![D
369 ALG PTG EBM Diabetes Mellitus
I
Diseases
andDisorders
(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 asso-
ciated with increased cardiac mortality,
independent of ejection fraction.
c. Polyradiculopathy: painful weakness and
atrophy in the distribution of ≥1 contigu-
ous nerve roots.
d. Mononeuropathy involving cranial nerves III,
IV,orVI 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 periph-
eral 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 (Charcot’s joints):
bone or joint deformities from repeated trau-
ma (secondary to peripheral neuropathy; Fig.
E1-311).
8. Necrobiosis lipoidica diabeticorum: plaque-
like 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 (pos-
sibly Coxsackie virus, mumps virus)
Type 2 DM: results from insulin resistance
and a progressive defect in insulin secre-
tion.
• 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: Cushing’s syndrome, acro-
megaly, glucagonoma, pheochromocytoma
• Drugs: glucocorticoids, diuretics, oral contra-
ceptives
• Insulin receptor unavailability (with or without
circulating antibodies)
• Pancreatic disease: pancreatitis, pancreatec-
tomy, 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, lipoat-
rophy
• Gestational diabetes (GDM): diabetes diag-
nosed during pregnancy that is due to preg-
nancy-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 occa-
sions
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%
• 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 fac-
tors for diabetes.
2. In those who are without these risk fac-
tors, testing should begin at age 45 yr.
3. If screen is normal, repeat testing
should be carried out at least at 3-yr
intervals.
• Detection and diagnosis of gestational diabe-
tes 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 mea-
surement of a 24-hour urine collection for
albumin, and creatinine clearance. The
urine albumin to creatinine ratio (ACR)
is independently associated with mortal-
ity 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 vari-
ability 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.
TABLE 1-161 Diagnostic Categories*: Diabetes Mellitus and At-Risk States
Fasting Plasma Glucose Level
2-HOUR (75-g) OGTT RESULT
140 mg/dl 140-199 mg/dl ≥200 mg/dl
100 mg/dl Normal IGT† DM
100-125 mg/dl IFG† IGT† and IFG† DM
≥126 mg/dl DM DM DM
HbA1C Level 5.7% 5.7-6.4% ≥6.5%
Normal High-risk† DM
*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 set-
ting 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: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.](https://image.slidesharecdn.com/ferrisclinicaladvisor2015-160930161633/85/Ferri-s-clinical-advisor-2015-2-320.jpg)
![374.e1Diabetes 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 aero-
bic 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 (includ-
ing 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 ob-
served 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 in-
vestigated the association between PA and mortality in individuals with
diabetes. In the EPIC study (European Prospective Investigation Into Can-
cer and Nutrition), a cohort was defined of 5859 individuals with diabe-
tes 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, 0.32-
0.81) 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 individu-
als 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 wide-
ly shared view that persons with diabetes should engage in regular PA. A
Evidence-Based References
1. Grnøtved A, Rimm EB,Willett WC et al: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 et al: Physical activity and mortality in
individuals with diabetes mellitus: a prospective study and meta-analysis, Arch
Intern Med 172:1285-1295, 2012. A
SUGGESTED READINGS
American Diabetes Association Position Statement: Standards of medical care in
diabetes-2010, Diabetes Care 33:S1, January 2010.
Balducci J et al: Effect of an intensive exercise intervention strategy on modifi-
able cardiovascular risk factors in subjects with type 2 DM, Arch Intern Med
170(20):1794-1803, 2010.
Culver A et al: Statin use and risk of diabetes mellitus in postmenopausal women
in the Women’s Health Initiative, Arch Intern Med 172(2):144-152, 2012.
Esposito K et al: Effects of a Mediterranean-style diet on the need for antihyper-
glycemic drug therapy in patients with newly diagnosed type 2 diabetes, Ann
Intern Med 151:306-314, 2009.
Fried LF et al: 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 et al: Management of hyperglycemia in type 2 diabetes: a patient-
centered approach. Position statement of the American Diabetes Association
and the European Association for the Study of Diabetes, Diabetes Care
35:1364, 2012.
