The ADA’s recommendation for alcohol is consistent with general recommendations
of no more than two alcoholic drinks/day for men or one drink/day for women. A
drink is equivalent to 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of distilled
spirits (each contains about 15 g of carbohydrate). Nevertheless, its caloric
contribution must be considered (1 alcoholic beverage = 2 fat exchanges), and it
should always be taken with food to minimize its hypoglycemic effect. In people with
diabetes, light-to-moderate alcohol intake (one to two drinks/day) is associated with
a decreased risk of CVD. A note of caution: Evening consumption of alcohol may
increase the risk of nocturnal and fasting hypoglycemia, particularly in people with
Physical activity is a key factor in the treatment of diabetes, particularly in Type 2
diabetes, because obesity and inactivity contribute to the development of glucose
intolerance in genetically predisposed individuals. Regular exercise reduces
cholesterol levels, raises HDL-C, lowers BP, augments weight-reduction diets,
reduces the dose requirements or need for insulin or antihyperglycemic agents,
enhances insulin sensitivity, and improves psychological well-being by reducing
stress. Exercise increases glucose utilization, which is provided initially from the
breakdown of muscle glycogen and, subsequently, from hepatic glycogenolysis and
gluconeogenesis. These effects are mediated through norepinephrine, epinephrine,
growth hormone, cortisol, and glucagon, along with the suppression of insulin
secretion. In patients using insulin, hyperglycemia, normoglycemia, or hypoglycemia
can occur secondary to exercise depending on the degree of control, recent
administration of rapid-acting insulin, and food intake. Exercise in patients taking
insulin must be tempered by increased food intake, potential delay in insulin
administration, decreased doses of insulin, or a combination of these actions to
In patients with Type 2 diabetes, plasma glucose concentrations usually decrease
in response to exercise, but symptomatic hypoglycemia is uncommon. The vascular
benefits of exercise are particularly helpful in patients with diabetes given their
predisposition to CVD. In general, exercise that produces moderate exertion
(increase in heart rate of 20%–40% from resting baseline) is recommended with a
starting goal of 150 minutes/week. The eventual goal is for patients to be able to
achieve 50% to 70% of their age-adjusted maximal heart rate.
Resistance exercise has been shown to improve insulin sensitivity. Therefore, in
the absence of any contraindications, people with Type 2 diabetes are encouraged to
perform resistance training 3 times/week. Patients with conditions that may preclude
certain types of physical activity (e.g., coronary artery disease, uncontrolled
hypertension, severe autonomic neuropathy, severe peripheral neuropathy or history
of foot lesions, and advanced retinopathy in which retinal detachment may occur)
should be carefully evaluated before starting an exercise regimen.
Insulin, along with diet, is crucial to the survival of individuals with Type 1 diabetes
and plays a major role in the therapy of people with Type 2 diabetes when their
symptoms cannot be controlled with diet or noninsulin antidiabetic agents. Insulin
also is used for people with Type 2 diabetes during periods of intercurrent illness or
stress (e.g., surgery, pregnancy). The use of antidiabetic agents is primarily reserved
for the treatment of patients with Type 2 diabetes whose symptoms cannot be
controlled with diet and exercise alone. The clinical use of these agents and the
complications associated with their use are discussed later in this chapter.
The overall goal of diabetes management is to prevent acute and chronic
complications. Periodic assessments of A1C coupled with regular measurement of
fasting, preprandial, and postprandial glucose levels should be used to assess
therapy. The following overall goals of therapy are agreed on by most
Landmark randomized, prospective trials of various interventional therapies in
patients with both Type 1 and Type 2 diabetes have clearly demonstrated that
reductions in hyperglycemia significantly decrease microvascular complications.
In both the UKPDS and the DCCT follow-up studies, significant reductions in
macrovascular complications were also observed. Target BG goals may need to
be adjusted for patients with frequent, severe hypoglycemia or hypoglycemia
unawareness (see Case 53-8, Questions 1–3, and Case 53-9), or with CVD. In
addition, established renal insufficiency, proliferative retinopathy, severe
neuropathy, and other advanced complications are not likely to be improved by
tight glucose control. See Table 53-5 for the ADA glycemic goals.
Association of Clinical Endocrinologists and the American College of
Endocrinology established glycemic goals as well (Table 53-5).
guidelines will be discussed throughout this chapter.
Try to keep patients free of symptoms associated with hyperglycemia (polyuria,
polydipsia, weight loss, fatigue, recurrent infection, ketoacidosis) or hypoglycemia
(hunger, anxiety, palpitations, sweatiness).
