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Why do type 1 diabetics experience hypoglycemia?

Why do type 1 diabetics experience hypoglycemia?


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I know that type 1 diabetics do not produce enough (possibly none) insulin since beta cells of pancreas are damaged and as far as I know glucagon is produced by alpha cells (which are healthy in diabetic body, I suppose). So, my question is that since glucagon is released when the blood glucose is low, why do the diabetics experience hypoglycemia? Shouldn't the glucagon be released and increase the blood sugar?


Note that in Role of Alpha Cells in Diabetes1, the following is stated:

Glucagon responses to hypoglycemia have been known to be blunted in type 1 diabetes of long duration, and this may be a result of a loss of alpha- and beta-cell communication secondary to insulin deficiency.


  1. Rudy W Bilous. Role of Alpha Cells in Diabetes - Medscape - Apr 11, 2003.

Key to this question is that untreated, type 1 diabetics would never have hypoglycemia. It is insulin treatment that causes the hypoglycemia. Insulin brings sugar down and without insulin (as the case with type 1 diabetics) sugar just goes up. Exogenous insulin will bring sugar down in anyone, diabetic or no. Since Type 1 diabetics use insulin all the time, there is more chance for an accident (hypoglycemia).

Also, some Type 1 diabetics might not compensate against hypoglycemia or correctly perceive that they are hypoglycemic. Reasons for this are laid out in the following article:

From Hypoglycemia in Type 1 Diabetes

Three major defects in this homeostatic response contribute to the high frequency of hypoglycemia in type 1 diabetes.

The article summarizes what those are - basically a blunting of normal reactions to hypoglycemia stemming from the disease itself. It then summarizes:

Thus, the glucose counterregulatory defense against hypoglycemia in individuals with diabetes becomes impaired at almost every level and rendered even more defective through intensive insulin therapy


Hyperglycemia and hypoglycemia in type 1 diabetes

Hyperglycemia occurs when blood sugar levels are too high. People develop hyperglycemia if their diabetes is not treated properly. Hypoglycemia sets in when blood sugar levels are too low. This is usually a side effect of treatment with blood-sugar-lowering medication.

Diabetes is a metabolic disease with far-reaching health effects. In type 1 diabetes, the body only produces very little insulin, or none at all. In type 2 diabetes , not enough insulin is released into the bloodstream, or the insulin cannot be used properly.

We need insulin to live. Without it, sugar (glucose) builds up in the blood because it cannot be taken out and used by the body. Very high blood sugar, known as hyperglycemia, leads to a number of symptoms. If blood sugar levels are too low, it is called hypoglycemia.


Causes of Low Blood Sugar

There are many reasons why you may have low blood sugar, including:

  • Taking too much insulin.
  • Not eating enough carbs for how much insulin you take.
  • Timing of when you take your insulin.
  • The amount and timing of physical activity.
  • Drinking alcohol.
  • How much fat, protein, and fiber are in your meal.
  • Hot and humid weather.
  • Unexpected changes in your schedule.
  • Spending time at a high altitude.
  • Going through puberty.
  • Menstruation.

Treatment—The "15-15 Rule"

The 15-15 rule—have 15 grams of carbohydrate to raise your blood sugar and check it after 15 minutes. If it’s still below 70 mg/dL, have another serving.

Repeat these steps until your blood sugar is at least 70 mg/dL. Once your blood sugar is back to normal, eat a meal or snack to make sure it doesn’t lower again.

  • Glucose tablets (see instructions)
  • Gel tube (see instructions)
  • 4 ounces (1/2 cup) of juice or regular soda (not diet)
  • 1 tablespoon of sugar, honey, or corn syrup
  • Hard candies, jellybeans or gumdrops—see food label for how many to consume

Make a note about any episodes of low blood sugar and talk with your health care team about why it happened. They can suggest ways to avoid low blood sugar in the future.

Many people tend to want to eat as much as they can until they feel better. This can cause blood sugar levels to shoot way up. Using the step-wise approach of the "15-15 Rule" can help you avoid this, preventing high blood sugar levels.

  • Young children usually need less than 15 grams of carbs to fix a low blood sugar level: Infants may need 6 grams, toddlers may need 8 grams, and small children may need 10 grams. This needs to be individualized for the patient, so discuss the amount needed with your diabetes team.
  • When treating a low, the choice of carbohydrate source is important. Complex carbohydrates, or foods that contain fats along with carbs (like chocolate) can slow the absorption of glucose and should not be used to treat an emergency low.

Causes of hypoglycemia

Some causes of hypoglycemia are things that you can control or prevent, but other causes are things you cannot control.

  • Taking too much insulin
  • Eating too few carbs for the amount of insulin you take
  • Not timing your insulin dose correctly
  • Not carefully monitoring blood sugar when engaging in exercise or drinking alcohol
  • Hot and humid weather
  • Interruptions in usual schedules due to travel
  • Spending time at high altitude
  • Going through puberty
  • Having your menstrual period

How to Recognize Hypoglycemia

The first signs of hypoglycemia include feeling sweaty, shaky, and hungry. However, not everyone has these symptoms or notices them in time to prevent low blood sugar from getting worse. It’s also important to know that your symptoms of hypoglycemia will change the longer you have T1D.