Kanji JN et al: Does this patient with diabetes have large-fiber peripheral neu-
ropathy, JAMA 303:1526-1532, 2010.
Kavanagh BP, McCowen KC: Glycemic control in the ICU, N Engl J Med 363:2540-
2546, 2010.
Kelly TN: Systematic review: Glucose control and cardiovascular disease in type 2
diabetes, Ann Intern Med 151:394-403, 2009.
Mauer M et al: Renal and retinal effects of enalapril and losartan in type 1 diabe-
tes, 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 et al: 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, func-
tions, and clinical implications, Am J Med 124:S3-S18, 2011.
O’Hare A et al: 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 et al: 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 consen-
sus document of the American College of Cardiology Foundation, Circulation
121:2694, 2010.
Qaseem A et al: 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 et al: Lifestyle change and mobility in obese adults with type 2 diabe-
tes, N Engl J Med 366:1209-1217, 2012.
Ripsin CM et al: 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 filtra-
tion rate in type 1 diabetes, N Engl J Med 365:2366, 2011.
The Task Force on Diabetes and Cardiovascular Diseases of the European Society
of Cardiology (ESC) and of the European Association for the Study of Diabetes
(EASD): Guidelines on diabetes, pre-diabetes, and cardiovascular disease:
executive summary, Eur Heart J 28:88-136, 2007.
Yeh HC et al: Smoking, smoking cessation, and risk for type 2 diabetes mellitus,
Ann Intern Med 152:10-17, 2010.](https://image.slidesharecdn.com/ferrisclinicaladvisor2015-160930161633/85/Ferri-s-clinical-advisor-2015-8-320.jpg)
![374.e2Diabetes Mellitus
FIGURE E1-311 Diabetic neuropathy of the
hindfoot. Destruction of the joint with collapse
and fragmentation. (From Hochberg MC et al [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 et al [eds]: Pathology of the skin with clinical correlations, ed 3, St
Louis, 2005, Mosby.)
CLINICAL EVALUATION OF DIABETIC NEPHROPATHY
Typical diabetic nephropathy
Type 1 diabetes for Ͼ10 years
Retinopathy
Previous microalbuminuria
No macroscopic hematuria
No red cell casts
Enlarged kidneys on ultrasound
No renal biopsy No renal biopsy
Atypical proteinuria
Type 1 diabetes for Ͻ10 years
No retinopathy
Nephrotic range proteinuria
without progression through
microalbuminuria
Macroscopic hematuria
Red cell casts
Renal biopsy
Atypical
Azotemia with proteinuria Ͻ1 g/day
Papillary necrosis (pyuria,
hematuria, scarring)
Tuberculosis (pyuria, hematuria)
Renovascular disease (other
occlusive vascular disease)
Exclude urinary tract infection
Urine microscopy: red cells, white-cell casts?
Quantitate proteinuria
Renal ultrasonography
Serology if glomerulonephritis suspected
ANCA, DNA antibodies, C3, C4
Diabetes proteinuria
FIGURE E1-313 Clinical evaluation of diabetic renal disease. ANCA, Antineutrophil cytoplasmic antibody. (From Floege J et al: Comprehensive clinical nephrology,
ed 4, Philadelphia, 2010, Saunders.)](https://image.slidesharecdn.com/ferrisclinicaladvisor2015-160930161633/85/Ferri-s-clinical-advisor-2015-9-320.jpg)
Ferri's clinical advisor 2015
- 1. 368 i 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 “insulin- dependent” and “non–insulin-dependent” dia- betes are obsolete because when a person with type 2 diabetes needs insulin, he or she remains labeled as type 2 and is not reclassi- fied 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 casu- al (random) plasma glucose ≥200 mg/ dl. Classic symptoms of hyperglycemia include polyuria, polydipsia, and unex- plained 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 (non–insulin-dependent diabetes mellitus) Type 1 diabetes mellitus (insulin-dependent diabetes mellitus) Type 2 diabetes mellitus (non–insulin-dependent diabetes mellitus) ICD-9CM CODES 250.0 Diabetes mellitus (NIDDM) 250.1 Insulin-dependent diabetes mellitus without complication (IDDM) ICD-10CM CODES E11.5 Type 2 diabetes mellitus with peripheral circulatory complications E11.6 Type 2 diabetes mellitus with other specified complications E11.7 Type 2 diabetes mellitus with multiple complications E11.8 Type 2 diabetes mellitus with unspecified complications E11.9 Type 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 pres- ence 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, atrioventric- ular shunts (2) Advanced stage: microinfarcts with cotton wool exudates, macular edema b. Proliferative retinopathy: characterized by formation of new vessels, vitreous hem- orrhages, fibrous scarring, and retinal de- tachment 3. Cataracts and glaucoma occur with in- creased frequency in patients with diabetes 4. Diabetic neuropathy a. Distal sensorimotor polyneuropathy (1) Symptoms include paresthesia, hyper- esthesia, or burning pain involving bilateral