Maintain normal growth and development in children. Intensive therapy is not
recommended across any age group with a goal A1C of <7.5%. Goals can be
individualized, targeting <7% if can be done so safely with minimum
hypoglycemia (see Case 53-4, Questions 2 and 3).
Eliminate or minimize all other cardiovascular risk factors (obesity, hypertension,
tobacco use, hyperlipidemia; see Table 53-5 for glycemic and blood pressure
Try to integrate the patient into the healthcare team through intensive education. The
patient’s knowledge and understanding of this disease can favorably influence its
outcomes (see Table 53-14 later in this chapter).
Methods of Monitoring Glycemic Control
In addition to monitoring signs and symptoms associated with hyperglycemia,
hypoglycemia, and the long-term complications of diabetes, an ongoing assessment of
metabolic control is an integral component of diabetes management. Ideally, SMBG
results combined with laboratory measures of acute and chronic glycemia can be
used to evaluate and adjust therapy.
38,56 SMBG and A1C levels continue to be the two
primary methods used to access glycemic control. Continuous glucose monitoring
(CGM) of interstitial fluid is also available for people with diabetes. CGM is
discussed somewhat briefly here because this method is currently recommended for
consideration, along with SMBG, for patients with Type 1 diabetes only, especially
those with hypoglycemic unawareness.
Ketone testing is recommended for patients with gestational and Type 1 diabetes.
Urine ketones (acetoacetic acid) should be evaluated when glucose concentrations
consistently exceed 300 mg/dL or during acute illness.
monitor that is able to measure blood β-ketones (e.g., the Precision Xtra has a
specific test strip to measure β-hydroxybutyric acid) can be used. Persistently high
glucose concentrations of this magnitude signal insulin deficiency that can, in turn,
lead to lipolysis and ketoacidosis. A positive test may indicate impending or
established ketoacidosis and demands a more extensive diagnostic workup. Testing
also is recommended during pregnancy and if the patient has symptoms of
ketoacidosis. Although there are generally no ketones in the urine, they may be
present in people who are on extremely low-caloric diets and in the first morning
sample of women who are pregnant. Also, see discussions of sick day management
and ketoacidosis in other sections of this chapter (Cases 53-7 and 53-13).
FPG concentrations are commonly used to assess glycemic control in the fasting state
because this is when glucose concentrations are most reproducible. FPG
concentrations generally reflect glucose derived from hepatic glucose production
because this is the primary source of glucose in the postabsorptive state. The FPG is
the most frequent test performed by patients when self-monitoring. Postprandial
glucose concentrations (1–2 hours after the start of the meal) also are used to assess
glycemic control when fasting glucose concentrations are within normal limits or
when there is a need to assess the effects of food or drugs (e.g., rapid-acting insulins,
glinides) on meal-related glycemia. In individuals without diabetes, glucose
concentrations generally return to less than 140 mg/dL within 2 hours after a meal.
Because glucose concentrations are affected by various factors (e.g., meals,
medications, stress), single-time point measurements cannot be used to assess a
patient’s overall control. Most laboratories measure plasma glucose concentrations
rather than whole blood because these values are not subject to changes in the
hematocrit. The majority of glucose monitors report plasma-referenced glucose
concentrations. Whole BG concentrations are approximately 10% to 15% lower than
plasma glucose concentrations because glucose is not distributed into red blood
SELF-MONITORING OF BLOOD GLUCOSE
SMBG has made euglycemia, both preprandially and postprandially, an achievable
goal. Patients and their healthcare providers can use SMBG to assess directly the
effects of drug dose changes, meals, exercise, and illness on BG concentrations. With
improved technology, decreasing costs, and increased coverage by health plans,
SMBG is the day-to-day monitoring test of choice for all patients with diabetes.
However, SMBG remains expensive for patients without health insurance, is
invasive, and can be difficult for some patients to perform depending on their
technical ability. Furthermore, to achieve maximal benefit from SMBG, both the
clinician and patient must be motivated and willing to spend the time required to
interpret the data and modify therapy to improve glycemic control. The frequency and
timing of performing SMBG should be dictated by the individual’s needs and goals.
Selection and use of SMBG testing materials are discussed in Case 53-2, Questions 9
and 10. Patients in whom SMBG is particularly valuable include the following:
Patients with Type 1 diabetes: Frequent BG measurements help the patient to
correlate meals, exercise, and insulin dose with BG concentrations. This instant
feedback gives the patient an increased sense of control and motivation, leading
Pregnant patients: Infant morbidity and mortality are associated with the mother’s
overall glucose control. Using SMBG, the mother with diabetes who achieves
normoglycemia before conception and throughout pregnancy improves her
chances of delivering a live, healthy infant.
