368

Diabetes Mellitus

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BASIC INFORMATION

DEFINITION
Diabetes mellitus (DM) refers to a syndrome of
hyperglycemia resulting from many different
causes (see Etiology). It is broadly classified
into type 1 and type 2 DM. The terms insulindependent and noninsulin-dependent diabetes are obsolete because when a person
with type 2 diabetes needs insulin, he or she
remains labeled as type 2 and is not reclassified as type 1. Table 1-160 provides a general
comparison of the two types of DM.


The American Diabetes Association (ADA)
defines DM as follows:
C A fasting plasma glucose (FPG) 126 mg/
dl, which should be confirmed with repeat
testing on a different day. Fasting is defined
as no caloric intake for at least 8 hr.
C Symptoms of hyperglycemia and a casual (random) plasma glucose 200 mg/
dl. Classic symptoms of hyperglycemia
include polyuria, polydipsia, and unexplained weight loss.
C An oral glucose tolerance test (OGTT) with a
plasma glucose 200 mg/dl 2 hr after a 75
g (100 g for pregnant women) glucose load.
C A hemoglobin A1c (HbA1c) value 6.5%.
Individuals with glucose levels higher than
normal but not high enough to meet the
criteria for diagnosis of DM are considered to
have prediabetes, the diagnosis of which is
made as follows:
C A fasting plasma glucose 100 to 125 mg/
dl; this is referred to as impaired fasting
glucose.
C After OGTT, a 2-hr plasma glucose 140 to
199; this is referred to as impaired glucose
tolerance.
C A hemoglobin A1c value 5.7% to 6.4%.

Table 1-161 describes diagnostic categories

for DM and at-risk states.

SYNONYMS
IDDM (insulin-dependent diabetes mellitus)
NIDDM (noninsulin-dependent diabetes mellitus)
Type 1 diabetes mellitus (insulin-dependent
diabetes mellitus)
Type 2 diabetes mellitus (noninsulin-dependent
diabetes mellitus)
ICD-9CM CODES
250.0Diabetes mellitus (NIDDM)
250.1Insulin-dependent diabetes mellitus
without complication (IDDM)
ICD-10CM CODES
E11.5Type 2 diabetes mellitus with
peripheral circulatory complications
E11.6Type 2 diabetes mellitus with other
specified complications
E11.7Type 2 diabetes mellitus with multiple
complications
E11.8Type 2 diabetes mellitus with
unspecified complications
E11.9Type 2 diabetes mellitus without
complications

EPIDEMIOLOGY &
DEMOGRAPHICS
DM affects 9% to 10% of the U.S. population.
Prevalence rates vary considerably by race/
ethnicity.
Incidence rate increases with age, varying
from 2% in persons age 20 to 44 yr to 18%
in persons 65 to 74 yr. Type 2 DM can have
a long presymptomatic phase, leading to a
4- to 7-yr delay in diagnosis.


Diabetes accounts for 8% of all legal
blindness in the United States and is the
leading cause of end-stage renal disease
(ESRD).

Patients with diabetes are 2-4 times more

likely than nondiabetic patients to experience
development of cardiovascular disease.

PHYSICAL FINDINGS & CLINICAL

PRESENTATION
1. Physical examination varies with the presence of complications and may be normal in
early stages
2. Diabetic retinopathy:
a. 
Nonproliferative (background diabetic
retinopathy):

(1) 
Initially: microaneurysms, capillary
dilation, waxy or hard exudates, dot
and flame hemorrhages, atrioventricular shunts

(2) 
Advanced stage: microinfarcts with
cotton wool exudates, macular edema
b. Proliferative retinopathy: characterized by
formation of new vessels, vitreous hemorrhages, fibrous scarring, and retinal detachment

3. 
Cataracts and glaucoma occur with increased frequency in patients with diabetes
4. Diabetic neuropathy
a. Distal sensorimotor polyneuropathy

(1) Symptoms include paresthesia, hyperesthesia, or burning pain involving
bilateral distal extremities, in a stocking-glove distribution. This can progress to motor weakness and ataxia.

(2) 
Physical examination may reveal
decreased pinprick sensation, sensation to light touch, vibration sense,
and loss of proprioception. Motor disturbances such as decreased deep
tendon reflexes and atrophy of interossei muscles can also be seen.
b. Autonomic neuropathy:

(1) GI disturbances: esophageal motility
abnormalities, gastroparesis, diarrhea
(usually nocturnal)

TABLE 1-160 General Comparison of the Two Types of Diabetes Mellitus

Previous terminology
Age of onset
Genetic predisposition
Human leukocyte antigen
associations
Other associations
Precipitating and risk factors
Findings at diagnosis
Endogenous insulin levels
Insulin resistance
Prolonged fast
Stress, withdrawal of insulin

Type 1

Type 2

Insulin-dependent diabetes mellitus (IDDM), type I, juvenile-

onset diabetes
Usually <30 yr, particularly childhood and adolescence, but
any age
Moderate; environmental factors required for expression;
35%-50% concordance in monozygotic twins; several
candidate genes proposed
Linkage to DQA and DQB, influenced by DRB (3 and 4) (DR2
protective)
Autoimmune; Graves disease, Hashimotos thyroiditis, vitiligo, Addisons disease, pernicious anemia
Largely unknown; microbial, chemical, dietary, other

Noninsulin-dependent diabetes mellitus, type II, adult-onset

diabetes
Usually >40 yr, but any age

85%-90% of patients have one and usually more autoantibodies to ICA512/IA-2/IA-2b, GAD65, insulin (IAA)
Low or absent
Only with hyperglycemia
Hyperglycemia, ketoacidosis
Ketoacidosis

Strong; 60%-90% concordance in monozygotic twins; many candidate genes proposed; some genes identified in maturity-onset
diabetes of the young
None known
Heterogenous group, ongoing subclassification based on identification of specific pathogenic processes and genetic defects
Age, obesity (central), sedentary lifestyle, previous gestational
diabetes
Possibly complications (microvascular and macrovascular) caused
by significant preceding asymptomatic period
Usually present (relative deficiency), early hyperinsulinemia
Mostly present
Euglycemia
Nonketotic hyperglycemia, occasionally ketoacidosis

GAD, Glutamic acid decarboxylase; IA-2/IA-2b, tyrosine phosphatases; IAA, insulin autoantibodies; ICA, islet cell antibody; ICA512, islet cell autoantigen 512 (fragment of IA-2).
From Andreoli TE (ed): Cecil essentials of medicine, ed 6, Philadelphia, 2005, Saunders.

