Mercy Family Practice SC
Table of Contents
Diabetes Mellitus (DM) has two major types: type I and type II. Type I diabetes mellitus used to be called juvenile diabetes or insulin dependent diabates and Type II used to be called adult onset diabetes or non-insulin dependent diabetes. Those latter terms are no longer used. Since the vast majority of adult medicine deals with type II diabetes mellitus, I will devote this section to this form of the disease.
DM Type II often develops during adulthood. If you have a positive family history of diabetes, as you age over 50 years, and if you gain weight, you have over a 50% chance of developing type II diabetes. As the Baby Boomers now reach well into their older years, we are experiencing a near epidemic of diabetes. Since over 1/3 of our current children are considered overweight, there is little to suggest that this disease will deminish in future years. That is the bad news. The good news is that there are now many treatments available for diabetics.
Insulin: Insulin is produced by the beta cell in the pancrease. The main problem in diabetes is a defect in the normal function of the insulin molecule. Insulin is composed of 51 amino acids. It consists of two chains linked by two disulfide bonds. Its main function is to allow glucose (sugar) to enter somatic cells such as a muscle or fat cell. Diabetes is a multifactorial disease which means there are many parts of the process that intefere with insulin to do its job. A misconception is that diabetes type II is a lack of insulin. On the contrary, there often is plenty of insuline. However, there may be defects which prevent the insulin that is present from doing its normal function. All the many facets involved are beyond the scope of this web page. Suffice it to say that for various reasons, diabetes type II is a disease in which there is relative insulin insensitivity which prevents the insulin from working effectively. It may be a defect at the receptor site, or a defect inside the somatic cell.
Figure 1, Insulin Molecule
Renal filtration is the process of clearing a substance from the body through the kidneys. I like to use the analagy of making spaghetti. After you boil a pot of spaghetti, one has to strain the water through a collander. Imagine the spaghetti as protein or large molecules and the water as fluid or small molecules. The collander holds the large molecules and the small molecules escape through the holes. The kidney works in much the same way. In figure 2, you can imagine the whole pot of spaghetti is poured into the kidney unit called a glomerulus. This entrance is called the afferent arteriole. Next, the blood travels through a complex of small leaky blood vessels. The glomerular blood vessel holds onto the large molecules and lets pass the small molecules into the glomerular capsule, where they pass downstream into the proximal convoluted tubule, where ultimately they end up in the urinary bladder as urine.
Figure 2, Pathophysiology of Insulin Defect
Glucagon: The production of insulin and its defect is only half the story: glucagon is the other half. For years, physicians only used glucogon to stimulate glucose production from the liver in the treatment of hypoglycemia. Patients whose glucose dropped too low and became less responsive, or unresponsive, got a shot of glucagon to wake them up. Over the years, reasearchers have now discovered their major role in glucose metabolism.
Figure 3, Glucagon molecule
Glucogon is produced by the alpha cell of the pancrease. Glucagon is released when glucose falls to low. It stimulates the liver to produce glucose and release it into the bloodstream. In the diabetic, there is a defect in which too much glucagon is circulating in the blood stream. This is analagous to pouring gasoline on a fire.
Figure 4, Excess Glucagon Leads to Excess Glucose Production
The old definition involved measureing fasting glucose and glucose following a bolus of ingested surger. This was called the glucose tolerance test. In short, if your fasting glucose level was above 120 mg% and your two your post prandial (after ingestion) glucose was above 200 mg%, you were diagnosed with diabetes mellitus. Fortunately this test has been replaced by the Glycosylated Hemoglobin test, also called the Hemoglobin A1c (HbA1c) test. HbA1c is often further abbreviated as A1c.
Since 2010, the American Diabetes Association and others consider this the Gold Standard. It is a random blood sample taken at any time: in other words, you do not have to fast. A normal value is below 6%, and an abnormal result is equal or above 6%. The easiest way to think about this is as follows. The hemoglobin molecule sits inside the red cell. The red cell is bathed in serum of the blod stream where glucose resides. If the red cell environment is high in glucose, then that glucose will diffuse into the hemoglobin molecule and link itself to it. This is called glycosylation. Once a hemoglobin molecule is glycosylated, it remains that way over the lifespan of the molecule.
Because the average life span of a red blood cell is about 120 days, and red cells are being added and subtracted from the blood stream at a constant rate, it is estimated that the HbA1c represents and average of blood glucose over about 2 months time. There is a linear relationship between the HbA1c level and the average glucose found in your blood streem.
