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 inject insulin every day (usually 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. It can also be given by inhalation into lungs just before meals (Afrezza®)
These insulins are injected before mealtimes, usually in proportion to the carbohydrate content of the meal. They act quickly (within 15-20 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®, Admelog®), as part (Novolog®), and glulisine (Apidra®). The fastest-working one is Fiasp®, essentially altered Novolog®, allowing more rapid onset of effect.
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 (up to 12 hours).
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.
Glargine (Lantus®, Toujeo®, Basaglar®) and detemir (Levemir®) insulins are up to 24-hour lasting, relatively “peakless” insulins. Degludec (Tresiba®) is the longest lasting, with effect for ups to 42 hours. They are usually injected once a day. They maintain a reasonably steady effect throughout the entire day. Some patients need to inject Levemir® twice daily to cover their needs for the entire day.
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 before meals.
Insulin Injection Devices
Insulin can be injected either by a special syringe which the patient fills with the appropriate amount of the specific type of insulin or, preferably, by an insulin pen. The pen devices are either disposable (prefilled with 300-900 units of insulin) or permanent into which prefilled insulin cartridges are fitted.
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 thin catheter 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. marketed by MiniMed/Medtronic, OmniPod/Insulet, T-slim/Tandem) cannot read sugar levels. Thus, the patient still has to monitor his or her own sugars either with fingersticks or by continuous glucose monitor to be able to adjust insulin infusion rates (“basal” rates and mealtime “boluses”). The MiniMed’s 670G system is the world’s first “hybrid” closed-loop device, the first step toward an “artificial pancreas”. The pump is wirelessly integrated with a continuous glucose sensor which directs the pump to deliver the needed amount of insulin to keep blood sugar at safe level. There are three additional continuous glucose monitoring systems on the market: Dexcom (G5 and G6 models), Abbott’s Freestyle Libre, and the only implantable (sensor under the skin for 90 days) one, Eversense®. V-Go is a disposable insulin delivery device which sends insulin continuously under the skin at one preset rate (basal) and is activated to deliver small amounts of insulin at mealtime. It is changed every day.
Oral Medications Used for Treatment of 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®) affects the way insulin works on the liver to decrease the amount of sugar the liver makes overnight. Metformin should not be used in patients with kidney failure.
Thiazolidinediones – (also called glitazones or TZDs) – rosiglitazone (Avandia®) and pioglitazone (Actos®) – help insulin to work especially on muscles and fat. They are long-acting, 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 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 in the urine
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 four such pills now approved by the FDA: canagliflozin (Invokana®), dapagliflozin (Farxiga®), empagliflozin (Jardiance®) and ertugliflozin (Steglatro®).
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 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 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 pioglitazone)
- Invokamet® (combination of Invokana and metformin)
- Synjardy® (combination of Jardiance and metformin)
- Glyxambi® (combination of Jardiance and Tradjenta)
- Xigduo® (combination of Farxiga and metformin)
- Qtern® (combination of Farxiga and Onglyza)
- Steglujan® (combination of Steglatro and Januvia)
Injectable Medications (non-insulin)
Symlin® (pramlintide) is a synthetic version of human amylin. Since amylin is normally 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”(GLP-1 analogs)
Byetta®, Bydureon® (exenatide), Adlyxin® (lixisenatide), Victoza® (liraglutide), Trulicity® (dulaglutide) and Ozempic® (semaglutide)
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. 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.
Bydureon® is a once-weekly injectable form of exenatide, Victoza®, is injected just once a day regardless of the time of the day. whileTrulicity® (dulaglutide) and Ozempic® (semaglutide) are injected just once a week. Patients using these medications can achieve better diabetes control and most experience weight loss. Initial nausea is the most common side effect (but it’s usually temporary and the vast majority of patients continue its use. Unlike insulin, they don’t cause hypoglycemia (low-sugar reactions).
Combination of insulin and GLP-1 analogs
For patients’ convenience, there have been two products introduced which combine in a single pen device both long-acting insulin and GLP-1 analog. It is injected just once a day. They are marketed as Soliqua (combining insulin Lantus® and lixisenatide) and Xultophy (combination of insulin Tresiba® and Victoza®).