distal extremities, in a “stock- ing-glove” distribution. This can prog- ress to motor weakness and ataxia. (2) Physical examination may reveal decreased pinprick sensation, sensa- tion to light touch, vibration sense, and loss of proprioception. Motor dis- turbances such as decreased deep tendon reflexes and atrophy of inter- ossei muscles can also be seen. b. Autonomic neuropathy: (1) GI disturbances: esophageal motility abnormalities, gastroparesis, diarrhea (usually nocturnal) Diabetes Mellitus PTG ALG EBM TABLE 1-160 General Comparison of the Two Types of Diabetes Mellitus Type 1 Type 2 Previous terminology Insulin-dependent diabetes mellitus (IDDM), type I, juvenile- onset diabetes Non–insulin-dependent diabetes mellitus, type II, adult-onset diabetes Age of onset Usually 30 yr, particularly childhood and adolescence, but any age Usually 40 yr, but any age Genetic predisposition Moderate; environmental factors required for expression; 35%-50% concordance in monozygotic twins; several candidate genes proposed Strong; 60%-90% concordance in monozygotic twins; many can- didate genes proposed; some genes identified in maturity-onset diabetes of the young Human leukocyte antigen associations Linkage to DQA and DQB, influenced by DRB (3 and 4) (DR2 protective) None known Other associations Autoimmune; Graves’ disease, Hashimoto’s thyroiditis, vit- iligo, Addison’s disease, pernicious anemia Heterogenous group, ongoing subclassification based on identifi- cation of specific pathogenic processes and genetic defects Precipitating and risk factors Largely unknown; microbial, chemical, dietary, other Age, obesity (central), sedentary lifestyle, previous gestational diabetes Findings at diagnosis 85%-90% of patients have one and usually more autoanti- bodies to ICA512/IA-2/IA-2b, GAD65, insulin (IAA) Possibly complications (microvascular and macrovascular) caused by significant preceding asymptomatic period Endogenous insulin levels Low or absent Usually present (relative deficiency), early hyperinsulinemia Insulin resistance Only with hyperglycemia Mostly present Prolonged fast Hyperglycemia, ketoacidosis Euglycemia Stress, withdrawal of insulin Ketoacidosis 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.
- 2. D 369 ALG PTG EBM Diabetes Mellitus I Diseases andDisorders (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 asso- ciated with increased cardiac mortality, independent of ejection fraction. c. Polyradiculopathy: painful weakness and atrophy in the distribution of ≥1 contigu- ous nerve roots. d. Mononeuropathy involving cranial nerves III, IV,orVI 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 periph- eral 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 (Charcot’s joints): bone or joint deformities from repeated trau- ma (secondary to peripheral neuropathy; Fig. E1-311). 8. Necrobiosis lipoidica diabeticorum: plaque- like 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 (pos- sibly Coxsackie virus, mumps virus) Type 2 DM: results from insulin resistance and a progressive defect in insulin secre- tion. • 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: Cushing’s syndrome, acro- megaly, glucagonoma, pheochromocytoma • Drugs: glucocorticoids, diuretics, oral contra- ceptives • Insulin receptor unavailability (with or without circulating antibodies) • Pancreatic disease: pancreatitis, pancreatec- tomy, 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, lipoat- rophy • Gestational diabetes (GDM): diabetes diag- nosed during pregnancy that is due to preg- nancy-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 occa- sions 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% • 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 fac- tors for diabetes. 2. In those who are without these risk fac- tors, testing should begin at age 45 yr. 3. If screen is normal, repeat testing should be carried out at least at 3-yr intervals. • Detection and diagnosis of gestational diabe- tes 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 mea- surement of a 24-hour urine collection for albumin, and creatinine clearance. The urine albumin to creatinine ratio (ACR) is independently associated with mortal- ity 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 vari- ability 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. TABLE 1-161 Diagnostic Categories*: Diabetes Mellitus and At-Risk States Fasting Plasma Glucose Level 2-HOUR (75-g) OGTT RESULT 140 mg/dl 140-199 mg/dl ≥200 mg/dl 100 mg/dl Normal IGT† DM 100-125 mg/dl IFG† IGT† and IFG† DM ≥126 mg/dl DM DM DM HbA1C Level 5.7% 5.7-6.4% ≥6.5% Normal High-risk† DM *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 set- ting 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: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.