ALG PTG EBM Diabetes Mellitus 369


TABLE 1-161 Diagnostic Categories*: Diabetes Mellitus and At-Risk States
2-HOUR (75-g) OGTT RESULT
Fasting Plasma Glucose Level
<100 mg/dl
100-125 mg/dl
126 mg/dl
HbA1C Level

<140 mg/dl

140-199 mg/dl

200 mg/dl

Normal
IFG
DM
<5.7%
Normal

IGT

DM
DM
DM
6.5%
DM

IGT and IFG

DM
5.7-6.4%
High-risk

(2) 
Genitourinary (GU) disturbances:
neurogenic bladder (hesitancy, weak
stream, and dribbling), impotence
(3) 
Cardiovascular (CV) disturbances:
orthostatic hypotension, tachycardia,
decreased heart rate variability (HRV).
Decreased heart rate variability is associated with increased cardiac mortality,
independent of ejection fraction.
c. Polyradiculopathy: painful weakness and
atrophy in the distribution of 1 contiguous nerve roots.
d. Mononeuropathy involving cranial nerves III,
IV, or VI or peripheral nerves can also occur.
5. Diabetic nephropathy: pedal edema, pallor,
weakness, uremic appearance
6. Foot ulcers: occur in 15% of individuals with
diabetes (annual incidence rate 2%) and are
the leading causes of hospitalization; they are
usually secondary to a combination of factors,
including peripheral vascular insufficiency,
repeated trauma (unrecognized because of
sensory loss), and superimposed infection.
a. Patient symptoms are usually less than
would be expected from clinical findings,
due to loss of sensation related to peripheral neuropathy.
b. Comprehensive foot exams include visual
inspection, assessment of pedal pulses, and
assessment of protective sensation using
a 10-g monofilament to test sensation.
c. Prevention of foot ulcers in an individual
with diabetes includes strict glucose
control, patient education, prescription

footwear, intensive podiatric care, and

evaluation for surgical interventions

7. 
Neuropathic arthropathy (Charcots joints):
bone or joint deformities from repeated trauma (secondary to peripheral neuropathy; Fig.
E1-311).
8. Necrobiosis lipoidica diabeticorum: plaquelike reddened areas with a central area that
fades to white-yellow found on the anterior
surfaces of the legs (Fig. E1-312); in these
areas, the skin becomes very thin and can
ulcerate easily.

ETIOLOGY
IDIOPATHIC DIABETES:
Type 1 DM: results from beta-cell destruction,
usually leading to absolute insulin deficiency

Hereditary factors:
1. 
Islet cell antibodies (found in 90% of
patients within the first yr of diagnosis)
2. 
Higher incidence of human leukocyte
antigen (HLA) types DR3, DR4
3. 50% concordance rate in identical twins

Environmental factors: viral infection (possibly Coxsackie virus, mumps virus)
Type 2 DM: results from insulin resistance
and a progressive defect in insulin secretion.
Hereditary factors: 90% concordance rate in
identical twins


Environmental factors: obesity, sedentary
lifestyle, high carbohydrate content in food
DIABETES SECONDARY TO OTHER FACTORS:
Hormonal excess: Cushings syndrome, acromegaly, glucagonoma, pheochromocytoma
Drugs: glucocorticoids, diuretics, oral contraceptives
Insulin receptor unavailability (with or without
circulating antibodies)
Pancreatic disease: pancreatitis, pancreatectomy, hemochromatosis, cystic fibrosis
Genetic syndromes: maturity onset diabetes
of the young (MODY, monogenetic diabetes
accounting for 2% to 5% of diabetes), familial
hyperlipidemias, myotonic dystrophy, lipoatrophy
Gestational diabetes (GDM): diabetes diagnosed during pregnancy that is due to pregnancy-related insulin resistance

Dx DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
Diabetes insipidus
Stress hyperglycemia


Diabetes secondary to hormonal excess,
drugs, pancreatic disease
LABORATORY TESTS
Diagnosis of DM is made on the basis of the
following tests:
1. Fasting glucose 126 mg/dl on two occasions
2. Non-FPG 200 mg/dl and symptoms of DM
3. OGTT (75-g glucose load for nonpregnant
individuals) with 2-hr value >200 mg/dl
4. Glycosylated hemoglobin (HbA1c) 6.5%

Diseases
and Disorders

*These diagnostic categories are based on the combined fasting plasma glucose level and a 2-hour, 75-g oral glucose tolerance
test (OGTT) result. Note that a confirmed random plasma glucose level of 200 mg/dl or higher in the appropriate clinical setting is diagnostic of diabetes and precludes the need for further testing.
May be referred to as prediabetes.
DM, Diabetes mellitus; IFG, impaired fasting glucose; IGT. impaired glucose tolerance.
From Goldman L, Schafer AI: Goldmans Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

Screening for prediabetes and diabetes in

asymptomatic patients (see Table 1-162):
1. Should be considered in adults of any age
who are overweight (body mass index
[BMI] >25 kg/m2) or obese (BMI >30) and
who have one or more additional risk factors for diabetes.
2. In those who are without these risk factors, testing should begin at age 45 yr.
3. 
I f screen is normal, repeat testing
should be carried out at least at 3-yr
intervals.
Detection and diagnosis of gestational diabetes mellitus (GDM)
1. Screen for GDM using risk factor analysis
and use of an OGTT. Pregnant women who
are not known to have diabetes should
be screened for gestational diabetes at
24 to 48 weeks gestation with a 75-g
oral glucose tolerance test. A diagnosis
of GDM is made if any of the following
levels of plasma glucose are exceeded:
92 mg/dl (5.1 mmol/L) when fasting,
80 mg/dl (10 mmol/L) at 1 hour, or 153
mg/dl (8.5 mmol/L) at 2 hours.
2. 
Women with GDM should be screened
for diabetes 6 to 12 wk postpartum
and should be followed with subsequent
screening for the development of diabetes
or prediabetes at least every 3 yr


