What is Diabetes?
Is characterized by destruction of the insulin-secreting cells of the pancreas, leading to an absolute deficiency of insulin. Even though type 1 diabetes can occur at any age, most patients develop it before the age of 30. The most common symptoms are lack of energy, constant hunger, sudden weight loss, frequent urination, excessive thirst, and blurred vision. These symptoms can be sudden in onset. Persons with type 1 diabetes can not survive without injecting insulin into their body. About 5% of persons with diabetes have type 1. Prior to 1997, type 1 diabetes was also known as insulin-dependent diabetes mellitus.
Is a term for individuals who have both insulin resistance (a condition in which the cells of the body resist the action of insulin) and insulin deficiency. People with type 2 range from predominantly insulin resistant with decreased insulin secretion to predominantly deficient in insulin secretion with some insulin resistance. Type 2 diabetes is increasing in frequency as people get older, more overweight and less physically active. Recently there has been an alarming increase in type 2 diabetes occurring in children and adolescents, consistent with changes in their lifestyles. The most common symptoms are, again, lack of energy, increased hunger and thirst, frequent urination, blurred vision, loss of feeling in hands and toes, slow healing of infections or wounds, and weight loss. These symptoms are usually gradual in onset. Persons with type 2 diabetes may initially be treated with diet and exercise and then with pills to treat their elevated blood sugar. Subsequently, however, for many insulin is the only effective treatment. About 90% – 95% of persons with diabetes have type 2 diabetes. Prior to 1997, type 2 diabetes was also known as non-insulin-dependent diabetes.
Occurs when a pregnant woman has blood sugar levels that are higher than normal because the body does not make enough insulin or does not use properly the insulin that is made. During normal pregnancy fasting blood sugars range between 60-90 mg/dl, lower than in non pregnant women. Gestational diabetes usually occurs in the last half of pregnancy, affecting up to 5% of all pregnant women. As a result, it is the most common problem of pregnancy today. After the baby is born, the mother’s blood sugar levels usually return to normal. Type 2 diabetes can develop later in life in majority of women who have had gestational diabetes and who are overweight. The baby may also develop diabetes as an adult, and girls may be prone to developing gestational diabetes.
This term was coined in 2001 to signify both the condition that precedes onset of frank type 2 diabetes and also the fact that onset of diabetes can be prevented at this stage (by calorie-restricted diet and increased physical activity). It is defined as that disease in which individuals have either “impaired fasting glucose” (i.e. plasma glucose between 100 and 125 mg/dl) or “impaired glucose tolerance” (i.e. plasma glucose between 140 and 199 mg/dl two hours after the 75-gram glucose-containing drink is ingested during oral glucose tolerance test).
How Do We Diagnose Diabetes?
Testing for diabetes should be done at age 45. If normal, repeat every 3 years. Testing should be done at a younger age, and more frequently in persons 45 and older, who:
- are obese (>120% desirable body weight or a body mass index (BMI) >27 kg/m2)
- have a first-degree relative with diabetes
- are a member of a high-risk ethnic population (African American, Hispanic, Native American, Asian)
- delivered a baby weighing over 9 lb. or were diagnosed with Gestational Diabetes Mellitus
- are hypertensive (blood pressure >140/80)
- have an HDL cholesterol level < 50 mg/dl
- on previous testing, had Impaired Glucose Tolerance or Impaired Fasting Glucose
There are 4 ways diabetes can be diagnosed:
- After at least 8 hours of not eating or drinking anything, blood is drawn and the Fasting Plasma Glucose is measured. A result of >126 mg/dl is indicative of diabetes. This is the preferred diagnostic test because of its ease of administration, convenience, and lower cost.