- 3. 370 Diabetes Mellitus PTG EBM ALG • 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 autoim- mune 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 inter- vention (diet and exercise) and metformin ini- tiation (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 initia- tion 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 (cardiovas- cular events) complications. • In Type 2 diabetes, intensive glycemic con- trol (HbA1c 7) has been shown in RCT to reduce the risk of microvascular com- plications. 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 glyce- mic 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 expectan- cies, 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% pro- tein. Daily cholesterol intake should not exceed 300 mg. (3) The emphasis should be on complex carbohydrates rather than simple and refined starches, and on polyunsatu- rated 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, muf- fins, spaghetti, potatoes, rice are in the bread group; meats, fish, eggs, cheese, peanut butter are in the pro- tein group). (3) The glycemic index compares the increase in blood sugar after the ingestion of simple sugars and com- plex 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 calo- ries 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 recom- mended (≤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 con- sidered: a. Exercise program must be individualized and built up slowly. Consider beginning with 15 min of low-impact aerobic exer- cise 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 in- jected into a limb that is then exercised, and this can result in hypoglycemia. c. Physical activity can result in hypoglyce- mia if medication dose or carbohydrate consumption is not modified. Ingestion of additional carbohydrates is recom- mended if pre-exercise glucose levels are 100 mg/dl. 3. Weight loss: to ideal body weight if the pa- tient 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 comprehen- sive eye examination and at least annually thereafter 5. Diabetes self-management education: could also address psychosocial issues 6. Self-monitoring of blood glucose should oc- cur 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 ther- apy 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 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 Ameri- can, 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: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.
- 4. D 371 ALG PTG EBM Diabetes Mellitus I Diseases andDisorders hypoglycemia, a more moderate glycemic target (HbA1c 7-8) may be appropriate 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 antihyperglyce- mic agents. • The primary mechanism of metformin is to decrease hepatic glucose production and improve insulin sensitivity. Because metfor- min 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 signifi- cant liver disease. • Sitagliptin, saxagliptin, vildagliptin, and lina- gliptin inhibit the enzyme DPP-4, responsible for inactivation and degradation of gluca- gon-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 sul- fonylureas 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 amy- lase and small intestinal glucosidases, there- by 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 sulfo- nylureas are contraindicated in patients who are allergic to sulfa. • Pramlintide is a synthetic analog of human amylin, which is synthesized by pancre- atic beta cells and cosecreted with insulin in response to food intake. It suppresses gluca- gon secretion and slows stomach emptying 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 rosi- glitazone) 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 osteo- porosis/fractures. Rosiglitazone has an FDA black box warning for heart failure exacerba- tions 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 inhibit- ing SGLT2, these medications decrease glu- cose 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 Property Lifestyle Insulins Sulfonylureas