Screening for diabetic nephropathy
(Fig. E1-313)
1. Screening should be done at diagnosis
and then yearly for type 2 diabetes and
5 yr after diagnosis then yearly in type 2
diabetics.
2. 
Screening can be performed using a
albumin:creatinine ratio (microalbumin) in
a random spot urine collection or by measurement of a 24-hour urine collection for
albumin, and creatinine clearance. The
urine albumin to creatinine ratio (ACR)
is independently associated with mortality at all levels of estimated glomerular
filtration rate (eGFR) in older adults with
diabetes.
3. The diagnosis of microalbuminuria (ACR
30-299 mg/24 hr) should be based on 2
to 3 elevated levels within a 3- to 6-mo
period because there is a marked variability in day-to-day albumin excretion.
Patients with overt macroalbuminuria
(>300 mg albumin/24 hr or albumin:
creatinine ratio >300) should be followed
by urine protein:creatinine ratio.
A fasting serum lipid panel, serum creatinine,
and electrolytes should be obtained yearly on
all adult patients with diabetes.
Self-monitoring of blood glucose (SMBG) is
crucial for assessing the effectiveness of the
management plan. The frequency and timing
of SMBG varies with the needs and goals
of each patient. In most patients with type
1 DM and pregnant women taking insulin,
SMBG is recommended at least 3 times/day.
In patients with type 2 DM not on insulin,
recommendations are unclear for SMBG, but
testing once or twice/day is acceptable in
most patients.

370

Diabetes Mellitus

PTG EBM ALG

TABLE 1-162 Criteria for Diabetes Screening in Asymptomatic Individuals

1. Testing should be considered in all adults who are overweight (BMI >25 kg/m2*) and have additional risk
factors:
Physical inactivity
A first-degree relative with diabetes
High-risk ethnic population (e.g., African American, Hispanic American, Native American, Asian American, Pacific Islander)
Delivered a baby weighing more than 9 lb or diagnosed with gestational diabetes mellitus
Systemic hypertension (blood pressure >140/90 mm Hg or on antihypertensive therapy)
High-density lipoprotein cholesterol level <35 mg/dl or triglyceride level >250 mg/dl
Polycystic ovary syndrome
Hemoglobin A1c 5.7%, impaired glucose tolerance or impaired fasting glucose on prior testing
Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)
History of cardiovascular disease
2. If none of the above criteria are present, screening for diabetes should begin at age 45 yr.
3. If the results are normal, screening should be repeated at least every 3 yr. Depending on initial results and
risk status, more frequent testing may need to be considered.
*In some ethnic groups, such as Asians, at-risk body mass index (BMI) may be lower.
Modified from American Diabetes Association, Diagnosis and classification of diabetes mellitus Diabetes Care 33(Suppl. 1):S14,
2010. Borrowed from Goldman L, Schafer AI: Goldmans Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

Screening for thyroid dysfunction (TSH level),

Vitamin B12 deficiency, and celiac disease
should be considered in type 1 diabetes due
to the increased frequency of other autoimmune diseases in these individuals.

Rx TREATMENT
Type 1 diabetes requires immediate initiation
of insulin therapy.
The ADA and European Association for the
Study of Diabetes recommend lifestyle intervention (diet and exercise) and metformin initiation (unless contraindication such as renal
failure) at the time of diagnosis of type 2
diabetes. Therapy should then be augmented
with additional agents (including early initiation of insulin therapy) to achieve adequate
glycemic control.
In Type 1 diabetes, intensive glycemic control
(HbA1c <7) has been shown in randomized
controlled trials (RCT) to reduce the risk
of microvascular (neuropathy, retinopathy,
nephropathy) and macrovascular (cardiovascular events) complications.
In Type 2 diabetes, intensive glycemic control (HbA1c <7) has been shown in RCT
to reduce the risk of microvascular complications. While intensive glucose control
reduced the risk of some cardiovascular
disease outcomes (such as nonfatal MI), it did
not reduce the risk of cardiovascular death or
all cause mortality and increased the risk of
severe hypoglycemia.
It is important to remember that tight glycemic control may burden patients with complex
treatment programs, hypoglycemia, weight
gain, and costs. Clinicians should individualize
HbA1c targets so that they are reasonable and
reflect patients personal and clinical contexts
and their informed values and preferences. A
target HbA1c >7 is reasonable for motivated
new diabetic patients with long life expectancies, whereas less stringent controls (HbA1c
7.5 or higher) may be reasonable in elderly
patients with limited life expectancy and
elevated risk of hypoglycemia.

NONPHARMACOLOGIC THERAPY
1. Diet
a. Calories

(1) 
The patient with diabetes can be
started on 15 calories/lb of ideal body
weight; this number can be increased
to 20 calories/lb for an active person
and 25 calories/lb if the patient does
heavy physical labor.

(2) The calories should be distributed as
45% to 65% carbohydrates, <30%
fat, with saturated fat limited to <7%
of total calories, and 10% to 30% protein. Daily cholesterol intake should
not exceed 300 mg.

(3) The emphasis should be on complex
carbohydrates rather than simple and
refined starches, and on polyunsaturated instead of saturated fats in a
ratio of 2:1.
b. Seven food groups

(1) The exchange diet of the ADA includes
bread or starches, meat or proteins,
vegetables, fruits, fats, milk, and free
foods (e.g., black tea, sugar-free
gelatin).

(2) The name of each exchange is meant
to be all-inclusive (e.g., cereal, muffins, spaghetti, potatoes, rice are in
the bread group; meats, fish, eggs,
cheese, peanut butter are in the protein group).

(3) 
The glycemic index compares the
increase in blood sugar after the
ingestion of simple sugars and complex carbohydrates with the increase
that occurs after the absorption of
glucose; equal amounts of starches
do not give the same increase in
plasma glucose (pasta equal in calories to a baked potato causes less of
an increase than the potato); thus, it is
helpful to know the glycemic index of
a particular food product.