- Before diagnosis of diabetes can be confirmed, the result (fasting plasma glucose > 126 mg/dl) needs to be repeated on a different day. Random (sometimes called “casual”) Plasma Glucose can also be done to diagnose diabetes. This test can be done at anytime without regard to the time of the last meal. A result higher than 200 mg/dl with classic symptoms (increased hunger, excessive thirst, and weight loss) denotes diabetes. If there are no symptoms the blood test has to be done on a different day.
- Oral Glucose Tolerance Test, involves drinking glucose dissolved in water and then having blood drawn two hours later. A result of >200 mg/dl signifies diabetes. To confirm the diagnosis, the test should be repeated on another day.
- Glycated hemoglobin (hemoglobin A1c, A1c) was adopted by the Amertican Diabetes Association as another way to diagnose diabetes. Level of 6.5% and above signifies diagnosis of diabetes. This test has not been accepted by other organizations yet as a reliable diagnostic criterion.
Diagnostic criteria are not treatment goals.
For patients checking their blood glucose levels, the American Diabetes Association guidelines call for preprandial (before meals) capillary glucose 70–130 mg/dl (5.0–7.2 mmol/l), peak postprandial (after meals) capillary glucose under 180 mg/dl and 100 -140 mg/dl at bedtime. The long-term control is assessed by a test called hemoglobin A1c (HgbA1c). An A1c score of 5.7 to 6.4 percent indicates prediabetes and an A1c level of 6.5 percent or higher is diagnostic of diabetes. The American Diabetes Association recommends that most people with diabetes maintain a goal of keeping A1C levels below 7 percent in order to properly manage their disease. The American College of Endocrinology suggests A1c at or below 6.5%, premeal glucose under 110 mg/dl and 2-hour after meal glucose of under 140 mg/dl.
How Do We Treat Diabetes
Insulin is a hormone necessary for survival. It regulates our metabolism (of carbohydrate, protein and fat) in countless ways. Patients with type 1 diabetes make none and, to survive, need to give themselves insulin every day (usually 3-4 times a day or through a continuous insulin infusion pump). Those with type 2 diabetes make too little insulin for their needs and secrete it usually too late to successfully cover their meal-related insulin demands. Thus, many persons with type 2 diabetes find it necessary to administer insulin, too (often alongside anti-diabetic pills or injections of other medications). Insulin cannot be ingested by mouth since the stomach juices would destroy it. In order to bypass the stomach, insulin is injected through the skin with a tiny (31 or 32-gauge, 3 to 5/16 inch long) needle. Theoretically, it could also be given in any number of other ways (by inhalation into lungs, by applying on oral or nasal mucosa, by a skin patch or by a rectal suppository).
Rapid-Acting Insulins These insulins are injected at mealtimes usually in proportion to the carbohydrate content of the meal. They act quickly (within 15 minutes), reach their maximum effect in 1.5 to two hours and last for a total of about four hours. These insulins are represented on the U.S. market by LisPro (Humalog®), aspart (Novolog®), and glulisine (Apidra®).
Short-Acting Insulins The only one used in the U.S. is Regular human insulin. It is injected 30 – 45 minutes before meals. It takes about an hour to start working, and its effect lasts about four to six (or even longer) hours. There is also a 5-times concentrated form of Regular insulin (Humulin® R U-500) which starts working at about the same time but stays active for longer (might be up to 12 hours).
Intermediate-Acting Insulins These insulins take four to six hours to start working and maintain their blood-sugar lowering effect for up to 12 to 16 hours. They are typically injected twice daily – in the morning and at bedtime. Because of their prolonged effect, their use is not tied to meals. NPH (N, cloudy) is a representative of this class.
Long-Acting Insulins Glargine (Lantus®) and detemir (Levemir®) insulins are up to 24-hour lasting, relatively “peakless” insulins. They are usually injected once a day. They reach their effects within a couple of hours and maintain a reasonably steady effect throughout the entire day. Some patients need to inject twice daily to avoid low sugar reactions. Ultralente (UL) insulin is used uncommonly nowadays. Its effect and duration are highly variable, typically lasting 24 – 36 hours.