As hypoglycemia gets worse, symptoms can include:

  • Feeling weak
  • Having difficulty walking or seeing clearly
  • Acting strange or getting disoriented
  • Having seizures

Severe hypoglycemia may make you faint or pass out. This is dangerous if you are driving, climbing stairs, or doing other activities where you need to stay aware of things around you.

Hypoglycemia can happen at night. If it does, you are likely to wake up, but it’s important not to rely on your body to wake you up. A continuous glucose monitor, or CGM, can alert you and those around you with an alarm to let you know if your blood sugar starts getting low while you are sleeping.

It’s a good idea to check your blood sugar often when lows are likely, such as in hot weather or when you travel. Your CGM can also let you know when your blood sugar is getting lower.

Watch out for “hypoglycemia unawareness.”

You might not have early warning signs of low blood sugar. This is called “hypoglycemia unawareness,” and it raises the risk of having severe lows. It is more likely if:

  • You have had diabetes longer than 5 or 10 years
  • You have frequent episodes of hypoglycemia
  • You take certain medicines, such as beta blockers for high blood pressure

Being Prepared for Hypoglycemia

Being prepared with the following will help you treat low blood sugar quickly:

  • A kit with emergency supplies , such as glucose tablets, snacks, and glucagon (a hormone that raises blood sugar available in an injection kit, pre-filled syringe, nasal spray, or auto-injector pen).
  • A medical alert bracelet with information about your T1D
  • A plan for family, friends, or coworkers to help, if necessary

Treating Mild to Moderate Hypoglycemia

If you start feeling any of the symptoms listed above, check your blood sugar as soon as possible, then follow the chart below to treat low blood sugar. If you have any concerns, or can’t test immediately, it’s best to treat first and check when possible.

If your blood sugar is …

10 to 15 grams of fast-acting carbs, such as 4 ounces of fruit juice, 6 to 8 hard candies, or 3 to 4 glucose tablets.

Test your blood sugar again in 15 minutes. Repeat the treatment if necessary.

Eat 20 to 30 grams of fast-acting carbs, such as 8 ounces of fruit juice, 12 to 16 hard candies, or 6 to 8 glucose tablets.

Test your blood sugar again in 15 minutes. Repeat the treatment if necessary.

Treating Severe Hypoglycemia

If you start feeling confused or disoriented or have trouble walking or seeing, you may have very low blood sugar. If you’re not able to test your blood glucose yourself, ask someone for help, if possible. You may also need help to treat a severe low, if your symptoms are so bad that you cannot think clearly or stay focused. It is important that friends, family, teachers, coaches, and other people who may be in a position to help you in the case of a severe low learn how to test your blood glucose and use glucagon BEFORE the need arises. That way they will be best prepared to help you quickly during an episode of severe hypoglycemia. In an emergency, a medical identification bracelet or necklace and carrying glucagon could make a dramatic difference in keeping you safe and healthy. Even if you wear a pump or CGM, emergency medical technicians (EMTs) are trained to look for medical identification.

To treat severe hypoglycemia, you need to have someone administer glucagon via syringe, nasal spray, or auto-injector pen.

The person with you should help you lie on your side to recover. You might throw up (vomit), and you could choke if you are lying on your back. You should start feeling better 10 to 15 minutes after a glucagon dose. If not, you need another dose.

When to Call 911

Your friend, relative, or coworker should call 911 for help if:

  • You pass out and no glucagon is available
  • You need a second dose of glucagon
  • You had glucagon, but are still confused
  • Your blood sugar stays too low 20 minutes after treatment or doesn’t respond to your usual treatments

The emergency medical technicians can give you IV sugar (into your vein). This raises your blood sugar level right away. You might need to stay in the hospital for a few hours.

NEVER be afraid to call 911 or ask someone to call 911 for you if you are concerned .

Other things to know about hypoglycemia:

It takes time for blood sugar to rise after eating, and it’s important to give your first treatment time to work. Use the table above to guide your treatment and timing instead of eating until you feel better, which will almost always lead to eating too much.

Hypoglycemia can be common with certain types of exercise. Managing blood sugar during and after physical activity is important and is something that a lot of people with T1D have questions about. JDRF has a number of resources available for people with T1D and their families, many of which can be found here.

After Hypoglycemia

After you treat your hypoglycemia and your blood sugar is back in its normal range, you may return to normal activities. If you needed glucagon, you should call your doctor. They need to know you had a severe low. They might also want to change your diabetes plan to avoid more severe lows or discuss using an insulin pump with a CGM to improve control of your blood sugar levels. CGM devices are extremely useful for avoiding and detecting hypoglycemia.

After a low blood sugar episode, you are less sensitive to the early symptoms of hypoglycemia for 48 to 72 hours. This makes you more likely to have another episode. Check your blood sugar regularly, especially before eating, exercising, or driving a car.

