Transcript of "Sample Chapter Endocrine Secrets 6e by McDermott To Order Call Sms at 91 8527622422"
Marissa Grotzke and Robert E. Jones
I FUEL METABOLISM
1. What is diabetes mellitus?
Diabetes mellitus comprises a group of chronic metabolic disorders characterized by abnormalities in
insulin secretion or action (or both) resulting in hyperglycemia. These conditions are associated with
disordered carbohydrate, fat, and protein metabolism and can lead to long-term complications involving
the nervous, cardiovascular, renal, and sensory organ systems. The types of diabetes are summarized
in Table 1-1.
2. What is the prevalence of diabetes?
According to 2011 statistics compiled by the U.S. Centers for Disease Control, 25.8 million children and
adults, or 8.3% of the U.S. population, have diabetes. Of those, 18.8 million have been diagnosed, and
7.0 million Americans have diabetes but are unaware of it. Of individuals 20 years or older, 25.6 million
(11.3%) have diabetes. In 2010, 1.9 million adults were newly diagnosed with diabetes. Additionally,
an estimated 35% of adults were classiﬁed as prediabetic.
3. What is monogenic diabetes?
In contrast to type 2 diabetes, which is clearly polygenic, monogenic diabetes is hyperglycemia due to a
single gene mutation. Monogenic diabetes is relatively rare, accounting for only 1% to 2% of all cases in
Europe. It is loosely divided into neonatal diabetes (diabetes appearing within the ﬁrst 6 months of life)
and maturity-onset diabetes of the young (MODY; diagnosed outside the neonatal period and generally
prior to 25 years of age). Mutations involving the beta-cell adenosine triphosphate–sensitive potassium
channel (KATP channel) account for most cases of neonatal diabetes, and the disease in patients with
these mutations responds to sulfonylureas, which block the persistently open, mutated KATP channels,
thus allowing insulin secretion. MODY is associated with mutations involving glucokinase or genes
coding transcription factors that are important in insulin signaling.
4. Who should be screened for diabetes?
Screening for type 1 diabetes is not feasible. Despite many studies, there is no effective means of
preventing diabetes in patients who test positive for autoantibodies associated with type 1 diabetes
without an abnormality in glucose tolerance, and there is no consensus as to what should be done
about positive results.
The risk for development of type 2 diabetes increases with age, obesity, and sedentary lifestyle.
There is an increased risk with a family history of diabetes, in certain ethnic groups, and in women with
a history of gestational diabetes. Current recommendations are to screen the general population at
3-year intervals starting at age 45. Earlier or more frequent screening should be performed in adults
with a body mass index (BMI) 25 kg/m2 or greater and additional risk factors (Table 1-2).
5. How is diabetes diagnosed?
There are four different testing options for the diagnosis of diabetes: a fasting plasma glucose
(FPG) test, a 75-g oral glucose tolerance test (OGTT), a hemoglobin A1C (HbA1C) measurement,
and random plasma glucose measurement. Both the HbA1C measurement and FPG test are more
convenient and less expensive and are, therefore, preferred. In a patient with a positive test result,
the test should be repeated on a different day to conﬁrm the diagnosis. Table 1-3 describes
8 CHAPTER 1 DIABETES MELLITUS
TABLE 1-1. TYPES OF DIABETES MELLITUS
Type 1 (T1DM)
Type 2 (T2DM)
Other speciﬁc types
Results from an absolute deﬁciency of insulin secretion due to beta-cell destruction (immune-mediated, 90% [type 1 A], or idiopathic [type 1B]). Patients require
insulin and are prone to ketoacidosis.
Results from a combination of insulin resistance and insulin deﬁciency, which is
often preceded by a period of abnormal carbohydrate metabolism (prediabetes).
Patients are typically overweight, may not immediately require insulin, and are
not usually prone to ketoacidosis.
Represents diabetes diagnosed during pregnancy and is based on speciﬁc
Diabetes caused by other conditions (chronic pancreatitis, pancreatectomy, acromegaly, hemochromatosis, hypercortisolism) or by medications (glucocorticoids,
atypical antipsychotics, antiretrovirals), and monogenetic diabetes, also called
maturity-onset diabetes of the young [MODY).