Pre-mixed insulins In some cases, physicians and their patients find it more convenient to use one of several pre-mixed insulin combinations. These are mixtures of either rapid-and intermediate-acting insulins (such as 25% Humalog & 75% NP-Humalog, 50% Humalog & 50% NP-Humalog or 30% Novolog & 70% NP-Novolog) or short- and intermediate-acting mixtures (such as 30% Regular & 70% NPH). These insulin mixes are injected at or before meals.
Insulin Injection Devices Insulin can be injected either by a special syringe which the patient fills with appropriate amount of the specific type of insulin or, preferably, by an insulin pen. The pen devices are either disposable (prefilled with 300 units of insulin) or permanent into which prefilled insulin cartridges are fitted. Needle-less devices also exist. These inject insulin through the skin under pressure.
Insulin Pumps Insulin can also be delivered under the skin by continuous infusion from an external pump (about the size of a pager). The reservoir inside the pump holds up to 300 units of insulin. Insulin is pumped through thin, plastic tubing, ending in a needle under the skin (OmniPod is a disposable pump which is attached in its entirety to the skin and does not need the tubing). These external pumps (in the U.S. most are marketed by MiniMed/Medtronic, Disetronic/Roche, Animas/J&J, OmniPod/Insulet, T-slim/Tandem) cannot read blood glucose levels. Thus, the patient still has to monitor his or her own sugars with fingersticks to be able to adjust insulin infusion rates (“basal” rates and mealtime “boluses”). The MiniMed’s Paradigm was the first insulin pump wirelessly integrated with a continuous glucose sensor. There are two additional continuous glucose monitoring systems on the market: Dexcom and Navigator (taken off the market in the US but still available in Europe). V-Go is a disposable insulin delivery device which sends insulin continuously under the skin at one preset rate (basal) and can be activated to deliver small amounts of insulin at mealtime.
Implantable Insulin Pumps These pacemaker-like devices infuse insulin into the peritoneal space (not under the skin). A remote-control device adjusts infusion rates. These pumps have been used in Europe for about two decades but remain “experimental” in the USA.
Oral Medications used in Type 2 Diabetes Drugs delaying glucose absorption from small intestine acarbose (Precose®) and miglitol (Glyset®). These are used at mealtime to lower after-meal hyperglycemia (high sugar).
Drugs increasing insulin secretion Short-acting: repaglinide (Prandin®) and nateglinide (Starlix®). These are used at mealtime to reduce after-meal sugar levels. Long-acting: sulfonylureas, such as glipizide (Glucotrol®), glyburide (Micronase®, Diaßeta®) and glimepiride (Amaryl®). These medications are used once or twice daily to lower overall, but especially overnight, sugar levels. They have to be used carefully because they can lower blood glucose too much and cause hypoglycemic (low-sugar) reactions.
Drugs improving insulin action Biguanides: metformin (Glucophage®) has major effect on the way insulin works on the liver to decrease the amount of sugar the liver makes. Metformin should not be used if the patient’s kidneys fail. Thiazolidinediones – (also called glitazones or TZDs) – rosiglitazone (Avandia®) and pioglitazone (Actos®) – help insulin to work especially on muscles and fat. They are long-acting, usually used once a day. They cannot be used when the patient has severe congestive heart failure.
Drugs preserving the “incretin” effect – DPP-4 inhibitors These pills inhibit the action of an enzyme (DPP-4) which breaks down “incretins” (see below). This allows your own incretins work longer and enables the pancreatic islet cells to make more insulin and less glucagon when you eat. As a consequence, glucose levels are lowered. Sitagliptin (Januvia®), saxagliptin (Onglyza®), linagliptin (Tradjenta®) and alogliptin (Nesina®) are currently representing this class on the U.S. market.