(4) Fiber: Insoluble fiber (bran, celery) and
soluble globular fiber (pectin in fruit)
delay glucose absorption and attenu-

ate the postprandial serum glucose

peak; they also appear to reduce
the increased triglyceride level often
present in patients with uncontrolled
diabetes. A diet high in fiber should be
emphasized (20 to 35 g/day of soluble
and insoluble fiber).
c. Other principles

(1) 
Modest sodium restriction to 2400
to 3000 mg/day. If hypertension is
present, restrict to <2400 mg/day;
if nephropathy and hypertension are
present, restrict to <2000 mg/day.

(2) Moderation of alcohol intake recommended (2 drinks/day in men, 1
drink/day in women).

(3) Non-nutritive artificial sweeteners are
acceptable in moderate amounts.

2. 
Exercise: increases the cellular glucose
uptake by increasing the number of insulin
receptors. The following points must be considered:
a. Exercise program must be individualized
and built up slowly. Consider beginning
with 15 min of low-impact aerobic exercise 3 times per wk and increasing the
frequency and duration to 30 to 45 min of
moderate aerobic activity (50% to 70% of
maximum age predicted heart rate) to 3
to 5 days/wk.

(1) In the absence of contraindications,
resistance training three times per wk
should be encouraged.
b. Insulin is more rapidly absorbed when injected into a limb that is then exercised,
and this can result in hypoglycemia.
c. Physical activity can result in hypoglycemia if medication dose or carbohydrate
consumption is not modified. Ingestion
of additional carbohydrates is recommended if pre-exercise glucose levels are
<100 mg/dl.
3. Weight loss: to ideal body weight if the patient is overweight. Recent trials have shown
that although weight loss has many positive
health benefits for people with type 2 DM,
such as slower decline in mobility, it does not
reduce the number of cardiovascular events.
4. Screening for nephropathy, neuropathy, and
retinopathy: annual serum creatinine and
urine albumin excretion; initial comprehensive eye examination and at least annually
thereafter
5. Diabetes self-management education: could
also address psychosocial issues
6. Self-monitoring of blood glucose should occur three to four times per day for patients
using multiple insulin injections or on insulin
pump therapy
7. Perform HbA1c at least two times a year in
patients who are meeting treatment goals
and who have stable glycemic control
C HbA1c quarterly in patients whose therapy has changed or who are not meeting
glycemic goals
C The HbA1c goal for nonpregnant adults in
general is <7%
C In the elderly, those with comorbidities,
or those at risk for complications from

ALG PTG EBM Diabetes Mellitus 371


hypoglycemia, a more moderate glycemic
target (HbA1c 7-8) may be appropriate

and can be used as an adjunctive treatment

for patients with type 1 or type 2 DM who
inject insulin at mealtime. Nausea is its major
side effect.


Thiazolidinediones (pioglitazone and rosiglitazone) increase insulin sensitivity and
have been used in the therapy of type 2
diabetes. Serum transaminase levels should
be obtained before starting therapy and
monitored periodically. Thiazolidinediones, in
general, result in moderate weight gain and
increase the risk for heart failure and osteoporosis/fractures. Rosiglitazone has an FDA
black box warning for heart failure exacerbations and myocardial ischemia. Pioglitazone
and rosiglitazone cause increased incidence
of bladder cancer.


Sodium-glucose co-transporter 2 (SGLT2)
inhibitors (e.g., canagliflozin, dapagliflozin)
have recently been approved by the FDA
for oral treatment of type 2 DM. By inhibiting SGLT2, these medications decrease glucose re-absorption, increase urinary glucose
excretion, and lower blood glucose levels
({down arrow} HbA1C by 0.7%). Side effects
include increased risk of genital mycotic
infections, UTIs, and volume depletion. Higher
cost and limited drug formulary availability
are limiting factors.

TABLE 1-163 Comparison of Therapies for Type 2 Diabetes

-Glucosidase
Inhibitors
Glitazones

Glinides

Exenatide Pramlintide

Liver

Gut

Muscle

Beta cell

Various

Brain

1-2

0.5-1

0.5-2

0.5

Good

Good

Poor

Poor

Poor

Excellent

Good

Good

Excellent

Excellent

Excellent

Yes

Yes

No

No

No

No

bid or tid

bid to qid

bid

tid

0 to 10
Modest
decrease
Minimal
decrease
None

Property

Lifestyle Insulins

Target tissue

Muscle or
fat
Variable

Beta cell
Beta cell
supplement
1->2
1-2

Good

Excellent

Good
No

HbA1c (%) as
(monotherapy)
Fasting effect
Postprandial
effect
Severe hypoglycemia
Dosing interval
Weight (lb/yr)
Insulin
LDL
HDL
TG
Common problem
Rare problem
Contraindications
Cost ($/mo)
Maximum effective dose

Sulfonylureas Metformin

Continuous qd to
qd to tid
continuous
+1
+3
+1 to 3
Variable
Increase
Increase
Minimal
decrease
Minimal
increase
Minimal
decrease
Recidivism,
injury

None

Minimal
decrease
None

None

0 to 6
Modest
decrease
Decrease

None

Increase

Decrease

None

Decrease

0-200

30-450
1-2U/kg per
day

Hypoglycemia, Hypoglycemia,
weight gain
weight gain

None
Allergy
10-15
maximum or
double starting

Transient GI

Minimal
decrease
Flatulence

Lactic acidosis

Renal failure,
Intestinal
Liver failure,
disease
CHF (>80yr old)
30-60
40-80
1000mg bid
50mg tid

Re: 1-2
N: 0.5-1
Good
Re: Moderate
N: Poor
Good
Re: Good
N: Excellent
No
Re: Yes
N: No
P: qd Ro: qd or bid tid to qid with
meals
+1 to 13
+1 to 3
Decrease
Increase

6 to 12 3 to 6
Increase
None

Increase

None

None

None

Increase

None

Decrease

None

P: Decrease Ro:
None
Weight gain,
edema, anemia
Hepatotoxicity?
Hepatocellular
disease

None

Decrease

None

Hypoglycemia

GI

GI

None

None

70-110
Re: 2mg tid
N: 120mg tid

170-200
10g bid

200-400
120g ac

75-180
P: 45mg qd
Ro: 4mg bid

, Change; ac, before food; CHF, congestive heart failure; GI, gastrointestinal disturbance; HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; N, nateglinide; P, pioglitazone; Re, repaglinide; Ro, rosiglitazone; TG, triglycerides.
From Melmed S, Polonsky KS, Larsen PR, Kronenberg HM: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.