TABLE 1-2. ADDITIONAL RISK FACTORS PROMPTING SCREENING FOR TYPE 2 DIABETES MELLITUS IN ADULTS
Diabetes in a ﬁrst-degree relative
High-risk ethnicity: African American, Native American, Latino, Paciﬁc Islander, Asian
History of gestational diabetes or of delivering a baby weighing Ͼ 9 lbs
Hypertension: blood pressure Ն 140 mm Hg systolic/90 mm Hg diastolic or current hypertension therapy
Lipid disorders: High-density lipoprotein (HDL) cholesterol Ͻ 35 mg/dL or triglycerides Ͼ 250 mg/dL
Polycystic ovarian syndrome (PCOS)
History of abnormal glucose metabolism noted in prior testing: fasting glucose Ն 100 mg/dL; hemoglobin
A1C Ն 5.7%; 2-hour oral glucose tolerance test (OGTT) result Ͼ 140 mg/dL
Clinical evidence of insulin resistance: acanthosis nigricans, pronounced obesity
TABLE 1-3. DIAGNOSTIC CRITERIA FOR ABNORMALITIES OF GLUCOSE METABOLISM
Oral glucose tolerance test, 2-hour
Must be repeated on a
Rarely diagnostic unless
Must be performed
according to Diabetes
Control and Complications Trial methodology
using an approved
CHAPTER 1 DIABETES MELLITUS 9
6. What are the genetics of type 1 diabetes?
The exact role of genetics versus environment in the development of type 1 diabetes is unknown.
Monozygotic twins have a 20% to 50% concordance for type 1 diabetes. The cumulative risk for
siblings of diabetic patients is 6% to 10%, versus 0.6% for the general population. Regarding the effect
of parental genes, the offspring of women with type 1 diabetes have a lower risk of disease (2.1%)
than those of men with type 1 diabetes (6.1%). The reason for this disparity is unknown. The susceptibility for type 1 diabetes is associated with the genetic expression of certain proteins coded by the
human leukocyte antigen (HLA) region of the major histocompatibility complex. These proteins are
present on the surfaces of lymphocytes and macrophages and are considered essential for triggering
the autoimmune destruction of beta cells. Although all of the genetic markers (HLA and others) for
type 1 diabetes are not known, future progress in this ﬁeld will allow population screening for genetic
susceptibility. Type 1 diabetes is a major element of autoimmune polyglandular syndrome type 2
(APS-2; see Chapter 52).
7. What are the genetics of type 2 diabetes?
As with type 1 diabetes, the exact interaction of genetics and environment in the development of
type 2 diabetes is unclear. However, the familial clustering of type 2 diabetes suggests a strong
genetic component. Monozygotic twins have a 60% to 90% concordance for type 2 diabetes. The
cumulative risk for type 2 diabetes in siblings of diabetic patients is 10% to 33%, versus 5% for
the general population. Offspring of women with type 2 diabetes have a twofold to threefold greater
risk of diabetes than offspring of men with the disease. The exact mode of inheritance for type 2
diabetes is not known but is thought to be polygenic. Speciﬁc mutations that are associated with
risk for type 2 diabetes have been identiﬁed, but many of these genes are widely found in the
population at large. Because type 2 diabetes is so commonly associated with obesity, many investigators suspect that genes that predispose to obesity are associated with type 2 diabetes as well.
There appears to be a strong interplay between genetic and environmental inﬂuences in the cause
of type 2 diabetes. One illustration is the demonstration of higher fasting insulin levels for every
weight category in the offspring of two parents with type 2 diabetes than in control subjects.
High insulin levels are a marker for insulin resistance and are predictive of progression to type
8. Describe the pathogenesis of type 1 diabetes.
Type 1 diabetes results from host T-cell destruction of beta cells within the pancreas, which causes
absolute insulin deﬁciency. Markers of this autoimmune process include antibodies to islet cells, insulin,
and glutamic acid decarboxylase. The autoimmune destruction is believed to be related to genetic
predispositions (HLA-DR/DQ alleles) in combination with poorly deﬁned environmental factors. Patients
with type 1 diabetes are prone to other autoimmune disorders (Grave’s disease and Hashimoto’s
thyroiditis, celiac sprue, etc.).