Metformin α-Glucosidase Inhibitors Glitazones Glinides Exenatide Pramlintide Target tissue Muscle or fat Beta cell supplement Beta cell Liver Gut Muscle Beta cell Various Brain ΔHbA1c (%) as (monotherapy) Variable 1-2 1-2 1-2 0.5-1 0.5-2 Re: 1-2 N: 0.5-1 ∼1 ∼0.5 Fasting effect Good Excellent Good Good Poor Good Re: Moderate N: Poor Poor Poor Postprandial effect Good Excellent Good Good Excellent Good Re: Good N: Excellent Excellent Excellent Severe hypogly- cemia No Yes Yes No No No Re: Yes N: No No No Dosing interval Continuous qd to continuous qd to tid bid or tid bid to qid P: qd Ro: qd or bid tid to qid with meals bid tid ΔWeight (lb/yr) +1 +3 +1 to 3 0 to −6 0 to −10 +1 to 13 +1 to 3 −6 to −12 −3 to −6 ΔInsulin Variable Increase Increase Modest decrease Modest decrease Decrease Increase Increase None ΔLDL Minimal decrease Minimal decrease None Decrease Minimal decrease Increase None None None ΔHDL Minimal increase None None Increase None Increase None Decrease None ΔTG Minimal decrease Decrease None Decrease Minimal decrease P: Decrease Ro: None None Decrease None Common problem Recidivism, injury Hypoglycemia, weight gain Hypoglycemia, weight gain Transient GI Flatulence Weight gain, edema, anemia Hypoglycemia GI GI Rare problem — — — Lactic acidosis — Hepatotoxicity? — — — Contraindications None None Allergy Renal failure, Liver failure, CHF (80 yr old) Intestinal disease Hepatocellular disease — None None Cost ($/mo) 0-200 30-450 10-15 30-60 40-80 75-180 70-110 170-200 200-400 Maximum effec- tive dose — 1-2 U/kg per day maximum or double starting 1000 mg bid 50 mg tid P: 45 mg qd Ro: 4 mg bid Re: 2 mg tid N: 120 mg tid 10 μg bid 120 μg ac Δ, Change; ac, before food; CHF, congestive heart failure; GI, gastrointestinal disturbance; HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; N, nateg- linide; P, pioglitazone; Re, repaglinide; Ro, rosiglitazone; TG, triglycerides. From Melmed S, Polonsky KS, Larsen PR, Kronenberg HM: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.
- 5. 372DiabetesMellitus PTG EBM ALG TABLE 1-164 Classes of Antihyperglycemic Therapy Class Representative Agents Major Action HbA1c Lowering (%) Fasting or Prandial Effect Usual Dosing Frequency (Doses/Day) Route Hypoglycemia Weight Effect CVD Risk Factor Benefits Important Contraindications Daily Cost ($) Lifestyle — Broad 1 Both — — No Loss Yes — — Biguanide Metformin Liver sensitizer 1 Fasting 1-2 Oral No Neutral Modest Renal or hepatic failure $1 Sulfonylurea Glimepiride, glipizide Insulin secretagogue 1 Fasting 1-2 Oral Yes Gain Negligible — $1 Meglitinide Repaglinide Insulin secretagogue 1 Both With meals Oral Yes Gain Negligible — ∼$5 Benzoic acid– derived Nateglinide Insulin secretagogue 1 Prandial With meals Oral Minimal Minimal Negligible — ∼$5 Basal insulin NPH, glargine, detemir Insulin supplement/ substitute 1 Fasting 1 SQ Yes++ Gain++ Lowers TG — ∼$5 Bolus insulin R, lispro, aspart, glulisine Insulin supplement/ substitute 1 Prandial With meals SQ Yes++ Gain++ Lowers TG — ∼$5 Thiazolidinediones Pioglitazone, rosi- glitazone Peripheral sensitizer 1 Fasting 1 Oral No Gain++ Variable (see text) Heart or liver failure ∼$5 α-Glucosidase inhibitors Acarbose, miglitol Slow carbohydrate absorption 1 Prandial With meals Oral No Neutral Negligible — ∼$3 Amylinomimetics Pramlintide Broad 1 Prandial With meals SQ No Loss Negligible — ∼$10 GLP1 receptor agonists Exenatide Broad ∼1 Prandial 2 SQ No Loss Modest with weight loss Pancreatitis, renal failure ∼$9 Long-acting GLP1 receptor agonists Liraglutide Broad 1 Both 1 SQ No Loss Lowers BP Pancreatitis, medul- lary thyroid cancer ∼$13 DPP4 inhibitors Sitagliptin, saxagliptin Improved insulin/ glucagon secretion 1 Both 1 Oral No Neutral Negligible Pancreatitis ∼$7 Bile acid sequestrants Colesevelam Uncertain 1 Prandial 1-2 Oral No Neutral Lowers LDL Hypertriglyceridemia ∼$9 Dopamine agonists Bromocriptine Uncertain 1 Fasting 1 Oral No Neutral Modest — NA 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.