Diseases
and Disorders

GENERAL Rx
When the previous measures fail to normalize
the serum glucose, oral hypoglycemic agents
should be added to the regimen in type 2 DM.
Tables 1-163 and 1-164 compare therapies
for type 2 DM and classes of antihyperglycemic agents.
The primary mechanism of metformin is to
decrease hepatic glucose production and
improve insulin sensitivity. Because metformin does not produce hypoglycemia when
used as a monotherapy, it is preferred initially
for most patients. Metformin reduces mean
HbA1c level by 1.1 %. It is contraindicated in
patients with severe renal insufficiency with
an estimated glomerular filtrate rate <30 ml/
min, heart failure, or other clinical states of
hypoperfusion, and in patients with significant liver disease.
Sitagliptin, saxagliptin, vildagliptin, and linagliptin inhibit the enzyme DPP-4, responsible
for inactivation and degradation of glucagon-like peptide-1 (GLP-1) and glucose-
dependent insulinotropic polypeptide (GIP).
These drugs, known as gliptins, raise blood
incretin levels, thereby inhibiting glucagon

release and lowering blood glucose levels.

When used with metfomin they do not cause
hypoglycemia and are preferred over sulfonylureas as second line agents. Cost is a
major barrier to their use.
Exenatide and liraglutide are glucagon-like
peptide-1 (GLP-1) agonists. They are incretin
mimetics that stimulate release of insulin
from pancreatic beta cells and can be used
as adjunctive therapy for patients with type 2
DM. GLP-1 agonists are not indicated in type
1 DM and are contraindicated in patients with
severe renal impairment. Cost is a barrier to
their use.
Acarbose and miglitol inhibit pancreatic amylase and small intestinal glucosidases, thereby delaying carbohydrate absorption in the
gut and reducing associated post-prandial
hyperglycemia. The major side effects are
flatulence, diarrhea, and abdominal cramps.
Sulfonylureas increase insulin secretion and
work best when given before meals. All sulfonylureas are contraindicated in patients who
are allergic to sulfa.
Pramlintide is a synthetic analog of human
amylin, which is synthesized by pancreatic beta cells and cosecreted with insulin in
response to food intake. It suppresses glucagon secretion and slows stomach emptying

372

HbA1c
Lowering
(%)

Usual Dosing
Fasting or
Frequency
Prandial Effect (Doses/Day)

Route

Hypoglycemia

Weight
Effect

CVD Risk Factor

Benefits

Important
Contraindications Daily Cost ($)

Lifestyle
Biguanide

Metformin

Broad
Liver sensitizer

>1
>1

Both
Fasting

1-2

Oral

No
No

Loss
Neutral

Yes
Modest

<$1

Sulfonylurea

Glimepiride,
glipizide
Repaglinide

Insulin
secretagogue
Insulin
secretagogue
Insulin
secretagogue
Insulin supplement/
substitute
Insulin supplement/
substitute
Peripheral sensitizer

>1

Fasting

1-2

Oral

Yes

Gain

Negligible

Renal or hepatic
failure

>1

Both

With meals

Oral

Yes

Gain

Negligible

$5

<1

Prandial

With meals

Oral

Minimal

Minimal

Negligible

$5

>1

Fasting

SQ

Yes++

Gain++

Lowers TG

$5

>1

Prandial

With meals

SQ

Yes++

Gain++

Lowers TG

$5

>1

Fasting

Oral

No

Gain++

Variable (see text)

Heart or liver failure

$5

<1

Prandial

With meals

Oral

No

Neutral

Negligible

$3

Pramlintide
Exenatide

Slow carbohydrate
absorption
Broad
Broad

<1
1

Prandial
Prandial

With meals
2

SQ
SQ

No
No

Loss
Loss

Broad

>1

Both

SQ

No

Loss

Pancreatitis, renal
failure
Pancreatitis, medullary thyroid cancer

$10
$9

Liraglutide

Negligible
Modest with weight
loss
Lowers BP

Sitagliptin,
saxagliptin
Colesevelam

Improved insulin/
glucagon secretion
Uncertain

<1

Both

Oral

No

Neutral

Negligible

Pancreatitis

$7

<1

Prandial

1-2

Oral

No

Neutral

Lowers LDL

Hypertriglyceridemia

$9

Bromocriptine

Uncertain

<1

Fasting

Oral

No

Neutral

Modest

NA

Meglitinide
Benzoic acid
derived
Basal insulin
Bolus insulin
Thiazolidinediones
-Glucosidase
inhibitors
Amylinomimetics
GLP1 receptor
agonists
Long-acting GLP1
receptor
agonists
DPP4 inhibitors
Bile acid
sequestrants
Dopamine
agonists

Nateglinide
NPH, glargine,
detemir
R, lispro, aspart,
glulisine
Pioglitazone, rosiglitazone
Acarbose, miglitol

BP, Blood pressure; CVD, cardiovascular disease; LDL, low-density lipoprotein; SQ, subcutaneous; TG, triglyceride.
From Melmed S, Polonsky KS, Larsen PR, Kronenberg HM: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.

<<$1

$13

PTG EBM ALG

Class

Representative
Agents
Major Action

Diabetes Mellitus

TABLE 1-164 Classes of Antihyperglycemic Therapy

ALG PTG EBM Diabetes Mellitus 373


presenting in childhood or adolescence and
during pregnancy. The guidelines for insulin
pump therapy from the American Association
of Diabetes Educators include frequent and
unpredictable fluctuations in blood glucose
and patient perceptions that diabetes management impedes the pursuit of personal or
professional goals.
Low-dose aspirin (ASA; 81 mg/day) has been
proven to lower the risk of subsequent myocardial infarction, stroke, or vascular death
in secondary prevention studies. The ADA
recommends low-dose aspirin for primary
prevention in diabetic patients with one additional cardiovascular risk factor, including age
older than 40 yr, cigarette smoking, hypertension, obesity, albuminuria, hyperlipidemia,
and family history of coronary artery disease.
Measure fasting lipid profile at least annually
in adults.
1. 
All patients with diabetes with one or
more additional risk factors for cardiovascular disease should be on statin therapy
together with lifestyle modification regardless of baseline lipid levels.
2. 
Diabetic patients aged 40-75 with LDL
cholesterol of 70-189 mg/dl and without clinical atherosclerotic cardiovascular
disease (ASCVD) should receive at least
moderate-intensity statin therapy and
consider high-intensity statin therapy if
10-year ASCVD risk is >=7.5%.
Aggressive antihypertensive therapy is recommended to keep systolic blood pressure
(BP) <130 and diastolic BP <80 mm Hg.

