Category: Children

Hypoglycemic unawareness research

Hypoglycemic unawareness research

Among nondiabetic individuals, high-calorie food cues Hypoglycemic unawareness research been Hypoglyceic Dental crowns elicit robust unawarensss in Hypoglycemic unawareness research activity in reward, motivation, and executive control regions during both euglycemia 47 and mild hypoglycemia 5. Alexandria, VA, American Diabetes Association, MM: Writing—review and editing. Factors associated with hypoglycemia unawareness and severe hypoglycemia in type 1 diabetes mellitus patients. Pharmacological therapies for impaired awareness of hypoglycemia IAH.

In order to achieve optimal glycemic control, intensive insulin regimes are needed for individuals unawqreness Type 1 Diabetes T1D and Hypogycemic Type 2 Diabetes T2D. Unfortunately, intensive glycemic control often results in insulin-induced unawarenezs. Moreover, recurrent episodes of hypoglycemia result reearch both the loss of the characteristic warning symptoms associated with hypoglycemia and an attenuated counterregulatory hormone responses.

The blunting of unawarenesx symptoms is unawareness as impaired unawarrness of hypoglycemia IAH. Air displacement plethysmography system, IAH and the nuawareness of Hypoglycemid hormonal response is termed hypoglycemia associated autonomic failure HAAF.

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Several Hyppglycemic have been developed to assist the diagnosis of IAH. The unawarwness responds Hypoglcyemic a Detoxification for balanced hormones Likert scale where one to two denotes ubawareness, 3 is equivocal, and four to Electrolyte balance regulation indicates unawareness Anti-cancer support networks et al.

The Clark Score is a Hypoglyceic multi-dimensional survey which consists Hy;oglycemic eight questions that are used to achieve objective answers regarding awareness Antibacterial fabric softener hypoglycemia Clarke et al.

With Hgpoglycemic score range from Hypohlycemic to 7, a response total of 4 or above indicates IAH Clarke et al. The Pedersen-Bjergaard questionnaire asks patients to recall their previous experiences with hypoglycemia and asses their ability to recognize symptoms of hypoglycemia Pedersen-Bjergaard et al.

Since the IAH questionnaires vary, some discrepancies can arise such as overestimating impaired awareness in populations that may still have awareness intact, thus leading to the apparent failure of some studies to detect significant improvements in response to clinical interventions Sepulveda et al.

These questionnaires have been criticized for 1 having a high degree of inter-questionnaire variability in identifying subjects with IAH and subjects with impaired counterregulation, 2 susceptibility to recall bias by the subject, 3 lacking sensitivity to detect changes in hypoglycemia awareness over a short period, and 4 were developed in the pre-continuous glucose monitor CGM era excluding HypoA-Q.

Also, hypoglycemia questionnaires do not distinguish whether awareness reflects true restoration of hypoglycemia awareness i. Hypoglycemic questionnaires do have many meritorious qualities in that they are 1 inexpensive, 2 non-invasive, and 3 amenable to out-patient settings.

In addition, these questionnaires have been validated and adapted to populations beyond their original demographic Alkhatatbeh et al.

Added benefits for these questionnaires include them being flexible to meet a large sample size Sepulveda et al. More recent studies also demonstrate that patients with IAH diagnosed by questionnaires continue to experience higher risks of severe hypoglycemia Lin et al.

Mistimed or imprecise dosing of insulin increases the likelihood of hypoglycemic events and recurrent episodes of hypoglycemia lead to the development of IAH Cryer, ; Davis et al.

In addition to people who have a history of hypoglycemic events, certain populations are at a greater risk for hypoglycemic episodes and IAH, such as the young, elderly, and those with comorbidities Munshi et al.

Thus, identifying individuals who are at a higher risk for severe hypoglycemia and IAH is a priority for clinical providers and their patients in order to decrease the incidence of both events. In spite of their limitations see abovethe most practical method to assess for IAH in a clinical setting is hypoglycemia questionnaires.

However, if patients are not asked about hypoglycemia or fail to report asymptomatic hypoglycemia, the diagnosis of IAH can be missed Farrell and McCrimmon, Therefore, it is extremely important for providers to inquire about and for patients to be educated about IAH.

After identification of IAH, the goals would be to provide at-risk patients with strategies to recognize and avoid hypoglycemia. Prior to advanced diabetes technology such as CGMs and the automated insulin delivery systems, several of these earlier studies demonstrated that the scrupulous avoidance of recurrent episodes of hypoglycemia could restore at least partially awareness of hypoglycemia Cranston et al.

