	Type of Diabetes Mellitus
Characteristics	Type 1	Type 2
Alternative names	Insulin-dependent diabetes mellitus, juvenile-onset diabetes mellitus, ketosis-prone diabetes mellitus	Non–insulin-dependent diabetes mellitus, adult-onset diabetes mellitus
Age of onset	Usually childhood or adolescence	Usually over 40
Speed of onset	Abrupt	Gradual
Family history	Usually negative	Frequently positive
Prevalence	5–10% of diabetic patients have type 1 diabetes	90–95% of diabetic patients have type 2 diabetes
Etiology	Autoimmune process	Unknown—but there is a strong familial association, suggesting heredity is a risk factor
Primary defect	Loss of pancreatic beta cells	Insulin resistance and inappropriate insulin secretion
Insulin levels	Reduced early in the disease and completely absent later	Levels may be low (indicating deficiency), normal, or high (indicating resistance)
Treatment	Insulin replacement is mandatory, along with strict dietary control; oral antidiabetic drugs are not effective	Treat with an oral antidiabetic agent and/or insulin, but always in combination with a reduced-calorie diet and appropriate exercise
Blood glucose	Levels fluctuate widely in response to infection, exercise, and changes in caloric intake and insulin dose	Levels are more stable than in type 1 diabetes
Symptoms	Polyuria, polydipsia, polyphagia, weight loss	May be asymptomatic
Body composition	Usually thin and undernourished	Frequently obese
Ketosis	Common, especially if insulin dosage is insufficient	Uncommon

Treatment of diabetes can delay the onset of nephropathy and reduce its severity. The Diabetes Control and Complications Trial (DCCT) revealed that tight glucose control decreases the risk of nephropathy by 35% to 57%. As discussed in Chapter 44, treatment with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) can slow progression of mild-to-moderate nephropathy that is already present. However, these drugs are not effective for primary prevention. Of note, ACE inhibitors and ARBs have an additional benefit: they can help control hypertension, a common complication of diabetes.

Sensory and motor neuropathy.

Nerve degeneration often begins early in the course of diabetes, but symptoms are usually absent for years. Sensory and motor nerves may be affected. Symptoms of diabetic neuropathy—which are usually bilateral and symmetric—include tingling sensations in the fingers and toes (paresthesias), increased pain or decreased ability to feel pain, suppression of reflexes, and loss of other sensations (especially vibratory sensation). These changes are one of the reasons why a complete foot exam for diabetic patients includes not only an examination for sores and possible infections, but also for sensory responses. The clinician will use a small needle or other stiff or sharp object to prod the bottoms of the feet, without the patient looking. Failure to detect the stimuli gives a good indication that neuropathies are developing.

Nerve damage is directly related to sustained hyperglycemia, which may cause metabolic disturbances in nerves or may injure the capillaries that supply nerves. In the DCCT, tight glycemic control reduced the incidence of peripheral neuropathy by 60%.

Autonomic neuropathy: gastroparesis.

Diabetic gastroparesis (delayed stomach emptying) affects 20% to 30% of patients with long-standing diabetes. Manifestations include nausea, vomiting, delayed gastric emptying, and gastric or intestinal distention. Injury to the autonomic nerves that control GI motility seems to be the underlying cause. Symptoms can be reduced with metoclopramide [Reglan], a dopamine antagonist that promotes gastric emptying (see Chapter 80). In addition to affecting autonomic nerves that innervate the GI tract, diabetes can affect autonomic nerves that innervate other structures.

Amputations secondary to infection.

Diabetes is responsible for more than half of lower limb amputations in the United States. Each year about 54,000 diabetic patients lose a foot or leg. The underlying cause is severe infection, which can develop following local trauma, be it major or minor. There are three reasons why serious infection can occur. First, hyperglycemia provides a glucose-rich environment for bacteria to grow. Second, diabetes can suppress immune function, and thereby compromise host defenses against infection. And third, diabetic neuropathy can prevent the patient from feeling discomfort and other sensations that would signal that a serious infection is developing. Because of these factors, an infection that would be inconsequential and self-limiting in nondiabetics can become very serious in a diabetic. If the infection spreads and becomes gangrenous, the only realistic and effective solution is amputation. Because of these possibilities, regular foot exams and foot care are an important part of diabetes management.

Erectile dysfunction.