9. Describe the pathogenesis of type 2 diabetes.
The pathogenesis of type 2 diabetes is multifactorial, although speciﬁc etiologies are unknown. Autoimmune beta-cell destruction does not occur in this form of diabetes, which accounts for 90% to 95% of
all cases of diabetes. Instead, type 2 diabetes is characterized by both a defect in insulin action (known
as insulin resistance) and a relative insulin deﬁciency. Years of hyperglycemia often precede the diagnosis, which typically occurs only after non-autoimmune beta-cell failure has begun. Loss of ﬁrst-phase
insulin secretion is the initial defect, with resulting postprandial glucose elevations. Eventually beta-cell
death accelerates, and glucose levels rise. It is estimated that by the time of diagnosis of diabetes,
patients have lost nearly 50% of their beta-cell mass.
With loss of beta-cell mass, insulin secretion is no longer sufﬁcient to compensate for insulin resistance,
deﬁned as a subnormal response to a given insulin concentration. Elevated fasting or postprandial insulin
values are the hallmark of insulin resistance, which is often associated with obesity; weight reduction may
improve insulin sensitivity.
10 CHAPTER 1 DIABETES MELLITUS
10. Can diabetes be prevented?
Several studies involving individuals at high risk for development of type 2 diabetes have documented potential beneﬁcial effects of thiazolidinediones (Troglitazone in Prevention of Diabetes
[TRIPOD] and Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication [DREAM]
studies), metformin (Diabetes Prevention Program [DPP]), alpha-glucosidase inhibitors (Study to
Prevent Non–Insulin-Dependent Diabetes Mellitus [STOP-NIDDM] study), intestinal lipase inhibitors
(XENical in the Prevention of Diabetes in Obese Subjects [XENDOS] study), and even insulin (Outcome
Reduction with Initial Glargine Intervention [ORIGIN] trial) in reducing the rate of progression to
overt diabetes. Individuals in the lifestyle modiﬁcation (7% weight loss and moderate exercise for
150 minutes/week) arm of the DPP showed excellent results, with a 60% lower risk for development
of diabetes than those receiving metformin (30%). However, the American Diabetes Association (ADA)
recommends pharmacotherapy only in patients who are at high risk for progression to diabetes
because of multiple risk factors or an HbA1C level higher than 6% despite lifestyle modiﬁcations.
The lower prevalence of type 1 diabetes has made determining who is at risk more difﬁcult.
Identifying people in the prediabetic phase of type 1 diabetes requires serial measurements of
beta-cell function and close monitoring of immunologic markers, making selection of an appropriate
cohort difﬁcult. Two studies, the Diabetes Prevention Trial–Type 1 (DPT-1) and the European Nicotinamide Diabetes Intervention Trial (ENDIT), overcame this issue and examined the use of insulin and
nicotinamide, respectively, in high-risk relatives of patients with type 1 diabetes. However, neither
study demonstrated effective prevention of progression to type 1 diabetes.
11. What techniques are available to assess insulin resistance?
Lack of standardization of insulin assays prevents use of a speciﬁc insulin concentration to deﬁne
insulin resistance. The gold standards for deﬁning insulin resistance are the intravenous glucose
tolerance test, insulin suppression test, and euglycemic insulin clamp. However, these research
tools are impractical in a clinical setting. A more clinically applicable tool is the homeostasis model
assessment of insulin resistance (HOMA-IR), deﬁned as the product of fasting insulin (in mU/L)
and fasting plasma glucose concentrations (in mmol/L) divided by a constant (22.5), as in the
HOMA-IR ϭ Fasting Insulin (mU/L) ϫ Fasting Glucose (mmol/L)/22.5
12. Describe metabolic syndrome.
Metabolic syndrome is deﬁned as the presence of three of the ﬁve following criteria:
■ Increased waist circumference (Ͼ 40 inches in men, Ͼ 35 inches in women)
■ Plasma triglycerides Ն 150 mg/dL
■ Plasma high-density lipoprotein cholesterol Ͻ 40 mg/dL in men, Ͻ 50 mg/dL in women
■ Blood pressure Ն 130 mm Hg systolic/85 mm Hg diastolic
■ Fasting plasma glucose Ն 100 mg/dL
In 2004, the American Heart Association modiﬁed this deﬁnition to include the use of medications
for hypertension or to the criteria for blood pressure and hyperglycemia to the fasting plasma glucose