Patients having difficulty recognizing hypoglycemia: With time, patients with
diabetes can develop a sluggish counter-regulatory response to hypoglycemia
whereby hypoglycemic symptoms are blunted or even absent. This is often
referred to as hypoglycemic unawareness. Routine SMBG to detect asymptomatic
hypoglycemia is essential in these individuals. In addition, acute anxiety attacks
or signs and symptoms associated with a rapidly falling BG concentration may
mimic a true hypoglycemic reaction. This can be evaluated easily by measuring a
Patients who are using physiologic (e.g., basal-bolus) insulin therapy: Individuals
who are on multiple daily doses of insulin or those using an insulin pump should
perform SMBG to evaluate the effectiveness of their insulin regimens and meal
plans and to check for hypoglycemic or hyperglycemic reactions (see Case 53-2,
Question 10). Knowledge of preprandial, postprandial, bedtime, and nocturnal
(e.g., 2 AM) BG concentrations is essential in determining basal and preprandial
Patients with Type 2 diabetes who are on therapy that can cause hypoglycemia:
Individuals taking glinides, a sulfonylurea, or insulin therapy should know how to
perform SMBG to detect hypoglycemia when experiencing symptoms consistent
Patients with Type 2 diabetes who are engaged in self-management of their
diabetes: Even individuals using noninsulin therapies can benefit from SMBG to
evaluate the impact of food, exercise, and antidiabetic medications on their BG.
Like SMBG, CGM provides real-time information on glucose concentrations.
However, the difference is that the CMG system automatically detects glucose
concentrations (subcutaneous interstitial fluid glucose concentrations) on a continual
basis. CGM systems use electrochemical sensors that are inserted into the skin.
Sensor probe length varies as does the duration that the sensor can remain in the skin
(3–7 days). The sensors transmit a signal to a receiver (wired or wireless), which
records and displays the data every 1 to 5 minutes. The sensors require
a warm-up or initialization period and have very specific calibration requirements.
Calibration is performed by using a BG monitor. Interstitial glucose levels lag behind
plasma or BG levels by 8 to 18 minutes, depending on the glucose rate of change.
Therefore, if a person’s glucose is low, or trending downward, SMBG is required.
CGM systems have alarms that can go off at certain high and low glucose thresholds.
The ability to detect hypoglycemia during the night with these alarms has been a very
attractive reason for using CGM. Another key feature is the ability to follow trends
and rates of change in BG levels. Any acute treatment changes still require SMBG.
Small, short-term studies have demonstrated modest improvements in A1C (0.3%–
0.6% reductions) in adults and children with Type 1 diabetes.
with a glucose meter, use of CGM requires a person to actively assess and react to
their readings for this self-management tool to have an impact on A1C.
The glycosylated hemoglobin, or A1C, has become the gold standard for measuring
chronic glycemia and is the clinical marker for predicting long-term complications,
particularly microvascular complications. A1C is most commonly measured because
it comprises the majority of A1C and is the least affected by recent fluctuations in
BG. A1C measures the percentage of hemoglobin A that has been irreversibly
glycosylated at the N-terminal amino group of the β-chain; the plasma glucose level
and the life span of a red blood cell (RBC; ~120 days) determine its value. Thus,
A1C is an indicator of glycemic control during the preceding 2 to 3 months. In
patients without diabetes, A1C comprises approximately 4% to 6% of the total
hemoglobin. Values may be 3 times this level in patients with diabetes.
The following formula was developed to convert an A1C into an average glucose:
28.7 × A1C − 46.7 = eAG (estimated average glucose). A formula that approximates
(not exact) this very closely and is much easier to use in practice is (A1C − 2) × 30.
The ADA now recommends reporting an eAG (units, mg/dL, or mmol/L) along with
the A1C. An eAG calculator is available on their website to do this conversion
(http://diabetes.org/professional/eAG). The correlation between A1C and eAG is
A1C (%) Estimated Average Plasma Glucose (mg/dL)
Hemoglobinopathies, such as sickle cell trait or chemically modified derivatives
of hemoglobin as seen in uremia, in which hemoglobin becomes carbamylated, or
acetylated hemoglobin with high-dose aspirin, can affect A1C values (increase or
decrease depending on the assay), resulting in inaccurate indications of glycemic
control. Alterations in red blood cell survival or turnover, seen in hemolytic anemia
and acute blood loss, can falsely lower the A1C. Also a recent blood transfusion or
use of intravenous (IV) iron therapy or erythropoietin-stimulating agents in patients
with chronic kidney disease can falsely lower A1C values. A glycated serum protein
(fructosamine) should be considered for these patients. Antioxidants such as vitamins
C and E also may interfere with the glycosylation process.
