Hypoglycemia diabetes type 2

Severe low blood sugar occurs often in patients with Type 2 diabetes

Low blood sugar, or hypoglycemia, can cause unpleasant symptoms but is typically treatable with food or a sweet drink. Severe hypoglycemia occurs when blood sugar gets so low a patient needs assistance, and may result in dizziness or mental confusion, injury, car accident, coma or, rarely, even death. Several recent studies have found that patients who experienced severe hypoglycemia were also at higher risk for dementia, falls, fractures and heart attacks, compared with patients who did not experience hypoglycemia.

“Many clinicians may assume that hypoglycemia is not much of a problem in poorly controlled type 2 diabetes given their high average blood-sugar levels,” said senior author and study principal investigator, Andrew Karter, PhD, of the Kaiser Permanente Division of Research. “This study suggests that we should pay much closer attention to hypoglycemia, even in poorly controlled patients. Providers should explain the symptoms of hypoglycemia, how to treat it, and how to avoid it — for example, by not skipping meals. Most of all, providers should ask all their diabetic patients whether they’ve experienced hypoglycemia, even those patients with very high average levels of blood sugar.”

The researchers surveyed patients with type 2 diabetes being treated with medications to lower their blood sugar and asked about their experiences with severe hypoglycemia. Nearly 11 percent of the more than 9,000 respondents experienced severe hypoglycemia in the prior year, and it occurred at all levels of blood-sugar control.

Researchers categorized patients into five categories of HbA1c, a measure of average blood sugar, ranging from lowest to highest. The prevalence of severe hypoglycemia was calculated for each category. Patients with the lowest and highest HbA1c values tended to be at higher risk for hypoglycemia, compared to those with HbA1c values in the middle range. However, the differences were small and hypoglycemia was common in all HbA1c categories.

“Hypoglycemia is the most common acute complication of diabetes therapy and is associated with poor health outcomes,” said lead author Kasia Lipska, MD, MHS, an endocrinologist from the Yale University School of Medicine. “In clinical trials, patients treated intensively, aiming for excellent blood-sugar control, experienced much more hypoglycemia than patients treated less aggressively. But we didn’t know as much about the relationship between blood-sugar control and hypoglycemia in everyday clinical practice. We wanted to understand whether patients who achieve the lowest average blood sugars are really at the greatest risk for hypoglycemia.”

“It is important to note that it’s not the HbA1c that directly causes hypoglycemia, it’s the therapies we use to lower it,” said Dr. Lipska. “Future research needs to better identify those patients at the highest risk for hypoglycemia so we can reduce the risk. For now, we know that poor control is certainly not protective.”

The researchers suggest that evaluations of quality of diabetes care should include adverse effects associated with treatment, such as hypoglycemia. “While aggressive treatment of high blood sugar was once considered a hallmark of better care, recent clinical trials have raised concerns about the risks of tight control, particularly in the frail and elderly,” said Karter.

Additional authors on the study include Margaret Warton, MPH, and Howard H. Moffet, MPH, of the Kaiser Permanente Division of Research; Elbert S. Huang, MD, MPH, of the University of Chicago School of Medicine; and Silvio E. Inzucchi, MD, and Harlan M. Krumholz, MD, SM, of the Yale University School of Medicine.

Hypoglycemia in type 2 diabetes: current controversies and changing practices

Attempts to determine whether intensive glycemic treatment would be associated with reduction in adverse cardiovascular outcomes led to three large recent randomized controlled trials: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, and the Veteran’s Administration Diabetes Trial (VADT). A widely held, but inaccurate interpretation has been that none of these studies suggested benefit from intensive glycemic control. In ADVANCE, the combination of intensive glycemic treatment along with blood pressure-lowering with a diuretic and angiotensin-directed therapy reduced mortality (Zoungas et al., 2009), and an epidemiologic analysis of different levels of on-trial glycemia showed optimal outcome with normal to near-normal A1c levels (Zoungas et al., 2012). In ACCORD there was consistent evidence of reduction in microvascular endpoints, with the intensively treated subgroup showing 30% reduction in retinopathy, while the likelihood of non-fatal myocardial infarction was significantly reduced by 21% (Boussageon et al., 2011; Hemmingsen et al., 2011). There was, however, a significant 26% increase in mortality in this study, which has been a major source of concern.

Over the past few years, there has been increasing recognition of the importance of hypoglycemia as an adverse consequence of treatment of type 2 diabetes. Previously, severe hypoglycemia was thought to be relatively rare in type 2 diabetes and perhaps not as important as in type 1 diabetes. The ACCORD, VADT, and ADVANCE trials have, however, underscored the concern with hypoglycemia-related adverse outcomes. Furthermore, hypoglycemia in type 2 diabetes is associated with longer length of hospital stay, greater cost, and higher mortality during hospitalization (Curkendall et al., 2009; Turchin et al., 2009). Important observations have shown greater risk of specific types of hypoglycemia. Spontaneous hypoglycemia following myocardial infarction is associated with increased mortality, while insulin-induced hypoglycemia after myocardial infarction was not, leading to the conclusion that persons experiencing hypoglycemia might be particularly at risk of adverse outcome not directly related to glucose effects, but rather because of concomitant underlying characteristics such as greater degrees of renal insufficiency (Kosiborod et al., 2009). Based on these observations, it has become apparent that it is important to include the implications of hypoglycemia in realistic goal-setting for treatment approaches in type 2 diabetes.

