I was going to do a brief review of insulin therapy here, but I found a good one at About.com. So why re-invent the wheel?
If interested, click through to the article by Michael Bihari, M.D.: Insulin for type 2 diabetes: What you need to know.
Drug Review: Insulin
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Brief Drug Review: Pramlintide
Pramlintide is sold in the U.S. as Symlin. It’s only used in patients already taking meal-time rapid-acting insulin. Pramlintide may have a role in treatment of overweight type 2 diabetics inadequately controlled on insulin, or who experience weight gain refractory to diet and exercise.
Remember that drug names vary by country and manufacturer. This is a brief review; consult your physician or pharmacist for details.
Class: amylin analogue
How does it work?
Amylin is a hormone stored in pancreas beta cells and is secreted along with insulin. It affects glucose levels by several mechanisms, including slowed stomach emptying, regulation of glucagon secretion after meals, and by reducing food intake. Amylin and insulin levels rise and fall together,working jointly to control blood sugar levels. Amylin is relatively deficient in many cases of type 2 diabetes.
Pramlintide is a chemical similar in structure to amylin, and causes similar effects. It allows insulin therapy to more easily match the body’s needs in the after-meal period. It also promotes modest weight loss in obese patients.
Pramlintide therapy reduces hemoglobin A1c by 0.5 to 1% (absolute decrease, not relative).
We have no data on long-term outcomes with this drug.
Uses
Pramlintide is FDA-approved for use in both type 1 diabetes and insulin-requiring type 2 diabetes. It can be used with metformin and/or sulfonylureas as long as insulin is also part of the regimen. It’s probably best not to use it with exenatide and other GLP-1-based therapies.
Dosing
It’s injected subcutaneously just before meals, starting with 60 mcg in type 2 diabetics. To avoid hypoglycemia at the start of treatment, the pre-meal rapid-acting injected insulin dose is usually reduced by half. Pramlintide should only be administered before meals that contain at least 30 grams of carbohydrate or 250 calories. The maximum dose is 120 mcg with each meal.
Side effects
Nausea is the most common side effect but clears up in a few weeks. Pramlintide by itself does not cause hypoglycemia, but since it is always used with injectable insulin, hypoglycemia may occur—usually within three hours.
Don’t use if you have . . .
. . . gastroparesis or hypoglycemia unawareness.
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Drug Review: Colesevelam
Colesevelam is used primarily to reduce elevated levels of LDL cholesterol. It’s sold in the U.S. as WelChol. Remember that drug names vary by country and manufacturer. This is a brief review; consult your physician or pharmacist for details.
Class: Bile acid sequestrant
How does it work? Unclear
Uses
Colesevelam is FDA-approved for treatment of type 2 diabetes in conjunction with insulin or diabetic pills.
Dosing
Three tablets twice daily with meals, or six tablets once daily with a meal.
Side effects
Constipation in one of every 10 users.
Do not use if you have . . .
. . . serum triglycerides over 500 mg/dl, or have gastroparesis, other gastrointestinal motility disorders, risk factors for bowel obstruction, or recent major gastrointestinal procedures.
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Drug Review: Dipeptidyl-Peptidase-4 Inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin)
The four dipeptidyl-peptidase-4 inhibitors available in the U.S. are sitagliptin (sold as Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina). Vildagliptin is available in other countries.
Remember that drug names vary by country and manufacturer. This is a brief drug review; consult your physician or pharmacist for details.
How do they work?
DPP-4 inhibitors decrease both fasting and after-meal blood sugar levels primarily by increasing insulin release from pancreas beta cells. How they do it is complicated.
First off, you need to know that two gastrointestinal hormones levels—glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide—increase in response to a meal. These hormones increase insulin secretion by pancreas beta cells, suppress glucagon secretion from pancreas alpha cells after meals, help suppress glucose production by the liver, and improve glucose uptake by tissues outside the liver. GLP-1 also slows emptying by the stomach and reduces food intake. All this tends to lower glucose levels after meals.
Did I mention it was complicated?
If we could make these gut hormones hang around longer, their glucose-lowering action would be enhanced. How can we make them hang around and work longer? Easy: suppress the enzyme that degrades them: dipeptidyl-peptidase-4. That’s what DPP-4 inhibitors do.
The small intestine hormone GLP-1 is a major player in normal carbohydrate metabolism. GLP-1 levels, by the way, are decreased in type 2 diabetes.
