Diabetes

The broad, sweeping term “diabetes” is used to describe a group of diseases consisting of different errors or faults in metabolic processes that culminate in high blood sugar. While the implications, treatment, and short-term complications seen with these various diseases can be quite different, they are all classified as diabetes.

The current definition of diabetes is a fasting glucose level greater than 140 mg/dL (7.8 mmol/L) or an oral glucose tolerance test greater than 200 mg/dL (11.1 mmol/L). As a practical point to emergency physicians, any measured glucose > 200 mg/dL should be considered diagnostic of diabetes (unless it has been drawn from the same venous runoff as currently infusing glucose solutions!).

Normal Glucose Physiology

Maintenance of blood glucose homeostasis is of paramount importance to the survival of the human body. The brain requires 75% of the glucose circulating in the blood. Both elevated and reduced levels of blood glucose trigger hormonal responses to restore glucose homeostasis. Low blood glucose triggers the release of glucagon from pancreatic alpha cells. High blood glucose triggers the release of insulin from pancreatic beta cells. Additional signals, adrenocorticotropic hormone (ACTH) and growth hormone released from the pituitary, increase blood glucose levels by inhibition of glucose uptake by extrahepatic tissues. Glucocorticoids also act to increase blood glucose levels by inhibition of glucose uptake. Cortisol is secreted by the adrenal cortex in response to the increased ACTH levels. The adrenal medullary hormone, epinephrine, stimulates the production of glucose by activation of glycogenolysis in response to stress.

Insulin

Insulin is initially synthesized in the form of proinsulin. In this form, the alpha and beta chains of active insulin are linked by a third polypeptide chain, called the connecting peptide (c-peptide for short). For every molecule of insulin produced, one molecule of c-peptide is also produced. Levels of c-peptide can be measured and used as an indicator of insulin production in cases where insulin has been injected and mixed with insulin produced by the body. The c-peptide test can also be used to assess if high blood sugar is due to reduced insulin production (as in type I diabetes) or to reduced glucose intake by the cells (as in type II diabetes). There is little or no c-peptide in the blood of type I diabetics, and c-peptide levels in type II diabetics can be reduced or normal. Normal serum concentrations of cpeptide range from 0.5-3.0 nanograms per milliliter.

Insulin levels can also be measured. The primary clinical utility of insulin measurement is in the evaluation of patients with fasting hypoglycemia, rather than diabetes. Insulin levels are inappropriately elevated by insulinsecreting tumors.⁹They may also be useful in predicting susceptibility to the development of type II diabetes, although c-peptide has largely supplanted direct insulin measurements for this role.

Epidemiology And Etiology

Previously, diabetes was classified as either insulin-dependent or non-insulin-dependent. The disease was often further separated into juvenile onset or adult onset. However, these terms are not only passé, but they may be quite inaccurate. Knowledge about diabetes mellitus and its management has steadily increased since the discovery of insulin in 1921. The emergency physician should be aware that some of the recent developments in diabetes care include further separation and identification of these disparate disease processes that can cause a high blood sugar.

Type I Diabetes

Type I diabetes is due to absolute insulin deficiency. These patients will have a lifetime dependence on exogenous insulin. The overall incidence of insulin-dependent diabetes is about 15 cases per 100,000 people per year. (About 50,000 are diagnosed with type I diabetes each year.) An estimated three of every 1000 children will develop insulin-dependent diabetes by the age of 20.¹¹²

Type I diabetes is primarily a disease of Caucasians. The worldwide incidence is highest in Finland and Sardinia and lowest in Asians and blacks. Type I diabetes is more frequently diagnosed in the winter months. (The reason for this is not known.) Interestingly, twins affected by type I diabetes are often discordant in the development of the disease.¹⁰

One of the most exciting findings of the past 10 years about diabetes is that most (about 95%) of type I diabetes is the result of a genetic defect of the immune system, exacerbated by environmental factors.¹⁰ The autoimmune destruction of the beta cells of the pancreas results in the inability to produce insulin. Inheritance of type I diabetes is carried in genes of the major histocompatibility complex (the human leukocyte antigen system). Eventually, this line of research may make it possible to identify all patients who are susceptible to diabetes by a simple blood test. Indeed, this research may lead to a vaccine using the insulin B chain 8-24 peptides to prevent type I diabetes.¹⁰