It had been thought for some time that with improvement in glycemic control, i.e., overall lowering of average glucose, the likelihood of hypoglycemia would increase. The concept seemed logical, and was indeed confirmed among type 1 diabetics in the Diabetes Control and Complications Trial where annual severe hypoglycemia frequency increased from ∼30 to 90 incidents per 100 person-years as mean A1c decreased from 9 to 6% (The Diabetes Control and Complications Trial Research Group, 1993). It should be noted that this trial preceded the newer and more predictable analog insulin preparations, and the widespread use of self monitoring of blood glucose levels.

In type 2 diabetes, however, the situation is more complex. Among diet, sulfonylurea (SU), or metformin-treated type 2 diabetic patients in the United Kingdom Prospective Diabetes Study (UKPDS), total annual hypoglycemia rates increased from ∼2 to 6% as the most recent on-trial A1c level decreased from 9 to 6%. Paradoxically, however, for insulin-treated patients in the study, almost all of whom were receiving just one daily long-acting insulin dose, the respective hypoglycemia rates actually decreased from ∼25 to 18% (Wright et al., 2006). Those persons who, despite the use of insulin, did not achieve good glycemic control were, then, particularly at risk of hypoglycemia (Figure 1A). The implication appears to be that insulin treatment in type 2 diabetes alters the equation, perhaps because, as observed in other trials, patients with better control actually have less hypoglycemia. This may relate to lesser degrees of insulin secretory deficiency, or to factors such as adherence, which are crucial in the successful outcome of any efforts to improve glycemic control.

FIGURE 1

These concepts are highly important in understanding the adverse outcome reported in the ACCORD study. The group with the worst outcome was the subset of the tight control group that could not, for whatever reason, achieve tight control (Figure 1B). An attractive hypothesis is that targeting near-normal levels of glucose may not be the problem, but rather that harm results from the treatments unsuccessfully employed to accomplish this in individuals who are nevertheless unable to improve glycemia. While we do not know what factors led to the failure of individuals to achieve best control, it seems reasonable to suspect that they had a higher rate of undocumented hypoglycemia which may have been responsible, at least in part, for their adverse outcome.

In UKPDS total hypoglycemia rates were more than 10-fold greater than rates of severe hypoglycemia, and insulin-treated patients had rates approximately three-fold greater than that of diet- and metformin-treated persons, while SU were associated with intermediate hypoglycemia rates . UKPDS was, it should be noted, conducted with older insulin preparations, which are less predictable, causing hypoglycemia with greater frequency than seen with newer analogs. The pattern of highest hypoglycemia rates with insulin and intermediate increase in hypoglycemia with SU has been reported in many studies of type 2 diabetes (Nissen et al., 2008), with further data suggesting that the SU are particularly likely to cause hypoglycemia during the first few months of their use (Bodmer et al., 2008), the period of their greatest glucose-lowering potency (Kahn et al., 2006). Increased hypoglycemia likelihood also is seen with SU in combination with metformin, with thiazolidinediones, and with incretin-based treatments (Buse et al., 2004; Kendall et al., 2005; Bolen et al., 2007; Nauck et al., 2007; Arechavaleta et al., 2011). In contrast, incretin-based treatments when given without a SU are noteworthy for the rarity of hypoglycemia, even with substantial glucose-lowering (Neumiller et al., 2010; MacConell et al., 2012).

Hypoglycemia is an important consideration in the choice of approaches to insulin treatment. Studies comparing insulin glargine with neutral protamine Hagedorn insulin show a reduction in total and severe hypoglycemia by ∼25% with the former (Riddle et al., 2003). The use of basal insulin detemir as primary treatment leads to two and threefold lower overall likelihood of hypoglycemia than multiple dose biphasic or prandial insulin (Holman et al., 2007, 2009). An even greater reduction of hypoglycemia was reported in a comparison of insulin glargine with insulin lispro three times daily (Bretzel et al., 2008).

Treatment associated with hypoglycemia may have substantial adverse clinical consequences. In the BARI 2D trial of therapies for type 2 diabetes in patients with coronary artery disease, treatment approaches based on use of SU and/or insulin were ∼50% more likely both to cause total and severe hypoglycemia than were insulin sensitization with metformin and rosiglitazone, with a suggestion of worse CV outcome (BARI 2D Study Group et al., 2009). One must wonder whether hypoglycemia, not only in the severe symptomatic form, but also in the much more common forms with minor symptoms or even altogether lacking symptoms, may have consequences in persons with coronary disease, cardiac arrhythmia, or diabetic autonomic neuropathy, because of increasing vasoactive cytokine release with consequent increase in myocardial ischemia. Certainly a number of arguments can be put forward to suggest that hypoglycemia may be pro-arrhythmic (Nordin, 2010) and/or that it may contribute to unstable atherosclerotic plaque and events weeks to months after the actual hypoglycemia.