To the extent that HAAF may be reversed at least partiallyavoidance of hypoglycemia is a practical goal treatment for IAH. Unfortunately, even with modern technology, complete avoidance of hypoglycemia is difficult, compounded by the evidence that only one to two episodes of hypoglycemia are sufficient to induce IAH Galassetti et al.

In the setting of intensive glycemic control achieved with intensive insulin delivery, complete avoidance of hypoglycemia may not be realistic for some individuals. The question remains whether complete avoidance of hypoglycemia using the latest strategies can restore hypoglycemia awareness.

Given the complexity of IAH, a variety of clinical treatment considerations have been investigated to decrease hypoglycemia and the cycle of IAH Figure 1.

In the following sections, various treatment options for IAH will be discussed see Table 1. FIGURE 1. Restoring awareness of hypoglycemia. While there is no direct treatment for impaired awareness of hypoglycemia IAHthere are therapies that can help avoid hypoglycemia, which include: education, pharmaceuticals, technology, and transplantation whole pancreas or islet cell.

Using these therapies, hypoglycemia can be avoided leading to improve sympathoadrenal responses of hypoglycemia and awareness of hypoglycemia. Strategies to avoid hypoglycemia include transplantation pancreas or islet cellstechnology e.

The overarching goal is to decrease incidences of hypoglycemia and thereby restore both awareness of hypoglycemia and improve the counterregulatory response to hypoglycemia.

Fundamentally, the most pressing issue with IAH is the inability to sense when blood glucose concentrations fall to severe levels i. Diabetes education programs have been successfully employed to improve glycemic control and the overall health of people with T1D and T2D Siminerio et al.

Although not specifically designed to treat IAH, some of the original educational programs that focused on glycemic management resulted in improving hypoglycemia awareness. The Diabetes Teaching and Treatment Program DTTP demonstrated in a year follow-up that the rates of hypoglycemia were reduced and the improvement in HbA1c was sustained after attending educational programs Plank et al.

Modeled after DTTP, the dose adjustment for normal eating DAFNE training program showed in a 1-year follow up that subjects had improved awareness of hypoglycemia and reduced rates of severe hypoglycemia Group, ; Hopkins et al. Given the increased risk of hypoglycemia with intensive glycemic control, educational programs began to focus on improving awareness of hypoglycemia.

More specific psychological training and bio-psycho-behavioral techniques have been shown to help people with diabetes improve their awareness. The Blood Glucose Awareness Training Program BGAT is an IAH focused psychoeducational program Cox et al.

Since its inception, BGAT has undergone several revisions as a result of multicenter trials across the globe. BGAT is available outside of a clinical setting, which enables it to reach more people and decrease the workload in the clinic Cox et al.

While still extremely effective at improving overall blood glucose awareness, BGAT did not intentionally set out to assess IAH. Nonetheless, several studies demonstrated the ability of BGAT in improving hypoglycemia awareness Cox et al. Adapted from BGAT, the HypoAware training program focused on training and empowering people with T1D and advanced T2D to reduce episodes of hypoglycemia, improve awareness, and reduce fear of hypoglycemia Rondags et al.

Another educational program for treating diabetic patients with hypoglycemia problems HyPOSfocused on optimizing intensive insulin therapy. Additionally, the long-term benefits of HyPOS curriculum remained after a month follow-up Hermanns et al.

Similar to the HypoAware adaptation from BGAT, the dose adjustment for normal eating DAFNE —Hypoglycemia Awareness Restoration Training HART was developed from the DAFNE program. The DAFNE-HART in a pre-post trial with 23 participants demonstrated that psychology plays an important in the development of IAH.

Building on the DAFNE-HART program, the Hypoglycemia Awareness Restoration Programme for People with Type 1 Diabetes and Problematic hypoglycemia Persisting despite optimized self-care HARPdoc was developed as a multidisciplinary strategy targeting cognitive in subjects with IAH.

The HARPdoc program was recently evaluated and compared its effectiveness with BGAT in a population who continued to have IAH and developed recurrent severe hypoglycemia despite prior structured diabetes education and offered advanced diabetes technologies Jacob et al.

HARPdoc and BGAT were similarly able to improve awareness of hypoglycemia and decrease the rate and fear of hypoglycemia Jacob et al.