For the DPP-4 inhibitors, we have no data on long-term safety, mortality, or diabetic complications.
Uses
Sitagliptin is FDA-approved as initial drug therapy for the treatment of type 2 diabetes, and as a second agent in those who do not respond to a single agent, such as metformin, a sulfonylurea, or a thiazolidinedione. It can also be used as a third agent when dual therapy with a sulfonylurea and metformin doesn’t provide adequate blood sugar control.
Saxagliptin, linagliptin, and alogliptin are FDA-approved as initial drug therapy for the treatment of type 2 diabetes (in adults) or as add-on drugs for those who do not respond to a single drug, such as metformin, a sulfonylurea, or a thiazolidinedione. In case you’re wondering, you wouldn’t use several of the DPP-4 inhibitors at the same time. In the summer of 2012, the FDA approved linagliptin as an add-on drug for type 2 diabetics already taking insulin. Linagliptin and alogliptin haven’t been studied in nursing or pregnant women; I’m not sure about sitagliptin and saxagliptin in those settings. Alogliptin is approved for combined use with metformin, pioglitazone, insulin, and perhaps sulfonylureas.
Dosing
The DPP-4 inhibitors are given by mouth. The usual dose of sitagliptin is 100 mg once daily, with reduction to 50 mg for moderate to severe kidney impairment and 25 mg for severe kidney impairment. The usual dose of saxagliptin is 2.5 or 5 mg once daily, with the 2.5 mg dose recommended for patients with moderate to severe kidney impairment. Linagliptin’s dose is 5 mg daily, regardless of liver or kidney funtion. The alogliptin dose is 25 mg daily, with lower doses for those with kidney impairment.
Side Effects
Generally well-tolerated. No risk of hypoglycemia when used as the sole diabetes drug. They do not cause weight gain. Sitagliptin, linagliptin, and alogliptin might cause pancreatitis. Alogliptin may cause liver disease or abnormal liver function blood tests. Saxagliptin and alogliptin may increase the risk of heart failure, particularly in those with pre-existing heart or kidney disease.
Don’t use if you have . . .
. . . moderate or severe kidney impairment (sitagliptin) or severe kidney impairment (saxagliptin).
Use sitagliptin or alogliptin with caution and careful monitoring if you have a history of pancreatitis.
Updated April 7, 2016
Filed under Drugs for Diabetes
Another Sacred Cow Slaughtered: Fruits and Vegetables DON’T Prevent Cancer
We’ve been told by the authorities repetitively that eating plenty of fruits and vegetables will lower our risk of cancer. However, a recent study in the American Journal of Clinical Nutrition says that ain’t so.
Fire up the grill—we’re havin’ steak tonight!
Researchers looked at data from over 450,000 participants (men and women over 50) in the National Institutes of Health—AARP Diet and Health Study. Diet data was collected by self-administered questionnaire. State-level cancer registries identified the cancers that developed during the average follow-up of seven years.
Their conclusions and selected comments:
Intake of fruit and vegetables was generally unrelated to total cancer incidence in this cohort.
However, on the basis of animal studies, human case control and cohort studies, and randomized controlled trials, there is likely no harm associated with the consumption of fruit and vegetables and their consumption may prevent cardiovascular disease.
Indeed, analyses in this cohort and in others that have investigated dietary patterns rich in fruit and vegetables have found reduced risks of colorectal cancer [three references cited] and mortality, including death from cardiovascular disease and all cancers [one reference was cited supporting reduced deaths from CVD and all cancers—a Mediterranean diet study].
As in all good science reports, the researchers compare and contrast their findings with similar published research. They note that theirs is one of only four large cohort studies that have examined this issue. Two of the other three (see references below) also found no association between total cancers and fruit and vegetable consumption. The one that did find a beneficial linkage was the smallest of the four, so not as compelling.
Before this research was published, some experts suggested that adequate fruit and vegetable intake could prevent between 5 and 12% of cancers.
Eat your fruits and vegetables because they taste good, provide myriad nutrients, and may have some other healthful properties. But not to lower overall cancer risk.
References:
George, Stephanie, et al. Fruit and vegetable intake and risk of cancer: a prospective cohort study. American Journal of Clinical Nutrition, 89 (2009): 347-353.
Hung, H.C., et al. Fruit and vegetable intake and risk of major chronic disease. Journal of the National Cancer Institute, 96 (2004): 1,577-1,584.