Your Diabetes Devices and Hypoglycemia

Several insulin pumps are now available that make managing blood sugar levels easier, particularly when connected to a glucose meter or a CGM.

Some of the most important advantages of CGM devices are the improved insulin control (and therefore fewer lows) and the ability to detect trends and lows early. With improved technology, it is now possible for parents to track blood sugar trends in their kids even when they are hundreds of miles apart (known as “remote detection”).

In addition, automated insulin delivery systems, also known an artificial pancreas or a hybrid closed-loop system, will automatically adjust insulin to match your body’s need (“gives less if low, gives more if high”) to help you spend more time in your target range.

Resources that provide people with T1D and their families with more detailed information about pumps and CGM devices are available through JDRF here. For people looking for a deeper understanding of technology that helps people with T1D better manage their blood sugar, JDRF resources are available here.

Children and Hypoglycemia

Children with T1D can get hypoglycemia for the same reasons as adults. They might get too much insulin for the amount of carbs they eat. They might skip a meal, eat different foods, or exercise harder than normal. Or, a parent or caregiver might give the wrong dose or type of insulin. Sometimes parents worry that hypoglycemia in children could lead to long-term brain damage, but doctors do not believe that this will happen.

Learning your child’s behavior when their blood sugar gets low can help you avoid severe lows. You can create a diabetes emergency kit for your child and make a low blood sugar plan with their school or daycare. Also, you may be able to set an alarm on your child’s CGM to warn you or caregivers of their lows. Click here for a downloadable guide on causes, symptoms, and treatments of hypoglycemia.


Footnotes

The authors of this article have no relevant duality of interest to declare.

This article is based on a presentation at the 1st World Congress of Controversies in Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this article were made possible by unrestricted educational grants from MSD, Roche, sanofi-aventis, Novo Nordisk, Medtronic, LifeScan, World Wide, Eli Lilly, Keryx, Abbott, Novartis, Pfizer, Generx Biotechnology, Schering, and Johnson & Johnson.


Counterregulatory Hormone Responses to Hypoglycemia in Older Adults

The risk of severe or fatal hypoglycemia associated with the use of oral hypoglycemic agents and insulin increases exponentially with age. 22,23 Also, older adults with comorbidities, those using multiple medications, and those who are frequently hospitalized are at greater risk for iatrogenic hypoglycemia. 24 Most people with type 2 diabetes are > 60 years of age. 8 Therefore, it is important to appreciate the idiosyncratic and agespecific manifestations of hypoglycemic symptoms. 9

Meneilly et al. 22 have investigated the effects of age on counterregulatory responses during clamped hypoglycemia. Older adults with type 2 diabetes demonstrated reduced glucagon and growth hormone responses but increased epinephrine and cortisol responses when compared to age-matched nondiabetic control subjects. However, hypoglycemic symptom scores were similar in both groups at all levels of glycemia.

Matyka et al., 25 on the other hand, found differences in hypoglycemic symptom responses when comparing healthy older men aged 60-70 years with younger men aged 22-26 years. During hyperinsulinemic-hypoglycemic clamp studies, neuroendocrine responses for the two groups were similar. However, symptoms began earlier in the younger men and were more intense. Measures of psychomotor coordination deteriorated earlier in the older subjects and to a greater degree. The usual 10-20 mg/dl plasma glucose difference between the subjective awareness of hypoglycemia and the onset of cognitive dysfunction was lost in the older men.

This altered counterregulatory effect may contribute to the altered cognitive response to reductions in blood glucose. Thus, the lower glycemic threshold to hypoglycemia in older people may limit the time available to self-treat and thereby increase the risk of developing incapacitating neuroglycopenia. 22,25 Additionally, these neurological symptoms of hypoglycemia may be misinterpreted in older patients because of coexisting illnesses, such as cerebrovascular diseases or dementia. 22,25


I NTRODUCTION

Following the publication of the results of the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes mellitus (T1DM) and the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetic patients (T2DM), strict glycemic control has been heavily emphasized in the management of diabetes.[1,2] These findings redirected patient care strategies, with several guidelines setting target glycated hemoglobin (HbA1c) values at 𢙇%.[3] However, three subsequent large randomized controlled trials (RCTs) looking at intensive glycemic control have either shown no benefit (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation, ADVANCE[4] and Veterans Affairs Diabetes Trial, VADT)[5] or an increase in all-cause mortality (Action to Control Cardiovascular Risk in Diabetes, ACCORD].[6] These trials have appropriately demonstrated that attempts made to achieve aggressive HbA1c goals (φ.5%) are associated with a three-fold increase in the risk of hypoglycemia, counterbalancing the benefits conferred by intensive glucose control.[7] Similar results were observed in Stockholm Diabetes Intervention study (SDIS) which showed a 2.5 times greater incidence of hypoglycemia in intensively treated patients with T1DM.[8] Likewise for patients with T2DM, the proportion of patients with one or more hypoglycemia episodes in a year was significantly higher in intensive treatment group compared to conventional group as observed in the UKPDS study.[2] Hypoglycemia, an often under-appreciated problem, is the most common and serious side effect of glucose-lowering therapies. Repeated episodes of hypoglycemia can adversely affect defense mechanisms against falling blood glucose, resulting in significant morbidity and mortality which is reportedly associated with a six-fold increase in death.[9,10]