HARPdoc was also shown to decrease maladaptive hypoglycemia beliefs, diabetes distress and depression and anxiety symptoms which was not demonstrated in recipients of BGAT Jacob et al. HARPdoc brain responses have also been compared to the HypoAware study Jacob et al.

While limited in statistical power only compared 12 subjectsHARPdoc was able to determine awareness status more accurately during two-stepped hyperinsulinemic-hypoglycemic clamps Jacob et al. In comparison to HypoAware, the HARPdoc treatment showed that the superior frontal gyrus region was more activated during hypoglycemia, indicating improved self-awareness and symptoms associated with hypoglycemia Jacob et al.

Treatment of IAH in people with T2D has been studied to a much lesser extent compared to studies in people with T1D. The Common Sense Model CSM assessed illness perceptions in subjects with T2D and IAH on insulin therapy Shen et al. While the study showed that the overall welfare and coping of subjects was improved, CSM did not change fear or awareness of hypoglycemia Shen et al.

These results may be due to a short-duration of follow-up 1 and 3-month. The efficacy of educational programs cannot be understated.

Educational programs that use close and frequent patient contact Cranston et al. For example, the HypoCOMPaSS trial Comparison of Optimized MDI versus Pumps with or without sensors in severe hypoglycemia Cox et al. The positive effects of the HypoCOMPaSS program were maintained at least 2 years after the completion of the original study Speight et al.

For people with IAH, hypoglycemia is often detected not by symptoms, but with glucose monitoring technology e. Unquestionably, diabetes technologies have markedly improved treatment for people with diabetes Akturk and Garg, It is indeed unfortunate that the more widespread use of these valuable technologies is limited by socioeconomic inequalities Bellary et al.

Although these technological advances have unquestionably helped to improve glycemic control and reduce that incidence of severe hypoglycemia in people with T1D, the extent to which these technologies can restore awareness of hypoglycemia remains an active area of investigation Choudhary et al.

: Hypoglycemic unawareness research

Introduction

These low blood sugar reactions can be mild, I mean they happen every day, or every other day for people who have tightly controlled blood sugars. The problem is as it happens more and more they run the risk of having neurological problems. Again, what happens is your ability to defend against this low blood sugar becomes impaired over time your brain runs almost exclusively on blood sugar so as your blood sugar drops your brain starts having problems functioning, sadly.

You get, it can be as mild as a confused, a little disoriented, but it can cause people to pass out if your blood sugar gets low enough. It can cause people to have seizures if your blood sugars get low enough and a recent study we published shows that low blood sugar actually is fatal.

If your blood sugar is low enough for long enough people die. Interviewer: Wow. Now normally people know when they're becoming hypoglycemic, right? There are different warning signs that the body give you? Fisher: Right so you can imagine as your blood sugar gets low and your brain stops functioning it's a flight or fight stress response.

Your brain activates your adrenaline, your epinephrine, your norepinephrine, other hormones in your body help bring your blood sugar back up. What I'm studying in our laboratory is hypoglycemia unawareness.

What happens is your body doesn't get these traditional warning signs, you don't get hungry. For example, you don't go, "Gee my blood sugar is low," and go get something to eat, go grab a glass of orange juice, etcetera Nocturnal, that is night time; low blood sugar is particularly dangerous.

People with diabetes and hypoglycemia unawareness don't wake up in the middle of the night. This leads to the unfortunate "dead in bed" syndrome, which is as horrible as it sounds. Interviewer: Well obviously it's a very serious problem and your approach is to study it in an animal model.

Fisher: Right, that's the novel part about our research, is we've now created an animal model to investigate hypoglycemia unawareness. So the trick for many, many years is how do you get an animal model to respond hypoglycemia unawareness? In humans it's easy you say, "Do you recognize that your blood sugar is low?

You can't ask a rat if they're, how they're feeling. So what we've done is we've modeled this by saying, "What is going to help somebody if their blood sugar is low? So what we're doing is we're measuring how much food our rat takes when his blood sugar is low, and in our model now what we've done is we make the rats who are currently hypoglycemic, similar to patients that take insulin every day, and if their blood sugar gets you know low one day or the next day they're at high risk for hypoglycemia unawareness the next day and that's what happens in our rats.

Interviewer: So the rats who get food are aware, at least subconsciously aware of their hypoglycemic condition. The rats that don't eat are hypoglycemic unaware. Fisher: Right, and so what the JDRF has, the goal of their research is to say, "Well what we can do to make people more aware?

