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Themes: The clinical perspective

A Blow to the Brain

Impaired awareness of hypoglycaemia (IAH) is a common, frustrating, and potentially dangerous problem for people with diabetes who use insulin. While researchers have yet to unravel the physiological underpinnings of IAH, neuroimaging studies have shed light on how the brain responds to hypoglycaemia—and how these responses may change as IAH sets in. In this article, two internationally recognized experts on the physiology and psychology of IAH review some of the patterns identified in neuroimaging studies and suggest how this knowledge could help lift hypoglycaemia’s clinical burden.

Neuroimaging studies are helping us understand how impaired awareness of hypoglycaemia affects the brain—and mind

Habituation is a physiological blunting process that occurs in response to repeated stimuli. Hypoglycaemia offers a case in point. Normally, the body and brain mount a strong counterregulatory response to a falling blood glucose that helps preserve glucose levels; however, recurrent episodes of hypoglycaemia may blunt this response on various levels, with the result that the affected person does not experience the expected warning signals in a timely fashion. This phenomenon, known as impaired awareness of hypoglycaemia (IAH), affects about a quarter of people with type 1 diabetes and 10% of those with type 2 diabetes who use insulin.

The brain’s responses to hypoglycaemia serve the adaptive purpose of preserving brain function and protecting the brain against structural damage. The progressive loss of awareness, however, is maladaptive in that it impairs the affected person’s ability to self-treat, thus raising the risk that the hypoglycaemia will become severe.

The hypoglycaemic brain in action

While the pathophysiology of IAH remains unclear, the science of neuroimaging offers intriguing clues. The technology identifies brain regions that become active in response to a stimulus, using a variety of markers—such as localized changes in blood flow or metabolic rate—to detect changes in brain activity. When studied in the context of hypoglycaemic stress, neuroimaging can help us understand some of the brain changes accompanying IAH and help us devise better ways of managing the problem.

In individuals without diabetes, experimentally-induced hypoglycaemia causes several regions of the brain to become active, including the basal ganglia, hypothalamus, pituitary, thalamus, and parts of the frontal cortex. Other regions, especially those involved in forming memories, may become deactivated. Neuroimaging studies have found these responses to differ in people with type 1 diabetes and between those with and without IAH.

In a study of men with type 1 diabetes, for example, subjects with IAH showed subtle differences not only in regions associated with the awareness of physiological responses to hypoglycaemia, but in regions associated with executive control, reward, memory, and emotional significance.1 In addition, differences in operculum activation in the IAH group raised the possibility that this group may be less driven to eat than those with intact awareness of hypoglycaemia.1

Another study involving people with type 1 diabetes found even more striking discrepancies: those with preserved awareness of hypoglycaemia showed changes in prefrontal cortex and angular gyrus activity in response to mild hypoglycaemia, but those with IAH failed to show any such changes.2

These alterations in neural activity have metabolic correlates. In one study, subjects with IAH showed increases in global cerebral blood flow compared to those without IAH and to healthy controls.3 The researchers speculated that “an increase in global cerebral blood flow may enhance nutrient supply to the brain, hence suppressing symptomatic awareness of hypoglycemia.”3 Another study saw brain levels of the non-glucose metabolic fuel lactate fall by about 20% in subjects with IAH—but not in those with normal awareness of hypoglycaemia and people without diabetes.4

Inside the patient’s head

Taken together, findings from neuroimaging studies underscore the fact that the experience of IAH goes beyond reduced awareness of symptoms. Affected individuals fail to perceive their condition as unpleasant or dangerous and lack the motivation to treat it. They may also fail to create normal memories of these incidents. These aberrations may prevent patients from engaging in healthy behaviours to avoid hypoglycaemia in the future, thus exacerbating and perpetuating the problem.

Strategies to help people with IAH “override” the perceptual distortions experienced in IAH may be the most effective clinical approach to reducing the occurrence of IAH and of hypoglycaemia itself. As a successful example, a pilot intervention targeting motivation and cognitions in people with resistant IAH (called DAFNE-HART) significantly improved hypoglycaemia awareness,5 supporting the hypothesis that problematic perceptions are key in persistent IAH.


  1. Dunn JT et al. The impact of hypoglycaemia awareness status on regional brain responses to acute hypoglycaemia in men with type 1 diabetes. Diabetologia 2018; 61:1676–87.
  2. Hwang JJ et al. Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia. J Clin Invest 2018; 128:1485-95.
  3. Wiegers EC et al. Cerebral blood flow response to hypoglycemia is altered in patients with type 1 diabetes and impaired awareness of hypoglycemia. J Cereb Blood Flow Metab 2017; 37:1994-2001.
  4. Wiegers EC et al. Brain Lactate concentration falls in response to hypoglycemia in patients with type 1 diabetes and impaired awareness of hypoglycemia. Diabetes 2016; 65:1601-5.
  5. de Zoysa N et al. A psychoeducational program to restore hypoglycemia awareness: the DAFNE-HART pilot study. Diabetes Care 2014;37:863-6.

