The goal of treatments for diabetes mellitus is glycemic
control, that is the prevention of hyperglycemia.
Chronic hyperglycemia leads to abnormal glycoslyation of
proteins, as well as other chemical changes. Ultimately, the
various chemical changes due to hyperglycemia are toxic to certain
tissues and diabetic complications ensue. The major
diabetic complications are listed below. We will discuss these in
more detail in Conjoint 402 and 403 when we discuss neural,
cardiovascular, and renal physiology.
Cardiovascular Disease (heart attack,
stroke, peripheral vascular disease)
Nephropathy (kidney failure)
Retinopathy (blindness)
Peripheral Neuropathy (loss of sensation,
autonomic dysfunction)
Foot Ulcers (amputation)
Several large prospective studies have demonstrated that diabetic complications can be significantly reduced by intensive glycemic control. An unfortunate adverse effect of more intensive diabetic therapy is that it increases the risk for hypoglycemia.
Glycemic control can be determined through frequent monitoring of
blood glucose, but in practice it is measured by measuring HbA1c,
or the percentage of glycosylated hemoglobin.
Hyperglycemia causes the non-enzymatic glycosylation of proteins,
and hemoglobin is a convenient protein to examine since it can be
obtained from a simple blood draw. HbA1c (expressed as a
percentage) reflects the degree of glycemic control in the
previous 4-8 weeks. The American Diabetes Association
recommends a HbA1c target of less than 7% for most diabetics.
Below are listed major drug treatments for diabetes mellitus that we have discussed in class.
Insulin therapy is necessary for type 1 diabetics because they have an absolute insulin deficiency due to the autoimmune destruction of the pancreatic beta cells. Insulin therapy is useful in type 2 diabetes because insulin resistance leads to a relative insulin deficiency. As the disease advances, many type 2 diabetics will require insulin therapy, because the beta cells are damaged by hyperglycemia, and patients develop significant defects in insulin secretion.
These drugs bind to and block the ATP-sensitive K+ channel on pancreatic beta cells, causing depolarization and increased insulin secretion (review Humoral Regulation). These drugs improve glycemic control, but patients taking them tend to gain weight. Sulfonylureas (glyburide, tolbutamide) are older drugs and less expensive. A potential problem is that they can induce too much insulin secretion and hypoglycemia can result. The meglitinides (repaglinide, nateglinide) are newer drugs that are designed to avoid this problem. They have a shorter half-life, and are taken at mealtimes to enhance insulin secretion and prevent postprandial hyperglycemia.
Incretins are gastrointestinal hormones that increase insulin secretion (review Incretins). Exenatide is a peptide GLP-1 agonist that was originally purified from lizard venom. It has a longer half-life than the native hormone because it is resistant to digestion by the protease DPP-4. Liraglutide is a newer GLP-1 agonist drug with an even longer half-life, that offers the advantage of once a day dosing. Sitagliptin, saxagliptin, and linagliptin are DPP-4 inhibitors, and so would prolong the action of native incretins.
GLP-1 agonists have the added benefit of inducing weight loss (several kilograms, depending upon the length of treatment). The mechanism is thought to be that GLP-1 delays stomach emptying into the small intestine, causing patients to eat less because they feel “full” sooner.
These drugs work to counteract the key problem of type 2 diabetes: insulin resistance (review Insulin Resistance). Metformin works by indirectly activating AMP-activated kinase (AMPK), a protein that works as a cellular energy sensor and regulator of metabolism. Metformin increases fatty acid oxidation in liver and muscle, and inhibits gluconeogenesis in liver. Metformin also helps patients lose weight. It is now one of the most widely prescribed drugs for type 2 diabetes. It is also used to treat pre-diabetics (patients with impaired fasting glucose or impaired glucose tolerance) to delay or prevent the onset of type 2 diabetes.
Thiazolidinediones (TZD’s; pioglitazone, rosiglitazone) are agonists for an intracellular receptor known as PPAR-gamma. This receptor is primarily expressed in adipocytes. Thiazolidinediones affect adipocyte gene expression, ultimately causing decreases in circulating fatty acids. They also affect adipocyte secretion of regulatory molecules: adipocytes secrete more adiponectin, which increases insulin sensitivity, and fewer adipokines that cause insulin resistance.
Two meta-analysis studies published in 2007 have linked use of
rosiglitazone (trade name: Avandia) to an increased risk of heart
attack. The FDA now requires a warning on the label for Avandia,
and has recently (September 2010) made recommendations against
prescribing it for new patients except under special
circumstances.
Glucagon is secreted by the alpha cells in the pancreatic islets of Langerhans. It is one of the postabsorptive state hormones, and functions to stimulate hepatic glucose production. Glucagon secretion can be higher than normal, particularly in type 1 diabetes mellitus. Reducing inappropriate glucagon secretion and hepatic glucose production helps to limit hyperglycemia. On type of drug in this category would be the GLP-1 agonists such as exenatide and liraglutide. The other is pramlintide, a synthetic analogue of the peptide hormone amylin, which is produced by the pancreatic beta cells. Amylin inhibits glucagon secretion and also slows stomach emptying. Pramlintide is recommended as an adjunct to insulin therapy for type 1 and type 2 diabetics who are having difficulty with glycemic control.