13. What causes beta-cell failure in type 2 diabetes?
It is estimated that at the time of diagnosis, patients with type 2 diabetes have lost nearly 50% of
their insulin-producing cells. The system of programmed beta-cell death (apoptosis) occurs progressively over the course of type 2 diabetes and has many potential triggers, although two speciﬁc
possibilities have been characterized. Elevations of glucose and free fatty acids, collectively called
glucolipotoxicity, and chronic increases in certain cytokines, notably tumor necrosis factor-alpha
(TNF-␣) and interleukin-1 beta (IL-1␤), have been documented to activate “death” genes (caspases)
in beta cells. Both of these conditions have been amply described in subjects with either prediabetes
or overt diabetes and clearly contribute to the genesis of type 2 diabetes by reducing the number of
functioning beta cells.
CHAPTER 1 DIABETES MELLITUS 11
14. What are the standards of care for the management of diabetes mellitus?
Both the ADA and the American Association of Clinical Endocrinologists (AACE) have published
evidence-based minimum standards of diabetes care. Both recommend that patients have a
complete history and physical examination at the initial visit. Laboratory testing should include a
fasting lipid proﬁle and measurement of HbA1C. Surveillance for complications should include an
annual physical examination, ophthalmologic examination, and a screen for microalbuminuria.
Overall glycemic control (HbA1C) should be assessed at least semiannually in all patients and
quarterly in insulin-treated patients and in patients with poorly controlled type 2 diabetes. Published targets include an HbA1C value under 7.0% (ADA) or 6.5% (AACE), low-density lipoprotein
(LDL) cholesterol less than 100 mg/dL (Ͻ 70 mg/dL in high-risk patients), and blood pressure
lower than 130/80 mm Hg.
15. Describe the current management approach to type 1 diabetes and the role
of intensive therapy modeled by the Diabetes Control and Complications
Diabetes is a self-management illness and requires that the patient be educated in glucose selfmonitoring, nutrition therapy, exercise, and the proper use of medications. Similarly, the patient must
be taught how to recognize and treat hypoglycemia. Because patients with type 1 diabetes are completely insulin deﬁcient, the medical regimen is straightforward and centered on insulin replacement.
The most physiologic replacement regimen, known as the basal-bolus technique, can be accomplished either with the use of a long-acting (basal) insulin in combination with a rapid-acting (bolus)
insulin or a continuous subcutaneous infusion using an insulin pump.
The DCCT showed a 34% to 76% reduction in clinically signiﬁcant diabetic microvascular
complications (retinopathy, neuropathy, and nephropathy) in type 1 diabetes subjects randomly
assigned to intensive insulin therapy in comparison with subjects assigned to standard diabetes
management. After an average 17 years of follow-up, the intensively treated cohort also enjoyed
an approximate 50% reduction in cardiovascular risk. The only major adverse effect of intensiﬁed
control was a threefold higher risk of severe hypoglycemia. An intensive therapy regimen requires
blood glucose monitoring four to eight times daily with multiple daily insulin injections or an insulin
pump and is best managed by a team comprising a physician, certiﬁed diabetes educator, nurse,
16. Is intensive diabetes therapy cost-effective?
The potential reduction in cost for treating diabetic complications (laser photocoagulation, dialysis,
kidney transplants, hospitalizations, and rehabilitation following amputations) has been shown to
justify the cost of personnel and supplies for intensive therapy. The risk-to-beneﬁt ratio for intensive
therapy may be less favorable for prepubertal children, patients with advanced complications, and
patients with coronary or cerebrovascular disease.