Evidence from several observational studies such as such as the UK Hypoglycemia Study,[11] a retrospective questionnaire based study from Denmark[12] and the Diabetes Audit and Research in Tayside, Scotland (DARTS) study[13] indicates that risk of hypoglycemia is particularly high among patients treated with insulin. Evidence from several studies suggests that severe hypoglycemia occurs in 35-42% of T1 DM patients and the rate of severe hypoglycemia is between 90-130 episodes/100 patient years.[14,15,16,17] The UK Hypoglycemia Study found that patients with longer duration of diabetes (㸕 years) experienced higher rates of severe hypoglycemia than those with smaller duration (ϥ years) (46% vs. 22%). The study also reported increased rates of hypoglycemia in those with longer duration of insulin treatment.[11] A retrospective questionnaire based study from Denmark in insulin treated type 2 diabetes patients reported at least one episode of severe hypoglycemia in 16.5% of patients with an incidence of 44 episodes/100 patient years.[12] Similarly, data from the DARTS study indicated that the severe hypoglycemia was 7.1% in patients with T1DM and 7.3% in patients with T2DM treated with insulin, compared with 0.8% in patients with T2DM treated with an oral sulfonylurea.[13] Moreover, hypoglycemic events, especially severe episodes, lead to a substantial increase in the direct and indirect costs of medical care.[13,18,19,20,21] People with T2DM lose on average three productive days, with a mean length of hospital stay between 6.6 and 9.5 days, following a severe hypoglycemic attack.[20,21] Given the compelling evidence of the potential harms associated with hypoglycemia, multiple strategies to minimize hypoglycemia should be adopted. The purpose of this review is to discuss the importance of hypoglycemia in the management of patients with DM, with an aim to improve understanding of the risk factors, impact and consequences of hypoglycemia. While recent progress related to prevention of hypoglycemia including patient education strategies and the use of newer therapeutic agents with a lower risk for hypoglycemia aim at achieving and maintaining optimal glycaemic control, hypoglycemia still remains a major challenge which needs to be addressed for better management and treatment of patients with diabetes.


Research Design and Methods

Sample

T1DM outpatients between 18 and 75 years old were recruited from April to October 2011 from a large university diabetes clinic (Radboud University Nijmegen Medical Centre, the Netherlands). Exclusion criteria were inability to speak, read, and write Dutch being hospitalized or terminally ill and—additionally for the substudy—suffering from significant comorbidity. The ethics committee approved the study, and written informed consent was obtained from all participants.

Matched population-based controls were derived from a cohort (n = 1,900) of panel members of CentERdata. Fatigue data were collected in summer 2012. CentERdata is a Dutch research institute at Tilburg University consisting of Dutch households (16) representative of the Dutch population with respect to age, sex, education, and social economic status.

Design

In this cohort study, T1DM patients were asked to complete questionnaires. Patients were matched on age and sex with a population-based control group. With a cross-sectional design, we answered the research questions on prevalence, impact, and possible determinants of chronic fatigue in T1DM patients. For the substudy, patients were followed for 5 days to investigate the contribution of blood glucose levels to acute (in a longitudinal design) and chronic (in a cross-sectional design) fatigue.

Procedure

From an outpatient cohort of 831 T1DM patients, 350 patients were randomly selected (see Power Calculation ). Eligible patients were informed about the study in writing and contacted by telephone. Patients who agreed to participate could complete the questionnaires using Internet or by paper and pencil. It took participants approximately 2 h to complete the set of questionnaires. Patients who refused to participate were asked to complete the short fatigue questionnaire (SFQ) (17) with the aim to compare the level of fatigue of nonparticipants with that of participants. Patients who did not return the questionnaires were send up to two reminders with the SFQ attached.

All participants received an additional letter with information about the substudy. Subsequently, a subset of eligible patients was contacted for an appointment. During the appointment, the use of the CGM system and the electronic fatigue diary (EFD) was explained. The FreeStyle Navigator CGM system was used in accordance with the guidelines of Abbott. Data were collected between June 2011 and January 2012.

Instruments

Main Study

Sex, age, and HbA1c were retrieved from the medical records. The presence of a comorbidity was assessed in two ways. First, patients were asked if they had other illnesses in addition to T1DM (patient-reported comorbidity: comorbidity_pr). Second, the first two authors screened the medical records to identify the presence of a significant comorbidity defined as a comorbidity affecting patients’ daily functioning (comorbidity based on medical records: comorbidity_mr). The two authors discussed arbitrary cases to reach consensus. All other data were collected using questionnaires.