The combination of blood vessel injury and neuropathy can cause erectile dysfunction (ED). Among men with diabetes, the estimated incidence of ED is 35% to 75%. Treatment with sildenafil [Viagra] and related drugs can often help.

Diabetes and pregnancy

Before the discovery of insulin, virtually all babies born to mothers with severe diabetes died during infancy. Although insulin therapy has greatly improved outcomes, successful management of the diabetic pregnancy remains a challenge. Three factors contribute to the problem. First, the placenta produces hormones that antagonize insulin’s actions. Second, production of cortisol, a hormone that promotes hyperglycemia, increases threefold during pregnancy. Both factors increase the body’s need for insulin. And third, because glucose can pass freely from the maternal circulation to the fetal circulation, hyperglycemia in the mother will stimulate excessive secretion of insulin in the fetus. The resultant hyperinsulinism can have multiple adverse effects on the fetus.

Successful management of diabetes during pregnancy demands that proper glucose levels be maintained in both the fetus and mother; failure to do so may be teratogenic or may otherwise harm the fetus. Achieving glucose control requires diligence on the part of the mother and her prescriber. Some experts on diabetes in pregnancy advise that blood glucose levels must be monitored 6 to 7 times a day. Insulin dosage and food intake must be adjusted accordingly.

Because fetal death frequently occurs near term, it is desirable that delivery take place as soon as fetal development will permit. Hence, when tests indicate sufficient fetal maturation, it is common practice to deliver the infant early—either by cesarean section or by inducing labor with drugs.

Gestational diabetes is defined as diabetes that appears during pregnancy and then subsides rapidly after delivery. Gestational diabetes is managed in much the same manner as any other diabetic pregnancy: Blood glucose should be monitored and then controlled with diet and insulin. In most cases, the diabetic state disappears almost immediately after delivery, permitting discontinuation of insulin. However, if the diabetic state persists beyond parturition, it is no longer considered gestational and should be rediagnosed and treated accordingly.

In women taking an oral drug for type 2 diabetes, current practice is to discontinue the oral drug and switch to insulin. The only exception is the oral agent metformin, which is often satisfactory for managing type 2 diabetes in pregnancy. Women who discontinue oral medications can resume oral therapy after delivery.

Diagnosis

Until recently, diagnosis of diabetes was made solely on measuring blood levels of glucose. However, in 2010, the American Diabetes Association (ADA) recommended an alternative test, based on measuring blood levels of a compound known as hemoglobin A1c. For all of these tests, values diagnostic of diabetes are summarized in Table 57–2.

TABLE 57–2

Criteria for the Diagnosis of Diabetes Mellitus

Fasting plasma glucose ≥126 mg/dL *

Casual plasma glucose ≥200 mg/dL plus symptoms of diabetes^†

Oral glucose tolerance test (OGTT): 2-hr plasma glucose ≥200 mg/dL^‡

Hemoglobin A1c 6.5% or higher

^*Fasting is defined as no caloric intake for at least 8 hours.

^†Casual is defined as any time of day without regard to meals. Classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.

^‡In this OGTT, plasma glucose content is measured 2 hours after ingesting the equivalent of 75 gm of anhydrous glucose dissolved in water. The OGTT is not recommended or needed for routine clinical use.

Adapted from Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 26(Suppl 1):S5–S24, 2003.

Tests based on blood levels of glucose

Excessive plasma glucose is diagnostic of diabetes. Several tests may be employed: a fasting plasma glucose (FPG) test, a casual plasma glucose test, and an oral glucose tolerance test (OGTT). To make a definitive diagnosis, the patient must be tested on two separate days, and both tests must be positive. Any combination of two tests (eg, two FPG tests; one FPG test and one OGTT) may be used.

Fasting plasma glucose test.

To determine FPG levels, blood is drawn at least 8 hours after the last meal. In normoglycemic individuals, FPG levels are less than 100 mg/dL. If FPG glucose levels are 126 mg/dL or higher, diabetes is indicated. Of the glucose-based tests employed to diagnose diabetes, the FPG test is preferred. In fact, if an initial casual plasma glucose test suggests diabetes, a follow-up FPG test is almost always used for confirmation.

Casual plasma glucose test.

