Harrison book based diabetes-Rupak1-3.pptx

Diabetes Mellitus:
Diagnosis, Classification, &
Pathophysiology
HARRISON’S PRINCIPLES OF INTERNAL MEDICINE 19TH EDITION

▶ Diabetes mellitus (DM) refers to a group of common metabolic disorders that share the
phenotype of hyperglycemia.
▶ Several distinct types of DM are caused by a complex interaction of genetics and
environmental factors.
▶ Depending on the etiology of the DM, factors contributing to hyperglycemia include
reduced insulin secretion, decreased glucose utilization, and increased glucose
production.
▶ The metabolic dysregulation associated with DM causes secondary pathophysiologic
changes in multiple organ systems that impose a tremendous burden on the individual
with diabetes and on the health care system.

▶ In the United States, DM is the leading cause of end-stage renal disease (ESRD),
nontraumatic lower extremity amputations, and adult blindness. It also predisposes
to CVD.
▶ With an increasing incidence worldwide, DM will be likely a leading cause of morbidity
and mortality in the future.

CLASSIFICATION
▶ DM is classified on the basis of the pathogenic process that leads to hyperglycemia, as
opposed to earlier criteria such as age of onset or type of therapy (Fig. 417-1)
▶ There are two broad categories of DM, designated type 1 and type 2 (Table 417-1).
▶ However, there is increasing recognition of other forms of diabetes in which the
pathogenesis is better understood.
▶ These other forms of diabetes may share features of type 1 and/or type 2 DM.
▶ Both type 1 and type 2 DM are preceded by a phase of abnormal glucose homeostasis
as the pathogenic processes progress.
▶ Type 1 DM is the result of complete or near-total insulin deficiency.

▶ Type 2 DM is a heterogeneous group of disorders characterized by
variable degrees of insulin resistance, impaired insulin secretion, and
increased glucose production.
▶ Distinct genetic and metabolic defects in insulin action and/or secretion
give rise to the common phenotype of hyperglycemia in type 2 DM and
have important potential therapeutic implications now that pharmacologic
agents are available to target specific metabolic derangements.
▶ Type 2 DM is preceded by a period of abnormal glucose homeostasis
classified as impaired fasting glucose (IFG) or impaired glucose tolerance
tolerance (IGT).

OTHER TYPES OF DM
▶ Other etiologies for DM include specific genetic defects in insulin secretion
or action, metabolic abnormalities that impair insulin secretion,
mitochondrial abnormalities, and a host of conditions that impair glucose
tolerance (Table 417-1).
▶ Maturity-onset diabetes of the young (MODY) and monogenic diabetes
are subtypes of DM characterized by autosomal dominant inheritance, early
onset of hyperglycemia (usually <25 years; sometimes in neonatal period),
and impaired insulin secretion.
▶ Mutations in the insulin receptor cause a group of rare disorders
characterized by severe insulin resistance.

▶ DM can result from pancreatic exocrine disease when the majority of
pancreatic islets are destroyed.
▶ Cystic fibrosis–related DM is an important consideration in that patient
population.
▶ Hormones that antagonize insulin action can also lead to DM.
▶ Thus, DM is often a feature of endocrinopathies such as acromegaly and
Cushing’s disease.
▶ Viral infections have been implicated in pancreatic islet destruction but are
an extremely rare cause of DM.
▶ A form of acute onset of type 1 diabetes, termed fulminant diabetes, has
been noted in Japan and may be related to viral infection of islets.

GESTATIONAL DIABETES MELLITUS
▶ Glucose intolerance developing during pregnancy is classified as gestational
diabetes mellitus (GDM).
▶ Insulin resistance is related to the metabolic changes of late pregnancy, and
the increased insulin requirements may lead to IGT or diabetes.
▶ GDM occurs in ~7% (range 1–14%) of pregnancies in the United States; most
women revert to normal glucose tolerance postpartum but have a substantial
risk (35–60%) of developing DM in the next 10–20 years.
▶ The International Association of the Diabetes and Pregnancy Study Groups and
the American Diabetes Association (ADA) recommend that diabetes diagnosed at
the initial prenatal visit should be classified as “overt” diabetes rather than GDM.
▶ With the rising rates of obesity, the number of women being diagnosed with
GDM or overt diabetes is rising worldwide.

