Hypoglycemia in Type 1 Diabetes Mellitus

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The limiting factor in glycemic control

The clinical problem of hypoglycemia in diabetes has been summarized1 and discussed in detail.2 Because it reduces microvascular complications3—retinopathy, nephropathy, and neuropathy—and may reduce macrovascular complications,4 glycemic control is generally in the best interest of people with type 1 diabetes mellitus (T1DM). Iatrogenic hypoglycemia, however, is the limiting factor in the glycemic management of T1DM.1, 2 It (1) causes recurrent morbidity in most people with T1DM and is

Incidence and impacts of hypoglycemia in T1DM

Iatrogenic hypoglycemia is a fact of life for people with T1DM.1, 2 They suffer untold numbers of episodes of asymptomatic hypoglycemia. In one study of subcutaneous glucose sensing in T1DM, glucose levels were less than or equal to 70 mg/dL (3.9 mmol/L) 1.5 hours per day (ie, 6.3% of the time).5 In a study involving nocturnal plasma glucose measurements every 15 minutes in T1DM, glucose levels were less than 70 mg/dL in 57% (12 of 21) of the patients.6 Many of these episodes are asymptomatic

Definition of hypoglycemia in T1DM

The American Diabetes Association (ADA) Workgroup on Hypoglycemia defined hypoglycemia in people with diabetes as “all episodes of abnormally low plasma glucose concentration that expose the individual to potential harm.”17 That includes episodes of asymptomatic hypoglycemia because those impair defenses against subsequent hypoglycemia.1, 2 It is not possible to state a specific plasma glucose concentration that defines hypoglycemia because the glycemic thresholds for symptoms, among other

Physiology of glucose counter-regulation

The physiologic defenses against falling plasma glucose (Fig. 1) concentrations in nondiabetic individuals include (1) decrements in pancreatic β-cell insulin secretion, (2) increments in pancreatic α-cell glucagon secretion, and, absent the latter, (3) increments in adrenomedullary epinephrine secretion.1, 2, 19 Lower insulin levels favor increased glucose production, which is also stimulated by glucagon and epinephrine. Epinephrine also limits glucose use and mobilizes gluconeogenic

Pathophysiology of glucose counter-regulation in T1DM

All insulin preparations are pharmacokinetically imperfect. Thus, episodes of therapeutic hyperinsulinemia occur from time to time in T1DM (see Fig. 1, Fig. 2). These cause declining plasma glucose concentrations that may, if not effectively countered, result in hypoglycemia. Absolute therapeutic insulin excess of sufficient magnitude can cause an isolated episode of hypoglycemia despite intact glucose counter-regulatory defenses (see Fig. 2).1, 2 But, hypoglycemia is more commonly the result

Conventional Risk Factors

The conventional risk factors for hypoglycemia in diabetes are based on the premise that relative or absolute therapeutic hyperinsulinemia is the sole determinant of risk.1, 2, 34 Relative—to low rates of glucose influx into the circulation or high rates of glucose efflux out of the circulation—or absolute therapeutic hyperinsulinemia occurs when (1) insulin doses are excessive, ill-timed, or of the wrong type; (2) exogenous glucose delivery is decreased (as after missed meals or during the

Minimizing the Risk of Hypoglycemia in T1DM

Minimizing the risk of hypoglycemia in T1DM involves the practice of hypoglycemia risk factor reduction.1, 2, 34, 36, 37 That includes four steps: (1) acknowledge the problem, (2) apply the principles of aggressive glycemic therapy, (3) consider the conventional risk factors for hypoglycemia, and (4) consider the risk factors indicative of HAAF in diabetes.

Oral Self-Treatment

Most episodes of asymptomatic or symptomatic hypoglycemia are effectively self-treated with glucose tablets or carbohydrate containing juice, soft drinks, candy, other snacks, or a meal by the person with T1DM1, 2 (20 g, repeated in 15 to 20 minutes if necessary, is a reasonable dose of carbohydrate).64 Because the glycemic response is transient,64 a subsequent more substantial snack or meal is generally advisable.

Parenteral Treatment

When hypoglycemic patients are unable or, because of neuroglycopenia, unwilling

Summary of recommendations

Because mean glycemia as close to the nondiabetic range as can be accomplished safely is in the best interest of patients with T1DM, it follows that caregivers should attempt to match insulin actions and circulating glucose availability at all times under all conditions so as to avoid severe hypoglycemia, hypoglycemia unawareness, and intolerable symptomatic hypoglycemia while maintaining a meaningful degree of glycemic control. Thus, the following are recommended (the strength of the evidence

Acknowledgments

The author is grateful for the contributions of postdoctoral fellows and the skilled nursing, technical, dietary, and data management/statistical assistance of the staff of the Washington University General Clinical Research Center. Janet Dedeke prepared this manuscript.

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    • Cited by (0)

    The author's original research cited was supported, in part, by National Institutes of Health grants R37 DK27085, MO1 RR00036 (now UL1 RR24992), P60 DK20579, and T32 DK07120 and a fellowship award from the American Diabetes Association.

    Disclosures: This article was written shortly after the publication of the author's book, Hypoglycemia in Diabetes: Pathophysiology, Prevalence, and Prevention, American Diabetes Association, Alexandria, Virginia, 2009.2 Therefore, much of the factual and interpretive content here is the same, as is no small part of the phraseology.

    The author has served as a consultant to several pharmaceutical or device firms, including Amgen Inc, Johnson & Johnson, MannKind Corp, Marcadia Biotech, Medtronic MiniMed Inc, Merck and Co, Novo Nordisk A/S, Takeda Pharmaceuticals North America, and TolerRx Inc, in recent years. He does not receive research funding from, hold stock in, or speak for any of these firms.

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