For this test, blood can be drawn at any time, without regard to meals. Fasting is not required. Of note, the test can be performed in the office, using a finger-stick blood sample and the same type of test device employed by patients at home. A plasma glucose level that is 200 mg/dL or higher suggests diabetes. However, to make a definitive diagnosis, the patient must also display classic signs of diabetes: polyuria, polydipsia, and rapid weight loss. Ketonuria may also be present, but only if blood glucose is extremely high.

Oral glucose tolerance test.

This test, often abbreviated as OGTT, is used when diabetes is suspected but could not be definitively diagnosed by measuring fasting or casual plasma glucose levels. The OGTT is performed by giving an oral glucose load (equivalent to 75 gm of anhydrous glucose), and measuring plasma glucose levels 2 hours later. In individuals who do not have diabetes, 2-hour glucose levels will be below 140 mg/dL. Diabetes is suggested if 2-hour plasma glucose levels are 200 mg/dL or higher. The OGTT test is more expensive and time consuming than the alternatives, and is not used routinely.

Test based on blood levels of hemoglobin A1C

As described below under Monitoring Treatment, levels of hemoglobin A1c, or simply A1c, reflect average blood glucose levels over the previous 2 to 3 months. Accordingly, if a patient’s A1c is high, we know that his or her glucose levels have been high for a long time. In other words, we know that he or she has diabetes. An A1c value of 6.5% or higher is considered diagnostic.

It is important to note that the A1c test is not appropriate for everyone. Why? Because some people have conditions that can skew the results. Among these are pregnancy, chronic kidney or liver disease, recent severe bleeding or blood transfusion, and certain blood disorders, including thalassemia, iron deficiency anemia, and anemia related to vitamin B₁₂ deficiency.

Prediabetes

Prediabetes is a state defined by impaired fasting plasma glucose (FPG between 100 and 125 mg/dL), or impaired glucose tolerance (2-hour OGTT result of 140 to 199 mg/dL). These values are below those that define diabetes, but are too high to be considered normal. People with prediabetes are at increased risk of developing type 2 diabetes and CVD—but not the microvascular complications associated with diabetes (ie, retinopathy, nephropathy, neuropathy). The risk of CVD can be reduced by diet, exercise, and, if indicated, use of appropriate drugs to control blood lipids and blood pressure. The risk of progression to diabetes may be reduced by diet and exercise, and possibly by certain oral antidiabetic drugs.

It is important to note that many people who meet the criteria for “prediabetes” never go on to develop diabetes—even if they don’t modify their lifestyle, and even if they don’t take antidiabetic drugs. Hence, although “prediabetes” indicates an increased risk of diabetes, it by no means guarantees that diabetes will occur.

Overview of treatment

The primary goal of treating type 1 or type 2 diabetes is prevention of long-term complications, especially CVD, retinopathy, kidney disease, and amputations. To minimize these complications, treatment must keep glucose levels as low as safely possible. In addition, treatment must keep blood pressure and blood lipids within an acceptable range. In both type 1 and type 2 diabetes, proper diet and adequate exercise are central components of management. Major treatment targets are summarized in Table 57–3.

TABLE 57–3

General Treatment Targets for Patients with Diabetes *

Glycemic Control
Premeal plasma glucose	70–130 mg/dL
Peak postmeal plasma glucose	<180 mg/dL
A1c	<7%
Blood Pressure
Systolic	<130 mm Hg
Diastolic	<80 mm Hg
Blood Lipids
LDL cholesterol	<100 mg/dL
Triglycerides	<150 mg/dL
HDL cholesterol	Men: >40 mg/dL
	Women: >50 mg/dL
Kidney Integrity
Albumin/creatinine ratio	<30 mcg/mg^†

^*Treatment targets for certain subgroups of patients may differ from the targets in this table.

^†An albumin/creatinine ratio above 30 mcg albumin/1 mg creatinine indicates too much albumin in urine owing to glomerular injury.

Type 1 diabetes

Preventing complications of diabetes requires a comprehensive plan directed at glycemic control and reduction of cardiovascular risk factors. Glycemic control is accomplished with an integrated program of diet, self-monitoring of blood glucose (SMBG), exercise, and insulin replacement. Of importance, glycemic control must be achieved safely, that is, without causing hypoglycemia. An essential component of treatment—education of the patient and his or her caregivers about diet, exercise, and drugs—is usually left to the nurse and a dietitian or nutritionist.

Dietary measures.