DIAGNOSIS
▶ Glucose tolerance is classified into three broad categories:
1. normal glucose homeostasis
2. DM
3. impaired glucose homeostasis.
▶ Glucose tolerance can be assessed using the fasting plasma glucose (FPG), the
response to oral glucose challenge, or the hemoglobin A1c (HbA1c).
▶ A FPG <5.6 mmol/L (100 mg/dL), a plasma glucose <140 mg/dL (11.1
mmol/L) following an oral glucose challenge, and an HbA1c <5.7% are
considered to define normal glucose tolerance.

▶ The International Expert Committee with members appointed by the ADA,
the European Association for the Study of Diabetes, and the International
Diabetes Federation have issued diagnostic criteria for DM (Table 417-2)
based on the following premises:
▶ (1) the FPG, the response to an oral glucose challenge (oral glucose tolerance
test [OGTT]), and HbA1c differ among individuals
▶ (2) DM is defined as the level of glycemia at which diabetes-specific
complications occur rather than on deviations from a population-based
mean.
▶ A random plasma glucose concentration ≥11.1 mmol/L (200 mg/dL)
accompanied by classic symptoms of DM (polyuria, polydipsia, weight loss)
is also sufficient for the diagnosis of DM

▶ The current criteria for the diagnosis of DM emphasize the HbA1c or
the FPG as the most reliable and convenient tests for identifying DM in
asymptomatic individuals (however, some individuals may meet criteria
for one test but not the other).
▶ OGTT, although still a valid means for diagnosing DM, is not often used
in routine clinical care.
▶ These criteria also allow for the diagnosis of DM to be withdrawn in
situations when the glucose intolerance reverts to normal.

▶ Type 1DM is the result of interactions of genetic, environmental and immunologic
factors that ultimately lead to the destruction of the pancreatic beta cells and insulin
deficiency.
▶ Type 1DM, which can develop at any age, develops most commonly before 20 years of
age.
▶ Worldwide, the incidence of type 1DM is increasing at the rate of 3–4% per year for
uncertain reasons.
▶ Type 1DM results from autoimmune beta cell destruction, and most, but not all,
individuals have evidence of islet-directed autoimmunity.

▶ Some individuals who have the clinical phenotype of type 1 DM lack
immunologic markers indicative of an autoimmune process involving the beta
cells and the genetic markers of type 1 DM.
▶ These individuals are thought to develop insulin deficiency by unknown,
nonimmune mechanisms and may be ketosis prone; many are African
American or Asian in heritage.

▶ Individuals with a genetic susceptibility are thought to have normal beta cell
mass at birth but begin to lose beta cells secondary to autoimmune
that occurs over months to years.
▶ This autoimmune process is thought to be triggered by an infectious or
environmental stimulus and to be sustained by a beta cell–specific molecule.
▶ In the majority of patients, immunologic markers appear after the triggering
event but before diabetes becomes clinically overt.
▶ Beta cell mass then begins to decrease, and insulin secretion progressively
declines, although normal glucose tolerance is maintained.
▶ The rate of decline in beta cell mass varies widely among individuals, with some
patients progressing rapidly to clinical diabetes and others evolving more slowly.
▶ Features of diabetes do not become evident until a majority of beta cells are
destroyed (70–80%).

▶ At this point, residual functional beta cells exist but are insufficient in
number to maintain glucose tolerance.
▶ The events that trigger the transition from glucose intolerance to diabetes
are often associated with increased insulin requirements, as might occur
during infections or puberty.
▶ After the initial clinical presentation of type 1 DM, a “honeymoon” phase
may ensue during which time glycemic control is achieved with modest
doses of insulin or, rarely, insulin is not needed.
▶ However, this fleeting phase of endogenous insulin production from residual
beta cells disappears and the individual becomes insulin deficient.
▶ Many individuals with long-standing type 1 DM produce a small amount of
insulin (as reflected by C-peptide production), and some individuals with
more than 50 years of type 1 DM have insulin-positive cells in the pancreas
at autopsy.