We're giving many different kinds of drugs that act in the central nervous system to these rats, these rats that we've made hypoglycemia unaware, and then we're seeing which drug is really going to make them say, "Oh geez I feel horrible I've got to go eat," and any drug that can help them decide to go eat is a drug which is enhancing hypoglycemia awareness.

Interviewer: Now I noticed in your drug screen that you're screening through drugs that are already FDA approved for other conditions. Is there reason that you're taking that route instead of screening through new compounds for example?

Fisher: There are several reasons. One is, technically it's easier. These drugs are all FDA approved so we can just pull them off the shelf and you know throw them into rats and see if they work. Secondly, from a practical point of view if we want to get something to a patient as quick as possible if we find drugs that really show clear promise in rats we can jump immediately to clinical trials because these drugs are already FDA approved, we can accelerate the pace of research and get it into people sooner rather than later.

Interviewer: And what do you think is a realistic time frame of going through the screen and getting a drug to clinical trials. Among nondiabetic individuals, mild glucose decrements alter brain activity in regions linked to reward, motivation, and executive control. Whether these effects differ in type 1 diabetes mellitus T1DM patients with and without hypoglycemia awareness remains unclear.

Mild hypoglycemia in HC subjects altered activity in the caudate, insula, prefrontal cortex, and angular gyrus, whereas T1DM-Aware subjects showed no caudate and insula changes, but showed altered activation patterns in the prefrontal cortex and angular gyrus.

Most strikingly, in direct contrast to HC and T1DM-Aware subjects, T1DM-Unaware subjects failed to show any hypoglycemia-induced changes in brain activity. These findings were also associated with blunted hormonal counterregulatory responses and hypoglycemia symptom scores during mild hypoglycemia.

In T1DM, and in particular T1DM-Unaware patients, there is a progressive blunting of brain responses in cortico-striatal and fronto-parietal neurocircuits in response to mild-moderate hypoglycemia. These findings have implications for understanding why individuals with impaired hypoglycemia awareness fail to respond appropriately to falling blood glucose levels.

This study was supported in part by NIH grants R01DK, P30 DK, K23DK, K08AA The Yale Center for Clinical Investigation is supported by an NIH Clinical Translational Science Award UL1 RR Patients with type 1 diabetes mellitus T1DM have long been constrained by the adverse effects of insulin-induced hypoglycemia.

The Diabetes Control and Complications Trial DCCT established the benefits of restoring mean blood glucose to near-normal levels in patients with T1DM, and while this has produced clear benefits in terms of the microvascular and macrovascular complications of T1DM, for many individuals, the widespread use of intensified insulin therapy has resulted in a much higher rate of severe hypoglycemia 1.

Frequent episodes of hypoglycemia can lead to hypoglycemia unawareness, which prevents patients from taking corrective action by eating. Thus, for many T1DM patients the immediate fear of hypoglycemia exceeds the fear of long-term complications 2 , 3.

In nondiabetic subjects, hypoglycemia is rare because, in response to falling blood glucose levels, an integrated physiologic response is triggered that suppresses endogenous insulin secretion, increases release of counterregulatory hormones, and provokes awareness of hypoglycemia, which act together to rapidly restore euglycemia by stimulating glucose production and food consumption.

We have previously reported using the glucose clamp technique together with functional magnetic resonance fMRI imaging, visual food cues, and behavioral measures that brain regions involved in stimulating motivation to eat are exquisitely sensitive to small reductions in glucose.

In T1DM, this critical hypoglycemia defense system may be interrupted at every level. Loss of endogenous insulin and reliance on peripheral exogenous hormone delivery make rapid insulin reductions impossible. β Cell destruction is also linked to loss of glucagon responses to hypoglycemia, a defect that develops in nearly all T1DM patients 6 , 7.

As a result, T1DM patients are particularly vulnerable to impairments in epinephrine release, which commonly follows iatrogenic insulin-induced hypoglycemia 8 — Frequent episodes of hypoglycemia in T1DM individuals commonly lead to hypoglycemia-associated autonomic failure HAAF , whereby significantly lower blood glucose levels are required to elicit a counterregulatory hormonal response as well as symptomatic awareness of hypoglycemia 2 , 3 , 9.

Whether loss of hypoglycemia awareness is also accompanied by a failure to activate the drive to eat, which is clinically the most effective way to reverse hypoglycemia, remains unknown. A study using fMRI reported that functional connectivity in brain regions that have been implicated in the control of feeding behavior including the basal ganglia, insula, and prefrontal cortex are altered in individuals with T1DM However, this study did not examine the specific effects of HAAF and hypoglycemia unawareness on brain activity.