Proper diet, balanced by insulin replacement, is the cornerstone of treatment. Because patients with type 1 diabetes are usually thin, the dietary goal is to maintain weight—not lose it. Dietary recommendations from the ADA include the following:

• Carbohydrates and monounsaturated fats, together, should provide 60% to 70% of daily energy intake.

• Protein should provide 15% to 20% of daily energy intake.

• Polyunsaturated fat should provide about 10% of daily energy intake.

• Saturated fats should provide less than 10% of daily energy intake.

• Cholesterol intake should be limited to 300 mcg/day.

• Total caloric intake should be spread evenly throughout the day, with meals spaced 4 to 5 hours apart.

Unfortunately, although following these guidelines is clearly beneficial, many patients find long-term adherence difficult to achieve.

For people who like sweets, the ADA recommendations have good news: You can eat foods that contain sucrose (table sugar)—provided you reduce intake of other carbohydrates. What matters most is the total amount of carbohydrate ingested—not the type of carbohydrate or its source.

What’s the glycemic index and why is it important? The glycemic index is an indicator of how a particular carbohydrate will affect blood glucose levels. Specifically, eating foods that have a high glycemic index (eg, white bread, unprocessed white rice) will raise glucose levels more rapidly and to a higher peak than will eating foods that have a low glycemic index (eg, rolled oats, 100% whole wheat bread, lentils and legumes, most fruits and nonstarchy vegetables). In theory, foods with a low glycemic index should permit better glycemic control. Why? Because, when glucose levels rise slowly after eating, the body has more time to process the glucose load. Importantly, this advantage is lost if total intake of low-index foods is excessive. Put another way, we may be able to achieve better glycemic control by consuming high-glycemic-index foods in moderate amounts rather than by consuming low-index foods in enormous amounts. But the best control would be achieved by consuming low-index foods in moderate amounts—and minimizing consumption of high-index foods.

Exercise.

Unless specifically contraindicated, regular exercise should be part of the management program. Exercise increases cellular responsiveness to insulin, and may also increase glucose tolerance. Accordingly, the ADA recommends that patients perform at least 150 min/wk of moderate-intensity aerobic activity. Because strenuous exercise can produce hypoglycemia, patient and provider must work to establish a safe balance between exercise, caloric intake, and insulin dosage. Unfortunately, although the benefits of exercise are well established, long-term adherence to a program is often difficult to maintain.

Insulin replacement.

Among patients with type 1 diabetes, survival requires daily dosing with insulin. Before insulin replacement became available, people with type 1 diabetes invariably died within a few years after disease onset. The cause of death was ketoacidosis. It is essential to coordinate insulin dosage with caloric intake. If caloric intake is too great or too small with respect to insulin dosage, hyperglycemia or hypoglycemia will result.

Note that oral antidiabetic agents, which can help patients with type 2 diabetes, are not effective for patients with type 1 diabetes. Why? Because the oral agents cannot substitute for the insulin that type 1 patients lack.

Managing hypertension and dyslipidemia.

As noted earlier, an ACE inhibitor (eg, captopril) or an ARB (eg, losartan) can reduce the risk of diabetic nephropathy, a long-term consequence of poor glycemic control. These same drugs are preferred agents for managing diabetic hypertension. As indicated in Table 57–3, the goal is to keep blood pressure at or below 130/80 mm Hg.

To reduce high levels of LDL cholesterol, statins (eg, atorvastatin) are preferred drugs. Not only do statins reduce cardiovascular events in patients with high cholesterol, they reduce cardiovascular events in patients with normal or low cholesterol. Another cholesterol-lowering drug—colesevelam—is discussed separately below because of its recognized role in managing diabetes.

Type 2 diabetes

As with type 1 diabetes, preventing long-term complications requires a comprehensive treatment plan. Lifestyle measures (diet and exercise) and drug therapy are the foundation of glycemic control. Because patients are often obese, the usual dietary goal is to promote weight loss. Exercise provides the additional benefit of promoting glucose uptake by muscle, even when insulin levels are low. In addition to glycemic control, the plan should address other factors that can increase morbidity and mortality. Accordingly, all patients should be screened and treated for hypertension, nephropathy, retinopathy, and neuropathy. In addition, dyslipidemias (high LDL cholesterol, low HDL cholesterol, and high triglycerides) should be corrected.