▶ Pathophysiology:
▶ Although other islet cell types (alpha cells [glucagonproducing], delta cells
[somatostatin-producing], or PP cells [pancreatic polypeptide-producing]) are
functionally and embryologically similar to beta cells and express most of
same proteins as beta cells, they are spared from the autoimmune
destruction.
▶ Pathologically, the pancreatic islets have a modest infiltration of lymphocytes
(a process termed insulitis). After beta cells are destroyed, it is thought that
the inflammatory process abates and the islets become atrophic.

▶ Studies of the autoimmune process in humans and in animal models of
type 1 DM (NOD mouse and BB rat) have identified the following
abnormalities in the humoral and cellular arms of the immune system:
▶ (1) islet cell autoantibodies;
▶ (2) activated lymphocytes in the islets, peripancreatic lymph nodes, and
systemic circulation;
▶ (3) T lymphocytes that proliferate when stimulated with islet proteins; and
▶ (4) release of cytokines within the insulitis

▶ Beta cells seem to be particularly susceptible to the toxic effect of some
cytokines (tumor necrosis factor α [TNF-α], interferon γ, and interleukin
1[IL-1]).
▶ The precise mechanisms of beta cell death are not known but may
involve formation of nitric oxide metabolites, apoptosis, and direct CD8+
CD8+ T cell cytotoxicity.
▶ The islet destruction is mediated by T lymphocytes rather than islet
autoantibodies, as these antibodies do not generally react with the cell
surface of islet cells and are not capable of transferring DM to animals.
▶ Efforts to suppress the autoimmune process at the time of diagnosis of
diabetes have largely been ineffective or only temporarily effective in
slowing beta cell destruction.

▶ Pancreatic islet molecules targeted by the autoimmune process include
insulin, glutamic acid decarboxylase (GAD; the biosynthetic enzyme for the
neurotransmitter GABA), ICA-512/IA-2 (homology with tyrosine phosphatases),
and a beta cell–specific zinc transporter (ZnT-8).
▶ Most of the autoantigens are not beta cell–specific, which raises the question
of how the beta cells are selectively destroyed.
▶ Current theories favor initiation of an autoimmune process directed at one
beta cell molecule, which then spreads to other islet molecules as the
process destroys beta cells and creates a series of secondary autoantigens.
▶ The beta cells of individuals who develop type 1 DM do not differ from
cells of normal individuals because islets transplanted from a genetically
identical twin are destroyed by a recurrence of the autoimmune process of type
1 DM.

▶ Prevention of Type 1 DM: A number of interventions have prevented diabetes
in animal models.
▶ None of these interventions have been successful in preventing type 1 DM
humans.
▶ For example, the Diabetes Prevention Trial–Type 1 concluded that
administering insulin (IV or PO) to individuals at high risk for developing type 1
DM did not prevent type 1 DM.

TYPE 2 DM
▶ Insulin resistance and abnormal insulin secretion are central to the
development of type 2 DM.
▶ Although the primary defect is controversial, most studies support the view that
insulin resistance precedes an insulin secretory defect but that diabetes
develops only when insulin secretion becomes inadequate.
▶
▶ Type 2 DM likely encompasses a range of disorders with common phenotype of
hyperglycemia.

▶ It is becoming increasing apparent that DM in other ethnic groups (Asian,
African, and Latin American) has a somewhat different, but yet undefined,
pathophysiology.
▶ In general, Latinos have greater insulin resistance and East Asians and South
Asians have more beta cell dysfunction, but both defects are present in both
populations.
▶ East and South Asians appear to develop type 2 DM at a younger age and a
low

Pathophysiology
▶ Pathophysiology Type 2 DM is characterized by impaired insulin secretion,
insulin resistance, excessive hepatic glucose production, and abnormal
fat metabolism.
▶ Obesity, particularly visceral or central (as evidenced by the hip-waist ratio), is
very common in type 2 DM (≥80% of patients are obese).
▶ In the early stages of the disorder, glucose tolerance remains near-normal,
despite insulin resistance, because the pancreatic beta cells compensate by
increasing insulin output (Fig. 417-7).
▶ As insulin resistance and compensatory hyperinsulinemia progress, the
pancreatic islets in certain individuals are unable to sustain the hyper
insulinemic state.