A1C can be measured without any special patient preparation (e.g., fasting) and
generally is not subject to acute changes in insulin dosing, exercise, or diet. A1C
values can be used as an adjunct to assess overall glycemic control in patients with
diabetes or to diagnose diabetes and prediabetes.
in BG concentrations. These values are needed to adjust the meal plan or medication
doses. Sometimes, an A1C is used to verify clinical impressions related to glucose
control and patient adherence. It should be measured quarterly in patients who do not
meet treatment goals, and at least semiannually in stable patients who are meeting
GLYCATED SERUM PROTEIN, GLYCATED SERUM ALBUMIN, AND
Assays for glycated serum proteins reflect the extent of glycosylation of a variety of
serum proteins, including glycated serum albumin.
56 The fructosamine assay is one of
the most widely used methods to measure glycated proteins (normal, 2–2.8 mmol/L).
Because the half-life of albumin is approximately 14 to 20 days, fructosamine
provides an indication of glycemic control during a shorter time frame (1–2 weeks)
than does the A1C. The ADA does not consider measurement of fructosamine
equivalent to that of A1C, although it correlates well with this value. Fructosamine
levels may be useful as an adjunct to A1C in determining whether a patient is
improving or worsening in the short term (e.g., a patient on insulin therapy
undergoing multiple dosage adjustments; for women with Type 2 diabetes during
pregnancy or gestational diabetes) or in patients with conditions such as hemolytic
anemia in whom the A1C test is inaccurate.
Insulin is a hormone secreted from the pancreatic β-cell in response to glucose and
other stimulants (e.g., amino acids, free fatty acids, gastric hormones,
parasympathetic stimulation, β-adrenergic stimulation).
of two polypeptide chains (a 21-amino acid A chain and a 30-amino acid B chain),
which are connected by two disulfide bonds. Proinsulin, the precursor of insulin, is a
single-chain, 86-amino acid polypeptide that is processed in the Golgi apparatus of
β-cells and then packaged into granules.
indicate the presence of endogenously produced insulin and functioning β-cells.
Insulin is crucial to the survival of individuals with Type 1 diabetes, whose β-cells
have been destroyed. It also plays a major role in the therapy of many individuals
with Type 2 diabetes in combination of antidiabetic agents. Insulin also is used in
patients with Type 2 diabetes during pregnancy or periods of illness or stress (e.g.,
Commercially available insulin products differ in their physical and chemical
properties as well as in the pharmacokinetics of their action. Prior issues with
immunogenicity have been eliminated through modern manufacturing processes and
the cessation of use of animal-derived insulin products. Consequently,
immunologically mediated sequelae, such as lipodystrophy, hypersensitivity, and
insulin resistance caused by “blocking” antibodies, are extremely rare.
Pharmacokinetics: Absorption, Distribution, and
The route of administration for insulin is primarily via SC injection. Regular insulin,
a solution, can be administered by any parenteral route: IV, intramuscularly (IM), or
subcutaneously (SC). Most other injectable insulins are only to be used SC with the
exception of insulin aspart and insulin lispro which may be used via IV route if they
are first diluted. Afrezza (insulin human) is the only insulin currently available as a
powder for inhalation. Other routes for insulin administration have been studied,
including dermal, nasal, buccal, and oral; however, these formulations are not
currently approved for use here in the United States.
After SC injection, insulin is absorbed directly into the bloodstream, bypassing the
lymphatic system. The rate-limiting step of insulin activity after SC administration is
absorption of insulin from the injection site, which depends on the type of insulin
administered, as well as a multitude of other factors. Variations in SC absorption can
occur, primarily related to changes in blood flow around the injection site.
Endogenous insulin is secreted directly into the portal circulation and thus is
primarily cleared by the liver in nondiabetic individuals (60%), with the kidneys
removing only 35% to 40% of it.
63 Exogenous insulin is degraded at both renal and
extrarenal (liver and muscle) sites. Degradation also takes place at the cellular level
after internalization of the insulin–receptor complex. In contrast to endogenously
secreted insulin, up to 60% of exogenous insulin is cleared from the systemic
circulation by the kidneys, with the liver accounting for only 30% to 40% of its
clearance. Insulin is filtered by glomerular capillaries, but more than 99% is
reabsorbed by the proximal tubules. The insulin is then degraded in glomerular
capillary cells and postglomerular peritubular cells.
