC AGENTS
WE’VE SEEN THAT injections of insulin manufactured outside the body cause weight gain. 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.
Sulfonylureas and metformin
SEVERAL PILLS ARE available for the drug treatment of type 2 diabetes. The sulfonylurea class work by stimulating the pancreas to produce more insulin to lower blood sugars. All drugs in this class are well known to cause weight gain.12
Another oral hypoglycemic agent is metformin. Metformin decreases the amount of glucose13 produced by the liver and increases glucose uptake by the muscles.14
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.15, 16
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.
Thiazolidinediones
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