Elsevier

Endocrine Practice

Volume 14, Issue 6, September 2008, Pages 750-756
Endocrine Practice

Review Article
Hypoglycemia: Still The Limiting Factor in the Glycemic Management of Diabetes

https://doi.org/10.4158/EP.14.6.750Get rights and content

ABSTRACT

Objective

To review the prevalence of, risk factors for, and prevention of hypoglycemia from the perspective of the pathophysiologic aspects of glucose counterregulation in diabetes.

Methods

This review is based on personal experience and research and the relevant literature.

Results

Although it can result from insulin excess alone, iatrogenic hypoglycemia is generally the result of the interplay of therapeutic insulin excess and compromised defenses against declining plasma glucose concentrations. Failure of β-cells of the pancreas—early in patients with type 1 diabetes mellitus but later in those with type 2 diabetes mellitus (T2DM)—causes loss of the first 2 physiologic defenses: a decrease in insulin and an increase in glucagon. Such patients are critically dependent on epinephrine, the third physiologic defense, and neurogenic symptoms that prompt the behavioral defense (carbohydrate ingestion). An attenuated sympathoadrenal response to declining glucose levels—caused by recent antecedent hypoglycemia, prior exercise, or sleep—causes hypoglycemia-associated autonomic failure (HAAF) and thus a vicious cycle of recurrent hypoglycemia. Accordingly, hypoglycemia is infrequent early in T2DM but becomes increasingly more frequent in advanced (absolutely endogenous insulin-deficient) T2DM, and risk factors for HAAF include absolute endogenous insulin deficiency; a history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se.

Conclusion

By practicing hypoglycemia risk reduction— addressing the issue, applying the principles of aggressive glycemic therapy, and considering both the conventional risk factors and those indicative of HAAF— it is possible both to improve glycemic control and to minimize the risk of hypoglycemia in many patients. (Endocr Pract. 2008;14:750-756)

Section snippets

The Clinical Problem

Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes (1). It causes recurrent morbidity in most patients with type 1 diabetes mellitus (T1DM) and many with advanced type 2 diabetes mellitus (T2DM), and sometimes it is fatal. In the short term, it impairs defenses against declining glucose levels and thus causes a vicious cycle of recurrent hypoglycemia. In the long term, it precludes maintenance of euglycemia over a lifetime of diabetes and thus full realization

Frequency of Hypoglycemia in Diabetes

Hypoglycemia is a fact of life for most patients with T1DM (1). During aggressive glycemic therapy, the average patient with T1DM may have plasma glucose levels less than 50 mg/dL about 10% of the time, has symptomatic hypoglycemia twice a week—thousands of episodes during a lifetime of diabetes—and has an episode of severe, temporarily disabling hypoglycemia about once a year. An estimated 2% to 4% of patients with T1DM die of hypoglycemia.

Overall, hypoglycemia is less frequent in T2DM than in

Pathophysiology of Glucose Counterregulation in Diabetes

Episodes of hyperinsulinemia occur during treatment of diabetes with an insulin secretagogue or insulin because the pharmacokinetics of these drugs do not replicate normal glucose-regulated insulin secretion. Although considerable insulin excess alone can cause hypoglycemia, the integrity of physiologic and behavioral defenses against decreasing plasma glucose concentrations determines whether less pronounced hyperinsulinemia, representative of that which occurs commonly during the treatment of

Risk Factors for Hypoglycemia in Diabetes

The conventional risk factors for hypoglycemia in diabetes (Table 1) are based on the premise that relative or absolute therapeutic insulin excess is the sole determinant of risk 1., 27.. Relative or absolute insulin excess occurs when insulin secretagogue or insulin doses are excessive, ill-timed, or of the wrong type. Relative insulin excess occurs when exogenous glucose delivery or endogenous glucose production is decreased, glucose utilization is increased, or sensitivity to insulin is

Hypoglycemia Risk Reduction in Diabetes

The prevention of iatrogenic hypoglycemia involves 4 steps 1., 27.. First, acknowledge the problem. The issue of hypoglycemia should be addressed in every patient con tact, at least those with patients treated with an insulin se - cretagogue or with insulin. Second, if hypoglycemia is a problem, apply the principles of aggressive glycemic therapy. Those principles include (1) patient education and empowerment; (2) frequent self-monitoring of plasma glucose, particularly as the therapeutic

Treatment of Hypoglycemia in Diabetes

Episodes of asymptomatic hypoglycemia (detected by self-monitoring of plasma glucose or continuous glucose sensing) and most episodes of symptomatic hypoglycemia are effectively self-treated by ingestion of glucose tablets or carbohydrate-containing snacks or meals (27). A reasonable dose is 20 g of glucose (51).

Parenteral treatment is necessary when a patient is unable or unwilling (because of neuroglycopenia) to take carbohydrate orally. Glucagon, injected subcutaneously or intramuscularly by

Perspective on Hypoglycemia in Diabetes

The underlying principle of the glycemic management of diabetes is maintenance of glycemia as close to the nondiabetic range as can be accomplished safely over time in a given patient. The degree of glycemic control that can be achieved and maintained is a function of many factors, including the type of diabetes and the stage in the evolution of the disease in an individual patient (6). Early in the course of T2DM, glycemic control can often be accomplished by lifestyle changes, particularly

ACKNOWLEDGMENT

The author’s original work cited was supported, in part, by National Institutes of Health grants R37 DK27085, MO1 RR00036, and P60 DK20579 and by a mentor-based fellowship award from the American Diabetes Association. This material was presented in part at the 17th Annual Meeting and Clinical Congress of the American Association of Clinical Endocrinologists; May 14-18, 2008; Orlando, Florida. Ms. Janet Dedeke prepared the submitted manuscript.

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    DISCLOSURE

    Dr. Cryer has served on advisory boards for MannKind Corporation, Merck & Co., Novo Nordisk Inc., and Takeda Pharmaceuticals America, Inc., and as a consultant for Amgen Inc., Johnson & Johnson, Marcadia Biotech, Medtronic MiniMed, Inc., and TolerRx Inc.

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