Diabetes Forecast

Perfecting Insulin

The challenges of making this lifesaver work like a pancreas

By Robert J. Tanenberg, MD, FACP, Former Editor in Chief of Diabetes Forecast , ,

In his Nobel Prize lecture in 1925, three years after the first insulin injection in a patient with diabetes, Dr. Frederick Banting said that "insulin is not a cure for diabetes; it is a treatment." Although insulin has been saving lives for 90 years, Banting was certainly correct. Insulin neither cures diabetes nor does it perfectly replicate the functioning of a healthy pancreas. Read on to find out why.

Treatment Today

The main treatment for type 1 diabetes (and, in many cases, type 2) has been daily injections of insulin, either from an animal source or, since 1982, biosynthetic human insulin. People can control blood glucose with insulin injections or an insulin pump well enough to function normally most of the time. Even properly administered insulin therapy, however, rarely prevents all short- and long-term complications.

There are three major reasons that current insulin therapy cannot control type 1 diabetes enough to completely normalize glucose and prevent complications.

1. Timing

In a person without diabetes, the beta cells in the pancreas release insulin minute by minute in precise amounts that depend on the body's metabolic state (such as having just eaten or needing to fuel the body's cells for physical activity). Before eating, insulin levels in a person without diabetes are very low but not absent. After eating foods that contain carbohydrate, however, a person's insulin level typically increases more than tenfold. Within two to three hours after the meal, the insulin level is almost back to baseline and the blood glucose level has remained steady.

Today's insulin products have advanced since the early days of animal insulin. Basal analog insulins, such as glargine (Lantus) and detemir (Levemir), are almost peakless in most people, last 24 hours, and cause less hypoglycemia than NPH. Short-acting insulin analogs, such as lispro (Humalog), aspart (NovoLog), and glulisine (Apidra), start faster, peak sooner, and have a shorter duration than conventional regular insulin. Since about 1980, finger-stick glucose testing and the A1C test have led to improved blood glucose control. Nonetheless, none of the commercially available injectable insulins can mimic the ability of the normal pancreas to control glucose for 24 hours.

Since the 1980s, many people with type 1 diabetes have used insulin pumps, which can deliver insulin in a way that more closely mimics the normal body's response than do injections. What's more, technology to measure tissue (interstitial) glucose with continuous glucose monitoring (CGM) is now commercially available. Researchers have worked for many years to develop closed-loop insulin pumps that will be able to quickly respond to changing glucose levels and thereby eliminate high and low blood glucose levels. In fact, the newest sensor-augmented insulin pumps (now available only in Europe) shut off insulin delivery when a sensor detects low blood glucose. These newer pumps have the capability to prevent severe hypoglycemia.

2. Absorption

The second major problem with insulin delivered as a medication is how it gets to where it needs to go. When functioning normally, the beta cells of the pancreas release insulin into the bloodstream and the insulin is immediately taken up by the liver to convert and store extra blood glucose as glycogen. About half the insulin passes out of the liver to help tissues use glucose as fuel. When insulin is injected, however, it forms a sort of blob or depot just under the skin, then is absorbed into the peripheral circulation before eventually getting to the liver. The type of insulin will determine how long it stays in the depot and at what rate it enters the bloodstream. Even the rapid-acting analog insulins cannot match the speed at which the body's own insulin gets to the cells in response to eating.

In hospitals, physicians are able to treat patients using intravenous (IV) insulin infusions. IV insulin can increase insulin levels very rapidly and can be shut off and reduce insulin levels to zero within minutes. When combined with frequent glucose testing, IV glucose, and a commercial computerized dosing program, these infusions can enable doctors to keep blood glucose in a narrow range (such as 110 to 140 or 140 to 180 mg/dl). In treating outpatients, the best results can be obtained with experimental implantable insulin pumps (no longer available in the United States) that deliver insulin into the abdominal (peritoneal) cavity, where it is immediately taken up by the liver. By avoiding the depot problem, intravenous and peritoneal insulin achieve better control than injected or pumped insulin.

3. Other Hormones

The final major problem with injectable insulin is that it fails to address deficiencies in other hormones that help regulate blood glucose levels. The alpha cells of the pancreas islets normally produce glucagon, a hormone that works with insulin to regulate carbohydrate metabolism. Glucagon levels are normally higher when a person hasn't eaten and lower with eating. In diabetes, however, people have too much secretion of glucagon, which increases glucose levels even when there is adequate insulin. To complicate matters, people with diabetes invariably lose their protective glucagon response to low blood glucose, worsening episodes of hypoglycemia.

Normally, in response to eating, the small intestine secretes glucagon-like peptide-1 (GLP-1). This hormone suppresses the glucagon level and, because it helps slow the rate at which food leaves the stomach, keeps after-eating levels in check. People with diabetes are deficient in GLP-1 and thus have higher glucagon levels and higher after-eating blood glucose levels. The three injectable GLP-1 drugs currently on the market (Bydureon, Byetta, and Victoza) are approved today only for type 2 diabetes. These drugs can help control diabetes when given with oral medications, background (basal) insulin, or both. The use of these drugs to help treat type 1 diabetes is under investigation.

In response to carbohydrate digestion, beta cells of a normal pancreas secrete the hormone amylin at the same time insulin is secreted. Like GLP-1, amylin inhibits secretion of glucagon and delays stomach emptying. People with type 1 diabetes make no amylin, and people with type 2 have reduced levels. For the past several years, a synthetic version of amylin (Symlin) has been on the market. In type 1 diabetes, this injectable drug has been successfully used to reduce after-eating glucose levels. It also decreases appetite and thus may help with weight loss. Because amylin inhibits glucagon, if there is too much insulin in the bloodstream, a severe low can result.

In the 90 years since the discovery of insulin, considerable progress has been made in using it to treat diabetes. Despite these achievements, there is still no ideal treatment for type 1 diabetes that is both practical and affordable and can fully prevent low and high blood glucose levels and microvascular complications, such as nerve or eye damage, in everyone. Research is promising, including advances in genetics and molecular biology, the use of stem cells to stimulate beta cells, and new versions of the artificial pancreas. New treatments will further improve blood glucose control, prevent complications, improve quality of life, and bring us much closer to a cure.

Talk Like a Doc

Endogenous insulin: Insulin produced by your body.

Exogenous insulin: Animal or biosynthetic insulin that is used as medication.

What About Transplants?

The first pancreas transplant was in 1966. Beta cell transplants also have been studied. Read about the pros and cons at forecast.diabetes.org/transplants-mar2012.



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