Fatigue

The subscale fatigue of the Checklist Individual Strength (CIS) was used to assess fatigue severity over the past 2 weeks (Cronbach α = 0.95). This subscale consists of eight items (scores range from 8 to 56). A score of 35 or higher, being two SDs above the mean of the original healthy reference group, is indicative for severe fatigue (18). The CIS is a well-validated instrument (18,19) and frequently used (2,3,20). Patients who indicated suffering from fatigue for 6 months or longer and scored >35 were viewed as being chronically fatigued. The SFQ was used to assess fatigue severity in nonparticipants. The SFQ consists of four items of the CIS-fatigue subscale (Cronbach α = 0.926) (17). All other instruments used are described in Supplementary Data (21–35).

Substudy

Blood Glucose

Glucose levels were continuously monitored for 5 days using the FreeStyle Navigator, which records glucose levels (mmol/L) every 10 min. Operationalization of glucose parameters are described in Statistical Analyses .

Acute Fatigue

The severity of acute fatigue was assessed using the EFD. Patients were asked to indicate how fatigued they were at that particular moment on a visual analog scale ranging from “not at all fatigued” (0) to “very severely fatigued” (100). This question was presented on a personal digital assistant at six moments, evenly divided over the day from 0830 h to 2230 h.

Power Calculation

Main Study

We selected 20 potential predictors for chronic fatigue. With 10 patients needed per predictor, 200 participants yielded adequate statistical power. An estimated response rate of 60% resulted in 350 patients to be contacted. For the substudy, CGM sensors were available for approximately 60 participants, and although no formal power calculation was performed for the substudy, we expected to have sufficient power to determine significant relationships between fatigue and glucose levels with repeated measures analyses and to compare chronically and nonchronically fatigued patients.

Statistical Analyses

T1DM patients were matched by age and sex with 214 population-based controls from the sample of CentERdata. Precision matching was done with STATA/SE 12.1. Differences between T1DM patients and matched population-based controls and differences between chronically fatigued and nonchronically fatigued T1DM patients were tested using unpaired t test and χ 2 . The mean burden of each diabetes symptom was calculated and ordered from the least to the most troublesome symptom. To identify potential determinants, Pearson’s correlations were calculated with fatigue severity, followed by a logistic regression analysis with chronic fatigue as dependent variable.

To assess whether blood glucose contributed to acute or chronic fatigue, between-subject effects (whether patients with high variability had more fatigue than those with low variability) and within-subject effects (whether, within one patient, blood glucose values were related to fatigue) were tested with t test, Pearson correlations, and generalized estimating equations (GEE).

Four different parameters of blood glucose were determined: 1) mean glucose level was assessed by calculating the mean of all glucose measurements of each participant (GLmean) 2) glucose variability was assessed by calculating the SD of all glucose measurements of each participant (Gvar) (36) 3) relative time spent in hyperglycemia was assessed by dividing the number of CGM observations above 10 mmol/L by the total number of CGM observations of each participant (hyper) and 4) relative time spend in hypoglycemia was calculated with CGM observations lower than 4 mmol/L (hypo). The severity of acute fatigue was assessed by calculating the mean of all EFD scores of each participant (EFDmean).

GEE was used to determine whether acute fatigue was predicted by blood glucose values in the preceding hour. GEE enables determination of between-subject effects using independent structure and within-subject effects using exchangeable structure. The mean glucose level (GLmean_hour) and the glucose variability (Gvar_hour) was assessed by calculating means and SDs of the recorded glucose values in the hour preceding an EFD score. GEE was performed with GLmean_hour, Gvar_hour as independent, and EFD scores as dependent variables. All analyses were performed with SPSS, version 16.0 (SPSS Inc., Chicago, IL). A level of P < 0.05, two-sided, was considered significant.


Root cause of blood vessel damage in diabetes discovered

A key mechanism that appears to contribute to blood vessel damage in people with diabetes has been identified by researchers at Washington University School of Medicine in St. Louis.

Blood vessel problems are a common diabetes complication. Many of the nearly 26 million Americans with the disease face the prospect of amputations, heart attack, stroke and vision loss because of damaged vessels.

Reporting in the Journal of Biological Chemistry, the Washington University researchers say studies in mice show that the damage appears to involve two enzymes, fatty acid synthase (FAS) and nitric oxide synthase (NOS), that interact in the cells that line blood vessel walls.

"We already knew that in diabetes there's a defect in the endothelial cells that line the blood vessels," says first author Xiaochao Wei, PhD. "People with diabetes also have depressed levels of fatty acid synthase. But this is the first time we've been able to link those observations together."

Wei is a postdoctoral research scholar in the lab of Clay F. Semenkovich, MD, the Herbert S. Gasser Professor of Medicine, professor of cell biology and physiology and chief of the Division of Endocrinology, Metabolism and Lipid Research.

Wei studied mice that had been genetically engineered to make FAS in all of their tissues except the endothelial cells that line blood vessels. These so-called FASTie mice experienced problems in the vessels that were similar to those seen in animals with diabetes.

"It turns out that there are strong parallels between the complete absence of FAS and the deficiencies in FAS induced by lack of insulin and by insulin resistance," Semenkovich says.