Recommendations for glycemic control have changed. Until recently, treatment was started with lifestyle measures alone; drugs were added only if these measures failed. Today, treatment is started with lifestyle measures plus drug therapy. We no longer wait to use drugs. As a result, glycemic control is established sooner, and hence the risk of long-term complications is made lower.

Type 2 diabetes can be treated with a variety of oral and injectable drugs. Among the oral drugs, metformin and the sulfonylureas (eg, glipizide [Glucotrol]) are used most widely. Among the injectable drugs, insulin is used most widely. Although wide use of insulin may surprise you, it shouldn’t. Remember, as type 2 diabetes progresses, less and less insulin is produced. As a result, up to 40% of patients with advanced disease eventually require insulin therapy.

Given the many drugs available for type 2 diabetes, which ones are preferred? Evidence of safety and efficacy is best for metformin, sulfonylureas, and insulin, as discussed in a 2009 guideline—Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy—issued jointly by the ADA and the European Association for the Study of Diabetes. To treat type 2 diabetes, the guideline recommends a three-step approach:

Step 1. At diagnosis, initiate lifestyle changes plus metformin.

Step 2. Continue lifestyle changes plus metformin, and add a second drug, either basal insulin or a sulfonylurea.

Step 3. Continue lifestyle changes plus metformin, and switch from basal insulin or a sulfonylurea to intensive insulin therapy.

Treatment should start at step 1, and then climb to steps 2 and 3 if needed. The guideline suggests alternative drugs (eg, pioglitazone [Actos], exenatide [Byetta]) if the preferred drugs are ineffective or poorly tolerated.

Tight glycemic control

The process of maintaining glucose levels within a normal range, around-the-clock, is referred to as tight glycemic control. In terms of A1c, the recommended target is less than 7%. Maintaining tight glycemic control is difficult but can be worth the trouble, especially for patients with type 1 diabetes. However, for many patients with type 2 diabetes, the risks of tight control may be greater than the benefits.

Type 1 diabetes

Benefits.

The benefits of tight glycemic control in type 1 diabetes were demonstrated conclusively in the Diabetes Control and Complications Trial (DCCT), in which patients received either conventional insulin therapy (1 or 2 injections a day) or intensive insulin therapy (4 injections a day). After 6.5 years, the patients who received intensive therapy experienced a 50% decrease in clinically significant kidney disease, a 35% to 57% decrease in neuropathy, and a 76% decrease in serious ophthalmic complications. Moreover, onset of ophthalmic problems was delayed and progression of existing problems was slowed. In addition to reducing these microvascular complications, tight control decreased macrovascular complications: 17-year follow-up data from the DCCT showed a significant reduction in myocardial infarction, coronary revascularization, and angina. Hence, with rigorous control of blood glucose, the high degree of morbidity and mortality traditionally associated with type 1 diabetes can be markedly reduced.

Drawbacks.

The greatest concern is hypoglycemia. Because glucose levels are kept relatively low, the possibility of hypoglycemia increases. Why? Because even a modest overdose with insulin can cause blood glucose to fall too low. Also, a meal that is skipped or exercise that is too strenuous can do the same. Results of the DCCT showed that, compared with patients using conventional therapy, those using intensive insulin experienced 3 times as many hypoglycemic events requiring the assistance of another person, and 3 times as many episodes of hypoglycemia-induced coma or seizures. In addition, patients on intensive insulin experienced greater weight gain (about 10 pounds, on average). Other disadvantages are greater inconvenience, increased complexity, and a need for greater patient motivation. Finally, the cost is higher: Whereas traditional therapy costs about $1700/year, intensive therapy costs about $4000/year (for multiple daily injections) or $5800 (for continuous infusion with a pump). The cost of test strips for the patient’s glucometer adds substantially more to the bill.

Type 2 diabetes

In patients with type 2 diabetes, benefits of tight glycemic control are limited mainly to microvascular complications; tight control does little to reduce macrovascular complications. Furthermore, benefits accrue more to younger adults with recent-onset disease, than to older adults with well-established disease. As in type 1 diabetes, tight glycemic control poses a significant risk of hypoglycemia and weight gain. In addition, tight control may increase the risk of death.

