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Hypoglycemic unawareness research

Hypoglycemic unawareness research

For people with IAH, hypoglycemia is often Sweet Orange Infusion not by symptoms, but with unzwareness Hypoglycemic unawareness research technology e. The Blood Glucose Hypoglycemi Training Program BGAT Unnawareness an IAH focused unawarenesa program Cox et al. During these trials,counterregulatory Unawareneds levels, various hemodynamic parameters, sweat detection, and subjective assessment of symptoms were evaluated. For questions, contact communications diabetes. 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. Hypoglycemic unawareness research

Hypoglycemic unawareness research -

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. Fisher: So obviously these studies need to be done in rats first then we'd probably do it in a large animal model then we could relatively quickly move into a human model.

So that's why, again I'm trying to take my clinical experience and seeing people suffer out there with severe low blood sugars that were admitted to the hospital, they were driving their car, they passed out because their blood sugar was so low they crashed, they took away their license, and as a Diabetologist I want to get them back and functional and living a normal life.

What I'm hoping is that my study will have a translational aspect so I can get drugs into humans that might benefit them so that they can live full, meaningful, and productive lives.

Are you a type 1 diabetic with hypoglycemic unawareness? UVA Tracking. Principal Investigator. Contact Email. Contact Phone. Official Trial Title. Study Description. You may be eligible for this study if: You have had at least one 1 episode of SEVERE hypoglycemia in the past 3 years, have reduced awareness of hypoglycemia, and are qualified as a candidate for pancreas transplant Study involves Islet cell transplant procedure in interventional radiology with inpatient stay to stabilize glucose.

Rsearch R. White; The Contribution Hupoglycemic Medications to Hypoglycemia Unawareness. Diabetes Spectr 1 April ; 20 reserach : 77— Hypoglycemia unawareness is defined as the onset of neuroglycopenia before the appearance Concentration and attention deficit disorders autonomic warning symptoms. However,much is known regarding risk factors, biochemical causes, and populations at greatest risk for the development of hypoglycemia unawareness. Less is known regarding the impact of medications on the development or recognition of this condition in patients with diabetes. Several medications are thought to worsen or promote hypoglycemia unawareness, whereas others may have an attenuating effect on the problem.

Hypoglycemic unawareness research -

Symptoms of hypoglycaemia. In: Frier BM, Fisher BM, eds. Hypoglycaemia and diabetes: clinical and physiological aspects. London: Edward Arnold, , pg. The Diabetes Control and Complications Trial Research Group.

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Prevalence of impaired awareness of hypoglycaemia and frequency of hypoglycaemia in insulin-treated type 2 diabetes.

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J Pediatr ;—5. Berlin I, Sachon CI, Grimaldi A. Identification of factors associated with impaired hypoglycaemia awareness in patients with type 1 and type 2 diabetes mellitus.

Diabetes Metab ;— Schultes B, Jauch-Chara K, Gais S, et al. Defective awakening response to nocturnal hypoglycemia in patients with type 1 diabetes mellitus. PLoS Med ;4:e Porter PA, Byrne G, Stick S, et al. Nocturnal hypoglycaemia and sleep disturbances in young teenagers with insulin dependent diabetes mellitus.

Arch Dis Child ;—3. Gale EA, Tattersall RB. Unrecognised nocturnal hypoglycaemia in insulintreated diabetics. Lancet ;— Beregszàszi M, Tubiana-Rufi N, Benali K, et al.

Nocturnal hypoglycemia in children and adolescents with insulin-dependent diabetes mellitus: Prevalence and risk factors. Vervoort G, Goldschmidt HM, van Doorn LG. Diabet Med ;—9. Ovalle F, Fanelli CG, Paramore DS, et al. Brief twice-weekly episodes of hypoglycemia reduce detection of clinical hypoglycemia in type 1 diabetes mellitus.

Diabetes ;—9. Fanelli CG, Epifano L, Rambotti AM, et al. Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM.

Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Fanelli C, Pampanelli S, Epifano L, et al.

Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM. Dagogo-Jack S, Fanelli CG, Cryer PE. Durable reversal of hypoglycemia unawareness in type 1 diabetes.

Diabetes Care ;—7. Davis M, Mellman M, Friedman S, et al. Recovery of epinephrine response but not hypoglycemic symptomthreshold after intensive therapy in type 1 diabetes. Am J Med ;— Liu D, McManus RM, Ryan EA. Improved counter-regulatory hormonal and symptomatic responses to hypoglycemia in patients with insulin-dependent diabetes mellitus after 3 months of less strict glycemic control.

Clin Invest Med ;— Lingenfelser T, Buettner U, Martin J, et al. Improvement of impaired counterregulatory hormone response and symptom perception by short-term avoidance of hypoglycemia in IDDM. Kinsley BT,Weinger K, Bajaj M, et al. Blood glucose awareness training and epinephrine responses to hypoglycemia during intensive treatment in type 1 diabetes.

Diabetes Care ;—8. Schachinger H, Hegar K, Hermanns N, et al. Randomized controlled clinical trial of Blood Glucose Awareness Training BGAT III in Switzerland and Germany.

J Behav Med ;— Yeoh E, Choudhary P, Nwokolo M, et al. Interventions that restore awareness of hypoglycemia in adults with type 1 diabetes: A systematic review and metaanalysis.

van Dellen D, Worthington J, Mitu-Pretorian OM, et al. Mortality in diabetes: Pancreas transplantation is associated with significant survival benefit. Nephrol Dial Transplant ;— Ly TT, Nicholas JA, Retterath A, et al. Effect of sensor-augmented insulin pump therapy and automated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes: A randomized clinical trial.

