Dr.Almoutaz Alkhier Ahmed,
Diabetologist
Gurayat Diabetes Center
Gurayat North, Saudi Arabia
P.O.Box 672
Email :khier2@yahoo.com

Hypoglycemia is feared by many patients not only because of the associated physical discomfort but mainly because of the risk of cognitive function deterioration that may lead to loss of personal control and adequate conscious behavior and eventually to coma.

Iatrogenic hypoglycemia has been described ever since the introduction of insulin therapy (1) especially among those attempting to optimize glycemic control (2). Many studies such as DCCT (3) and UKPDS (4) have established the reverse relationship between HbA1c and risk for hypoglycemic events. In the DCCT, the rate of severe hyperglycemia increased from 20 episodes/100 patients/year to 60 episode/100 patients/year during intensified treatment (3).

Role of insulin in risk of hypoglycemia (5) (6):
The normal insulin goes through the following manner illustrated in Figure 1:

Figure 1: The insulin's pathway in case of normal secreted insulin

Under physiological conditions, a considerable part of the secreted insulin is degraded by the liver and the remaining part reaches the peripheral tissues to exert its action. When the insulin is injected into subcutaneous tissue, it reaches the circulation directly and bypasses the liver, so most of the injected amount of insulin will reach the peripheral tissues. With injection of insulin the possibility of hypoglycemic episodes usually will be increased.

Normal glucose counter-regulation:
Glucose homeostasis is based on the equilibrium between insulin and glucagon and other counter-regularity hormones (Figure 2).

Figure 2: Glucose homeostasis
FBG= Fasting Blood Glucose, 2hPPBG=2 hours Post Prandial Blood Glucose,
RBG=Random Blood Glucose

Glucose counter-regulation in diabetes:
In type 1 diabetes, loss of insulin triggering to alpha cells in the pancreas make patients unable to use this line of defense when there is decrease in glucose level. So, hypoglycemia usually fails to trigger glucagons responses in type 1 diabetes within years after diagnosis.

Therefore hypoglycemia usually fails to trigger glucagon responses in type 1 diabetes within years after diagnosis. When glucagon responses to hypoglycemia are deficient, adrenalin and autonomic warning symptoms become critical for the integrity of glucose counter-regulation.

Iatrogenic hypoglycemia however attenuates magnitude of adrenaline and autonomic symptoms responses to a subsequent hypoglycemic episode through:

- Shifts the glycemic threshold for these responses to lower levels of glycemia (7)
- Impairs hypoglycemic perceptibility clinically (8)
- Possibly reduces beta adrenergic sensitivity (9)

Any hypoglycemia whether mild, asymptomatic (10), nocturnal (11) or brief (12) can provoke this phenomenon and at the end worsening counter-regulation and recurrent hypoglycemia may ultimately lead to hypoglycemia unawareness.

So, hypoglycemia unawareness is defined as onset of neuroglycopenia before the appearance of autonomic warning symptoms and typified clinically by the inability to perceive hypoglycemia by symptoms.

Various terms are used for the combination of defective hormonal counter-regulation and hypoglycemia unawareness such as counter-regulatory failure, Hypoglycemia Associated Autonomic Failure (HAAF) and hypoglycemia unawareness syndrome.

Pathogenesis of counter-regulatory failure:
Different hypotheses were postulated by the researchers of this paper to explain the counterregulatory failure:

1) It has been hypothesized that increased cortisol levels during antecedent hypoglycemia could act as mediator to reduce counterregulatory responses to subsequent hypoglycemia (13).

2) Many studies on the pathogenesis of counter-regularity failure have focused on the brain. In humans and rodents, prolonged hyperglycemia was found to increase cerebral glucose uptake. These data lead to the suggestion that recurrent hypoglycemia events preserved or increase brain glucose uptake, thereby shifting hypoglycemic symptoms perception and onset of counter-regulatory responses to lower levels of hypoglycemia (14)

3) Recent antecedent episodes cause alterations in the brain's glucose sensing neurons in the ventromedial hypothalamus that initiate glucose counter-regularity responses. As a result, the onset of counter-regularity responses would then shift to deeper levels of hypoglycemia.

4) Increased glucokinase activity (15), decreased AMP activated PK activity (16), reduced insulin signaling (17) and channel closure (18) have all been suggested as an underlying mechanism but it has not been universally established.

5) Hypoglycemia induced brain metabolism alteration may be involved in the pathogenesis of counter-regulatory defects. Administration of non- glucose substrates for metabolism such as beta hydroxybutarate or lactate during hypoglycemia suppresses counter-regulatory responses (19).

Diagnosis of clinical hypoglycemia unawareness:
Frankly, diagnosis of hypoglycemia unawareness is subject to clinical judgment and there is no specific tool to test for hypoglycemia unawareness.

Clinical signs suggestive of hypoglycemia unawareness include:

- Self reporting of biochemical hypoglycemia unaccompanied by symptoms.
- Loss of autonomic symptoms as initial signs of hypoglycemia
- Recurrent history of severe hypoglycemia
- Reporting lower blood glucose levels are required to elicit symptoms
- Continuous glucose monitoring may help to detect nocturnal or otherwise asymptomatic hypoglycemia

Treatment of hypoglycemia unawareness:

- Reducing hypoglycemic risk factors
- Optimizing insulin treatment
- Pharmacological therapy:
- Alanine to stimulate glucagon response
- Beta2 adrenergic agonist
- Methylxanthine derivative to stimulate CNS
- K channel modulators
- Blood glucose awareness training
- High intensity exercise

In my opinion, the most effective treatment is to decrease the current treatment particularly insulin to avid iatrogenic hypoglycemic attacks. This can be done for 2-3 months before restarting readjustment.