Important: this text discusses the underlying mechanisms of glucose uptake. It has little clinical significance. Diabetics should continue to use insulin as prescribed by their doctor.

As a medical student, i’ve been taught that cells need insulin to absorb glucose. Insulin causes a glucose transporter (glut) to rise to the cell surface. This transporter creates a channel for glucose to flow through. There are about 13 different gluts, and the one that needs insulin is glut4 (possibly 12, also). According to the misconception, glut4 is required for glucose uptake, and that is why insulin is necessary. Without insulin, there will be no glut4, and so we’re told that the cell cannot consume glucose, which causes glucose to build up in the blood – hyperglycemia. This is demonstrably false, as many experiments have shown. While insulin does impact absorption by doubling the glucose uptake speed, we’ll see that it is not required. ¹

While it is true that glut4 is largely insulin dependent, it has almost a dozen brothers that function quite well without insulin. ² take, for example, glut1. It’s nearly everywhere in the body, all the time, and it’s as powerful as the glut4. Glut1 is the day-to-day glucose transporter responsible for basal glucose uptake. It doesn’t need insulin. It has been hypothesized that glut1 alone can sustain an adequate uptake of glucose in muscle. ³ there mere existence of this glut1 is enough to question the notion that glucose uptake must be insulin mediated.

We’ve quickly established that glucose uptake occurs without insulin, but how much? In 1983, the peer reviewed american journal of physiology published a study which concluded:

These results indicate that in postabsorptive human subjects 75-85% of glucose uptake is noninsulin-mediated and provide additional support for the concept that insulin may increase glucose uptake merely by providing additional transport sites. ⁴

Around 80% of glucose uptake is insulin independent. That’s quite a lot. If you’re inclined to reject this study based on its age, consider the glucose clamp technique they’ve used: developed in 1979, it is still the gold standard today. ⁵ this means that it has been known for more than 30 years that there is considerable glucose uptake without insulin. Why then do medical schools teach students that insulin is an absolute requirement for glucose uptake?

In 1994, another study consisting of almost a 100 human subjects, published in the journal diabetes, said:

We conclude that insulin-independent glucose uptake is a major determinant of intravenous glucose tolerance … ⁶

A 2001 review in the journal of endocrinology:

We now know that there is a sufficient population of glucose transporters in all cell membranes at all times to ensure enough glucose uptake to satisfy the cell’s respiration, even in the absence of insulin. Insulin can and does increase the number of these transporters in some cells but glucose uptake is never truly insulin dependent – in fact, even in uncontrolled diabetic hyperglycaemia, whole body glucose uptake is inevitably increased (unless there is severe ketosis). ⁷

The article continues:

When insulin is administered to people with diabetes who are fasting, blood glucose concentration falls. It is generally assumed that this is because insulin increases glucose uptake into tissues, particularly muscle. In fact this is not the case and is another error arising from extrapolating from in vitro rat data. It has been shown quite unequivocally that insulin at concentrations that are within the normal physiological range lowers blood glucose through inhibiting hepatic glucose production (ra) without stimulating peripheral glucose uptake ⁸

Some think that without insulin, glucose just piles up outside the cell, causing high blood sugar and leaving the cell lacking glucose. In fact, during hyperglycemia, there is more glucose inside the cell than during normoglycemia. Again, from the 2001 review:

Contrary to most textbooks and previous teaching, glucose uptake is therefore actually increased in uncontrolled diabetes and decreased by insulin administration! The explanation for this is that because, even in the face of insulin deficiency, there are plenty of glucose transporters in the cell membranes. The factor determining glucose uptake under these conditions is the concentration gradient across the cell membrane; this is highest in uncontrolled diabetes and falls as insulin lowers blood glucose concentration primarily (at physiological insulin concentrations) through reducing hepatic glucose production. ⁹

The liver is the main reason that blood sugars rise ¹⁰, and insulin lowers blood sugar by telling the liver to stop releasing sugar into the blood.

If you still believe that hyperglycemia is due to cells not taking up glucose, consider that hyperglycemia itself causes increased glucose uptake. A 2012 study on rats assessed the effects of hyperglycemia on how much and how fast cells import glucose. Using somatostatin they suppressed insulin and isolated the effects of hyperglycemia. They had this to say:

… The model detects increases in both interstitial and intracellular glucose concentrations, increases in the maximal velocity of glucose transport and increases in the rate of glucose transport, all in response to hyperglycemia. ¹¹

Hyperglycemia actually increases glucose uptake, while during hyperglycemia insulin actually decreases glucose uptake.

We’ve talked about insulin and we’ve discussed hyperglycemia. Now let’s talk some more about glut4. What happens when there is no glut4? Mice who have no glut4 develop enlarged hearts, shorter life-span and growth retardation. But, they do not develop diabetes, and clear up blood glucose just like normal subjects. Here’s a quote from a study published the journal nature:

The glut4-null mice demonstrate that functional glut4 protein is not required for maintaining nearly normal glycaemia but that glut4 is absolutely essential for sustained growth, normal cellular glucose and fat metabolism, and expected longevity. ¹²

Another study, aptly named “normal muscle glucose uptake in mice deficient in muscle glut4” says:

Our study demonstrates that deletion of muscle glut4 does not adversely affect glucose disposal and glucose tolerance and that compensation from other transporters may contribute to this unaltered homoeostasis of glucose. ¹³

Glut4 does not seem to be as important in glucose uptake as we’re taught.

Lastly, is the cell starving during hyperglycemia? No. While glucose uptake is increased during hyperglycemia, glucose metabolism is down regulated and out competed by fat metabolism. ¹⁴

I hope you found this article helpful. Please share your thoughts in the comments field below.