In ACCORD, annual hypoglycemia rates were 3.3 vs. 1.1% in the intensive vs. standard control group (Miller et al., 2010). About 9,546 participants did not have documented severe hypoglycemia, and those randomized to intensive treatment had a 1.24-fold greater annual mortality than those in the standard treatment group. However, 705 participants had one or more episode of severe hypoglycemia, with annual mortality approximately 3-fold that in those not experiencing hypoglycemia. In the group with hypoglycemia, paradoxically, the mortality risk was ∼60% lower among those assigned to intensive glycemic treatment (Figure 2A). Severe hypoglycemia was more common with longer duration of diabetes, with lower body weight, with greater degrees of renal disease (both in terms of albuminuria and serum creatinine), with peripheral neuropathy, in African-Americans, and in females. Similarly, in ACCORD, in both the intensive and standard treatment groups the severe hypoglycemia rates were more frequent in those with higher, rather than lower, levels of A1c (Figure 1B). Furthermore, those in the intensive treatment group who failed to show at least a 0.5% reduction in A1c during the first year of the study had higher mortality, with higher mean on-trial A1c in this group associated with greater likelihood of mortality (Riddle et al., 2010). Two thirds of deaths were in the “unexpected/sudden” category (Action to Control Cardiovascular Risk in Diabetes Study Group et al., 2008), consistent with the association with hypoglycemia. In keeping with the supposition that those having greater difficulty attaining glycemic control might be at a particular risk due to intensive treatment, analysis showed no increase in mortality among those in the intensive treatment group with baseline A1c <7.5%, or 7.5–8.5%, while mortality was 1.7-fold increased in those in the intensive treatment group with baseline A1c >8.5% (Calles-Escandón et al., 2010). In other words, it bears repeated emphasis that it was the failure to achieve tight control despite best efforts that was the reason for excess mortality in the most intensively treated group in ACCORD. Those with lower A1c levels did better than those with higher A1c.

FIGURE 2

Figure 2. (A) Association of severe hypoglycemia with mortality in intensive and standard treatment groups in ACCORD replotted from Bonds et al. (2010). (B) Association of severe hypoglycemia with mortality in intensive and standard treatment groups in ADVANCE replotted from Holman et al. (2009).

The ADVANCE trial showed a remarkably similar relationship to that in ACCORD between severe hypoglycemia, treatment assigned, and mortality risk (Figure 2B). Severe hypoglycemia risk factors, as in ACCORD, were longer duration of diabetes, lower body weight, greater degrees of renal disease (both higher serum creatinine and albuminuria), and cigarette smoking. Interestingly, in ADVANCE there were associations of severe hypoglycemia with total and CV mortality, as well as with microvascular and macrovascular events, and respiratory, skin, and digestive tract illnesses. These associations have led some to hypothesize that hypoglycemia may be a marker of propensity to develop illness, rather than itself being causally related to the various complications (Zoungas et al., 2010). Macrovascular events and CV mortality not only occurred around the time of episodes of severe hypoglycemia, but continued to occur with increased frequency for 2 years after the index hypoglycemic event, supporting the hypothesis that hypoglycemia may be a marker of poor prognosis, rather than its cause. Interestingly, minor hypoglycemia had entirely different associations in the trial, being associated with lower rates of macrovascular disease and of total and cardiovascular mortality. In the VADT too, severe hypoglycemia rates were threefold greater with intensive treatment, and hypoglycemia increased mortality risk, with sudden death again appearing to account for the excess in mortality in the intensive treatment group (Bloomgarden, 2008).

The ACCORD investigators report, however, that severe hypoglycemia did not appear to explain the increase in mortality seen in the intensively treated group. It is difficult to fully support this viewpoint, as severe hypoglycemia certainly was associated with increased mortality in this and in the other trials, and as the glycemic intervention was itself associated with an increase in the likelihood of severe hypoglycemia. The lack of association of severe hypoglycemia with mortality may reflect incomplete ascertainment of events, as the investigators only tracked severe symptomatic hypoglycemia, while, in fact, episodes with minor symptoms or lacking symptoms occur more frequently than symptomatic ones (Swinnen et al., 2009). Clearly, full analysis of self-monitored blood glucose measurements performed by the participants in ACCORD would be likely to give much more information about hypoglycemia risk in this population (Kovatchev et al., 2000), which would clarify whether there is indeed a relationship between hypoglycemia and adverse outcome. The alternative hypothesis discussed above is that hypoglycemia may be seen as a marker of greater “illness,” in association with multiple adverse outcomes, some of which may not be directly related to the blood sugar, so that more frail patients may be at risk both for hypoglycemia and for mortality. Behavioral and psychological factors associated with being unable to adhere to a diabetes regimen have also been hypothesized.

The risk of hypoglycemia per se should perhaps not be used as a rationale to not attempt best possible, safe glycemic control. Better A1c still provides better outcomes, recognizing that the degree of glucose-lowering must be individualized based on multiple different characteristics of individual patients (Blonde, 2012). Agents that can reduce A1c without hypoglycemia risk, such as the incretins and the TZDs, may deserve prominence in the treatment algorithm, and we look forward to studies designed to test the hypothesis of whether this is in fact the case. Glycemic variability may be another factor explaining adverse outcome (Hirsch and Brownlee, 2005), although the argument for this as a factor independent of hypoglycemia is by no means definite (Kilpatrick, 2009). We may, then, paraphrase Joslin’s remark, made shortly after the introduction of insulin, to state, “intensive diabetes management is a remedy primarily for the wise and not for the foolish, whether they be patients or doctors.” (Joslin, 1928).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Bloomgarden, Z. T. (2008). Glycemic control in diabetes: a tale of three studies. Diabetes Care 31, 1913–1919.

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Joslin, E. P. (1928). Insulin, Section II: The Treatment of Diabetes Mellitus. Philadelphia: Lea & Febiger, 69.

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Kilpatrick, E. S. (2009). Arguments for and against the role of glucose variability in the development of diabetes complications. J. Diabetes Sci. Technol. 3, 649–655.

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Nordin, C. (2010). The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia 53, 1552–1561.

