The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (27 page)

Research into reversing or preventing type 1 diabetes has greatly accelerated in recent years. Tests are being conducted of gene therapy, immune-based drug therapies, vaccines, transplants of insulin-producing islet cells, and several artificial pancreas device systems (APDS).

This wearable technology, using already-approved insulin pumps and glucose monitors, is designed to maintain blood sugar within a target range or
at a target level, using an algorithm managed by a smartphone.
¹⁶
Using continuous glucose monitoring, the system would automatically increase or decrease insulin delivery when it senses blood sugar is above or below the range or target level. Another type of system, designed to be a backup, would suspend glucose delivery when blood glucose drops below a certain threshold.
¹⁷

However, people would still need to manually tell the pump to dispense insulin at mealtimes, and adjust levels based on factors such as physical activity. Systems being tested use insulin alone (single pump) or a combination of insulin and glucagon (with dual pumps).

The Artificial Pancreas Consortium, supported by the Juvenile Diabetes Research Foundation (JDRF), is funding clinical trials of the devices in the United States, and similar systems are being tested in Europe.
¹⁸

Researchers at Boston University and Harvard report the system improves glucose levels and reduces episodes of hypoglycemia in type 1 diabetes more effectively than a conventional insulin pump.
¹⁹

Transplants of islet cells have also met with some success. Back in 2002, a small study from Edmonton, Canada, using a new protocol for islet cell transplantation, found that half of the patients who’d had a transplant didn’t need insulin injections for two years afterward. Since then, a consortium of scientists has been working to perfect new transplant techniques and looking for ways for patients to avoid a lifetime of immunosuppressant drugs. Researchers from Harvard Medical School say they may be able to help
regrow
islet cells—and even get rid of the wayward immune cells that attack the pancreas.

One potential gene therapy would infuse into the pancreas islet cells lacking the genetic defects that lead to type 1 diabetes. Another promising strategy, being tested at the University of California, San Francisco, involves coaxing embryonic stem cells (which can grow into almost any cell type), into becoming insulin-producing beta cells.
²⁰

Dr. Denise Faustman at Massachusetts General Hospital and Harvard Medical School is researching a possible treatment to reverse type 1 diabetes, using a bacterium called
Bacillus Calmette-Guérin (BCG)
that stops the immune system attack on beta cells, allowing the pancreas to regenerate and produce insulin again.

“These trials are already in Phase II and are the first trials in the world to use a safe immune intervention in people with the disease, not just immune
therapy in new onset disease,” says Dr. Faustman. “This therapy targets and kills the disease-causing white blood cells and boosts the beneficial T cells called Tregs. The 100-year-old generic BCG drug originally developed as a vaccine for tuberculosis prevention now has appeal as a simple cost-effective approach with global human clinical trials in multiple sclerosis, Sjögren’s syndrome, and type 1 diabetes.”

Early clinical trials sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) show that two courses of the immune suppressant drug
alefacept (Amevive)
given to people soon after a diagnosis of type 1 diabetes preserved beta cell function for as long as one year, compared to those who received a placebo. The NIAID reports that patients who received alefacept needed less insulin and experienced fewer episodes of hypoglycemia, possibly because their insulin production was sufficient to maintain levels of blood sugar within a target range.
²¹

Other immune therapies use cocktails of drugs. One combination uses
thymoglobulin
, a drug initially developed for kidney transplants, to kill immune cells that attack beta cells in the pancreas, while
pegfilgrastim (Neulasta)
, a drug used to treat neutropenia associated with chemotherapy, triggers production of healthy new immune cells. Studies show patients given the dual-drug therapy regained the ability to produce insulin while those given a placebo did not.
²²
An experimental drug called
DiaPep277
appears to “reeducate” the immune system rather than suppress it, stops destruction of beta cells, and reduces the need for insulin.
²³