Figure 5, Relationship between Glycosylated Hemoglobin (HbA1c) and Average Glucose Concentration in Plasma
The first rule is that all diabetics need to follow a diet that reduces carbohydrates (CHO). CHO is a facy way to describe anything that the body can break down into sugar. Examples of CHO include table sugar, and starch, which can be found in bread or spaghetti. It turns out that most of our diet consists of CHO. The other two components include fats and protein. (To see a lengthy discussion about fats, go to the section on cholesterol.)
Current recommendations is that diabetics consume CHO in the form of complex CHO. Examples of this include rye bread or whole grain pasta. The concept here is that you do not want to consume simple CHO that will be broken down into sugar to flood a blood stream that is already is elevated. You want to consume complex CHO that will give the body time to process the glucose. A full discussion of diet is beyond the scope of this web page; however, you may use the following web pages as a resource:
Metformin has been the mainstay of therapy for over 15 years. Metformin is a biguanide, and works by decreasing glucose production from the liver (gluconeogenesis). It also decreases fasting and postprandial glucose concentration. It reduces absorption of glucose in the gastrointestinal tract and it increases insulin sensitivity at the somatic cell in peripheral tissues. Its main side effect is gastrointestinal: it can cause nausea and diarrhea. This is mitigated by giving the medication during meals. Also, there are long acting forms of the medication that may be better tolerated.
Insulin secretagogues increase the slow, second phase of insulin secretion from the pancrease. In older patients, they may be associated with hypoglycemia. For decades, sulfonylureas (SU) were the only available insulin secretagogues. Examples of SU are glyburide (DiaBeta, Micronase), chlorpropamide (Diabinese), glimepiride (Amaryl), glipizide (Glucotrol), tolazamide (generic), and tolbutamide (generic). Insulin secretagogues also include the newer agents repaglinide (Prandin) and nateglinide (Starlix). Repaglinide and nateglinide act faster than SU and are less associated with hypoglycemia. Due to their short action, repaglinide and nateglinide need to be given just before mealtime. In general, insulin secretagogues are less effective than TZDs and AGIs.
Dipeptidyl-Peptidase-4 Inhibitors (DPP-4)
Dipeptidyl-Peptidase-4 Inhibitors (DPP-4) have been introduced recently. This is an oral agent that inhibits the DPP-4 enzyme which decreases the metabolism of incretins, glucose like peptide-1 (GLP-1) and gastric inhibitory polypeptide. Inhibition of incretin metabolism will delay gastric emptying which will slow the release of glucose fromthe gastrointestinal tract. GLP-1 is a main incretin. Inhibition of the DPP-4 enzyme decreases metabolism of GLP-1 which increases GLP-1 which in turn decreases glucose levels (see below). Examples of DPP-4 Inhibitors include: Sitagliptin (Januvia) and Saxagliptin (Onglyza).
Thiazolidinediones have been available in the mid-1990s. TZDs work by increasing insulin sensitivity of skeletal muscle and adipose tissue. There are several serious side effects of TZD medications: increase in weight, fluid retention, peripheral edema and congestive heart failure. The first TZD, troglitazone, was discontinued due to the rare cases of liver damage. I tend not to use this medication due to these side effects. The two TZDs now available are pioglitazone (Actos) and rosiglitazone (Avandia).
Alpha-Glucosidase Inhibitors (AGI)
Alpha-glucosidase inhibitors (AGI) inhibit conversion of oligosaccharides into monosaccharides in the intestinal brush border. In other words, large sugar molecules are broken down into small sugar molecules which are necessary to pass throught the small bowel lining into the blood stream. This reduces glucose in the blood stream during digestion. Due to their action in the GI tract, their main side effect is abdominal discomfort, flatus and diarrhea. This is due to the extra sugar being passed downstream to the colon where bacteria (lactobacili) use the sugar as their own food source and produce gas. When used alone, they are not associated with hypoglycemia. Examples of AGI include acarbose (Precose) and miglitol (Glyset).
Glucose like peptide-1 Analogues (GLP-1)
Glucose like peptide-1 (GLP-1) is the main incretin hormone which has three effects (a) decreases glucagon production which leads to reduced glucose production from the liver (b) increases beta cell mass and stimulates insulin production from the beta cell of the pancrease, and (c) CNS effects to increase satiety and lead to weight reduction. Examples of GLP-1 are exenatide (Byetta, Bydureon) and liraglutide (Victoza). Exenatide comes from the salivary gland of the Gila monster, which is a highly venomous lizard. Human GLP-1 only stays in the blood stream for 30 to 90 seconds. However, Exenatide is 50% homologous to human GLP-1 but resists inactivation by the DPP-4 enzyme; therefore, it stays in the blood stream for hours. Its major side effect is nausea and emesis which occurs in only a few percent of patients. Currently this category is only available in injectable form.