17. What is the United Kingdom Prospective Diabetes Study (UKPDS)?
The UKPDS is the largest and longest prospective study on type 2 diabetes ever conducted. Investigators recruited 5102 patients with newly diagnosed type 2 diabetes in 23 centers within the United
Kingdom between 1977 and 1991. Patients were followed up for an average of 10 years to determine
the impact of intensive therapy using pharmacologic agents in comparison with dietary therapy
alone. The study also tested the relative efﬁcacy of intensive (tight) blood pressure control and “less
tight blood pressure control.” The results of the study showed a signiﬁcant reduction in microvascular
complications in patients randomly assigned to the intensive therapy arm. Tight blood pressure
control was associated with a reduction in both microvascular and macrovascular events. When the
entire cohort of patients was studied together, the mean HbA1C level for the duration of the study was
a strong positive predictor of all diabetes-related end points, including death, amputation, myocardial
infarction, and stroke. The beneﬁts of early glucose and blood pressure control in reducing the both
the microvascular and macrovascular complications and all-cause mortality persisted 10 years
after the end of the original trial.
12 CHAPTER 1 DIABETES MELLITUS
18. What is the current management approach to type 2 diabetes?
Because type 2 diabetes is a heterogeneous disorder and patients may have other comorbid illnesses, treatment and therapeutic targets must be individualized. A patient-centered approach has
been advocated. The foundation of therapy is diet, exercise, and patient education; unless there are
contraindications to its use, metformin should be started at the time of diagnosis. The next steps
may involve additional oral agents or injectable medications, and all further treatment decisions must
consider the individual characteristics of the patient as well as comorbidities. Ultimately, the majority
of patients requires supplemental insulin. Emphasis should be placed on addressing cardiovascular
risk reduction (blood pressure, lipids) at each encounter with the patient.
19. What are the clinical implications of the ACCORD trial?
The Action to Control Cardiovascular Risk in Type 2 Diabetes (ACCORD) trial was undertaken to
address whether intensive versus standard glucose control (HbA1C target Ͻ 6% vs. 7.0%-7.9%),
intensive versus standard blood pressure control (systolic blood pressure Ͻ 120 mm Hg vs.
Ͻ 140 mm Hg), and fenoﬁbrate versus placebo (both treatment arms were allowed statins) further
reduced cardiovascular outcomes in patients with long-standing type 2 diabetes. In all study arms
there was no reduction in the primary outcome, which was a composite of cardiovascular death,
nonfatal myocardial infarction, and nonfatal stroke. Unexpectedly, both total mortality (hazard ratio
1.22) and cardiovascular death (hazard ratio 1.35) were increased in the intensive glucose control
arm. Beneﬁts were seen, however, in some secondary cardiovascular and microvascular outcomes.
The clinical translation of the ACCORD study is somewhat murky, but it is apparent that intensive
glucose management with the intention of normalizing HbA1C (HbA1C Ͻ 6%) is likely not warranted.
Another lesson learned from ACCORD is that the management of people with type 2 diabetes must
20. What are insulin analogs?
Insulin analogs are recombinant proteins that are based on the structure of human insulin but that
have undergone selected amino acid substitutions, deletions, or additions. These amino acid alterations are designed to either enhance or protract the subcutaneous absorption of the molecule without
altering its biologic properties. Native human insulin (regular) exists as a molecular hexamer that
must be progressively broken down into dimers and then monomers before absorption. Amino acid
substitutions in the carboxy-terminal region of the beta chain of insulin tend to destabilize hexamer
formation and speed the rate of absorption. Examples of these analogs are the insulins lispro
(Humalog), aspart (NovoLog), and glulisine (Apidra). These insulins are excellent for premeal use,
and because they also have a shorter duration of action than native human insulin (regular), they
provide better mealtime coverage with a lower risk of postmeal hypoglycemia.
Conversely, basal insulin should have both a peakless action proﬁle and a prolonged duration of
action. In the case of insulin glargine (Lantus), these features are achieved by amino acid additions
that shift the isoelectric point to promote hexamer formation. After injection, glargine is buffered to
a physiologic pH and forms a microprecipitate that is then slowly absorbed. The protraction of
insulin detemir (Levemir) is due to fatty acylation of the insulin molecule, which results in albumin
binding. Degludec, a fatty acylated insulin, is currently undergoing review by the U.S. Food and Drug