A “reverse” vaccine (called
BHT-3021
) is also being tested. In contrast to conventional vaccines, which stimulate an immune response, BHT-3021 dampens the immune response against insulin. In a recent clinical trial, the plasmid vaccine not only shut down the attack on beta cells, but also seemed to preserve pancreatic function.
²⁴

Women diagnosed with type 1 diabetes in adolescence often get their periods late (at ages 13 to 15, versus the average age of 12.1), and more than a third have menstrual irregularities.
²⁵
These problems can include the absence of periods (
amenorrhea
) due to anovulation, scanty periods (
oligomenorrhea
), and more frequent menstrual cycles (
polymenorrhea
) with less time in between periods.

The fluctuating levels of hormones that underlie these problems can make it harder to control blood glucose. Some studies suggest that high progesterone may affect the action of insulin within cells, causing a slight insulin resistance and raising blood glucose. At the same time, elevated estrogen levels may improve the action of insulin, so blood glucose may be lower than normal when estrogen is high or “unopposed” by progesterone.

The high levels of both estrogen and progesterone during the premenstrual period can wreak havoc with blood glucose. “Women with diabetes who have this problem typically report that their blood glucose is elevated during the week before they get their period, then after they get their period, their sugars come crashing down,” says Dr. Levy, who’s also an associate professor of obstetrics, gynecology and reproductive science at New York’s Mount Sinai and director of the type 1 diabetes/diabetes in pregnancy program there. “Or, some women will tell me their sugars are crazy at certain times of the month and they can’t figure out why. So I will have them chart their glucose in relation to their cycles, which is very helpful. It enables us to tailor the insulin regimen to different times in the menstrual cycle.”

For example, if you have regular menstrual cycles, your insulin dose may be increased the week before your period. Once you get your period, the dose may be cut back. “Some women don’t have predictable cycles, so they don’t know when they are going to get those glucose highs and lows. And other women have pretty severe fluctuations in spite of everything. Those women, we will sometimes put on birth control pills to stabilize their cycle, to try to make things more predictable,” says Dr. Levy.

Monophasic birth control pills (which do not change the hormone levels during the 21 days you take the active pill) may help minimize changes in blood glucose. Women who have high blood pressure or peripheral vascular disease or who smoke should not take the pill. Progesterone can cause
elevations in glucose, and pills containing newer forms, such as
desogestrel
,
norgestrel
,
norgestimate
, and
drospirenone
can make a huge difference, says Dr. Levy. “The risks with birth control pills are in the amount of estrogen, which can increase the risk of blood clots in some women, and the newer pills have a much lower estrogen dose.” Low-dose pills contain 20 micrograms of estrogen. Some newer progestins may also have less clotting risk.

If you seem to have lower than usual blood sugar right before your period, discuss with your doctor the advisability of gradually reducing the dose premenstrually. And you may want to up your carbohydrate intake (but go for the healthier carbs, like fresh vegetables). Cut back on alcohol, chocolate, and caffeine; they can affect blood glucose as well as mood. Stick with your meal plans and eat at regular intervals, since large blood glucose swings can affect mood, exacerbating PMS.

If you have type 1 diabetes, you may also have menstrual irregularities, which may make it harder to predict when you’ll get your period, possibly interfering with your ability to become pregnant. In women who don’t ovulate or menstruate, estrogen is produced but not progesterone (which triggers shedding of the menstrual lining each month). A study from the University of Pittsburgh comparing 143 women with type 1 diabetes to 186 nondiabetic women without diabetes found that, on average, women with type 1 diabetes had a 17 percent decrease in the number of reproductive years.