Comparing FASTie mice to normal animals, as well as to mice with diabetes, Wei and Semenkovich determined that mice without FAS, and with low levels of FAS, could not make the substance that anchors nitric oxide synthase to the endothelial cells in blood vessels.

"We've known for many years that to have an effect, NOS has to be anchored to the wall of the vessel," Semenkovich says. "Xiaochao discovered that fatty acid synthase preferentially makes a lipid that attaches to NOS, allowing it to hook to the cell membrane and to produce normal, healthy blood vessels."

In the FASTie mice, blood vessels were leaky, and in cases when the vessel was injured, the mice were unable to generate new blood vessel growth.

The actual mechanism involved in binding NOS to the endothelial cells is called palmitoylation. Without FAS, the genetically engineered mice lose NOS palmitoylation and are unable to modify NOS so that it will interact with the endothelial cell membrane. That results in blood vessel problems.

"In animals that don't have fatty acid synthase and normal nitric oxide synthase in endothelial cells, we saw a lot of leaky blood vessels," Semenkovich explains. "The mice also were more susceptible to the consequences of infection, and they couldn't repair damage that occurred -- problems that also tend to be common in people with diabetes."

In one set of experiments, the researchers interrupted blood flow in the leg of a normal mouse and in a FASTie mouse.

"The control animals regained blood vessel formation promptly," Semenkovich says, "but that did not happen in the animals that were modified to be missing fatty acid synthase."

It's a long way, however, from a mouse to a person, so the researchers next looked at human endothelial cells, and they found that a similar mechanism was at work.

"Our findings strongly suggest that if we can use a drug or another enzyme to promote fatty acid synthase activity, specifically in blood vessels, it might be helpful to patients with diabetes," Wei says. "We also have been able to demonstrate that palmitoylation of nitric oxide synthase is impaired in diabetes, and if we can find a way to promote the palmitoylation of NOS, even independent of fatty acid synthase, it may be possible to treat some of the vascular complications of diabetes."

And it shouldn't matter whether a person has type 1 diabetes and can't manufacture insulin or the more common type 2 diabetes, in which a person becomes resistant to insulin.

"That's one of the key findings," Semenkovich says. "It won't matter whether it's an absence of insulin or resistance to insulin: both are associated with defects in FAS."


Severe Hypoglycemia

Hypoglycemia is the medical term used when the amount of glucose (sugar) in someone&rsquos blood is lower than it should be. Glucose is the main source of energy for the body and the brain. When blood glucose is low, the body doesn&rsquot have the fuel to function the right way. If blood glucose drops really low, the person is not able to function because physical and mental changes occur. They can have seizures or become unconscious. Hypoglycemia is a very dangerous situation but a person can take steps to prevent it. If severe hypoglycemia does occur, quick action is needed. If not, it can lead to death.

What is severe hypoglycemia?

Hypoglycemia can be mild, moderate, or severe based on the person&rsquos blood glucose and condition. Here are the levels:

  • Level 1 (mild) hypoglycemia: Blood glucose is less than 70 mg/dL but is 54 mg/dL or higher.
  • Level 2 (moderate) hypoglycemia: Blood glucose is less than 54 mg/dL.
  • Level 3 (severe) hypoglycemia: A person is unable to function because of mental or physical changes. They need help from another person. In this case, blood glucose is often below 40mg/dL.

What are the signs and symptoms of hypoglycemia?

Often, before a person&rsquos blood glucose drops to a severely low level, they may have some early signs and symptoms. However, some people may not feel any signs or symptoms so they are unaware that their blood glucose is low. This is a rare condition called &ldquohypoglycemia unawareness&rdquo which is most common in patients taking insulin who have chronically low blood glucose levels. If present, some early signs and symptoms of hypoglycemia may:

  • Sweating or cold, clammy skin
  • Shakiness or dizziness
  • Headache
  • Fast, pounding heart rate

As blood glucose continues to drop, other signs and symptoms may occur, such as:

  • Changes in behavior, such as confusion, irritability, or sleepiness
  • Feelings of being anxious or weak
  • Problems speaking clearly, such as slurring words
  • Problems with vision, such as seeing double or things appearing blurred

As their blood glucose goes even lower, the person may become very confused. Seizures or convulsions may occur. They may lose consciousness and be unable to respond. At this point, they can&rsquot care for themselves and need help. Family, friends, and caregivers will need to act quickly to raise the person&rsquos blood glucose.

Mild hypoglycemia can happen to anyone. For someone who doesn&rsquot have diabetes, severe hypoglycemia is rare, but can also occur as a result of another disease or medicine.

Most cases of severe hypoglycemia occur in people with diabetes who take insulin or certain diabetes medications like sulfonlyureas. Severe hypoglycemia is more common in people with type 1 diabetes since they take multiple injections of insulin daily But, it can also happen in people with type 2 diabetes, especially in those that take insulin. The reason is often due to changes in the balance of the person&rsquos food intake, exercise level, or medicine while taking insulin or other medications for diabetes.