CHAPTER 1 DIABETES MELLITUS 13
21. What is amylin?
Amylin is a beta-cell hormone that is co-secreted with but structurally distinct from insulin. Under
normal circumstances, amylin acts to reduce postprandial glucose excursions by reducing the gastric
emptying rate and suppressing glucagon production, thereby reducing postprandial hepatic glucose
production. It is also believed to inhibit the stomach hormone ghrelin, resulting in appetite suppression. In addition to an absolute insulin deﬁciency, patients with type 1 diabetes also have a complete
deﬁciency of amylin, and patients with type 2 diabetes taking insulin have clearly reduced amylin
responses to meals. Mealtime replacement of amylin in subjects who required insulin was shown to
reduce HbA1C levels modestly while promoting weight loss. Currently available as the synthetic analog
pramlintide, amylin is approved for use in type 1 and type 2 diabetics as an injection before meals.
22. What are incretins?
The incretin effect refers to the enhanced insulin secretory response observed after an oral glucose
load in comparison with an intravenous or parenteral glucose load. After eating, the cells of the
distal small intestine release incretins such as glucagon-like peptide-1 (GLP-1) into the blood. GLP-1
secretion is under neurogenic control. It acts to increase glucose-dependent insulin secretion, suppress glucagon release, delay gastric emptying, enhance satiety through a direct effect on the central
nervous system, reduce beta-cell apoptosis, and possibly stimulate beta-cell neogenesis. GLP-1 is
quickly inactivated by an enzyme, dipeptidyl peptidase IV (DPP-IV); as a result, the therapeutic
potential for GLP-1 is limited by its extremely short half-life.
23. How are incretins used to treat type 2 diabetes?
There are currently two types of incretin-based therapies available, GLP-1 analogs, which are not
substrates for DPP-IV, and DPP-IV inhibitors, which protract the half-life of endogenous GLP-1. The
two GLP-1 analogs available are exenatide and liraglutide. Both are given by injection and are associated with moderate weight loss in addition to modest HbA1C lowering (0.6%-1.2%). The three DPP-IV
inhibitors are available in the United States, sitagliptin, saxagliptin, and linagliptin. In comparison with
the GLP-1 analogs, DPP-IV inhibitors are associated with lower weight loss and less HbA1C lowering
is; however, they are administered orally. Both types of incretins can be used as monotherapy or in
combination with other available antihyperglycemia agents.
24. What are the classes of oral diabetes medications? How do they work?
In addition to the DPP-IV inhibitors mentioned earlier, several classes of diabetes medications are available for optimizing glycemic control in people with type 2 diabetes (Table 1-4). Sulfonylureas (glyburide,
glipizide, and glimepiride) and meglitinides (repaglinide and nateglinide) enhance the secretion of
endogenous insulin through membrane-associated receptors. Metformin, the only biguanide available,
reduces hepatic gluconeogenesis, thereby indirectly increasing peripheral insulin sensitivity. The alphaglucosidase inhibitors (miglitol and acarbose) slow the absorption of dietary carbohydrates by inhibiting
the intestinal brush-border enzymes (Table 1-4) that break down polysaccharides into absorbable
monosaccharides. The thiazolidinediones (pioglitazone and rosiglitazone) act by binding nuclear
peroxisome proliferator–activated receptor-gamma (PPAR-␥) to increase insulin sensitivity and directly
enhance insulin action in muscle and fat cells. Rosiglitazone has been linked to nonfatal myocardial
infarction, and observational studies have associated pioglitazone with a risk of bladder cancer.
Bile salt binders
TABLE 1-4. ORAL DIABETIC MEDICATIONS
g Prandial glucose
g Prandial glucose
g Hepatic glucose
h Insulin sensitivity
h Insulin secretion
h Insulin secretion
Central effect and h
g Bile acid reabsorption
g Intestinal absorption of
Inhibit degradation of
Closes beta-cell KATP
Closes beta-cell KATP
(HEMOGLOBIN A1C LOWERING) (%)
Weight neutral; may reduce
Congestive heart failure;
edema; may be associated with nonfatal
myocardial infarction and
Gastrointestinal side effects:
Hypoglycemia; weight gain
14 CHAPTER 1 DIABETES MELLITUS
CHAPTER 1 DIABETES MELLITUS 15
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