There’s also an increased incidence of polycystic ovary syndrome (PCOS) due to elevated androgens; 30 to 40 percent of women with type 1 diabetes may have PCOS.
²⁶

“Women with type 1 diabetes have more anovulatory cycles, but the reasons for this are not well understood,” comments Mary Loeken, PhD, an investigator in the Section on Islet Cell and Regenerative Biology at the Joslin Diabetes Center in Boston Joslin and an associate professor of medicine at Harvard Medical School. “One of the things we do know is that you need to have a certain amount of fat mass in order to cycle appropriately. Just as athletes who overtrain and lose too much body fat stop cycling, women with type 1 diabetes may lack sufficient fat, especially if the disease is not well controlled. One of the hormones secreted by fat is leptin. It’s associated with weight gain, but it’s also required for menstruation. There are leptin receptors in the brain, and leptin receptor signaling triggers the release of neurotransmitters that control the hypothalamus and the pituitary and, in turn, the ovaries.”

You also need a certain amount of body fat to maintain a pregnancy, adds Dr. Loeken. “So leptin production is nature’s way of ensuring that the mother will be nutritionally able to support the pregnancy. In addition, ovarian hormones are also needed to build up the lining of the uterus. If a woman’s glucose is out of control, she may have enough body fat to ovulate and conceive, but not enough for normal hormone production, so the embryo will not implant in the uterus. It may die before it’s implanted. Women with type 1 diabetes may have unrecognized early miscarriages.”

If you have menstrual irregularities, a home ovulation test kit can be helpful to tell when you are ovulating, as can taking your basal (morning) body temperature, which is normally 98.6 degrees and may rise as much as 0.5 to 1 degree at ovulation.

Diabetes can lead to a number of complications during pregnancy, including a higher risk of preeclampsia, a pregnancy-induced disorder characterized by high blood pressure, protein in the urine, headaches, and fluid retention (edema).

Pregnancy may increase (or decrease) the need for insulin at different stages of pregnancy and may requiremore frequent glucose testing.

“Once you become pregnant, there are a lot of changes in the energy requirements, not just for the mother but for the developing embryo, which, because it’s growing so rapidly, consumes a lot of glucose. So the mother needs to be able to provide enough fuel,” explains Dr. Loeken. “The body also reacts to hormones produced during pregnancy by very rapidly increasing the production of adrenal steroid hormones, mostly cortisol. Those hormones interfere with the action of insulin. They increase glucose output by the liver, change fat composition of the body, and mobilize fat for energy.”

However, you need to get your glucose under tight control if you’re even thinking about becoming pregnant, says Dr. Loeken. “The formation of major organ structures takes place about the time a woman misses her period and first suspects she’s pregnant. If a woman’s glucose levels go too high, those organ systems may be formed in an abnormal way and the baby develops a congenital malformation. A woman doesn’t usually have her first obstetrics appointment until around 11 weeks, and by then a malformation may have
already occurred. So it’s important to discuss with your doctor your plans to become pregnant so you can maintain tight glucose control from the start.”

While problems with fetal development can arise in the second or third trimester, birth defects do not occur after the first trimester because the organ systems are already laid down. Congenital abnormalities can occur in as many as 6 to 12 percent of babies born to women with diabetes. Potential problems can include abnormalities of the heart, kidney, and central nervous system.

Keeping tight control of blood glucose and carefully monitoring the baby’s growth can prevent these problems and others, including having a large baby (
macrosomia
, which can cause injury to the mother and baby during delivery or lead to a Cesarean section) and lung problems. “If the mother is hyperglycemic, glucose is delivered to the fetus at a high concentration, and the baby’s pancreas responds by producing insulin. Insulin acts like a growth factor in a fetus. So you get a lot of glycogen storage in the liver and fat deposition, you get a big baby,” explains Dr. Loeken. “Insulin also interferes with fetal adrenal steroids that stimulate lung maturation. So high insulin can hamper maturation of the baby’s lungs, and the baby can suffer from respiratory distress syndrome.”

Because of the genetic component of type 1 diabetes, a child has a greater risk of developing diabetes sometime in his or her life time if either parent is affected. However, for reasons we don’t understand, the risk is six times less if the mother has diabetes than if the father does.