Another study in a small number of individuals with T1DM who were both aware or unaware of hypoglycemia using [ 18 F]fluorodeoxyglucose FDG PET scanning suggested that acute hypoglycemia may increase ventral striatum FDG uptake and that a small diminution of this response may have occurred in unaware patients However, FDG uptake may not accurately reflect glucose uptake during hypoglycemia, since acute hypoglycemia and likely antecedent hypoglycemia alters the lumped constant used to calculate glucose uptake Therefore, in this study, we specifically sought to determine how T1DM individuals with or without hypoglycemia unawareness respond to milder degrees of hypoglycemia in an effort to more effectively distinguish the CNS defects at an earlier time point leading to unawareness in the course of developing moderate-severe hypoglycemia.

Thirteen HC individuals, 16 T1DM-Aware individuals as assessed by the Clarke score 14 , and 13 T1DM-Unaware individuals participated in this study.

Demographic and clinical characteristics are presented in Table 1. Compared with HC individuals, both T1DM-Aware individuals and T1DM-Unaware individuals were similar in age, gender, and education. Both T1DM-Aware and T1DM-Unaware groups were indistinguishable in terms of percentage glycated hemoglobin HbA1c , and there were no differences across all 3 groups for gender and education as well as measures of disordered eating and cognitive function Table 1.

As seen in Figure 1B , both groups of individuals with T1DM had modestly higher blood glucose levels at the beginning of the study compared with HC subjects. However, using repeated-measures linear regression analysis and adjusting for age, BMI, and gender, there were no overall differences in plasma glucose levels during the course of the study between T1DM-Aware and T1DM-Unaware subjects least squares mean 5.

Notably, during the times of fMRI blood oxygen level—dependent BOLD data acquisition euglycemia at 45—60 minutes and hypoglycemia at 90— minutes , plasma glucose levels were virtually identical across all 3 groups and were at target mean plasma glucose at euglycemia T1DM-Aware 8. T1DM-Unaware 7.

T1DM-Aware 6. T1DM-Unaware 4. Study design. A Schematic representation of 2-step hyperinsulinemic euglycemic-hypoglycemia clamp during fMRI BOLD scanning in response to visual cues.

Data presented as the mean ± SEM. Statistical comparisons were performed using mixed-model linear regression adjusting for age, gender, and BMI. Mean plasma epinephrine, norepinephrine, glucagon, and cortisol levels at euglycemia and hypoglycemia are shown in Figure 2.

Notably, plasma epinephrine levels rose significantly in response to hypoglycemia in all 3 groups. HC and T1DM-Aware subjects had a nearly 3-fold increase in epinephrine levels, whereas T1DM-Unaware individuals had a much more modest response, i.

In contrast, only the HCs had a significant increase in plasma glucagon and cortisol during the hypoglycemic phase of the study. No significant changes in plasma norepinephrine were detected in the 3 groups during this relatively mild hypoglycemic stimulus.

A Epinephrine, B norepinephrine, C glucagon, D cortisol. Open bars denote euglycemia, black bars denote hypoglycemia. Euglycemia values were averaged from those obtained at 45—60 minutes of clamp. Hypoglycemia values were averaged from those obtained at 90— minutes of clamp. While in the scanner and prior to the fMRI BOLD acquisitions at 30 and 75 minutes , participants were asked to rate their symptoms of hypoglycemia using the Edinburgh hypoglycemia score Both T1DM-Aware and HC subjects exhibited a statistically significant increase in symptom response during hypoglycemia, whereas there was no significant change in symptoms in the T1DM-Unaware group Figure 3.

Interestingly, hypoglycemia symptoms were different across groups during hypoglycemia HC, As a result, all fMRI-based analyses were run with and without this participant.

Given that there were no significant changes in the results, this participant was included in all subsequent analyses. Symptoms of hypoglycemia from the Edinburgh hypoglycemia symptom score were administered on a Likert scale 1 — 7 and results were summed.

Overall relationship between groups and glycemia group × condition effects. To give a sense of directionality of change, a region of interest was defined from the significant cluster in the right caudate and mean general linear model GLM β-weights were extracted for each subject.