Mild hypoglycemia can be seen in normal individuals when:

Severe hypoglycemia can occur in people with diabetes who are taking insulin and certain diabetes medications, or changes in overall health. For Example:

  • Eating less than the usual amount
  • Skipping a meal
  • Taking too much diabetes medicine
  • Taking diabetes medicine and not eating
  • Exercising too much
  • Drinking alcohol on an empty stomach or drinking too much alcohol
  • Declining kidney function

How do you prevent severe hypoglycemia?

For a person with diabetes, the first step in preventing severe hypoglycemia is to keep blood glucose levels under good control. This includes:

  • Eating meals and snacks on a regular schedule after you take your diabetes medications
  • Checking blood glucose levels as directed, especially during the times you are most likely to have a low value (during exercise, when drinking alcohol, when skipping meals, etc.)
  • Sticking to a suggested exercise plan
  • Taking medicines for diabetes on time and as directed
  • Talking to your doctor if you are experiencing frequent episodes of hypoglycemia
  • Carrying juice, candy, or glucose tablets at all times, in the event that one develops symptoms of hypoglycemia

Another step in preventing severe hypoglycemia is to be prepared. It&rsquos important to recognize the signs and symptoms of hypoglycemia, and once you experience these symptoms check blood glucose levels right away to confirm that you are truly hypoglycemic. If you have a loved one who takes insulin or other diabetes medications, it&rsquos important to check in with the person to make sure that they are checking their blood glucose and following their diabetes plan.

Prevention also means having some type of sugar easily available to treat symptoms if they occur. If blood glucose is low, you can help the person treat the signs and symptoms. Offer them some type of sugar. This can be glucose tablets or gel, fruit juice or regular soda, or some other type of sugar, such as table sugar, honey, corn syrup, or hard candy. Your action can help prevent blood glucose from dropping to severe levels.

How is severe hypoglycemia treated?

Severe hypoglycemia is an emergency. Treatment focuses on raising the person&rsquos blood glucose quickly with a medicine called glucagon . As a family member, friend, or caregiver, you must step in to help because the person is not able to act on their own. Call 911 or the local emergency immediately is you find someone who is unconscious. Glucagon kits are available by prescription from a doctor. Glucagon is a medicine that is given by injection (auto-injector or intravenously), through oral tablets, or by nasal format. Know how to use a glucagon kit so you can act quickly to help raise the person&rsquos blood glucose. The person usually becomes conscious again in about 5 to 15 minutes after you administer glucagon.

Once the person is awake and can swallow, have them eat something that has sugar in it. For example, offer a small piece of fruit, juice, candy, sugar dissolved in water, etc. This will help raise their blood glucose a little higher. Also, have them check their blood glucose after 15 minutes to be sure it is improving.

Call 911 or the local emergency number if:

  • A glucagon kit is not available
  • The person does not respond to the emergency glucagon
  • Blood glucose level is still low even after giving glucagon

What is glucagon?

Glucagon is a hormone that works hand-in hand with insulin and other hormones in your body to control glucose levels in the blood. Made in the pancreas, glucose helps to raise blood glucose levels if they are low and insulin helps to lower blood glucose levels if they are high.

Normally, glucagon begins to act when blood glucose levels are low. It causes the liver to change glycogen (stored glucose) to glucose. This glucose then travels to the bloodstream so the cells can use it for energy. Glucagon also stops the liver from taking in and storing glucose. As a result, more glucose stays in the blood. In addition, glucagon helps the body make glucose from other sources, such as amino acids. This will also add more glucose to the blood.

Why do patients need emergency glucagon?

Normally, glucagon works with insulin in the body to keep blood glucose levels stable. Insulin stops glucose levels from getting too high. Glucagon keeps glucose levels from going too low. But with diabetes, this balance gets upset and the hormones don&rsquot function as they should. In persons with diabetes, when blood glucose goes too low, the body is not able to use its own glucagon efficiently to raise blood glucose. That&rsquos why emergency glucagon is given for severe hypoglycemia. It raises blood glucose quickly.

What are the benefits of using emergency glucagon?

Glucagon helps raise a person&rsquos blood glucose level when it has dropped to dangerous levels. At this point, the person cannot eat or drink anything to help raise their blood glucose. So giving emergency glucagon is the only way to prevent blood glucose levels from dropping even lower.

Glucagon acts quickly. It causes blood glucose levels to rise within 5 to 15 minutes. The person often becomes conscious again at this time. Glucagon can cause nausea and vomiting. Be alert for these as the person awakens.

Glucagon&rsquos effect on blood glucose lasts only a short time. Be sure the person eats some fast-acting carbohydrate as soon as they are able. This helps to keep blood glucose levels from falling back down.

Who should have glucagon emergency kits?

Glucagon emergency kits are appropriate for anyone who have had previous episodes of severe hyperglycemia, as well as anyone with type 1 diabetes or type 2 diabetes using multiple shots of insulin a day. If the patient is unaware that their blood glucose is low because they do not feel symptoms, an emergency glucagon kit would also be very helpful.