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The Diabetes Control and Complications Trial Research Group. (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977–986.

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UK Prospective Diabetes Study (UKPDS) Group. (1998). Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352, 837–853.

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Nocturnal Hypoglycemia

Thanks to the Diabetes Control and Complications Trial (DCCT), it is now well recognized that intensive glycemic control can reduce the risk of diabetes complications. Despite this knowledge, one of the biggest barriers in reaching glycemic targets is the increased risk of hypoglycemia that comes with tighter blood glucose control.

Hypoglycemia is often reported to be one of the most feared complications of diabetes. With nocturnal hypoglycemia being especially worrisome for those who live alone or travel alone. It can also be concerning (not to mention disruptive) for a significant other that you share a bed with.

  • Nocturnal hypoglycemia is a low blood sugar that occurs overnight while you are asleep. It is common to sleep through a low blood sugar when it occurs during sleep.

How common is nocturnal hypoglycemia?

  • According to a journal article from Medscape General Medicine:
      • During the DCCT 43 percent of all hypoglycemia episodes and 55 percent of severe episodes reported occurred during sleep. Incidence rates vary from 12 to 56 percent, however because 49 to 100 percent of episodes occur without symptoms the actual incidence may be much higher.1

Why is nocturnal hypoglycemia concerning?

  • Nocturnal hypoglycemia can be especially dangerous because an individual is unlikely to recognize symptoms or wake up during an episode.
  • Undetected nocturnal hypoglycemia is a risk factor for hypoglycemia unawareness:
    • Hypoglycemia unawareness is low blood glucose that occurs without symptoms, therefore, the person is unaware of the drop in their blood glucose, ultimately delaying treatment.
  • Nocturnal hypoglycemia may also result in physical injury, poor quality of life and possibly impairment in cognitive function.
  • Severe hypoglycemia can cause seizures and unconsciousness, requiring emergency care.

Why does low blood glucose go undetected at night?

  • When a low blood glucose occurs counterregulatory hormones (such as glucagon and epinephrine) are released to raise blood glucose. The release of these hormones provides the initial symptoms (shaking, sweating, rapid heart beat, etc.) that an individual may feel when their blood glucose is low. Such symptoms will likely trigger an individual to treat a low blood glucose.
  • However, while asleep such symptoms/signals are suppressed and/or go unnoticed.
  • There is also evidence that release of counterregulatory hormones are suppressed to some extent during sleep.

What increases the risk of nocturnal hypoglycemia?

  • Any of the following medications may cause hypoglycemia (including nocturnal hypoglycemia):
    • Insulin
    • Sulfonylureas
      • (Diabeta, Micronase, Glucotrol, Glucotrol XL, Amaryl, Glynase)
    • Meglitinides
      • (Prandin, Starlix)
    • Exercise (especially if exercise was longer or more intense than usual)
    • Alcohol (especially if consumed before bed)
    • Low blood glucose in past 24 hours

Signs and symptoms of nocturnal hypoglycemia:

  • Vivid dreams or nightmares
  • Restless sleep
  • Morning headache
  • Night sweats
  • Mood changes
  • Fatigue
  • Convulsions

Prevention of nocturnal hypoglycemia:

  • Check your blood glucose before going to bed.
    • Discuss with your health care provider a safe blood glucose target for bedtime.
    • Many people feel comfortable if their blood glucose is at least 100 mg/dL before going to sleep.
  • If your blood sugar is less than 100 mg/dL (discuss a blood glucose target for bedtime with your health care provider) eat at low to moderate glycemic index snack before going to bed
    • Whole wheat bread with peanut butter or whole grain crackers with a slice of cheese
  • If you were more active than usual, consumed alcohol in the evening, or had a low blood glucose during the day, set an alarm to check your blood glucose at 2 a.m. or 3 a.m. in the morning.
  • If you currently take the intermediate-acting insulin, NPH, speak with your health care provider about switching to a long acting insulin such as, Lantus, Levemir, or Tresiba. Long acting insulin has a flat action profile and does not have variable peaks (like NPH does) therefore the risk of nocturnal hypoglycemia is reduced.
  • If you have a history of nocturnal hypoglycemia, hypoglycemia unawareness or have experienced a severe low blood glucose, a continuous glucose monitor (CGM) may be helpful.
    • A CGM may also be beneficial if you live alone or travel alone as you can set an alarm for when your blood glucose drops below a set threshold (i.e. <70 mg/dL).

*Insurance coverage can be a challenge*

Treatment of nocturnal hypoglycemia:

  • If you are woken up by a low blood glucose, first check your blood glucose to confirm it is low (<70 mg/dL).
  • Treat a low blood glucose with quick acting carbs such as juice (4 ounces) or glucose tablets (3 to 4 tablets).
  • Retest blood glucose in 15 minutes. If blood glucose remains below 70 mg/dL, repeat the above treatment.
  • Once your blood glucose is above 70 mg/dL, if your typical breakfast time is still several hours away have a small snack that includes both a carb and a protein, such as peanut butter crackers.
  • Make sure to discuss with your health care provider specifics on how he/she would like you to manage/treat nocturnal hypoglycemia.
  • If you take insulin speak with your health care provider about getting a prescription for emergency Glucagon.

Have you experienced nocturnal hypoglycemia? Please share your experience with the type 2 diabetes community

Can you have low blood sugar with type 2 diabetes?

So… what do I need to know?