In response to hypoglycemia, HC subjects had relatively decreased activity in the caudate, whereas T1DM-Aware and T1DM-Unaware individuals had minimal changes Figure 4B. Thus, all analyses using all 3 groups were collapsed across tasks visual food and non-food cues. Furthermore, although all 3 groups had similar plasma glucose levels by 20 minutes prior to the time of BOLD acquisitions, the T1DM-Aware group had higher plasma glucose levels at the start of the clamps.

To assess whether these differences in starting glucose levels affected brain activity during euglycemia BOLD acquisitions ~45 minutes later , we assessed across-group and between-group interactions at euglycemia alone and found no significant differences.

Group × glycemia effects. B Region of interest ROI identified from significant cluster in right striatum caudate. The HC, T1DM-Aware, and T1DM-Unaware subjects had strikingly different patterns of brain responses to mild hypoglycemia, even after adjusting for age and BMI.

In contrast, while the T1DM-Aware individuals also had relatively decreased activity in the vmPFC and OFC, they did not have any significant differences in activity in the caudate, insula, or dlPFC. Interestingly, the T1DM-Aware individuals had relatively increased activity in the inferior parietal lobe, particularly the right angular gyrus as well as the right vlPFC.

In contrast, T1DM-Unaware individuals showed no significant changes in brain activity in any of the regions that were different among the other 2 groups.

Differences in regional brain responses between mild hypoglycemia and euglycemia conditions. Given that changes in plasma epinephrine levels are believed to be a particularly sensitive marker for defective counterregulation among T1DM individuals, we assessed the relationship between changes in plasma epinephrine levels and changes in brain responses in the regions identified in Figure 5.

There were no associations between brain activity in any of the above regions and epinephrine levels at euglycemia or hypoglycemia alone. This interaction was not present under non-food visual stimuli conditions. Notably, T1DM-Aware individuals had a significant decrease in brain activity during high-calorie food in the medial OFC Brodmann area 11 , while T1DM-Unaware individuals showed no statistically significant change in brain activity in this region Figure 6.

There were no significant correlations between brain activity in this region and counterregulatory hormones.

Brain responses to high-calorie food cues. Moreover, the pattern of loss of brain responses appears to involve cortico-striatal and fronto-parietal neurocircuits that are known to play important roles in regulating motivation and goal-directed behavior as well as attention, and thus are likely to have implications for understanding why individuals with hypoglycemia unawareness fail to respond appropriately to falling blood glucose levels.

The basal ganglia, and in particular the caudate, has been consistently shown in studies across species and imaging modalities to play an important role in the ability to respond appropriately to environmental changes and to regulate goal-directed behavioral inputs 17 — The caudate has direct physical and functional connections with executive control regions in the frontal cortex including the medial, ventral, and dorsolateral PFC 22 , Among HC individuals, mild hypoglycemia was sufficient to elicit changes in the caudate, cortical regions such as the vmPFC and vlPFC, and the insula, which is consistent with previous studies that have shown that the caudate, PFC, and insula are responsive to changes in circulating glucose levels 5 , 12 , 24 , In contrast, T1DM-Aware individuals had altered patterns of cortico-striatal activity with no significant changes in the caudate or insula during hypoglycemia.

The angular gyrus, located in the inferior parietal lobe, has direct projections to the dlPFC 26 and together they are part of a larger, well-studied, fronto-parietal circuit 27 — In contrast, T1DM-Aware individuals had no brain responses in the left dlPFC or left angular gyrus, but instead showed markedly increased activity in the right angular gyrus.

The markedly increased angular gyrus activity seen in the T1DM-Aware group during mild hypoglycemia may reflect differences in attention to or sensing of the stimulus Thus, the T1DM-Aware individuals may have heightened awareness to hypoglycemia sensory inputs compared with HC subjects, which would be consistent with their higher reported ratings of hypoglycemia symptoms both at euglycemia and at hypoglycemia.

Most strikingly, compared with T1DM-Aware and HC subjects, the T1DM-Unaware participants showed virtually no changes in brain activity in response to mild hypoglycemia. Very little is known about the impact of hypoglycemia unawareness on regional brain responses; however, these findings would be consistent with the blunted symptom scores as well as the blunted counterregulatory hormone responses to hypoglycemia observed in the T1DM-Unaware group.

The underlying mechanism mediating the lack of change among the T1DM-Unaware individuals remains uncertain; however, it is likely due to brain adaptations to frequent episodes of severe hypoglycemia in the preceding year of the study.