TABLE 1-165 Types of Insulina

Preparation

Brand

Onset (hr)b

Peak (hr)

Duration (hr)c

Route

Insulin Aspart
Insulin Aspart
Protamine/Insulin
Aspart
Insulin Detemir
Insulin Glargine
Insulin Glulisine
Insulin Lispro
Insulin Lispro
Protamine/Insulin
Lispro
Insulin Injection
Regular (R)

NovoLogd
NovoLog Mix 70/30d

<0.25
<0.25

1-3
1-4

3-5
24

SC, IV, CSII

SC

Levemire
Lantusd
Apidrad
Humalogd
Humalog Mix 75/25d
Humalog Mix 50/50d

1
1.1
0.25
<0.25
0.25
0.25

None
None
1
1
0.5-1.5
1

24
24
2-4
3.5-4.5
24
16

SC
SC
SC, IV
SC
SC
SC

Humulin Rf
Novolin Ne
Humulin 70/30f
Humulin 50/50f
Novolin 70/30e
Humulin Nf
Novolin Ne

0.5
0.5
0.5
0.5
0.5
1-2
1.5

2-4
2.5-5
2-12
3-5
2-12
6-12
4-12

6-8
8
24
24
24
18-24
24

SC, IM, IV
SC, IM, IV
SC
SC
SC
SC
SC

Insulin Isophane
Suspension (NPH)/
Regular Insulin (R)
Insulin Isophane
Suspension (NPH)
aInjectable

insulins listed are available in a concentration of 100 U/ml; Humulin R, in a concentration of 500 U/ml for SC
injection. SC injection only is available by prescription from Lilly for insulin-resistant patients who are hospitalized or in
need of medical supervision.
bOnset for injectable formulations is always for the subcutaneous (SC) route. All times are approximate.
cMaximum effect occurs between these times; actual effect may last longer.
dRecombinant human insulin analogue (using E. coli).
eRecombinant (using S. cerevisiae).
fRecombinant (using E. coli).
CSII, Continuous subcutaneous infusion; IM, intramuscularly; IV, intravenously.

Use of angiotensin-converting enzyme (ACE)

inhibitors or angiotensin receptor blockers
(ARBs) to decrease albuminuria and for prevention of progression of kidney disease
should be considered regardless of presence
of hypertension. Combination therapy with an
ACE inhibitor and an ARB should be avoided
due to increased risk of adverse effects
among patients with diabetic nephropathy.


Bariatric surgery should be considered in
adults with BMI >35 kg/m2 and type 2 diabetes, especially if the diabetes is difficult
to control with lifestyle and pharmacologic
therapy.
Treat hypoglycemia in a conscious person
with glucose tab or gel 15 to 20 g, and
intramuscular injection of glucagon if unconscious. Patient and family members should
be instructed on the administration of glucagon for individuals at significant risk for
severe hypoglycemia.

DISPOSITION
Diabetic retinopathy occurs in nearly 15% of
patients with diabetes after 15 yr of diagnosis
and increases 1%/yr after diagnosis. Retinal
laser photocoagulation and vitrectomy are
effective treatment modalities. Prevention
is best accomplished by strict glucose and
BP control. Early blockade of the reninangiotensin system has been shown to slow
progression of retinopathy in patients with
type 1 diabetes.


The frequency of neuropathy in patients
with type 2 diabetes approaches 70% to
80%. It can be subdivided into sensorimotor neuropathy and autonomic neuropathy.
Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, is effective and
FDA approved for relief of diabetic peripheral
neuropathy. Pregabalin and gabapentin (900
to 3600 mg/day) are also effective for the
symptomatic treatment of peripheral neuropathic pain. Topical capsaicin, 5% lidocaine
transdermal patches, amitriptyline, and carbamazepine are also modestly effective.
Diabetic gastroparesis is most often seen in
patients who have had diabetes for at least
10 yr and typically have retinopathy, neuropathy, and nephropathy. Major manifestations
are postprandial fullness, nausea, vomiting, and bloating. Pharmacologic therapy
involves prokinetic agents (metoclopramide).
Endoscopic injection of botulinum toxin into
the pylorus and gastric electrical stimulation
(using f electrodes placed laparoscopically
in the muscle wall of the stomach antrum
and connected to a neurostimulator) represent newer approaches to nonpharmacologic
therapy.
Nephropathy: The first sign of renal involvement in patients with DM is most often
microalbuminuria, which is classified as
incipient nephropathy. Before the current
period of intensive glycemic control and
blood pressure with ACE inhibitors and angiotensin receptor blockade, it was suggested
that 25% to 45% of diabetic patients would
develop clinically evident renal disease (pro-

Diseases
and Disorders

Combination therapy of various hypoglycemic

agents is commonly used when monotherapy
results in inadequate glycemic control.
Insulin is indicated for the treatment of all
type 1 DM and for type 2 DM patients whose
condition cannot be adequately controlled
with diet and oral agents. The American
College of Endocrinology and the American
Association of Clinical Endocrinologists
recommend initiation of insulin therapy in
patients with type 2 diabetes and an initial HbA1c level >9%, or if the diabetes is
uncontrolled despite optimal oral glycemic
therapy. Insulin therapy may be initiated as
augmentation, starting at 0.3 unit/kg, or as
replacement, starting at 0.6 to 1.0 unit/kg.
Table 1-165 describes commonly used types
of insulin.
1. The risks of insulin therapy include weight
gain, hypoglycemia, and in rare cases,
allergic or cutaneous reactions.
2. 
Replacement insulin therapy should
mimic normal release patterns.

a. Approximately 50% to 60% of daily
insulin can be given as a long-acting insulin (NPH, ultralente, glargine,
detemir) injected once or twice daily

b. The remaining 40% to 50% can be
short-acting (regular) or rapid-acting
(lispro, aspart, glulysine) to cover
mealtime carbohydrates and correct
increased current glucose levels.