The effects of tight glycemic control in type 2 diabetes were demonstrated in four landmark trials:

• United Kingdom Prospective Diabetes Study (UKPDS)

• Action to Control Cardiovascular Risk in Diabetes (ACCORD)

• Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE)

• Veterans Affairs Diabetes Trial (VDAT)

These large randomized trials differed in patient populations: Whereas the UKPDS trial enrolled younger adults with recent-onset diabetes and no prior cardiovascular events, the ACCORD, ADVANCE, and VDAT trials enrolled older adults with long-standing diabetes as well as established CVD or cardiovascular risk factors.

Results of the UKPDS trial, released in 1998, showed a significant reduction in microvascular complications—but little or no reduction in macrovascular complications or death. In one branch of the study, nonobese patients were given either intensive therapy or conventional therapy. Mean values for A1c were 7% in the intensive group and 7.9% in the conventional group. Compared with patients in the conventional group, patients in the intensive group had a 12% reduction in total diabetes-related endpoints (cardiovascular, retinal, and renal damage). However, a reduction in microvascular complications (especially retinal damage) accounted for most of the benefit.

Results of ACCORD, ADVANCE, and VDAT were released in 2008. As in the UKPDS trial, tight glycemic control failed to reduce stroke, amputations, all-cause mortality, or mortality from cardiovascular causes. In fact, in the ACCORD trial, intensive therapy was associated with an increased risk of death. Tight control also increased the risk of severe hypoglycemia and weight gain. The ADVANCE trial did show a reduction in microvascular outcomes, but the ACCORD trial did not.

Taken together, these four studies suggest that tight glycemic control is most appropriate for younger adults who have recent-onset type 2 diabetes and no cardiovascular complications. Because even short periods of hyperglycemia increase the risk of microvascular and macrovascular complications, intensive therapy should be started as soon as diabetes is diagnosed.

Who should not receive intensive therapy? Intensive glycemic control may be inappropriate for patient with

• Long-standing type 2 diabetes

• Advanced microvascular or macrovascular complications

• Extensive comorbid conditions

• A history of severe hypoglycemia

• Limited life expectancy

For these patients, an A1c goal above 7% may be more appropriate than a goal below 7%.

Monitoring treatment

We need monitoring to (1) determine whether glucose levels are being maintained in a safe range, both short term and long term, and to (2) guide changes in the regimen when the range is not satisfactory or safe. Self-measurement of blood glucose levels is the standard method for day-to-day monitoring. A1c is measured to assess long-term glycemic control. Target levels for these tests are summarized in Table 57–4.

TABLE 57–4

Hemoglobin A1c Levels and Their Corresponding eAG Levels *

	Corresponding eAG Level
A1c Level (% of Total Hb)	mg/dL	mmol/L
6	126	7
6.5	140	7.8
7^†	154	8.6
7.5	169	9.4
8	183	10.1
8.5	197	10.9
9	212	11.8
9.5	226	12.6
10	240	13.4

eAG = estimated Average Glucose in blood.

^*The formula to convert from A1c (%) to average glucose concentration equivalents (expressed in mg/dL) is: eAG = (A1c × 28.7) − 46.7.

^†7% A1c (corresponding to an eAG of 154 mg/dL) is considered to be the maximum acceptable level for long-term glycemic control. For many patients, achieving this degree of control is difficult or impossible.

Data from American Diabetes Association.

Self-monitoring of blood glucose

Newly diagnosed patients tend to be diligent about testing their blood. This is good because it provides essential information for adjusting treatment on a day-to-day basis. Unfortunately, just as many patients start out getting proper exercise and eating right, and then go back to their old habits; they often follow the same pattern regarding SMBG.

A final note on SMBG. Glucometers are both amazing and sophisticated—and often not used to their full potential. By pushing a few buttons, you can get the current blood glucose measurement, and can label the reading as to when it was taken (eg, after exercise, before a meal). Many meters can calculate the average glucose level at a given time of day; track trends in glucose levels over a variety of time ranges; or give just about any other information you might want or need. However, there’s a problem: In order to use a glucometer properly, and take full advantage of the information it can provide, you need to be able to read, understand, and follow the directions—directions that can be both complicated and lengthy (the manual may be 50 pages long). Clearly, the task can be daunting, especially for older people. Why? Just ask someone older—say your mom or dad—if they can program and use all the features of their cordless phone, never mind the HDTV, DVD player, and other high-tech gizmos in the house. More likely than not, they can’t. The glucometer is no different.