Recurrent hypoglycemia alters brain glucose transport kinetics as well as promotes increased utilization of alternate fuels such as monocarboxylic acids lactate, ketones, and acetate in humans when the availability of glucose diminishes 36 , Furthermore, T1DM individuals with hypoglycemia unawareness may have alterations in cerebral blood flow during hypoglycemia 38 , 39 , which may also affect BOLD signal.

Interestingly, a recent study has reported that individuals with T1DM and hypoglycemia unawareness have increased cerebral blood flow during acute hypoglycemia compared with T1DM-Aware and HC subjects The current findings would be consistent with these observations that the brain adapts to ensure sufficient substrate glucose delivery to the brain.

In keeping with these human studies, data in rodents have also demonstrated that prior exposure to hypoglycemia induces upregulation of blood-brain-barrier glucose transport, leading to more efficient glucose utilization during hypoglycemia 40 , Thus, the lack of change in brain activity among T1DM-Unaware individuals in response to mild hypoglycemia may be the culmination of a variety of adaptive changes in cerebral blood flow, glucose transport, cerebral glucose metabolism, or some combination of each of these factors.

It is important to note that induction of hypoglycemia results in a series of dynamic changes in brain activation and deactivation, and thus time intervals when the scans are acquired over the course of hypoglycemia may directly impact the directionality and regional changes observed This, as well as other factors such as hypoglycemia target, timing of image acquisition, and imaging modality, may all contribute to the heterogeneity of brain responses to hypoglycemia previously reported in the literature.

For example, we did not observe hypoglycemia-induced changes in the hypothalamus, which has been reported by some groups 25 , but not others 42 to be altered during hypoglycemia in T1DM individuals.

Thus, our findings must be interpreted cautiously given that we are only observing a snapshot of the dynamic brain changes produced over the course of falling blood glucose levels, a critical time for prevention of hypoglycemia-induced brain injury.

Importantly, it remains uncertain whether lower glycemic thresholds will be able to elicit changes in brain activation responses among T1DM-Unaware individuals and whether the brain responses will be in a similar pattern to that observed among T1DM-Aware individuals.

However, it remains uncertain whether lower glucose thresholds are the only difference between T1DM-Aware and -Unaware individuals. Furthermore, whether these changes are reversible and whether strict avoidance of hypoglycemia can restore brain responses remains to be assessed.

Of note, prior studies using strict avoidance of hypoglycemia have also resulted in worsening of glycemic control 44 — 46 , which could also have an impact on glucose transport capacity into the brain.

Among nondiabetic individuals, high-calorie food cues have been shown to elicit robust changes in brain activity in reward, motivation, and executive control regions during both euglycemia 47 and mild hypoglycemia 5.

Consistent with these findings reported in nondiabetic individuals, the current data demonstrate that T1DM-Aware individuals also had a pronounced change in the medial OFC when viewing high-calorie food cues that was not present when looking at pictures of non-food objects.

Notably, the medial OFC plays an important role in reward-guided decision making 48 , Furthermore, because it has dense direct connections with the hypothalamus 50 , 51 , it has been shown to play a particularly important role in regulating feeding behavior 52 — Thus, it is particularly noteworthy that in contrast to T1DM-Aware individuals, high-calorie food cues had no effect on medial OFC brain activity during mild hypoglycemia in T1DM-Unaware individuals, suggesting a diminished drive to eat, which may be a critical early defect in the defense against hypoglycemia.

Interestingly, we found no relationship between changes in brain activity to high-calorie foods and the counterregulatory hormone response. Whether the lack of brain response is due to intrinsic CNS differences or secondary to the blunted rise in circulating counterregulatory hormone levels remains unclear and further studies will be needed to address this question and prove causality.

However, given that in nondiabetic subjects changes in brain activity induce and occur prior to changes in counterregulatory hormones 4 , it is likely that changes in brain activity are not primarily driven by the counterregulatory response, but rather play the key role in protecting the brain by initiating appropriate defenses against falling glucose levels.

Prior studies have also noted a dissociation between counterregulatory hormone responses and awareness of hypoglycemia It is noteworthy that there are some considerations and limitations to the current study. While we defined our groups using widely accepted and validated questionnaires for hypoglycemia unawareness, the Clarke and Gold scores, these are subjective reports and we did not collect data on glycemic variability and objective rates of hypoglycemia in the months preceding our studies.

In addition, our T1DM-Unaware participants were approximately 10 years older and had diabetes for a longer duration than the T1DM-Aware group. Although we covaried for age, BMI, and duration of diabetes, our findings among the T1DM-Unaware individuals should still be interpreted cautiously with recognition that it may be very difficult experimentally to separate the effects of age and longer duration of T1DM from the effects of hypoglycemia unawareness itself.