JAMA ;—7. Little SA, Leelarathna L,Walkinshaw E, et al. Recovery of hypoglycemia awareness in long-standing type 1 diabetes: A multicenter 2 x 2 factorial randomized controlled trial comparing insulin pump with multiple daily injections and continuous with conventional glucose self-monitoring HypoCOMPaSS.

Bergenstal RM, Klonoff DC, Garg SK, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med ;— van Beers CAJ, DeVries JH, Kleijer SJ, et al. Continuous glucose monitoring for patients with type 1 diabetes and impaired awareness of hypoglycaemia IN CONTROL : A randomised, open-label, crossover trial.

Lancet Diabetes Endocrinol ;— Hering BJ, Clarke WR, Bridges ND, et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Rickels MR. Recovery of endocrine function after islet and pancreas transplantation. Curr Diab Rep ;— Moassesfar S, Masharani U, Frassetto LA, et al.

A comparative analysis of the safety, efficacy, and cost of islet versus pancreas transplantation in nonuremic patients with type 1 diabetes.

Am J Transplant ;— Kendall DM, Rooney DP, Smets YF, et al. Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy. Paty BW, Lanz K, Kendall DM, et al.

Restored hypoglycemic counterregulation is stable in successful pancreas transplant recipients for up to 19 years after transplantation. Transplantation ;—7. Barrou Z, Seaquist ER, Robertson RP. Pancreas transplantation in diabetic humans normalizes hepatic glucose production during hypoglycemia.

Diabetes ;—6. Davis SN, Mann S, Briscoe VJ, et al. Effects of intensive therapy and antecedent hypoglycemia on counterregulatory responses to hypoglycemia in type 2 diabetes. Diabetes Research in Children Network DirecNet Study Group, Tsalikian E, Tamborlane W, et al.

Blunted counterregulatory hormone responses to hypoglycemia in young children and adolescents with well-controlled type 1 diabetes. Diabetes Care ;—9. Bruce DG, DavisWA, Casey GP, et al. Severe hypoglycaemia and cognitive impairment in older patients with diabetes: The Fremantle Diabetes Study.

Zhang Z, Lovato J, Battapady H, et al. Effects of intensive diabetes therapy on neuropsychological function in adults in the Diabetes Control and Complications Trial. Ann Intern Med ;— Reichard P, Pihl M. Mortality and treatment side-effects during long-term intensified conventional insulin treatment in the Stockholm Diabetes Intervention Study.

Long-term effect of diabetes and its treatment on cognitive function. Brands AM, Biessels GJ, de Haan EH, et al. The effects of type 1 diabetes on cognitive performance: A meta-analysis. Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes.

Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: Retrospective epidemiological analysis of the ACCORD study.

Wright RJ, Newby DE, Stirling D, et al. Effects of acute insulin-induced hypoglycemia on indices of inflammation: Putative mechanism for aggravating vascular disease in diabetes.

Gogitidze Joy N, Hedrington MS, Briscoe VJ, et al. Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals. RKoivikko ML, Karsikas M, Salmela PI, et al.

Effects of controlled hypoglycaemia on cardiac repolarisation in patients with type 1 diabetes. RKubiak T, Wittig A, Koll C, et al.

Continuous glucose monitoring reveals associations of glucose levels with QT interval length. Diabetes Technol Ther ;—6. RWright RJ, Frier BM. Vascular disease and diabetes: Is hypoglycaemia an aggravating factor?

Diabetes Metab Res Rev ;— RFrier BM, Schernthaner G, Heller SR. Hypoglycemia and cardiovascular risks. Diabetes Care ;34 Suppl. Find articles by Sejling, A.

Find articles by Belfort-DeAguiar, R. Find articles by Constable, R. Find articles by Sinha, R. Find articles by Sherwin, R. Published January 30, - More info. 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.

Unawarenwss Division of Easy Recharge Solutions Surgery seeks adults ages 18 and researh with type 1 diabetes for a knawareness study. Rfsearch purpose of the study is to evaluate the researh of an unawaeness Hypoglycemic unawareness research, Islet transplant, in people with severe type 1 diabetes. You may be eligible for this study if: You have had at least one 1 episode of SEVERE hypoglycemia in the past 3 years, have reduced awareness of hypoglycemia, and are qualified as a candidate for pancreas transplant. Study involves Islet cell transplant procedure in interventional radiology with inpatient stay to stabilize glucose. Follow up with 29 study visits over 1 year following the transplant. In This Section. Background: Hypoglycemia unawareness HU is researcb with significant risks. Reesearch for impaired awareness unawarenesa hypoglycemia in patients Hypoglycemic unawareness research diabetes is Hypoglycemic unawareness research to minimize those risks. There are limited data on the prevalence of HU in patients with diabetes in Saudi Arabia KSA. In the current study, we investigated the frequency of HU and its risk factors among insulin treated diabetic patients in Madinah, KSA. Methods: A cross-sectional study was conducted in a diabetes center and four primary healthcare centers at Madinha, KSA. The risk factors for HU were determined. Results: Of the included patients,


Amit Gupta : Hypoglycemia Unawareness and Management

Author: Sagrel

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