The Persistent Complication of Hypoglycemia in Diabetics
Published Online: May 22, 2014
Surabhi Dangi-Garimella, PhD
Hypoglycemia, also referred to as insulin reaction or insulin shock, is defined as abnormally low glucose in the blood (low blood sugar), usually below 70 mg/dL. The condition is usually associated with several symptoms, including shakiness, nervousness, sweating, chills and clamminess, dizziness, hunger and nausea, confusion, weakness, sleepiness, seizures, and losing consciousness.
Severe hypoglycemia can cause accidents, injuries, coma, and may even prove fatal.1 Recent studies have associated severe hypoglycemia as a risk factor for dementia, falls, fractures, and heart attacks.2 The simplest solution under hypoglycemic conditions is to provide a sugar source to the patient. However, managing the condition can prove especially challenging in individuals who are hypoglycemic without any evident symptoms, defined as hypoglycemia unawareness. Patients suffering from hypoglycemia unawareness would be difficult to wake from sleep if they do get hypoglycemic at night. This condition is most commonly observed in individuals who experience frequent episodes of hypoglycemia, among chronic diabetics, or in those with tightly controlled diabetes.1
However, a collaborative study between Kaiser Permanente and Yale University School of Medicine, published last year in the journal Diabetes Care, revealed that hypoglycemia can also affect those with poorly controlled diabetes. The authors stated that nearly 11% of the more than 9000 responders who had participated in the survey had experienced hypoglycemia, independent of blood sugar control.3
Two recent papers in Diabetes, a collaboration between 2 laboratories at the Department of Biological Sciences, University of Southern California, delved into the details of the feedback signals received by the brain following a drop in blood sugar in hypoglycemic diabetics. Their research identified a startling difference in neuronal firing between slow-onset hypoglycemia and rapid-onset hypoglycemia.4,5
Disease Burden on Healthcare
A study conducted by the pharmaceutical company Novo Nordisk, in association with the health technology assessment company Heron Evidence Development, identified that a greater number of comorbidities (excluding dyslipidemia) were prevalent in hypoglycemic diabetic patients than in their matched controls, diabetics who had not presented with any hypoglycemic events. A majority (97%) of the patients were persons with type 2 diabetes mellitus (T2DM) who were documented to have required medical attention during 2009.
The analysis, presented at the meeting of the International Society for Pharmacoeconomics and Outcomes Research, showed that patients experiencing hypoglycemic events had significantly higher all-cause annual healthcare costs over controls ($32,337 vs $19,786). The study identified nonsurgical inpatient costs as the primary driver of the significant difference between the cohorts. On the contrary, controls had higher outpatient costs over the controls.6
Another study evaluating the cost of hypoglycemia in 536,581 patients with T2DM estimated the total cost during a 4-year study period (2004-2008) at $52,223,675, accounting for 1% of all inpatient costs, 2% of emergency department (ED) costs, and 0.3% of outpatient costs. The average costs for hypoglycemia visits were high for an inpatient admission ($17,564) compared with an outpatient visit ($394), which mirrored the findings of the Novo Nordisk study.7 The authors reiterated the need for continued vigilance and efforts to develop strategies to curb these
avoidable costs. Analysis of ED visits for insulin-related hypoglycemia over a 5-year period found that the United States healthcare system had forfeited $600 million, excluding hospitalization
What Prevents the Brain From Generating Feedback Compensation in Diabetics?
Patients suffering from type 1 diabetes mellitus as well as T2DM often face a recurring issue in disease management: iatrogenic hypoglycemia. It is defined as an abnormally low plasma
glucose concentration that exposes the individual to potential harm, a definition coined by a joint work group of the American Diabetes Association and The Endocrine Society.9
Normally, following a drop in the blood glucose level, the body compensates by reducing insulin secretion (which lowers glucose) and increasing glucagon secretion (which increases
glucose) by the pancreas, along with increasing epinephrine secretion by the adrenal gland. These physiological responses prompt the behavioral response of carbohydrate ingestion
prompted by neurogenic symptoms that originate from a sympathetic neural response (Figure 1). Altogether, a continuous supply of glucose to the brain is ensured.10
In diabetics, however, due to the lack of insulin-producing pancreatic beta cells, the feedback mechanisms that regulate insulin levels are obsolete. So the exogenously administered insulin
is regulated merely by absorption and clearance. Additionally, the pancreas fails to secrete increased glucagon and the adrenal gland fails to increase epinephrine production (Figure 2).
Together, these compromised physiological conditions in patients with diabetes result in a defective glucose counter-regulatory response (CRR) and increases their risk of hypoglycemic
episodes at least 25-fold. Additionally, lack of symptoms of hypoglycemia due to attenuation of the sympathoadrenal response results in hypoglycemia unawareness, further increasing the risk of severe hypoglycemia 6-fold or more.10
The results alluded to earlier, published in the journal Diabetes, teased out the exact mechanism of failure of the sympathoadrenal CRR in a rat model. It has been long known that the rate
of fall of blood glucose determines the participation of the brain (central nervous system) versus the peripheral nervous system to activate the CRRs.
Rapid-onset hypoglycemia results in the activation of the brain glucosensing elements (hindbrain), whereas slow-onset hypoglycemia stimulates participation by the portal-mesenteric vein (PMV). However, the specific role of catecholamine neurons of the hindbrain in glucosensing has not been clear. In this paper, the authors highlighted that catecholamine neurons
stimulate sympathoadrenal CRR during slow-onset hypoglycemia and that rate of onset is a major determinant of the mechanism adopted for the CRR.4
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