Maybe it’s more accurate to say that people with type 2 diabetes who take certain types of medication are more at risk for lows. We’re getting closer! But to get to the truth, we should take a look at someone without diabetes. Is it possible for them to have lows, too?

Theoretically yes, especially if doing long-lasting physical activities without proper food intake. Additionally, extreme stress and binge drinking are also common causes of low blood sugar for people without diabetes.

However, it’s pretty rare because as soon as BG’s drop below 80 mg/dl (4.4 mmol/L), the natural counterregulatory system kicks in, raising blood sugar back to normal levels.

I’ve never experienced hypoglycemia (a fancy word for low blood sugar), even though I am very active and eat a rather low carb diet.

Low blood sugar risks with insulin and sulfonylureas

There are different types of drugs used to manage diabetes. They are put into different classes depending on how they work.

Enviably, those who manage their blood sugar with diet and exercise don’t have to worry much. The risk of hypoglycemia is the same as non-diabetics.

Reassuringly, those who only take drugs that limit the amount of sugar released from the liver and slow down the absorption of carbohydrates in the intestines (Metformin, for example), also have a very low risk.

Those using insulinotropic agents (sulfonylureas like Glipizide, Glyburide, etc.), which stimulate or affect the production of insulin, need to be especially careful, as does anyone using insulin.

Shockingly, while insulin-dependent diabetics experience many more low blood sugars, it is the patient group using sulfonylureas who have more severe low blood sugars requiring emergency assistance. That may ultimately be because those using insulin understand the risks for lows and are often better prepared for them.

Hypoglycemia symptoms with normal glucose levels

There is such a thing as pseudo-hypoglycemia. This happens when glucose levels are continuously high for a long time then are suddenly brought down to normal. It’s as if the body becomes accustomed to the higher range then panics when levels drop to normal, responding with hormones like cortisol and adrenaline.

Info: Hypoglycemia is usually defined as blood glucose levels below 70 mg/dl (or 4.0 mmol/L). However, your doctor may give you a different blood glucose number that is considered too low for you.

Diabetes: Could targeting this protein prevent hypoglycemia?

People with type 1 or type 2 diabetes who take insulin have a higher risk of developing hypoglycemia, or low blood sugar. Now, a study of how a protein works in the pancreas could lead to new treatments for protecting against the potentially life-threatening condition.

Share on PinterestResearchers may have found a way to prevent hypoglycemia in people with diabetes.

Dr. Gina L. C. Yosten, who is an assistant professor of pharmacology and physiology at Saint Louis University in Missouri, and her team discovered the protein, which has the name neuronostatin, in earlier work.

They found that neuronostatin could prevent hypoglycemia by getting the pancreas to raise blood sugar in two ways. One way is to make less insulin, which is a hormone that reduces blood sugar, and the other is to produce more glucagon, a hormone that increases blood sugar.

In the more recent investigation, the scientists showed that injecting rats with neuronostatin raised the animals’ blood sugar levels.

They also found that low blood sugar causes human pancreatic tissue to release more neuronostatin and that treatment with glucagon triggers more neuronostatin release.

The team says that, with more research, these findings could lead to neuronostatin becoming a target for drugs to prevent and treat hypoglycemia in people with type 1 and type 2 diabetes.

The study has featured at the annual meeting of the American Physiological Society during the Experimental Biology 2019 interdisciplinary meeting, which is taking place from April 6–9 in Orlando, FL.

“There are very few options,” says Stephen Grote, a doctoral student in Dr. Yosten’s group, “for preventing hypoglycemia or treating hypoglycemia unawareness other than avoiding low blood sugar as much as possible.”

“Understanding what neuronostatin does and how it works will provide valuable information for preventing hypoglycemia and provide more complete knowledge into how the pancreas manages blood sugar normally,” he adds.

Diabetes and the pancreas

Diabetes arises because the body has problems making or using insulin, which is a hormone that helps cells to take in glucose, or blood sugar, and use it for energy.

Without effective treatment, diabetes results in high blood sugar, or hyperglycemia, which can lead to kidney failure, blindness, stroke, heart attack, and amputation of feet and lower legs.

There are two main types of diabetes: type 1 and type 2. The vast majority of people with diabetes have type 2.

In type 1 diabetes, the body does not make enough insulin, and so people with this type need to take insulin every day to stop their blood sugar rising to dangerous levels.

In type 2 diabetes, the cells of the body cannot use insulin effectively. The pancreas tries to make up for it by making even more insulin, but, eventually, this is not enough, and people need to take extra insulin to control their blood sugar.

According to the World Health Organization (WHO), the number of people worldwide with diabetes rose from 108 to 422 million during 1980–2014.

In the United States, there are around 30 million people with diabetes of which 90–95 percent have type 2.

A need for better treatments

People with diabetes who take too much insulin may experience low blood sugar that can leave them dizzy and sleepy. If their sugar levels continue to drop, there is a high risk that more severe symptoms will follow, including seizures and loss of consciousness.

There is also a risk that episodes of hypoglycemia can develop into a vicious cycle of increasing severity, as the condition can reduce people’s ability to notice the symptoms and, consequently, the chance to intervene.

There is a need, therefore, for improved treatments and a deeper understanding of how hypoglycemia develops in diabetes.

In the new study, Dr. Yosten and her team showed how neuronostatin increased glucagon by interacting with certain types of receptor proteins in the pancreatic alpha cells that release the hormone.

In addition, they demonstrated that, in response to higher glucose levels, neuronostatin reduced insulin production by pancreatic beta cells.