Takachi, R., et al. Fruit and vegetable intake and risk of total cancer and cardiovascular disease [in Japan]. American Journal of Epidemiology, 167 (2008): 59-70.
Benetou, V., et al. Vegetables and fruit in relation to cancer risk: evidence from the Greek EPIC Cohort Study. Cancer Epidemiology, Biomarkers, and Prevention, 17 (2008): 387-392.
Filed under cancer, Fruits, Mediterranean Diet, Vegetables
Drug Review: Sulfonylureas
Sulfonylureas (SUs) in 2010 are still the most widely used drugs for treatment of type 2 diabetes. At least six different SUs are in common usage in the U.S., including glipizide, glimiperide, and glyburide. They are often prescribed for patients who do not respond adequately to lifestyle modification and are intolerant of metformin, the usual first-choice drug.
Sulfonlylureas make the pancreas beta cells secrete more insulin into the bloodstream. The other drugs that do this are the meglitinides; these two classes are sometimes lumped together as insulin secretagogues. The sulfonylureas are less expensive.
This is a brief review pertinent to type 2 diabetes only—consult your physician or pharmacist for details. Remember that drug names vary by country and manufacturer.
How do they work?
Sulfonylureas increase the pancreas’ production of insulin after a meal (second phase insulin secretion). If the pancreas beta cells are no longer producing any insulin, SUs won’t work. SUs decrease fasting blood sugar by about 20% and hemoglobin A1c by 1 or 2% (absolute, not relative).
[Metiglinides have about the same effectiveness as SUs. Repaglinide and nateglinide increase the pancreas’ output of insulin, working faster than sulfonylureas. They don’t last as long as sulfonylureas, which may help avoid hypoglycemia. These two “glinides” work mostly to reduce sugar levels after meals.]
We don’t know if these SUs affect death rates.
Uses
May be used alone or in combination with certain other diabetic drugs. Since they have the same mechanism of action, sulfonylureas and meglitinides would not normally be used together. In combination therapy, you want to use drug classes that work by different mechanisms.
Dosing
SU dose depends on the particular one used. Some are taken by mouth once daily, others twice.
Side effects
Hypoglycemia is the most severe adverse effect of the sulfonylureas. The duration of hypoglycemia seen with SUs is often much longer than you would predict by how much drug is in the bloodstream. Hypoglycemia is more common with the longer-acting drugs, such as glyburide and chlorpropamide. There is some concern that sulfonylureas are linked to poorer outcomes after a heart attack. SUs occasionally cause nausea, skin reactions, and elevations of liver function tests.
Weight gain is common.
When used with insulin or thiazolidinediones, these sulfonylurea adverse effects are more likely to appear: weight gain, fluid retention, congestive heart failure.
Precautions . . .
Consult your personal physician or pharmacist.
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You Know About Insulin. And Now, the REST of the Story . . .
When we digest carbohydrates, blood sugar rises. If it goes too high it causes problems. 
Everybody knows that insulin lowers blood sugar levels, right? Less well-known is that regulation of blood sugar is the result of complex interactions of multiple hormones, not just insulin.
[As is my habit, I will use “sugar” and “glucose” interchangeably in this post.]
Allow me to review the main hormones involved in blood glucose regulation:
1. Insulin is made and stored in pancreas beta cells. As a meal is digested, blood sugar rises; the pancreas releases insulin to bring blood sugar back down by driving it into cells.
2. Amylin is also made and stored in pancreas beta cells and works to reduce blood sugar levels. Blood levels of amylin rise and fall in concert with insulin levels. Amylin slows emptying of the stomach, reduces food consumption, and regulates another hormone—glucagon—after meals.
3. Glucagon is from pancreas alpha cells. It works to raise blood sugar by promoting the liver’s breakdown of glycogen into glucose, and by promoting the liver’s manufacture of new glucose molecules.
4. Glucagon-like peptide -1 (GLP-1) is produced in small intestine cells and it’s main action is to promote insulin secretion by the pancreas beta cells after absorption of food, which lowers blood sugar levels. GLP-1 (like amylin) also inhibits emptying of the stomach, inhibits glucagon release, and inhibits appetite, all of which would tend to keep a lid on blood sugar levels.
5. Gastric inhibitory polypeptide (GIP) promotes secretion of insulin following absorption of food. GIP is also known as glucose-dependent insulinotropic polypeptide.