Drugs which lower both glucose and cholesterol Colesevelam (Welchol®) lowers both blood sugar and “bad” (LDL) cholesterol. It works by binding bile acids but it’s not clear exactly how that lowers glucose.
Drugs with central nervous system effects Cycloset® (bromocriptine QR) is a pill which works at the level of the brain; it improves insulin action, does not cause hypoglycemia nor weight gain and might have beneficial cardiovascular effects.
Drugs which make kidneys excrete glucose These medications block the normal ability of the kidneys to re-absorb all the glucose from the urine back into the bloodstream (normally, we don’t have any sugar in the urine). In patients with diabetes, these pills lower blood sugar by making patients excrete it in their urine. There are three such pills now approved by the FDA: canagliflozin (Invokana®), dapagliflozin (Farxiga®), and empagliflozin (Jardiance®).
Drugs combining effects These medications combine the insulin-action improving and insulin-secreting effects of the above-mentioned drugs.
- Avandamet® (combination of Avandia and metformin)
- Avandaryl® (combination of Avandia and Amaryl/glimepiride)
- Glucovance® (combination of glyburide and metformin)
- Metaglip® (combination of glipizide and metformin)
- ACTOplus Met® (combination of Actos and metformin)
- Duetact® (combination of Actos and Amaryl/glimepiride)
- PrandiMet® (combination of Prandin and metformin)
- JanuMet® (combination of Januvia and metformin)
- Kombiglyze XR® (combination of Onglyza and metformin)
- Jentadueto® (combination of Tradjenta and metformin)
- Kazano® (combination of Nesina and metformin)
- Oseni® (combination of Nesina and Actos/pioglitazone)
- Invokamet® (combination of Invokana and metformin)
Injectable Medications Symlin® (pramlintide) When a healthy person eats, pancreatic beta cells make two hormones to handle the dietary load: insulin and amylin. We have provided patients with mealtime insulin since 1922. It has been only since 2005 that we have been able to provide the other necessary hormone: amylin. Amylin normally complements insulin’s effects: it works through brain and decreases the amount of your own sugar made by the liver (you don’t need it since you are eating), it slows stomach emptying thus decreasing the sugar spikes after meals, and it increases the sense of satiety and decreases appetite – patients wind up eating less before they feel full.
Symlin® is a synthetic version of human amylin. Since amylin is made by the same cells as insulin, it stands to reason that patients with type 1 diabetes make none and those with type 2 diabetes make too little of it. Symlin® is, therefore, given by patients with either type 1 or type 2 diabetes (by a disposable pen device with the usual tiny needle) at mealtime alongside their rapid-acting insulin. The possible advantages of using Symlin ® are better, smoother glucose control (while using less mealtime insulin), and weight loss.
“Incretin mimetics”: Byetta®, Bydureon® (exenatide), Victoza® (liraglutide), Tanzeum® (albiglutide) Several hormones are also normally released from the small intestine when we eat. They are called “incretins”. Byetta® was the first analog of an important human incretin (glucagon-like peptide 1 or GLP-1) approved by the FDA in 2005 to be used in the U.S. by patients with type 2 diabetes to improve glucose control. This hormone, injected by a pen device twice daily (before breakfast and before dinner), acts at four different places: it tells the pancreatic islet beta cells to make more insulin at mealtimes; it tells the pancreatic islet alpha cells to make less glucagon (which in turn means your liver will make less sugar at mealtime); it tells the stomach to slow down its emptying (so there is less sugar spike after meals) and finally, it tells the brain that you are full, decreasing appetite and food intake (through a different mechanism from Symlin®).
Bydureon® is a once-weekly injectable form of exenatide, approved in 2012; Tanzeum®, approved in 2014, is also injected just once a week.
Victoza®, approved by the FDA in 2010, works in a similar way but is injected just once a day regardless of the time of the day. As a result of these drug effects, patients can achieve better diabetes control, sometimes can decrease the amount of pills they take for sugar control, and most experience weight loss.