In a meeting abstract about the study, the team notes that this suggested that neuronostatin “is a pancreatic component of the counterregulatory response to hypoglycemia.”

To confirm this, the researchers then showed that infusing male rats with neuronostatin for 30 minutes “substantially increased” their blood glucose levels.

Also, treatment with neuronostatin slowed down the clearance of glucose and reduced the production of insulin in response to hyperglycemia.

Further tests also revealed that pancreatic cells exposed to low glucose released neuronostatin, and that fasting blood glucose raised blood levels of neuronostatin in rats.

Potential to protect against hypoglycemia

The researchers say that scientists need to do further studies now to confirm that neuronostatin can prevent or reverse hypoglycemia, and to find out which mechanisms and signaling pathways the body uses.

“We propose,” they note, “that could represent a novel therapeutic target for the treatment and prevention of hypoglycemia in diabetes.”

The team is carrying on with its work to find out how the body controls neuronostatin and how it interacts with mechanisms of insulin and glucagon release in the pancreas.

“Neuronostatin is a truly novel factor,” Grote explains, “and everything we find about it pushes our knowledge of its therapeutic potential just a bit further.”

“We believe that studying neuronostatin could ultimately reveal a way to use it to help prevent and reverse vicious cycles of hypoglycemia by helping the body respond appropriately to the low blood sugar with more glucagon.”

Stephen Grote

  • Monarch
  • March 10, 2017

Hypoglycemia is a condition characterized by abnormally low blood glucose (blood sugar) levels, usually less than 70 mg/dL. This condition is recognized to be one of the main restrictions in achieving normal control in type 1 diabetes. Historically, the risk of hypoglycemia has been considered lower in type 2 diabetes, however, with the increasing use of insulin to treat type 2 diabetes, the occurrence of hypoglycemia has the potential to intensify.

The focus on the relationship between hypoglycemia and type 1 diabetes is due to the frequency of hypoglycemia in these patients. Per the American Diabetes Association, on average, people with type 1 diabetes experience hypoglycemia around twice a week. This number equates to a prevalence of 30% – 40% a year.

It is more difficult to originate equivalent figures for patients with type 2 diabetes because of the diversity. Statistically, the majority of people with type 2 diabetes are middle aged or elderly, and accurate measures of the frequency of hypoglycemia in elderly people are most likely underestimated.¹ In addition to this, when people with type 2 diabetes become insulin deficient, they experience hypoglycemia as frequently as people with type 1 diabetes, and it may go unreported.

Studies behind hypoglycemia and type 1 diabetes show that severe hypoglycemia is reported robustly over a period of one year, and mild hypoglycemia is unreliable after only one week.²,³ Likewise, studies supporting insulin-treated type 2 diabetes report severe hypoglycemia over a period of one year, but the difference is in the results of mild hypoglycemia. Some studies focused on hypoglycemia in type 2 diabetes have overlooked the effects of ageing by selecting middle-aged subjects. The scarcity of elderly people is concerning because this age-group is at the greatest risk of illness as a result of hypoglycemia, especially since their symptoms are often masked and they do not receive prompt treatment.

The frequency of hypoglycemia in type 2 diabetes may not be considered as common as hypoglycemia in type 1 diabetes, but misleading information may have caused this misperception. Hypoglycemia occurs most frequently with insulin therapy, which can occur in type 1 and type 2 diabetes. With the rise in the need of insulin therapy in both illnesses, the risk of hypoglycemia should not be underestimated.

Source: DiabetesCare

  1. McAulay V, Frier BM: Hypoglycaemia. InDiabetes in Old Age. 2nd ed. Sinclair AJ, Finucane P, Eds. Chichester, U.K., John Wiley and Sons,2001 , p. 133 –152
  2. Pramming S, Thorsteinsson B, Bendtson I, Binder C: Symptomatic hypoglycaemia in 411 type 1 diabetic patients.Diabet Med 8 : 217 –222,1991
  3. Pedersen-Bjergaard U, Pramming S, Thorsteinsson B: Recall of severe hypoglycemia and self-estimated state of awareness in type 1 diabetes.Diabetes Metab Res Rev 19 : 232 –240,2003

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Hypoglycemia Goes Undetected Too Often in People With Type 2 Diabetes, Article Suggests

Although hypoglycemia, or low blood sugar, is usually associated with type 1 diabetes, the problem can also pose health harms to people with type 2 diabetes — and doctors and patients need to be aware of these risks, the authors of a new article argue.

In the article, which was published in the March 2018 edition of the Journal of Clinical Endocrinology & Metabolism, authors from the Endocrine Society and Avalere Health, a Washington, DC–based national healthcare advisory firm, analyzed various materials regarding hypoglycemia, including 31 articles, 20 clinical guidance documents, and more than 50 clinician and patient tools. Their aim: to understand the prevalence of hypoglycemic episodes among people with type 2 diabetes and the corresponding health consequences.

They report that severe cases of hypoglycemia led to 30,000 emergency room visits among people with both type 1 and type 2 diabetes in 2009. They also reported that in 2010, about 18 percent of Medicare beneficiaries who were hospitalized due to hypoglycemia were readmitted within 30 days, and 5 percent died within that time period.

“I’ve been a practicing endocrinologist for 25 years, and I was taken aback by how big a problem this really is,” says Robert Lash, MD, of Washington, DC, the chief professional and clinical affairs officer of the Endocrine Society and the lead author of the paper.