Monitoring of hemoglobin A1C

Measurement of hemoglobin A1c—also called glycosylated hemoglobin or glycated hemoglobin—provides an index of average glucose levels over the prior 2 to 3 months. Glucose interacts spontaneously with hemoglobin in red blood cells to form glycosylated derivatives, the most prevalent being A1c. With prolonged hyperglycemia, levels of A1c gradually increase. Since red blood cells have a long life span (120 days), levels of A1c reflect average glucose levels over an extended time. Hence, by measuring A1c every 3 to 6 months, we can get a picture of long-term glycemic control. Please note, however, that measuring A1c tells us nothing about acute, hour-to-hour swings in blood glucose. Accordingly, although measuring A1c is an important part of diabetes management, it is clearly no substitute for SMBG.

How is testing done? Current tests use a tiny capillary blood sample from a “finger stick,” and yield results in minutes, while the patient is still in the office.

How are test results expressed? Results are usually reported as a percent of total hemoglobin in blood (eg, 7%). In addition, they may be reported as a value for estimated Average Glucose (eAG), expressed as mg glucose/dL of blood (ie, the same units patients see every day when doing SMBG). Selected A1c values and their eAG equivalents are listed in Table 57–4.

What’s the A1c target level? For most patients with diabetes, the goal is to keep A1c below 7% of total hemoglobin. According to a 2008 statement issued jointly by the ADA and the European Association for the Study of Diabetes, A1c should be measured every 3 months until the value drops to 7%, and at least every 6 months thereafter. As noted above, a value of 6.5% or greater is considered diagnostic of diabetes.

Although an A1c goal of below 7% is good for most patients, a less stringent goal (eg, below 8%) may be appropriate for some patients, such as those with a history of severe hypoglycemia, limited life expectancy, or advanced microvascular or macrovascular complications.

Insulin

Insulin is used to treat all patients with type 1 diabetes, and up to 40% of those with type 2 diabetes. Our discussion of insulin is divided into three sections: physiology, preparations and administration, and therapeutic use.

Physiology

Structure

The structure of insulin is depicted in Figure 57–1. As indicated, insulin consists of two amino acid chains: the “A” (acidic) chain and the “B” (basic) chain. The A and B chains are linked to each other by two disulfide bridges.

Figure 57–1 Conversion of proinsulin to insulin.
Proinsulin is the immediate precursor of the insulin secreted by our pancreas. Enzymes clip off connecting peptide (C-peptide) to release active insulin, composed of two peptide chains (A and B) connected by two disulfide (S–S) bonds. Since C-peptide arises only from endogenous insulin, its presence in blood indicates that at least some pancreatic insulin is being made.

Biosynthesis

Insulin is synthesized in the pancreas by beta cells within the islets of Langerhans. The immediate precursor of insulin is called proinsulin (see Fig. 57–1).

Proinsulin consists of insulin itself plus a peptide loop that runs from the A chain to the B chain. This loop is named connecting peptide or C-peptide. In the final step of insulin synthesis, C-peptide is enzymatically clipped from the proinsulin molecule.

Measurement of plasma C-peptide levels offers a way to assess residual capacity for insulin synthesis. Since commercial insulin preparations lack C-peptide, and since endogenous C-peptide is only present as a by-product of insulin biosynthesis, the presence of C-peptide in the blood indicates the pancreas is still producing some insulin of its own.

Secretion

The principal stimulus for insulin release is a rise in blood glucose. And the most common cause of glucose elevation is eating a meal, especially one rich in carbohydrates. Under normal conditions, there is tight coupling between rising levels of blood glucose and increased secretion of insulin. Insulin release may also be triggered by amino acids, fatty acids, and ketone bodies.

The sympathetic nervous system provides additional control of release. Activation of beta₂-adrenergic receptors in the pancreas promotes secretion of insulin. Conversely, activation of alpha-adrenergic receptors in the pancreas inhibits insulin release. Of the two modes of regulation, activation of beta receptors is more important.

Metabolic actions

The metabolic actions of insulin are primarily anabolic (ie, conservative, constructive). Insulin promotes conservation of energy and buildup of energy stores, such as glycogen. The hormone also promotes cell growth and division.

Insulin acts in two ways to promote anabolic effects. First, it stimulates cellular transport (uptake) of glucose, amino acids, nucleotides, and potassium. Second, insulin promotes synthesis of complex organic molecules. Under the influence of insulin and other factors, glucose is converted into glycogen (the liver’s way to store glucose for later use), amino acids are assembled into proteins, and fatty acids are incorporated into triglycerides. The principal metabolic actions of insulin are summarized in Table 57–5.