65 See Case 53-6 for changes in
insulin requirement in renal dysfunction.
Clinically, the most important differences among insulin products relate to their
onset, peak, and duration of action (not the actual insulin levels, which is
pharmacokinetics). Current insulin products can be categorized as rapid-acting,
short-acting, intermediate-acting, and long-acting insulin. Products available in the
United States are listed in Table 53-6, and the onset of action, peak effect, and
durations of action of each insulin category are listed in Table 53-7. However, these
data are derived primarily from studies in normal, healthy volunteers in the fasting
state or in well-controlled patients with diabetes stabilized in a metabolic ward. In
actuality, intersubject and intrasubject variations in response to insulin can be
substantial because an individual pattern of response to insulin can be affected by
ambient temperature, and interactions between insulins that have been mixed
together; see Table 53-8 later in this chapter and Case 53-2, Question 14).
Nevertheless, knowledge of when one might expect the various insulins to exert their
effects is absolutely essential to the rational adjustment of insulin dosages.
Insulins Available in the United States
Type/Duration of Action Brand Name Manufacturer
Insulin aspart NovoLog Novo Nordisk
Insulin glulisine Apidra Sanofi Aventis
NPH (isophane insulin suspension) Humulin N Lilly
Insulin glargine Lantus Sanofi Aventis
Insulin detemir Levemir Novo Nordisk
Insulin degludec Tresiba (U-100 and U200)
NPH/regular (70%/30%) Humulin 70/30 Lilly
Insulin aspart protamine suspension/insulin aspart (70%/30%) NovoLog Mix 70/30 Novo Nordisk
Insulin lispro protamine suspension/insulin lispro (75%/25%) Humalog Mix 75/25 Lilly
Insulin lispro protamine suspension/insulin lispro (50%/50%) Humalog Mix 50/50 Lilly
Insulin degludec/Insulin aspart (70%/30%) Ryzodeg 70/30 Novo Nordisk
Regular insulin Afrezza MannKind
requiring very large insulin doses.
NPH, neutral protamine Hagedorn, or isophane insulin suspension.
(hours) Peak (hours) Duration (hours) Appearance
Rapid-acting (insulin aspart, glulisine,
5–15 minutes 30–90 minutes <5 Clear
Insulin glargine U-100 1.5 No pronounced
Insulin glargine U-300 6 None 24 Clear
Insulin detemir 0.8–2 Relatively flat 5.7–23.2 Clear
Insulin degludec 1 None 42 Clear
Insulin inhalation regular ≤15 minutes 1 3–5
aShould not be mixed with other insulins. Some patients require twice-daily dosing.
Insulin lispro (Humalog) was the first available rapid-acting insulin analog. The
natural amino acid sequence of the insulin B chain at positions 28 (proline) and 29
(lysine) is inverted to form lispro. This change results in an insulin molecule that
more loosely self-associates into hexamers than does regular human insulin.
Consequently, the active monomeric form is more readily available, resulting in an
onset of activity (15 minutes), peak action (30–90 minutes), and duration (3–4 hours)
that more closely simulates physiologic insulin secretion relative to meals. Because
it can be injected shortly before eating (0–15 minutes), lispro, and all rapid-acting
insulins, provides patients greater flexibility in lifestyle. These insulins lower 2-hour
postprandial BG levels and can decrease the risk of late postprandial and nocturnal
hypoglycemia compared with regular insulin formulations.
insulin pump most often use a rapid-acting insulin instead of regular insulin. One
randomized, two-way, crossover, open-label study compared lispro with regular
insulin administered for 3 months by continuous SC insulin infusion.
in A1C values that were significantly lower than those produced by regular insulin
(7.41% vs. 7.65%). There were no differences in adverse events. Because lispro has
a shorter duration of action than regular insulin, hyperglycemia and ketosis may occur
more rapidly in patients with Type 1 diabetes if insulin pump delivery is
inadvertently interrupted or if the basal insulin dose is missed. Insulin lispro is
approved for use in pediatrics (studies included children of age 3 and older), and it
is pregnancy category B. Insulin lispro is available in concentrations as both 100 and
200 units/mL. Both formulations are available as an insulin pen (Kwikpen); however,
insulin lispro 100 units/mL is available in both vial and insulin pen formulations. The
availability of the 200-units/mL formulation allows patients to inject a greater
amount of insulin in an overall smaller volume.
Factors Altering Onset and Duration of Insulin Action
Route of administration Onset of action more rapid and duration of action shorter for IV > IM >
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