Of note in this regard, increasing age has been associated with increases in baseline epinephrine levels 55 and our T1DM-Unaware cohort was slightly older and had higher baseline epinephrine levels; however, we did not observe any relationships between epinephrine levels at euglycemia or hypoglycemia and brain responses.

Furthermore, prior studies have examined the effects of age on counterregulatory responses to hypoglycemia among nondiabetic individuals. In these studies, where the mean age of the older groups was markedly older than our cohort age 60—70s , they found modest 55 or no 56 differences in counterregulatory responses to hypoglycemia.

It is also noteworthy that increased age and duration of diabetes may be associated with cerebrovascular dysfunction. Increased presence of cerebral small vessel disease such as white matter hyperintensities and lacunes have been reported among individuals with T1DM mean age 50 years 57 , 58 ; however, other studies among older T1DM patients mean age ~60 years and with known microvascular complications 59 have reported no significant differences in white matter lesions or microinfarcts compared with control subjects.

While we cannot exclude the possibility that occult cerebrovascular disease may also contribute to the differences observed in the T1DM-Unaware individuals, this appears less likely given our participants had well-controlled diabetes, had no history of cerebrovascular disease or cardiovascular disease, and were significantly younger mean age 30 and 40 years for T1DM-Aware and -Unaware, respectively than the groups reported in the literature.

Finally, even though our study includes larger numbers of T1DM-Aware and T1DM-Unaware participants than prior fMRI-based studies investigating hypoglycemia unawareness, our sample sizes remain a limitation. To minimize the risk of false positives, we used a P -value threshold of less than 0.

Currently, best practice guidelines for conducting fMRI based studies typically recommend at least 20 subjects per group to minimize false positives 60 ; however, these recommendations may not be directly applicable to studies among relatively rare disease groups such as individuals with T1DM and hypoglycemia unawareness or in study designs using highly controlled physiologic manipulations such as in a 2-step euglycemic-hypoglycemic clamp where individuals are compared to themselves at 2 well-defined, but different states.

Top bar navigation Interviewer: Dental crowns diabetics experience dangerous fluctuations in blood sugar levels Probiotics for pets the problem is compounded Hypoglyfemic what they don't even resexrch it's Ujawareness. Anawalt, M. However, T1DM patients with hypoglycemia unawareness fail to respond acutely to mild hypoglycemia in cortico-striatal and fronto-parietal brain regions. NIH support DK, DK to SF, DK to YL, TL1TR to MD, as well as support from the University of Kentucky Barnstable Brown Diabetes Center and the Diabetes and Obesity Research Priority Area. Robertson, R. Google Scholar. Diabetes Care ;—7.
Hypoglycemic Counterregulation However, using Citrus aurantium dosage linear regression analysis and adjusting for age, Hypogljcemic and gender, there resezrch no overall differences in resfarch glucose levels researcu the course of the Hypoglcemic Hypoglycemic unawareness research T1DM-Aware and T1DM-Unaware subjects least squares mean 5. Emergency management of high blood sugar : Unawarsness and neuroglycopenic Dental crowns are present. Effects of low and moderate antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes. Search Dropdown Menu. Davis TM, Brown SG, Jacobs IG, et al. Furthermore, because it has dense direct connections with the hypothalamus 5051it has been shown to play a particularly important role in regulating feeding behavior 52 — In the first 48 to 72 hours after a low blood glucose episode, you may have difficulty recognizing the symptoms of low blood glucose.
Key Messages Announcer: Interesting, informative, and all in the name of better health. Effectiveness-implementation hybrid type 2 trial evaluating two psychoeducational programmes for severe hypoglycaemia in type 1 diabetes: implementation study protocol. Thus, the lack of change in brain activity among T1DM-Unaware individuals in response to mild hypoglycemia may be the culmination of a variety of adaptive changes in cerebral blood flow, glucose transport, cerebral glucose metabolism, or some combination of each of these factors. While formoterol and miglitol improved counterregulation and hepatic glucose production of HAAF, awareness was not assessed in those studies and the effects of those drugs on IAH remain unknown. As previously noted,insulin-induced antecedent hypoglycemia is a strong predictor of subsequent hypoglycemia unawareness.
Hypoglycemic unawareness research

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What should I do with hypoglycemia unawareness?

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