RELATED: Treating Type 2 Diabetes From the Inside Out: Tips for Self-Care, Medication, and Insulin

In one meta-analysis the authors looked at, researchers observed that people with type 2 diabetes have an average of 23 mild or moderate episodes of hypoglycemia per year, suggesting that despite a lack of firm statistics on such episodes, people with type 2 are certainly affected. “For patients with type 2 diabetes, hypoglycemia doesn’t always rise to the top of the list,” says Dr. Lash, explaining that usually, the goal for these patients is to help reduce high blood sugar levels, or hyperglycemia, which correspond to an elevated A1C, the two- to three-month average of a patient’s blood sugar levels.

David Bradley, MD, an assistant professor of endocrinology, diabetes and metabolism at the Ohio State University Wexner Medical Center in Columbus, who was not involved in the analysis, agrees. “The authors bring about a very valid point: that, as practitioners, we have often sacrificed a lowering of A1C and intensive glucose control to lower microvascular complications, without leveraging the risks of hypoglycemia,” Dr. Bradley says. “This has extended to most of our quality care measures that strive for an optimal A1C but do not take into account hypoglycemia.”

If you have type 2 or are a doctor treating people with type 2, it’s important to be aware of these risks, as well as the signs and symptoms of very low blood sugar, Lash and his team say. According to the American Diabetes Association (ADA), shakiness, fatigue, rapid heartbeat, and nausea are some signs of hypoglycemia.

Particularly, people with type 2 diabetes who are older than 65, on insulin, or taking a class of drugs called sulfonylureas are at the greatest risk for severe hypoglycemia, the authors of the paper reported. The ADA notes that low blood sugar can lead to serious complications such as diabetic coma, seizures, and even death.

RELATED: 10 Warning Signs of Low Blood Sugar

What the Findings of the Analysis Mean for Your Health if You Have Diabetes

Bradley points out the article is only a preliminary statement and not a systematic review of scientific literature. But Lash says analyzing the instances of hypoglycemia in people with type 2 diabetes and communicating those findings in this article is the first step in establishing more precise guidelines for detecting and treating these episodes.

Generally, hypoglycemia is defined as when blood sugar levels drop below 70 milligrams per deciliter (mg/dl), according to the National Institute of Diabetes and Digestive and Kidney Diseases. However, in their article, Lash and his team propose the following new categories for hypoglycemia to help inform treatment and prevent health complications:

  1. Level 1 Blood glucose levels of less than 70 mg/dl, where patients may be unaware of hypoglycemia (called hypoglycemia unawareness)
  2. Level 2 Blood glucose levels of less than 54 mg/dl
  3. Level 3 Independent of blood glucose levels, any severe event that includes an altered mental or physical status requiring assistance

If you’re managing type 2 diabetes now and are older, on insulin, or take sulfonylureas, you can help prevent severe episodes of hypoglycemia by making sure you follow your medication regimen, check your blood sugar regularly, and have hard candies or glucose tablets handy in the event that your levels dip too low.

And if that happens? “They need to make sure their physician or other provider knows,” Lash says, “because there are things we can do to help reduce the incidence of hypoglycemia while still working towards good control of their diabetes.”

All about hypoglycemia (low blood sugar)

Hypoglycemia can occur for various reasons.

Blood sugar regulation

The digestive system breaks down carbohydrates from food. One of the molecules this creates is glucose, the body’s main source of energy.

Glucose enters the bloodstream after we eat. However, glucose needs insulin — a hormone that the pancreas produces — before it can enter a cell. In other words, even if there is plenty of glucose available, a cell will starve of energy if there is no insulin.

After eating, the pancreas automatically releases the right amount of insulin to move the glucose in blood into the cells. As glucose enters the cells, the blood sugar levels fall.

Any extra glucose goes into the liver and muscles in the form of glycogen, or stored glucose. The body can use this glucose later when it needs more energy.

Insulin is responsible for bringing high blood sugar levels back to normal.

If glucose levels fall because an individual has not eaten for a while, the pancreas secretes glucagon — another hormone — which triggers the breakdown of stored glycogen into glucose.

The body then releases the glycogen into the bloodstream, bringing glucose levels back up.

Hypoglycemia and diabetes

Share on PinterestTesting blood sugar regularly can help those with diabetes to prevent hypoglycemia.

Both type 1 and type 2 diabetes involve a problem with insulin.

Type 1 diabetes: Damage to the cells that normally produce insulin means that the body cannot produce insulin.

Type 2 diabetes: The body’s cells do not respond properly to insulin or the pancreas may not release enough insulin.

In both types of diabetes, the cells do not get enough energy.

People with type 1 diabetes and some people with type 2 need to take insulin or other drugs to reduce their blood sugar levels.

If the dose is too high, blood sugar levels can fall too far, leading to hypoglycemia.

Hypoglycemia can also occur if the person exercises more than usual or does not eat enough.

A person does not need to increase their dose to have too much insulin in their body. It may be that the insulin they took was more than their body needed at that moment.

According to the NIDDK, both insulin and two other drugs can result in hypoglycemia. These drugs are sulfonylureas and meglitinides.

Hypoglycemia in children: Pediatric ketotic hypoglycemia

Some children experience pediatric ketotic hypoglycemia, involving low blood sugar levels and high levels of a substance known as ketones.

Doctors do not know exactly why this happens, but causes may include:

  • metabolism problems that the child was born
  • conditions that lead to excess production of certain hormones

Symptoms usually appear after the age of 6 months and disappear before adolescence.