You can see that some hormonal mechanisms raise glucose levels; others lower glucose levels. Homeostasis is all about reaching a happy medium between the two, without wild swings one way or the other. In healthy people, eating food leads to release of gastrointestinal peptides (GLP-1 and GIP), insulin, and amylin. The interaction among them keeps blood sugar levels in a fairly level low range. In diabetes, one or more malfunctions in the system leads to abnormally high blood sugars.
The good news is that scientists have used this knowledge to devise new, effective treatments for diabetes. Examples are GLP-1 analogues and DPP-4 inhibitors.
PS: In lab animals, GLP-1 stimulates formation of new pancreas beta cells, so it hold promise in halting the progressive beta cell failure characteristic of type 2 diabetes.
Filed under Carbohydrate, Causes of Diabetes
Drug Review: Alpha-Glucosidase Inhibitors (acarbose and miglitol)
Alpha-glucosidase inhibitors (AGIs) available in the U.S. are acarbose (Precose) and miglitol (Glyset). Drug names vary by country and manufacturer.
This is only a brief review: consult your physician or pharmacist for full details.
How do they work?
Many of the carbohydrates we eat are just basic sugar molecules joined to each other by chemical bonds, creating disaccherides, oligosaccharides, and polysaccharides. This is as true for bread and potatoes as it is for table sugar. To digest and absorb them, we have to break them down into the basic sugar molecules (monosaccharides). AGIs inhibit this breakdown process inside our intestine, decreasing the rise in blood sugar after we eat complex carbohydrates. They delay glucose absorption. So AGIs mainly decrease after-meal glucose levels.
Uses
They work alone or in combination with other diabetic medications, especially if the diet contains over 50% of energy in the form of complex carbohydrates. They are FDA-approved only for use in type 2 diabetes, but they have also been used in type 1.
Dosing
The starting dose is the same for both: 25 mg by mouth three times daily with the first bite of each main meal.
Side effects
Belly pain, intestinal gas, diarrhea. Slight risk of hypoglycemia when its used alone; higher risk when used with insulin shots or insulin secretagogues. If hypoglycemia occurs, you have to eat glucose to counteract it, not your usual non-glucose items because you won’t absorb them properly.
Don’t use if you have . . .
. . . Liver cirrhosis (refers to acarbose: miglitol can be used), kidney impairment, or intestinal problems.
Filed under Drugs for Diabetes
What Is Normal Blood Sugar?
Lately I’ve been thinking about which carbohydrates might be added to the Ketogenic Mediterranean Diet to make it healthier yet remain diabetic-friendly. Carbohydrates—some more than others—tend to elevate blood sugars in diabetics. If I’m going to recommend adding carbs to the KMD, I have to give some idea what an acceptable blood sugar response would be. An excessive rise in blood sugar level would necessitate eliminating that carbohydrate, reducing the serving size, or changing the diabetic medication regimen (increase a dose or add a new drug?)
First off, I’ve reviewed what constitutes blood sugar levels in healthy non-diabetics before and after meals. Those levels might give us some idea what to shoot for in diabetics.
The following numbers refer to average blood sugar (glucose) levels in venous plasma, as measured in a lab. Portable home glucose meters measure sugar in capillary whole blood. Many, but not all, meters in 2010 are calibrated to compare directly to venous plasma levels.
Fasting blood sugar after a night of sleep and before breakfast: 85 mg/dl (4.72 mmol/l)
One hour after a meal: 110 mg/dl (6.11 mmol/l)
Two hours after a meal: 95 mg/dl (5.28 mmol/l)
Five hours after a meal: 85 (4.72 mmol/l)
(The aforementioned meal derives 50–55% of its energy from carbohydrate)
♦ ♦ ♦
Ranges of blood sugar for young healthy non-diabetic adults:
Fasting blood sugar: 70–90 mg/dl (3.89–5.00 mmol/l)
One hour after a typical meal: 90–125 mg/dl (5.00–6.94 mmol/l)
Two hours after a typical meal: 90–110 mg/dl (5.00–6.11 mmol/l)
Five hours after a typical meal: 70–90 mg/dl (3.89–5.00 mmol/l)
♦ ♦ ♦
Another way to consider normal blood sugar levels is to look at a blood test called hemoglobin A1c, which is an indicator of average blood sugar readings over the prior three months. The average healthy non-diabetic adult hemoglobin A1c is 5% and translates into an average blood sugar of 100 mg/dl (5.56 mmol/l). This will vary a bit from lab to lab. Most healthy non-diabetics would be under 5.7%.