If you breast-feed, you will need to consume more calories than if you do not breast-feed, and a lot of the nutrients that you consume will be delivered to the baby in your milk. You should make sure that you stay properly hydrated and monitor your blood sugar frequently to adjust your insulin dose.

Women with diabetes have an increased risk of gum inflammation (
periodontitis
), and the damage can be more severe. So get regular dental care, especially during pregnancy.

An important note here about
gestational diabetes (GD)
: This form of diabetes, which develops during pregnancy, is not an autoimmune disease and about 60 percent of the time resolves itself after delivery or goes into remission. However, in a small percentage of cases, what appears to be GD may actually be the onset of type 1 or type 2 diabetes. “Because we screen every woman for gestational diabetes, sometimes it may actually unmask diabetes, and we can treat a woman before she gets into trouble,” remarks Dr. Levy. “If your diabetes doesn’t go away after you deliver, you’re not overweight, and you
don’t have a strong family history of diabetes, we have to consider whether this is actually early type 1 diabetes.” For women with GD, adopting a low glycemic index (GI) diet may result in lower insulin use and lower birthweights for their babies.
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Mary Kay’s story continues:

I started taking estrogen replacement therapy in my mid-forties. I was having very, very strong premenopausal symptoms. I am Irish, and thin, and my mom was on estrogen for a long time to prevent osteoporosis. So when I started having menopausal symptoms, I didn’t feel it was dangerous for me to take estrogen—actually, the opposite. For the first month I was on estrogen, I doubled my daily blood testing to see if taking estrogen would affect my glucose level or increase my need for insulin. It didn’t, in my case. But I was also switching from one kind of insulin to a more human insulin, so that may have made a difference. My gynecologist never told me to increase my daily testing, even though she knew I had diabetes. I knew about gestational diabetes, how high estrogen affects glucose, and it just made sense to me that taking estrogen could affect my need for insulin. I had no idea that diabetes could bring on menopause early. My gynecologist never mentioned it. But my mother went through menopause in her fifties, and I was in my forties, so I guess I was about six years earlier than my mother.

Just when you thought you’d gotten the hang of controlling those monthly blood glucose swings, you start to approach menopause and things are thrown out of kilter again. Perimenopause can occur any time after age 35, and, far from being a long decline in estrogen, this transition period can be a hormonal roller-coaster ride, with irregular periods and months where you don’t ovulate at all. Increases in hormones can boost blood sugar; decreases can send it plummeting. Low-dose birth control pills can help regulate your cycle.

Recent studies suggest that women with diabetes undergo an earlier menopause, sometimes by six to seven years. One study found that women with diabetes went through menopause at an average age of 41.6, compared to those who didn’t have diabetes, whose average age at menopause was closer to 50.
²⁸
“There’s just something about type 1 diabetes that totally disrupts the regulatory cycle for menses, and some women develop a condition called hypothalamic amenorrhea. No one knows for sure why type 1 women develop it, but the pituitary gland just shuts off. We’re unsure of the reasons for this, but it might be dependent on blood sugar control, low body weight, or stress levels,” remarks Dr. Levy.

“We will measure estrogen and follicle stimulating hormone (FSH) in women who have trouble getting pregnant or whose periods stop. If estrogen levels are low and FSH is high, you’ve gone through menopause.”

During this period, episodes of hypoglycemia may become more frequent and more severe. Low blood sugar can disrupt your sleep, along with hot flashes. In fact, menopausal symptoms can be confused with low (or high) blood sugar, especially moodiness and inability to concentrate or short-term memory loss.

You’ll need to test glucose more frequently during the menopausal transition. Loss of estrogen after menopause can decrease the body’s sensitivity to insulin, requiring adjustments in your insulin dose.