They include:

  • fatigue
  • headaches
  • pale skin
  • confusion
  • dizziness
  • irritability
  • mood changes
  • clumsy or jerky movements

If a child shows any of the above signs or symptoms, they should see a doctor as soon as possible.

Insulin autoimmune syndrome

Another possible cause of hypoglycemia is insulin autoimmune syndrome, a rare disease that happens when the body’s immune system attacks insulin, mistaking it for an unwanted substance.

Symptoms tend to appear suddenly, according to the Genetic and Rare Diseases Information Center (GARD). They often go away after a few months, but sometimes they come back again.

Treatment can usually control the symptoms.

Symptoms and treatment are similar to those for hypoglycemia due to other causes.

Other causes

People may experience hypoglycemia for other reasons.

Some medications: Quinine, a drug that prevents malaria, can trigger hypoglycemia. High doses of salicylates, used to treat rheumatic disease, or propranolol for hypertension (high blood pressure) may also cause blood sugar levels to drop. It can also happen when a person takes diabetes medication without having diabetes.

Alcohol consumption: Drinking large amounts of alcohol can cause the liver to stop releasing stored glucose into the bloodstream.

Some liver diseases: Drug-induced hepatitis can lead to hypoglycemia, because it affects the liver.

Kidney disorders: People with a kidney disorder may have problems excreting medications. This can result in low blood sugar levels.

Not eating enough: People with eating disorders, such as anorexia nervosa, may experience dramatic falls in their blood sugar levels. Fasting or missing a meal may lead to low blood sugar levels.

Insulinoma: A tumor in the pancreas can cause the pancreas to produce too much insulin.

Increased activity: Increasing levels of physical activity can lower blood sugar levels for some time.

Endocrine problems: Some disorders of the adrenal and pituitary glands can lead to hypoglycemia. This is more common in children than adults.

Reactive, or postprandial, hypoglycemia: The pancreas produces too much insulin after a meal.

Tumors: Rarely, a tumor in a part of the body other than the pancreas can cause hypoglycemia.

Severe illness: Some diseases, such as cancer, can affect many different organs, including the pancreas. This can lead to hypoglycemia.

What to Do if Your Blood Sugar Is Too Low

You’ll need to test your blood sugar if you think you have hypoglycemia. (ARTIGA PHOTO/CORBIS)

You’ll need to test your blood sugar if you think you have hypoglycemia.(ARTIGA PHOTO/CORBIS)

Although type 2 diabetes is characterized by blood sugar that is too high, some people take insulin and others medications (such as sulfonylureas) that can occasionally drive blood sugar too low.

When blood sugar is too low—generally less than 70 mg/dL—it’s called hypoglycemia, and it can become a medical emergency. (The normal range for fasting blood sugar is 70 to 99 mg/dL, though it varies somewhat with age, and is lower during pregnancy and in children.)

You can lose consciousness
Hypoglycemia is more likely to occur when you start taking a new medication (it can take practice to match your food intake to your insulin dose, for example) or if you exercise more than usual.

As blood sugar drops to low levels, you may feel:

• Shaky
• Irritable
• Sweaty

This can occur within 10 to 15 minutes, and in extreme cases you can even lose consciousness and experience seizures if you don’t consume some glucose (though hypoglycemia is usually mild in people with type 2 diabetes, and readily fixed by drinking juice or eating other sugar-containing items, such as glucose tablets or four to six pieces of hard candy).

You’ll need to test your blood sugar to confirm that you’re having hypoglycemia—some people become irritable if blood sugar is too high, so it’s not always obvious.

If you drink sugar-containing juice, or some other form of carbohydrate, it should bring blood sugar back into the normal range. You can also purchase glucose pills or gels in the pharmacy that can get blood sugar back on track.

“You should always have a glucose source in the car,” says Yvonne Thigpen, RD, diabetes program coordinator at Mount Clemens Regional Medical Center in Mt. Clemens, Mich. You never know when youll hit construction or get stuck in traffic, she says.

Hypoglycemia can occur at night
Dick Robbins, 72, of Hot Springs Village, Ark., was diagnosed with type 2 diabetes in 2001, and is now taking metformin (an oral medication that doesn’t typically cause hypoglycemia), as well as a short-acting insulin, Novolog (insulin aspart), and a long-acting insulin, Lantus (insulin glargine). In that time hes had six or seven episodes of hypoglycemia.

“It usually occurs between midnight and 1 a.m. and I always wake up soaking wet—but only from the waist up. My head, shoulders, and upper back are just dripping with sweat,” he says.

He checks his blood sugar, and if its low, he goes straight to the refrigerator and drinks some pineapple juice and eats a peanut butter sandwich. He waits 45 minutes or so, and then checks his blood sugar again. If its in the normal range, he heads back to bed.

You can have hypoglycemia without knowing it
Some patients with diabetic nerve damage, known as neuropathy, may not experience any of the symptoms of hypoglycemia, even when their blood sugar is very low.

In that case, you may need to test your blood more often and rely on family and friends to help you notice if blood sugar starts to drop.

“My mom is one of them,” says Thigpen. “Her blood sugar can go down to 30 mg/dl and all she says is shes kind of tired.” In those cases, family members can help determine if blood sugar is heading into the danger zone.

“You want to offer them a source of quick-acting carbohydrates,” says Thigpen. “The gold standard of that treatment would be 15 grams of glucose,” she says, which can be purchased over-the-counter in pill or gel form at the pharmacy.

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