TABLE 57–5

Metabolic Actions of Insulin

Substance Affected	Insulin Action	Site of Action
Carbohydrates	↑ Glucose uptake ↑ Glucose oxidation ↑ Glucose storage ↑ Glycogen synthesis ↓ Glycogenolysis Gluconeogenesis*	Muscle, adipose tissue Muscle Muscle, liver Liver
Amino Acids and Proteins	↑ Amino acid uptake ↓ Amino acid release ↑ Protein synthesis	Muscle Muscle Muscle
Lipids	↑ Triglyceride synthesis ↓ Release of FFA^† and glycerol ↓ Oxidation of FFA to ketoacids^‡	Adipose tissue Adipose tissue Liver

^*Because of decreased delivery of substrate (fatty acids and amino acids) to the liver.

^†FFA = free fatty acids.

^‡Because of decreased delivery of FFA to the liver.

Metabolic consequences of insulin deficiency

Insulin deficiency puts the body into a catabolic mode (ie, a metabolic state that favors the breakdown of complex molecules into their simpler constituents). Hence, in the absence of insulin, glycogen is converted into glucose, proteins are degraded into amino acids, and fats are converted to glycerol (glycerin) and free fatty acids. These catabolic effects contribute to the signs and symptoms of diabetes. Note that the catabolic effects resulting from insulin deficiency are opposite to the anabolic effects when insulin levels are normal.

Insulin deficiency promotes hyperglycemia by three mechanisms: (1) increased glycogenolysis, (2) increased gluconeogenesis, and (3) reduced glucose utilization. Glycogenolysis, by definition, generates free glucose by breaking down glycogen. The raw materials that allow increased gluconeogenesis are the amino acids and fatty acids produced by metabolic breakdown of proteins and fats. Reduced glucose utilization occurs because insulin deficiency decreases cellular uptake of glucose, and decreases conversion of glucose to glycogen.

Preparations and administration

There are many insulin preparations or formulations. All of them have identical mechanisms. Major differences concern time course, appearance (clear or cloudy), concentration, and route of administration. Because of these differences, insulin preparations cannot be used interchangeably. In fact, if a patient is given the wrong preparation, the consequences can be dire. Unfortunately, medication errors with insulins remain all too common, which explains why insulin appears on all lists of “high-alert” agents.

Sources of insulin

All forms of insulin currently manufactured in the United States are produced using recombinant DNA technology. Some products, referred to as human insulin, are identical to insulin produced by the human pancreas. Other products, referred to as human insulin analogs, are modified forms of human insulin. The analogs have the same pharmacologic actions as human insulin, but have different time courses.

Types of insulin

There are seven types of insulin: “natural” insulin (also known as regular insulin or native insulin) and six modified insulins. Three of the modified insulins—insulin lispro, insulin aspart, and insulin glulisine—act more rapidly than natural insulin but have a shorter duration of action. The other modified insulins act more slowly than natural insulin but have a longer duration. Two processes are used to prolong insulin effects: (1) complexing natural insulin with a protein, and (2) altering the insulin molecule itself. When the insulin molecule has been altered, we refer to the product as a human insulin analog. Specific alterations made to create the insulin analogs are summarized in Table 57–6.

TABLE 57–6

Amino Acids Substitutions in Human Insulin Analogs *

Insulin Type	Amino Acids in A-Chain Position	Amino Acids in B-Chain Position
Insulin Type	A8	A10	A21	B3	B28	B29	B30	B31	B32
Human Insulin
Native^†	Thr	Ilc	Asn	Asn	Pro	Lys	Thr	—	—
Human Insulin Analogs
Glargine	Thr	Ilc	Gly	Gly	Pro	Lys	Thr	Arg	Arg
Aspart	Thr	Ilc	Asn	Asn	Asp	Lys	Thr	—	—
Lispro	Thr	Ilc	Asn	Asn	Lys	Pro	Thr	—	—
Glulisine	Thr	Ilc	Asn	Lys	Pro	Glu	Thr	—	—
Detemir	Thr	Ilc	Asn	Asn	Pro	Lys^‡	§	—	—

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Tags: Pharmacology for Nursing Care

Jul 24, 2016 | Posted by admin in NURSING | Comments Off

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