Tailored Targets – When to loosen the reins on glucose control

Tight glucose control improves clinical outcomes. While this evidence-based principle continues to guide diabetes management, the truth is not so simple.

Some people with type 2 diabetes may reach glucose targets through lifestyle modification alone, especially in the early years after diagnosis. Diabetes being a progressive disease, however, most of these patients come to rely on glucose-lowering medications, as do all patients witih type 1 diabetes. Some of these medications—especially insulin—incur a substantial risk of hypoglycaemia and its potentially serious consequences. For certain populations, a slavish adherence to strict glucose targets may cause more harm than good and may thus constitute overtreatment.

The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recognized the need to individualize glucose targets in a 2012 joint position statement. The authors of the document maintained that glucose targets “should be considered within the context of the needs, preferences, and tolerances of each patient and that “individualization of treatment is the cornerstone of success.”1

In my experience, however, time pressures and other barriers—especially in busy practices with patients presenting with multimorbid conditions—make it a challenge to individualize therapy. At worst, therapeutic inertia may set in and obscure patients’ changing needs.

Vulnerable populations

When setting glucose targets, factors to consider include age, disease duration, risk of hypoglycaemia and chronic comorbidities. Tight glucose control tends to increase the risk of hypoglycaemia, and recent studies suggest that older adults, in particular, incur significant risks from hypoglycaemic episodes. Indeed, hypoglycaemia accounts for more hospitalizations than hyperglycaemia in older US adults receiving Medicare.2 

Despite this very real risk, older people are often encouraged to pursue the same targets as their younger counterparts. In a cross-sectional analysis of over 1,000 subjects with diabetes from the National Health and Nutrition Examination Survey (NHANES), the proportion with a HbA1C less than 7% did not differ based on health status.2 Similarly, health status did not have a bearing on the proportion being treated with insulin or sulfonylureas—medications associated with hypoglycaemia.2

Patients with recurrent hypoglycaemia constitute an especially vulnerable group. Repeated hypoglycaemic episodes promote impaired awareness of hypoglycaemia (IAH), a condition characterized by lack of subjectively perceived hypoglycaemia symptoms. In a study of 153 unselected patients with type 1 diabetes, asymptomatic hypoglycaemic events were tightly correlated with the risk of severe hypoglycaemia, indicating that this group of patients merits particular consideration in clinical practice.3

Patient preferences and attitudes also come into play. In a study estimating the effect of HbA1C reduction on diabetes outcomes and quality-adjusted life years (QALYs), investigators concluded that for most patients over 50 with a HbA1C below 9% on metformin, further glycaemic treatment offers only modest benefits, which are contingent on patient perceptions of the treatment burden.4 By the same token, even small adverse treatment effects may result in net harm in this group.4

My own practice includes nurse practitioners who have more time to spend with patients and who take a holistic approach that considers not just target HbA1c, but patient circumstances and preferences. I have found this approach to support patient motivation and adherence.

A patient-centred approach

Despite the evidence and guideline recommendations for glucose targets, many clinicians delay treatment intensification, resulting in suboptimal glucose control.5 At the other end of the spectrum are those patients being treated to lower targets than required. When individualizing therapy, clinicians need to take into account the risks of hypoglycaemia in groups such as the elderly, the frail, those with IAH, and those with chronic co-morbidities. Patient preferences and quality-of-life issues must also be given reasonable consideration.6

Health providers who manage patients with diabetes need to know not only when to escalate therapy but also to recognize those patients who will get more harm than benefits from tight glucose control. Failure to de-intensify therapy in these patients is as much a form of “therapeutic inertia” as failure to intensify therapy.7 Clinician awareness and education can help counter these tendencies.


  1. Inzucchi SE et al. ADA/EASD Position Statement. Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach. Diabetes Care 2012; 35:1364-1379.
  2. Lipska KJ et al. Potential overtreatment of diabetes mellitus in older adults with tight glycemic control. JAMA Intern Med 2015;175:356-62.
  3. Henriksen MM et al. Hypoglycemic Exposure and Risk of Asymptomatic Hypoglycemia in Type 1 Diabetes assessed by Continuous Glucose Monitoring. J Clin Endocrinol Metab 2018 Mar 29. doi: 10.1210/jc.2018-00142.
    [Epub ahead of print]
  5. Vijan S et al. Effect of patients’ risks and preferences on health gains with plasma glucose level lowering in type 2 diabetes mellitus. JAMA Intern Med 2014;174:1227–34.
  6. Khunti K et al. Clinical Inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes Care 2013; 36:3411-17.
  7. Sleath JD. In pursuit of normoglycaemia: the overtreatment of type 2 diabetes in general practice. Br J Gen Pract 2015;65:334-35.
  8. Khunti K, Davies MJ. Clinical inertia—Time to reappraise the terminology? Primary Care Diabetes 2017; 11:105-6.