Continuous subcutaneous insulin infusion
(CSII, or insulin pump) provides comparable
or slightly better control than multiple daily
injections. It should be considered for diabetes

374

Diabetes Mellitus

PTG EBM ALG

teinuria) and 4% to 17% would pregress to

end-stage renal disease. In the current era
of intensive glycemic and blood pressure
control and ACE/ARB use, clinically evident
diabetic nephropathy has declined to 9% and
end-stage renal disease 2% to 7%.


Infections are generally more common in
patients with diabetes because of multiple
factors, such as impaired leukocyte function,
decreased tissue perfusion secondary to
vascular disease, repeated trauma because
of loss of sensation, and urinary retention
secondary to neuropathy.
Prevention/delay of type 2 diabetes: Patients
with prediabetes should achieve weight loss
of 5% to 10% of body weight and increase
physical activity to at least 150 min/wk of
moderate activity such as walking. Metformin
therapy may be considered in those at high
risk, especially if they have hyperglycemia
(HbA1c 6) despite lifestyle interventions.

REFERRAL
Patients with diabetes should be advised to
have annual ophthalmologic examinations.
In type 1 DM, ophthalmologic visits should
begin within 3 to 5 yr of diagnosis, whereas
type 2 DM patients should be seen from
disease onset.
Podiatric care can significantly reduce the
rate of foot infections and amputations in
patients with DM. Noninfected neuropathic
foot ulcers require debridement and reduction of pressure.


Nephrology consultation in all cases of
proteinuria, hyperkalemia, uncontrolled BP,
and when GFR has decreased to <30 ml/
min/1.73 m2.

PEARLS &
CONSIDERATIONS

COMMENTS


Because normalization of serum glucose
level is the ultimate goal, every patient with
diabetes should measure his or her blood
glucose with commercially available glucometers unless contraindicated by senility or
blindness.
Underinsured children and those with psychiatric illness are at greater risk for acute complications in type 1 DM and require frequent
monitoring and aggressive risk management
with diet, exercise, and periodic laboratory
evaluation.
Significant sustained weight loss using bariatric surgery has been reported as effective
in achieving remission of type 2 diabetes in
morbidly obese patients. Bariatric surgery
may be considered for adults with BMI
>35 kg/m2 and type 2 DM, especially if
diabetes or associated comorbidities are
difficult to control with lifestyle and pharmacologic therapy.

Cigarette smoking predicts incident type 2

diabetes. For a smoker at risk for diabetes,
smoking cessation should be coupled with
strategies for diabetes prevention and early
detection.


Glycemic control in hospitalized patients:
The American College of Physicans (ACP)
recommends against using intensive insulin
therapy to strictly control blood glucose in
non-surgical intensive care unit (SICU)/medical intensive care unit (MICU) in patients with
or without DM. The ACP recommends a target
blood glucose level of 140 to 200 mg/dl if
insulin therapy is used.

SUGGESTED READINGS
available at www.expertconsult.com
RELATED CONTENT
Diabetic Ketoacidosis (Related Key Topic)
Diabetic Polyneuropathy (Related Key Topic)
Diabetic Retinopathy (Related Key Topic)
Gestational Diabetes Mellitus (Related Key
Topic)
Hyperosmolar Hyperglycemic Syndrome
(Related Key Topic)
Diabetes Mellitus Type 1 (Patient Information)
Diabetes Mellitus Type 2 (Patient Information)
AUTHORS: HILARY B. WHITLATCH, M.D., SAINATH
GADDAM, M.D., and FRED F. FERRI, M.D.

Diabetes Mellitus
EVIDENCE
Abstract[1]

Background:
The role of weight training in the primary prevention of type 2 diabetes
mellitus (T2DM) is largely unknown.
Methods:
To examine the association of weight training with risk of T2DM in US
men and to assess the influence of combining weight training and aerobic exercise, we performed a prospective cohort study of 32,002 men
from the Health Professionals Follow-up Study observed from 1990 to
2008. Weekly time spent on weight training and aerobic exercise (including brisk walking, jogging, running, bicycling, swimming, tennis, squash,
and calisthenics/rowing) was obtained from questionnaires at baseline
and biennially during follow-up.
Results:
During 508 332 person-years of follow-up (18 years), we documented
2278 new cases of T2DM. In multivariable-adjusted models, we observed a dose-response relationship between an increasing amount of
time spent on weight training or aerobic exercise and lower risk of T2DM
(P < .001 for trend). Engaging in weight training or aerobic exercise for at
least 150 minutes per week was independently associated with a lower
risk of T2DM of 34% (95% CI, 7%-54%) and 52% (95% CI, 45%-58%),
respectively. Men who engaged in aerobic exercise and weight training
for at least 150 minutes per week had the greatest reduction in T2DM
risk (59%; 95% CI, 39%-73%).
Conclusions:
Weight training was associated with a significantly lower risk of T2DM,
independent of aerobic exercise. Combined weight training and aerobic
exercise conferred a greater benefit. A
Abstract[2]
Background:
Physical activity (PA) is considered a cornerstone of diabetes mellitus
management to prevent complications, but conclusive evidence is lacking.
Methods:
This prospective cohort study and meta-analysis of existing studies investigated the association between PA and mortality in individuals with
diabetes. In the EPIC study (European Prospective Investigation Into Cancer and Nutrition), a cohort was defined of 5859 individuals with diabetes at baseline. Associations of leisure-time and total PA and walking
with cardiovascular disease (CVD) and total mortality were studied using
multivariable Cox proportional hazards regression models. Fixed- and
random-effects meta-analyses of prospective studies published up to
December 2010 were pooled with inverse variance weighting.
Results:
In the prospective analysis, total PA was associated with lower risk of CVD
and total mortality. Compared with physically inactive persons, the lowest
mortality risk was observed in moderately active persons: hazard ratios
were 0.62 (95% CI, 0.49-0.78) for total mortality and 0.51 (95%CI, 0.320.81) for CVD mortality. Leisure-time PA was associated with lower total
mortality risk, and walking was associated with lower CVD mortality risk. In
the meta-analysis, the pooled random-effects hazard ratio from 5 studies for
high vs low total PA and all-cause mortality was 0.60 (95% CI, 0.49-0.73).
Conclusions:
Higher levels of PA were associated with lower mortality risk in individuals with diabetes. Even those undertaking moderate amounts of activity
were at appreciably lower risk for early death compared with inactive
persons. These findings provide empirical evidence supporting the widely shared view that persons with diabetes should engage in regular PA. A