It is currently thought that islet cells damaged by a virus produce a membrane antigen that may stimulate a response by T killer cells of the immune system in the genetically susceptible patient. The T killer cells misidentify the beta cell as foreign and destroy it. As the beta cells in the pancreas are destroyed, the remaining beta cells must increase their metabolism and, thus, the turnover of membrane antigen in order to keep up with insulin demands. More membrane antigen means that more T killer cells are activated and, hence, more islet cell destruction. This sets up a vicious cycle that ends in the destruction of the entire beta cell mass and the symptoms of clinical diabetes.

This chronic destructive process involves humoral and cellular components that are detectable in the peripheral blood months, or even years, before the onset of clinical diabetes. Throughout this long “pre-diabetic” period, metabolic changes including a decrease in insulin secretion with altered glucose tolerance develop at variable rates, leading to full-blown diabetes.

Early recognition of diabetes and adequate supplemental insulin may reverse this process and prevent the immune response.¹⁰This preservation and possible recovery of the beta cell mass is thought to be the basis of the “honeymoon”period seen after insulin is started in the patient with newonset type I diabetes. Early identification and adequate treatment with insulin may initiate, sustain, and even extend this partial remission.

Latent Autoimmune Diabetes Of Adults

To further complicate the picture, in older people, type I diabetes does not present as it does in childhood. When clinical type I diabetes develops in people over the age of 15, beta cell function is preserved much longer. This translates into about 70% of the older type I diabetics having relativelyhigh c-peptide levels after two years of the disease.¹¹ When diabetes is diagnosed before age 15, only about 10% of the patients will have normal c-peptide levels after two years.¹¹³

The process is much slower and may be, in the early phases, indistinguishable from type II diabetes.¹² The clinical presentation is often not catastrophic and may occur over years or months. These older patients with type I diabetes may have more insulin secretory capacity and may do well on oral agents at first.

While the various autoantibody measurements that can define a type I diabetic are beyond the scope of this article, about 5% of adults diagnosed with type II diabetes have positive autoantibodies.¹² This puts them into a group known as latent autoimmune diabetes of adults (LADA). LADA patients all require insulin therapy eventually, and this therapy is often started early in the disease process. In the older literature, LADA cases were described as type II diabetes that “converted” to type I diabetes—when, in fact, the LADA patients had type I diabetes all along.

Medications For Type I Diabetes

The FDA approved insulin in 1939.¹³ Early insulin preparations were crude extractions from the pancreases of pigs or cows. These preparations were purified, but they still contained a number of additional substances such as proinsulin, insulin derivatives, and other active peptides found in the pancreas. Since then, purer forms of insulin with various time profiles of action have been developed.¹⁴ (SeeTable 1.)

 

Type II Diabetes

Typical type II diabetes is a heterogeneous glucose disorder found most often in patients over 40 years of age and associated with a family history of diabetes. Type II diabetes is usually characterized by a resistance to the patient’s own insulin that may or may not be coupled with a defect in insulin secretion of varying severity. These defects lead to an increase in the liver’s production of glucose and subsequent fasting hyperglycemia.

Type II diabetes is increasing in incidence as the population ages and becomes more affluent. The major risk factor for type II diabetes appears to be obesity—and obesity has become an epidemic in the United States for all ethnic subtypes.¹⁵ Obesity is associated with insulin resistance, which worsens diabetes in any case. If the type II diabetic loses weight and adheres to a strict diet, often no medication at all is required.

DKA is uncommon in the type II diabetic, since the majority of these patients have some insulin secretion. The type II diabetic patient is often considered to require insulin for control but not to be “insulin-dependent.”

Although type II diabetes was formerly considered to be a disease of people older than 40, emergency physicians are seeing increasing numbers of patients in their 20s or 30s with type II diabetes. It is seen more frequently in younger people in association with childhood obesity.^16,17 Type II diabetes is even found in adolescents. (These patients have the slow clinical course of type II diabetics without the development of DKA.)