- 6. D 373 ALG PTG EBM Diabetes Mellitus I Diseases andDisorders • 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 ini- tial 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-act- ing 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 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 man- agement impedes the pursuit of personal or professional goals.” • Low-dose aspirin (ASA; 81 mg/day) has been proven to lower the risk of subsequent myo- cardial infarction, stroke, or vascular death in secondary prevention studies. The ADA recommends low-dose aspirin for primary prevention in diabetic patients with one addi- tional cardiovascular risk factor, including age older than 40 yr, cigarette smoking, hyperten- sion, 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 cardiovas- cular disease should be on statin therapy together with lifestyle modification regard- less of baseline lipid levels. 2. Diabetic patients aged 40-75 with LDL cholesterol of 70-189 mg/dl and with- out 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 rec- ommended to keep systolic blood pressure (BP) 130 and diastolic BP 80 mm Hg. Use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to decrease albuminuria and for pre- vention 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 dia- betes, 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 uncon- scious. Patient and family members should be instructed on the administration of glu- cagon 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 renin- angiotensin 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 sensorimo- tor neuropathy and autonomic neuropathy. Duloxetine, a selective serotonin and norepi- nephrine 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 neuro- pathic pain. Topical capsaicin, 5% lidocaine transdermal patches, amitriptyline, and car- bamazepine 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, neurop- athy, and nephropathy. Major manifestations are postprandial fullness, nausea, vomit- ing, 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) repre- sent newer approaches to nonpharmacologic therapy. • Nephropathy: The first sign of renal involve- ment 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 angio- tensin receptor blockade, it was suggested that 25% to 45% of diabetic patients would develop clinically evident renal disease (pro- TABLE 1-165 Types of Insulina Preparation Brand Onset (hr)b Peak (hr) Duration (hr)c Route Insulin Aspart NovoLogd 0.25 1-3 3-5 SC, IV, CSII Insulin Aspart Protamine/Insulin Aspart NovoLog Mix 70/30d 0.25 1-4 24 SC Insulin Detemir Levemire 1 None 24 SC Insulin Glargine Lantusd 1.1 None ≥24 SC Insulin Glulisine Apidrad ≤0.25 1 2-4 SC, IV Insulin Lispro Humalogd 0.25 1 3.5-4.5 SC Insulin Lispro Protamine/Insulin Lispro Humalog Mix 75/25d ≤0.25 0.5-1.5 24 SC Humalog Mix 50/50d ≤0.25 1 16 SC Insulin Injection Regular (R) Humulin Rf 0.5 2-4 6-8 SC, IM, IV Novolin Ne 0.5 2.5-5 8 SC, IM, IV Insulin Isophane Suspension (NPH)/ Regular Insulin (R) Humulin 70/30f 0.5 2-12 24 SC Humulin 50/50f 0.5 3-5 24 SC Novolin 70/30e 0.5 2-12 24 SC Insulin Isophane Suspension (NPH) Humulin Nf 1-2 6-12 18-24 SC Novolin Ne 1.5 4-12 24 SC 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.
- 7. 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 reduc- tion 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 glucom- eters unless contraindicated by senility or blindness. • Underinsured children and those with psychi- atric illness are at greater risk for acute com- plications in type 1 DM and require frequent monitoring and aggressive risk management with diet, exercise, and periodic laboratory evaluation. • Significant sustained weight loss using bar- iatric 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 pharma- cologic 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)/medi- cal 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.