Evidence-Based References
1. Grntved A, Rimm EB, Willett WC etal: A prospective study of weight training and
risk of type 2 diabetes mellitus in men, Arch Intern Med 172:1306-1312, 2012. A
2. Sluik D, Buijsse B, Muckelbauer R etal: Physical activity and mortality in
individuals with diabetes mellitus: a prospective study and meta-analysis, Arch
Intern Med 172:1285-1295, 2012. A

374.e1

SUGGESTED READINGS
American Diabetes Association Position Statement: Standards of medical care in
diabetes-2010, Diabetes Care 33:S1, January 2010.
Balducci J etal: Effect of an intensive exercise intervention strategy on modifiable cardiovascular risk factors in subjects with type 2 DM, Arch Intern Med
170(20):1794-1803, 2010.
Culver A etal: Statin use and risk of diabetes mellitus in postmenopausal women
in the Womens Health Initiative, Arch Intern Med 172(2):144-152, 2012.
Esposito K etal: Effects of a Mediterranean-style diet on the need for antihyperglycemic drug therapy in patients with newly diagnosed type 2 diabetes, Ann
Intern Med 151:306-314, 2009.
Fried LF etal: Combined angiotensin inhibition for the treatment of diabetic
nephropathy, N Engl J Med 369:1892-1903, 2013.
Inzucchi SE: Diagnosis of diabetes, N Engl J Med 367:542-550, 2012.
Inzucchi SE: Management of hyperglycemia in the hospital setting, N Engl J Med
355:1903, 2006.
Inzucchi SE etal: Management of hyperglycemia in type 2 diabetes: a patientcentered approach. Position statement of the American Diabetes Association
and the European Association for the Study of Diabetes, Diabetes Care
35:1364, 2012.
Kanji JN etal: Does this patient with diabetes have large-fiber peripheral neuropathy, JAMA 303:1526-1532, 2010.
Kavanagh BP, McCowen KC: Glycemic control in the ICU, N Engl J Med 363:25402546, 2010.
Kelly TN: Systematic review: Glucose control and cardiovascular disease in type 2
diabetes, Ann Intern Med 151:394-403, 2009.
Mauer M etal: Renal and retinal effects of enalapril and losartan in type 1 diabetes, N Engl J Med 361:40-51, 2009.
Montori V, Fernandez-Balsells M: Glycemic control in type 2 diabetes: time for an
evidence-based about-face? Ann Intern Med 150:803-808, 2009.
Mooradian A etal: Narrative review: a rational approach to starting insulin therapy,
Ann Intern Med 145:125, 2006.
Nauck M: Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications, Am J Med 124:S3-S18, 2011.
OHare A etal: Prognostic implications of the urinary albumin to creatinine ratio
in veterans of different ages with diabetes, Arch Intern Med 170(11):930-936,
2010.
Petnick A: Insulin management of type 2 diabetes mellitus, Am Fam Phys
84(2):183-190, 2011.
Pickup JC: Insulin-pump therapy for type 1 diabetes mellitus, N Engl J Med
366:1616-1624, 2012.
Pignone M etal: Aspirin for primary prevention of cardiovascular events in people
with diabetes: a position statement of the American Diabetes Association, a
scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation, Circulation
121:2694, 2010.
Qaseem A etal: Use of intensive insulin therapy for the management of glycemic
control in hospitalized patients: a clinical practice guideline from the American
College of Physicians, Ann Intern Med 154:260-267, 2011.
Rejeski WJ etal: Lifestyle change and mobility in obese adults with type 2 diabetes, N Engl J Med 366:1209-1217, 2012.
Ripsin CM etal: Management of blood glucose in type 2 diabetes mellitus, Am
Fam Phys 79(1):29-36, 2009.
The DCCT/EDIC Research Group: Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes, N Engl J Med 365:2366, 2011.
The Task Force on Diabetes and Cardiovascular Diseases of the European Society
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Ann Intern Med 152:10-17, 2010.

Diabetes Mellitus

374.e2

FIGURE E1-311 Diabetic neuropathy of the

hindfoot. Destruction of the joint with collapse
and fragmentation. (From Hochberg MC etal [eds]:
Rheumatology, ed 3, St Louis, 2003, Mosby.)

FIGURE E1-312 Necrobiosis lipoidica: symmetrical early lesions with erythema. (Courtesy of the
Institute of Dermatology; from McKee PH etal [eds]: Pathology of the skin with clinical correlations, ed 3, St
Louis, 2005, Mosby.)

CLINICAL EVALUATION OF DIABETIC NEPHROPATHY

Diabetes proteinuria

Exclude urinary tract infection

Urine microscopy: red cells, white-cell casts?
Quantitate proteinuria
Renal ultrasonography
Serology if glomerulonephritis suspected
ANCA, DNA antibodies, C3, C4

Typical diabetic nephropathy

Type 1 diabetes for 10 years
Retinopathy
Previous microalbuminuria
No macroscopic hematuria
No red cell casts
Enlarged kidneys on ultrasound

Atypical proteinuria
Type 1 diabetes for 10 years
No retinopathy
Nephrotic range proteinuria
without progression through
microalbuminuria
Macroscopic hematuria
Red cell casts

Atypical
Azotemia with proteinuria 1 g/day
Papillary necrosis (pyuria,
hematuria, scarring)
Tuberculosis (pyuria, hematuria)
Renovascular disease (other
occlusive vascular disease)

No renal biopsy

Renal biopsy

No renal biopsy

FIGURE E1-313 Clinical evaluation of diabetic renal disease. ANCA, Antineutrophil cytoplasmic antibody. (From Floege J etal: Comprehensive clinical nephrology,
ed 4, Philadelphia, 2010, Saunders.)