High blood sugars in type II diabetics can be associated with obesity, high blood pressure, renal failure, and accelerated coronary artery disease. Prolonged hyperglycemia will increase the rate of development of all of these diseases.18 Prolonged high blood sugars will also reduce the effect of insulin (insulin resistance) and decrease the secretion of insulin (glucose toxicity).¹⁹ When the pancreas quits making insulin, then the type II diabetic needs insulin as much as the type I diabetic.²⁰ (As noted, these patients often will secrete enough insulin to stave off ketoacidosis, but not enough to prevent profound hyperglycemia.)

Maturity Onset Diabetes Of The Young

Maturity onset diabetes of the young (MODY) is a familial form of type II diabetes that was described as a separate entity from type II diabetes by many researchers. ^21-24MODY represents a very small subset of type II diabetes. It is estimated that only 1%-5% of all type II diabetics may have MODY.^21-24

A typical MODY patient has a diagnosis of diabetes that is not type I diabetes, is less than 25 years old, and has a positive family history with a dominant mode of inheritance. These patients are often lean and do not appear to be insulin-resistant. There are several types that have been identified and classified by the type of genetic defect involved. A monogenic defect in insulin secretion is responsible for all forms of MODY, and genetic tests can confirm the clinical suspicion.^25-31

Medications For Type II Diabetes

Oral medications for the treatment of type II diabetes have been around since the 1950s. Recently, there has been a marked increase in the number and kinds of drugs that are seen by the emergency physician. (See Table 2)

 Oral medications work by causing the pancreas to make more insulin, by making the tissues more sensitive to the effects of insulin, by decreasing hepatic output of glucose, or by decreasing absorption of glucose from the gut. No single medication uses all four mechanisms, but most will have one or more effects.

A new, cutting-edge drug, exenatide, actually cause the pancreas to produce more islet cells and hence produce more natural insulin.³²

Secondary Diabetes

Severe pancreatic disorders, including pancreatic cancer, chronic pancreatitis, hemachromatosis, and cystic fibrosis, can lead to insulin deficiency and subsequent diabetes. Since the pancreatic tissue in these individuals is destroyed, these patients clinically resemble type I diabetics and require insulin.

Other patients may have diseases or hormonal syndromes that interfere with insulin secretion (such as pheochromocytoma) or insulin use (such as acromegaly, Cushing’s syndrome, and pheochromocytoma). These cases more closely resemble type II diabetes.

Several common medications can impair the body’s use of insulin and produce diabetes. The most commonly seen is probably associated with glucocorticosteroids such as methylprednisolone or prednisone. Treatment for high blood pressure (furosemide, clonidine, and thiazide diuretics), other drugs with hormonal activity (oral contraceptives, thyroid hormone, and progestins), and the antiinflammatory drug indomethacin can also cause or exacerbate diabetes. Numerous other drugs can impair glucose absorption, such as haloperidol, lithium, phenothiazines, tricyclic antidepressants, isoniazid, nicotinic acid, heparin, and cimetidine.

Drug-induced diabetes may or may not require insulin and may simply resolve after the drug is stopped. Drug-induced diabetes may resemble either type I or type II diabetes.

Gestational Diabetes

Gestational diabetes is glucose intolerance during pregnancy. About 4% of all pregnancies are complicated by gestational diabetes.¹¹⁴ Mothers with gestational diabetes have higher rates of cesarean delivery and chronic hypertension. ¹¹⁴Their children may have macrosomia, hypoglycemia, hypocalcemia, and hyperbilirubinemia. (A complete discussion of gestational diabetes is beyond the scope of this review.)

Impaired Glucose Tolerance

An impaired glucose tolerance is defined as a fasting glucose of greater than 110 mg/dL (6.1 mmol/L) but less than 140 mg/dL.^115,116 It is also defined as a patient who has a glucose tolerance test with ranges between 140 mg/dL (7.8 mmol/L) and 199 mg/dL.^115,116 Impaired glucose tolerance was formerly known as borderline, chemical, or latent diabetes.^115,116(Impaired glucose tolerance and its implications are not covered in this review.)

 

 

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