Diabetes Management
Figure 1: Glycemic Thresholds for Secretion of Counter-regulatory Hormones and Onset of Physiological, Symptomatic, and Cognitive Changes in Response to Hypoglycemia in the Non-diabetic Human
90.0 82.8 mg/dl
Inhibition of endogeous insulin secretion
68.4 mg/dl 72.0
Counter-regulatory hormone release • Glucagon • Epinephrine
54.0
57.6–50.4 mg/dl
Onset of symptoms • Autonomic
• Neuroglycopenic 36.0 <27.0 mg/dl 18.0
Severe neuroglycopenia • Reduced conscious level • Convulsions • Coma
0 EEG = electroencephalogram. Reproduced from Frier and Fisher in Hypoglycaemia in Clinical Diabetes, 1999. Reproduced with permission of John Wiley & Sons Ltd.
symptoms, and it is generally accepted that a severe hypoglycemic event (HE) is one in which a patient is unable to self-treat and requires assistance,6
regardless of the glucose level. Pathophysiology of Hypoglycemia
The brain primarily uses glucose as a source of energy, but is unable to synthesize or store it; hence, it is vulnerable to hypoglycemia. Physiological mechanisms that protect the brain from the effects of hypoglycemia, known as the counter-regulatory response (CRR) to hypoglycemia, involve the suppression of insulin release and activation of hormones such as glucagon and epinephrine that stimulate hepatic glucose production and inhibit peripheral glucose uptake.9
These usually
remain functional until an advanced disease state. In non-diabetic adults, this response to a fall in blood glucose levels, along with the onset of symptoms of hypoglycemia, occur at reproducible blood glucose thresholds (see Figure 1). Recurrent hypoglycemia impairs the ability of the brain to detect and initiate the CRR to subsequent hypoglycemia.10
Although the physiology of the CRR is well understood, the underlying cellular mechanisms by which the brain senses hypoglycemia and initiates the CRR have only been elucidated in recent years. Absence of the glucagon response to falling plasma glucose concentrations plays a key role in the pathogenesis of hypoglycemia.11
During
hypoglycemia, central and peripheral glucose sensors detect declining glucose levels and initiate the CRR. Recent studies have found that impairment of the CRR is accompanied by a deficient response of ventromedial hypothalamic glucose-inhibited neurons to decreased glucose levels. Nitric oxide (NO) production in the ventromedial hypothalamus is critical for both the CRR and glucose sensing by glucose-inhibited neurons.11–16
96
Prevalence of Hypoglycemia in Type 2 Diabetes Since there is little consistency among diabetes studies regarding the definition of hypoglycemia, assessments of the prevalence of hypoglycemia among patients with type 2 diabetes should be interpreted with caution. A prevalence of 3.1 % was reported in a recent large sample cohort of 860,845 patients.17–22
Other reported
34 % in self-reported patients treated with metformin and a sulfonylurea for at least six months (n=400);21
prevalence data include 8.8 % in older patients (mean age 65, n=16,667);22
between 12 % using
diet alone, and 30 % using insulin, in a study in which hypoglycemia was defined as typical symptoms relieved by eating and/or blood glucose level <59.4 mg/dl;19
and 63 % (46 % mild, 37 % moderate, 13 %
severe, and 4 % very severe) in a study in which patients were treated with oral antihyperglycemic drugs (OADs) and episodes of hypoglycemia were self-reported.18
The wide range of the reported incidence illustrates the difficulty in assessing the prevalence of hypoglycemia. Variables include the type of hypoglycemia (for example, hypoglycemia requiring medical intervention versus mild hypoglycemia self-defined by the patient), as well as different study durations, treatment regimens, disease duration, and patient characteristics. These studies also fail to take into account nocturnal HEs, for which reported data are often sparse and imprecise.23 Nocturnal hypoglycemia is likely to be underreported and is particularly dangerous because patients are unlikely to recognize symptoms or awaken during an episode.
Health Impact of Hypoglycemia
A recent literature review highlighted the potential impact of hypoglycemia on the lives of people with type 2 diabetes, including depression, heightened anxiety, and impairment of the ability to drive,
US ENDOCRINOLOGY 54.0–43.2 mg/dl
Neurophysiological dysfunction
• Evoked responses 54.0 mg/dl
Widespread EEG changes
50.4 mg/dl
Cognitive dysfunction • Inability to perform complex tasks
Arterialised venous blood glucose concentration (mg/dl)
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