Lack of insulin affects bone formation and, together with estrogen loss, can increase your risk of osteoporosis.
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One recent study found that women with type 1 diabetes were more than 12 times more likely to report hip fractures compared to those without the disease. (Falls and fracture risk can be increased by vision problems, nerve damage, and the effects of hypoglycemia.)

For women with osteoporosis, once-a-week formulations of
alendronate (Fosamax)
or
risedronate (Actonel)
can make these drugs easier to take. You’re also at increased risk of high blood pressure and high cholesterol—both risk factors for heart disease—and those problems may need to be treated separately with appropriate medications.

There are conflicting data about the effects of postmenopausal estrogen for women with type 1 diabetes. Some studies suggest that combination hormone therapy (HT) with estrogen and progestin can help combat the effects of hormone loss on glucose levels and make them easier to regulate.
³⁰

“It is true that women with diabetes have a higher risk of cardiovascular disease, but in studies that suggest estrogen can worsen coronary disease, the risk in women who don’t have the disease appears to be due to blood clotting, and it may well be the type of estrogen,” she comments. “In my clinical experience, on occasion I have seen type 1 diabetes improve in women with HT,” remarks Dr. Levy.

Studies are mixed. A 2003 study of 20,000 female nurses age 45 and over in Denmark found that current estrogen users with diabetes had over four times the risk of heart disease, and nine times the risk of heart attack compared with those who never used estrogen.
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Other recent studies, including the Women’s Health Initiative (WHI, see
page 53
) indicate that HT can not only increase the risk of heart disease and stroke in older women, but that progestin may also increase breast cancer risk. One clinical trial suggests low-dose HT may have less impact on heart risk.
³²
However, a recent review says there are still not enough definitive data on the impact of HT on glycemic control and cardiovascular risk in women with type 1 diabetes.
³³
So it’s important to discuss the risks and benefits with your healthcare team.

The combination of diabetes and menopause can also affect your sex life. Reduced circulation to the genital area may make it harder to lubricate during arousal and more difficult to achieve orgasms. The normal decline in testosterone can also lower your sex drive.
³⁴
Again, some form of hormone therapy may help (see
pages 52
to
54
).

Autoimmune diseases that affect other components of the endocrine system in women include
Addison’s disease (adrenal insufficiency)
,
hypoparathyroidism
, and
autoimmune ovarian failure (or premature menopause)
. Ovarian failure can also occur as part of an
autoimmune polyglandular syndrome
and in connective tissue diseases such as lupus. Ovarian autoimmune disease itself has only recently been recognized as a single entity.

The ductless glands of the endocrine system—the thyroid, pancreas, pituitary, and adrenal glands—secrete hormones that affect almost every body function, including reproduction. You may not think of the ovaries as endocrine glands, but sex hormones (estrogen and androgens) are actually steroid hormones that regulate not only reproduction but many other functions in the body. For example, estrogen is needed to maintain bone density.

The endocrine glands also aid our responses to internal or external stimuli. The adrenal glands secrete “stress” hormones (like
adrenaline
, also known as
epinephrine
) to assist us in the primitive fight-or-flight syndrome by increasing heart rate and breathing, and pushing more blood into the muscles. Endocrine cells can also be found in other organs (e.g., gastric cells in the stomach).

Like the thyroid, other endocrine organs are regulated in a feedback loop by the hypothalamus, an area in the brain that controls the pituitary, in a sense the master of the “master gland.” It produces “releasing” hormones, to send a
signal to the pituitary, which in turn sends out a chemical messenger to stimulate other endocrine glands. In the case of the ovaries, one chemical messenger is
follicle stimulating hormone (FSH)
, which stimulates the follicles to secrete estrogen and to produce an egg each month. Not surprisingly, when one of the endocrine glands isn’t working right, it can throw off the entire system.

But endocrine disorders don’t usually come on dramatically; they develop gradually over a period of years, and you may not even pay much attention. The diagnosis usually involves blood tests for hormone deficiency, and the treatment is replacing the lost hormone (or hormones).