- 8. 374.e1Diabetes 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 aero- bic 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 (includ- ing 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 ob- served 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 in- vestigated the association between PA and mortality in individuals with diabetes. In the EPIC study (European Prospective Investigation Into Can- cer and Nutrition), a cohort was defined of 5859 individuals with diabe- tes 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, 0.32- 0.81) 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 individu- als 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 wide- ly shared view that persons with diabetes should engage in regular PA. A Evidence-Based References 1. Grnøtved A, Rimm EB,Willett WC et al: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 et al: Physical activity and mortality in individuals with diabetes mellitus: a prospective study and meta-analysis, Arch Intern Med 172:1285-1295, 2012. A SUGGESTED READINGS American Diabetes Association Position Statement: Standards of medical care in diabetes-2010, Diabetes Care 33:S1, January 2010. Balducci J et al: Effect of an intensive exercise intervention strategy on modifi- able cardiovascular risk factors in subjects with type 2 DM, Arch Intern Med 170(20):1794-1803, 2010. Culver A et al: Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative, Arch Intern Med 172(2):144-152, 2012. Esposito K et al: Effects of a Mediterranean-style diet on the need for antihyper- glycemic drug therapy in patients with newly diagnosed type 2 diabetes, Ann Intern Med 151:306-314, 2009. Fried LF et al: 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 et al: Management of hyperglycemia in type 2 diabetes: a patient- centered approach. Position statement of the American Diabetes Association and the European Association for the Study of Diabetes, Diabetes Care 35:1364, 2012. Kanji JN et al: Does this patient with diabetes have large-fiber peripheral neu- ropathy, JAMA 303:1526-1532, 2010. Kavanagh BP, McCowen KC: Glycemic control in the ICU, N Engl J Med 363:2540- 2546, 2010. Kelly TN: Systematic review: Glucose control and cardiovascular disease in type 2 diabetes, Ann Intern Med 151:394-403, 2009. Mauer M et al: Renal and retinal effects of enalapril and losartan in type 1 diabe- tes, 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 et al: 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, func- tions, and clinical implications, Am J Med 124:S3-S18, 2011. O’Hare A et al: 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 et al: 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 consen- sus document of the American College of Cardiology Foundation, Circulation 121:2694, 2010. Qaseem A et al: 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 et al: Lifestyle change and mobility in obese adults with type 2 diabe- tes, N Engl J Med 366:1209-1217, 2012. Ripsin CM et al: 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 filtra- tion rate in type 1 diabetes, N Engl J Med 365:2366, 2011. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD): Guidelines on diabetes, pre-diabetes, and cardiovascular disease: executive summary, Eur Heart J 28:88-136, 2007. Yeh HC et al: Smoking, smoking cessation, and risk for type 2 diabetes mellitus, Ann Intern Med 152:10-17, 2010.
- 9. 374.e2Diabetes Mellitus FIGURE E1-311 Diabetic neuropathy of the hindfoot. Destruction of the joint with collapse and fragmentation. (From Hochberg MC et al [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 et al [eds]: Pathology of the skin with clinical correlations, ed 3, St Louis, 2005, Mosby.) CLINICAL EVALUATION OF DIABETIC NEPHROPATHY Typical diabetic nephropathy Type 1 diabetes for Ͼ10 years Retinopathy Previous microalbuminuria No macroscopic hematuria No red cell casts Enlarged kidneys on ultrasound No renal biopsy No renal biopsy Atypical proteinuria Type 1 diabetes for Ͻ10 years No retinopathy Nephrotic range proteinuria without progression through microalbuminuria Macroscopic hematuria Red cell casts Renal biopsy Atypical Azotemia with proteinuria Ͻ1 g/day Papillary necrosis (pyuria, hematuria, scarring) Tuberculosis (pyuria, hematuria) Renovascular disease (other occlusive vascular disease) Exclude urinary tract infection Urine microscopy: red cells, white-cell casts? Quantitate proteinuria Renal ultrasonography Serology if glomerulonephritis suspected ANCA, DNA antibodies, C3, C4 Diabetes proteinuria FIGURE E1-313 Clinical evaluation of diabetic renal disease. ANCA, Antineutrophil cytoplasmic antibody. (From Floege J et al: Comprehensive clinical nephrology, ed 4, Philadelphia, 2010, Saunders.)