How do I use an emergency glucagon kit?

Most often, an emergency glucagon kit contains a vial of powder (glucagon), a syringe already filled with saline (salt water). Other kits may include an auto-injector, or a nasal spray (see instructions for use of these medications).

To use a kit by injection, follow these steps:

  1. Check the date on the label to make sure the medicine hasn&rsquot expired.
  2. Remove the vial of powder and syringe from the kit.
  3. Remove the covers from the vial and the needle.
  4. Insert the needle into the vial. Push on the plunger to move the saline into the vial. Remove the syringe from the vial.
  5. Mix the saline and the powder. Gently swirl or roll the vial until the liquid looks clear.
  6. Insert the needle into the vial and draw back all of the liquid into the syringe.
  7. Remove the syringe from the vial.
  8. Inject the needle into the outer part of the person&rsquos thigh, mid-way between the hip and knee or into the arm muscle.
  9. Turn the person onto their side and watch for them to wake up. It may take from 5 to 15 minutes for the glucagon to act.

What&rsquos needed to be prepared for severe hypoglycemia?

Being prepared for severe hypoglycemia is an important part of diabetes management. This involves the person talking with their doctors about the signs and symptoms of low blood glucose and the actions to take. Other areas would likely include keeping blood glucose under control and wearing a diabetes identification bracelet or necklace to ensure proper emergency care for severe hypoglycemia. Using a glucagon kit would also be part of this conversation.

Hypoglycemia Unawareness or Impaired Awareness

The goal is to help a person recognize symptoms of hypoglycemia early on so they can take action sooner. In some cases, if a person does not experience the perceived signs of hypoglycemia this can cause an unawareness. Hypoglycemia unawareness can occur in those patients with diabetes who live with chronically low blood glucose levels. Elderly patients on insulin are at higher risk for hypoglycemia unawareness. The brain and body of those with hypoglycemia unawareness is accustomed to long-standing hypoglycemia, so their normal physiologic response to hypoglycemia is impaired. These people may function and live normally with blood glucose values in the 70's, and only experience symptoms of hypoglycemia when the glucose values drop into the 50's or below. People with hypoglycemia unawareness are at much greater risk of experiencing severe hypoglycemia. It is important to identify those who suffer from hypoglycemia unawareness and find a medication regimen for their diabetes which is safe for them.

As a family member, friend, or caregiver of someone with diabetes, sit down and talk with that person. Find out what their signs and symptoms are and what you should do. Find out at what glucose values do they actually have symptoms of hypoglycemia. If they are not experiencing any signs of hypoglycemia when their glucose levels are in the 60's, this can be life threatening and should be discussed with the doctor right away. Encourage them to wear some type of diabetes identification. Know where their glucagon kit is for home and work, and when and how to use it.

What new technology is being created to treat severe hypoglycemia?

Studies show that repeated episodes of severe hypoglycemia can have a major effect on a person&rsquos ability to manage diabetes and control blood glucose. This condition has also been tied to an increase in heart disease and overall deaths in patients with type 1 and type 2 diabetes. In addition, severe hypoglycemia may have negative effects on a person&rsquos emotional status and quality of life. Scientists are looking for ways to lessen these effects. Here are some things they are working on.

Easy-to-use glucagon. New products are being developed. These include giving glucagon as a nasal spray, in a patch through a tiny needle, and in a pre-filled pen. Another idea is the use of micro-doses of glucagon contained in a pen-like device that a person can use when they have mild hypoglycemia.

Improved blood glucose monitoring. Blood glucose monitoring is one area where technology is advancing. Continuous glucose monitors are devices that are worn on one&rsquos body that are continuously monitoring your blood glucose 24/7. It allows for patients to know their glucose levels throughout the entire day. Some continuous glucose monitoring devices currently available have alarms or alerts to let the person know when glucose levels are too high or too low. These devices can also predict if the glucose level might be trending high or low. The patient can obtain the information through the device&rsquos software or a smartphone app. Other devices can record reports of past levels. This information can be used to predict future levels. All these developments can help the person plan ahead and take action before levels become dangerous.

Dual hormone artificial pancreas. Several companies are working to develop an artificial pancreas with two hormones. It would give the person insulin and glucagon to control blood glucose levels. The device would include three elements. A pump would deliver the medicines. A continuous glucose monitoring device would check blood glucose levels. Software would interpret the information from the glucose monitoring device. The software would convert the information into instructions for the pump. The pump would give the person a specific amount of insulin or glucagon based on blood glucose readings.

Questions to ask your healthcare team

  • What blood glucose level should alert me to a possible problem?
  • Should I have a glucagon emergency kit? If so, how many do I need?
  • Where should I store the emergency kits?
  • Should I talk with a diabetes educator?

Questions a caregivers should ask

As a family member, friend, or caregiver, you want to do your best to keep your loved one, friend, or patient safe from severe hypoglycemia. But knowing what&rsquos best can be overwhelming. Here are some questions to help you get started.



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