What Level of Blood Sugar Defines Diabetes and Prediabetes?
According to the 2007 guidelines issued by the American Association of Clinical Endocrinologists:
Prediabetes (or impaired fasting glucose): fasting blood sugar 100–125 mg/dl (5.56–6.94 mmol/l)
Prediabetes (or impaired glucose tolerance): blood sugar 140–199 mg/dl (7.78–11.06 mmol/l) two hours after ingesting 75 grams of glucose
Diabetes: blood sugar 200 mg/dl (11.11 mmol/l) or greater two hours after ingesting 75 grams of glucose
Diabetes: random blood sugar 200 mg/dl (11.11 mmol/l) or greater, plus symptoms of diabetes
For my current thoughts on blood sugar goals for diabetics and prediabetics, please see the bottom half of my “What is Normal Blood Sugar” page.
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Drug Review: Thiazolidinediones (pioglitazone, rosiglitazone)
Thiazolidinediones are more easily referred to as TZDs or glitazones. Compared to the usual first-choice drug for type 2 diabetes (metformin), the TZDs are significantly more expensive.
Remember that drug names—both generic and brand—may vary depending on country and manufacturer. In the U.S., rosiglitazone is sold as Avandia; pioglitazone is Actos. This is just a brief overview: consult your physician or pharmacist for full details.
How do they work?
In short, TZDs increase glucose utilization and decrease glucose production, leading to lower blood sugar levels. They sensitize several tissues to the effect of insulin. Insulin, among other actions, helps put circulating blood sugar into our muscles, fat cells, and (to a lesser extent) liver cells. So blood sugar levels fall. Thiazolidinediones (aka TZDs) make these tissues more sensitive to this effect of insulin. Insulin also suppresses glucose production by the liver, an effect enhanced by TZDs. They reduce insulin resistance.
TZDs may also help preserve pancreas beta cell function. Beta cells produce insulin.
They reduce both fasting and after-meal glucose levels. Fasting blood sugar drops and average of 40 mg/dl. Hemoglobin A1c falls by 1 to 1.5% (absolute, not relative).
TZDs tend to improve blood lipids: lower triglycerides, higher HDL cholesterol, decreased small, dense LDL cholesterol. Pioglitazone has the more pronouned effect.
On a cellular level, they activate peroxisome proliferator-activated receptor-gamma, so they are sometimes referred to as PPAR-gamma agonists. Pioglitazone also affects PPAR-alpha.
Uses
TZDs can be used alone or in combination with insulin, metformin, and sulfonylureas in people with type 2 diabetes.
Dosing
Note that onset of action is delayed by several weeks, perhaps as many as 8-12 weeks.
Pioglitazone: Start at 15-30 mg/day by mouth. Maximum dose is 45 mg/day.
Rosiglitizone: Start at 4 mg/day by mouth. After 8-12 weeks, dose may be increased to 8 mg/day.
Side effects
Weight gain is fairly common, through both fluid retention and increase in fat tissue. Weight gain with pioglitazone, for example, is around 6–12 pounds (3–5 kg). Mild anemia and puffy feet and hands (edema from fluid retention) are also seen. Fluid retention may ultimately cause congestive heart failure. This drug-induced fluid retention does not respond very well to fluid pills (diuretics).
The combination of insulin injections and TZD may increase the risk of heart failure.
Some studies suggest that rosiglitazone increases the risk of heart attacks, heart failure, and death. That’s why the Food and Drug Administration in 2011 drastically curtailed use of the drug. The FDA re-examined the date in 2013 and decided that rosiglitazone didn’t increase cardiovascular risk after all.
Preliminary data suggest a link between bladder cancer and pioglitazone.
TZDs are associated with increased risk for broken bones, perhaps doubling the risk.
Macular edema—manifested by blurry vision—may occur infrequently.
When used as the sole diabetic medication, TZDs do not cause hypglycemia. But when used with insulin injections or insulin secretagogues, low blood sugar can occur.
Don’t use if you . . .
. . . have a significant degree of congestive heart failure or active liver disease. Even a history of heart failure may be a reason to avoid TZDs. TZDs should probably not be used in women with low bone density or anyone else prone to fractures.
Updated December 26, 2013
Filed under Drugs for Diabetes
Diabetic Mediterranean Diet 