It is useful to know what happend in the normal person. When you are in the fasting state, your body has to produce glucose in a constant rate. You need a basal rate of insulin to accomodate this glucose. It is mandatory for certain organs such as the brain, the heart and the kidneys. However, during a meal, you have a rapid bolus of glucose. The pancrease responds with a rapid bolus of insulin. In Insulin therapy, we try to mimic this as much as possible. The basal rate of insulin is accomplished by the use of long acting insulin. The two on the market are insulin glargine (Lantus) and insulin detemir (Levemir). The bolus of insulin is accomplished by the use of short acting insulin. Both human and analog insulins are available. Human insulin was the first to be released in the market over a decade ago. Analog insulin is favored over human insulin because it binds to albumin in the blood stream for a longer period and is released in an even rate. insulin aspart (NovoLog) is currently the most widely used analog insulin.
Figure 6, Normal Glucose and Insulin Production
Alternatively, early on, many diabetics can get by using Lantus and Metformin or Lantus exenatide (Byetta), a GLP-1. This is because the basal insulin is supplied by the Lantus, and the bolus insulin is obtained from the pancrease through the use of an oral agent such as Metformin or Byetta. This works because early on, within eight years of diagnosis, diabetics still have enough insulin production from their pancrease, and the oral agents make that insulin work more efficiently (enhanses insulin sensitivity).
Stratification Based on A1c Level
After diet and weight loss, the second treatment option depends on your Glycosylated Hemoglobin (HbA1c or A1c). A new consensus paper has looked at all the recent literature and has changed the way initial diabetes therapy is considered. The theory is that if your A1c level is low, you have a good chance at reversing the effects of diabetes with aggressive lifestyle changes such as diet, exercise, along with significant weight loss if you are overweight. On the other extreme, if your A1c is very high, you need aggressive control with insulin therapy early since all other measures will fall short of reducing the A1c < 6.0%.
1. A1c <= 7.5%
(a) Monotherapy: It is possible to reduce your A1c level to less than 6.0% with a single agent. Oral agents are often the first choice.
(b) Dual Therapy (see below)
2. A1c 7.6 to 9.0%
(a) Dual Therapy: In order to reduce your A1c level to a large degree, it is necessary to combine agents. Often oral agents are tried at first; however, many researchers have suggested to start with Metformin conbined with long acting insulin, such as Lantus or Levemir.
(b) Triple Therapy: A combination of three oral agents
3. A1c > 9.0%
(a) Insulin alone
(b) Insulin + Oral agents
(c) Oral agents alone
Figure 7, Algorithm for Treatment of Diabetes
Liraglutide vs Sitagliptin
There is only one head to head study to compare liraglutide (Victoza) to sitagliptin (Januvia) conducted by Novo Nordisk, the maker of liraglutide. The study was randomized and controled; however, it was unblinded since liraglutide is an injection and sitagliptin is oral. The study enrolled 665 patients and randomly assigned them to three groups and followed them over six months. The study was conducted in 158 sites in 11 countries, including the United States. Patients were only allowed to take Insulin and Metformin, making liraglutide and sitagliptin the independent variables. The results were statistically significant and are shown below. The higher dose of liraglutide was shown superior to sitabliptin in reducing HbA1c levels of approximately 1.5% and weight reduction of approximately 3 lbs.
Figure 8, Liraglutide vs Sitagliptin
Liraglutide vs Exenatide
There is a head to head study  that compares liraglutide (Victoza) to exenatide (Byetta) which are both injectable routes. Liraglutide is a GLP-1 analogue where exenatide is a GLP-1 receptor agonist. Both agents act by suppressing glucagon and glucose production during the fasting state. The study was a randomized, 26-week open-label, parallel-group, multinational study. It took diabetic patients with a mean HbA1c above 8.2% and treated each of two groups with either liraglutide or exenatide. The findings show that liraglutide reduced HbA1c levels significantly over exenatide, with p<0.0001. Liraglutide reduced HbA1c levels by -1.12%. The major side effects of liraglutide are nausea and gastrointestinal with a frequency of 8%. On average patients lost 4-5 lbs in weight equally in each group.
Figure 9, Liraglutide vs Exenatide
Table 1, Antidiabetic Medication by Class
Table 2, Types of Insulin
Table 3, Summary of Insulin Regimens
Table 4, List of Oral Medications and Insulin
Abbreviations: / means a ratio such as numerator divided by denominator, u/ml means units per mililiter; # means number as in dispensing;< means less than; bid means twice a day; CHO means carbohydrate; ER means extended release; h means hour; hs means hour of sleep, or bedtime; kg means kilograms; Max means maximum; min means minute; ml means mililiter; po means orally qd means daily qwk means once a week; sc means subcutaneous;tabs means tablets u means units; XR means extended release.
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