▶ IGT,characterized by elevations in postprandial glucose, then
develops.
▶ A further decline in insulin secretion and an increase in hepatic
glucose production lead to overt diabetes with fasting
hyperglycemia.
▶ Ultimately, beta cell failure ensues.
▶ Although both insulin resistance and impaired insulin secretion
contribute to the pathogenesis of type 2 DM, the relative
contribution of each varies from individual to individual.

▶ Prevention Type 2 DM is preceded by a period of IGT or IFG, and a number
of lifestyle modifications and pharmacologic agents prevent or delay the
onset of DM.
▶ Individuals with prediabetes or increased risk of diabetes should be referred
referred to a structured program to reduce body weight and increase
physical activity as well as being screened for cardiovascular disease.
▶ The Diabetes Prevention Program (DPP) demonstrated that intensive
changes in lifestyle (diet and exercise for 30 min/d five times/week) in
individuals with IGT prevented or delayed the development of type 2 DM
by 58% compared to placebo.
▶ This effect was seen in individuals regardless of age, sex, or ethnic group.
▶ In the same study, metformin prevented or delayed diabetes by 3
1
%
compared to placebo.
▶ The lifestyle intervention group lost 5–7% of their body weight during the 3
years of the study

▶ Individuals with a strong family history of type 2 DM and individuals with
IFG or IGT should be strongly encouraged to maintain a normal BMI and
engage in regular physical activity.
▶ Pharmacologic therapy for individuals with prediabetes is currently
controversial because its cost effectiveness and safety profile are not
known.

▶ The ADA has suggested that metformin be considered in individuals with
both IFG and IGT who are at very high risk for progression to diabetes
(age <60 years, BMI ≥35 kg/m2, family history of diabetes in first-
relative, and women with a history of GDM).
▶ Individuals with IFG, IGT, or an HbA1c of 5.7–6.4% should be monitored
annually to determine if diagnostic criteria for diabetes are present.

Medical nutrition therapy
 ▶ Nutrition Medical nutrition therapy (MNT) is a term used by the
ADA to describe the optimal coordination of caloric intake with
other aspects of diabetes therapy (insulin, exercise, weight
loss).
 ▶Primary prevention measures of MNT are directed at
preventing or delaying the onset of type 2 DM in high-risk
individuals (obese or with prediabetes) by promoting weight
reduction.
 ▶Medical treatment of obesity is a rapidly evolving area and is
discussed in Chap. 416.
 ▶Secondary prevention measures of MNT are directed at
preventing or delaying

▶ Tertiary prevention measures of MNT are directed at managing diabetes-related
complications (cardiovascular disease, nephropathy) in diabetic individuals. MNT
in patients with diabetes and cardiovascular disease should incorporate dietary
principles used in nondiabetic patients with cardiovascular disease.
▶ Although the recommendations for all three types of MNT overlap, this chapter
emphasizes secondary prevention measures of MNT.
▶ Pharmacologic approaches that facilitate weight loss and bariatric surgery should
be considered in selected patients (Chaps. 415e and 416).
▶ In general, the components of optimal MNT are similar for individuals with type 1
or type 2 DM and similar to those for the general population (fruits, vegetables,
fiber-containing foods, and low fat; Table 418-3).
▶ MNT education is an important component of comprehensive diabetes care and
should be reinforced by regular patient education.

▶ Historically, nutrition education imposed restrictive, complicated regimens on the
patient.
▶ Current practices have greatly changed, although many patients and health care
providers still view the diabetic diet as monolithic and static.
▶ For example, MNT now includes foods with sucrose and seeks to modify other
risk factors such as hyperlipidemia and hypertension rather than focusing
exclusively on weight loss in individuals with type 2 DM.
▶ The glycemic index is an estimate of the postprandial rise in the blood glucose
when a certain amount of that food is consumed.
▶ Consumption of foods with a low glycemic index appears to reduce postprandial
glucose excursions and improve glycemic control. Reduced-calorie and
nonnutritive sweeteners are useful.
▶ Currently, evidence does not support supplementation of the diet with vitamins,
antioxidants (vitamin C and E), or micronutrients (chromium) in patients with
diabetes.

▶ The goal of MNT in the individual with type 1 DM is to coordinate and match
the caloric intake, both temporally and quantitatively, with the appropriate
amount of insulin.
▶ MNT in type 1 DM and selfmonitoring of blood glucose must be integrated to
define the optimal insulin regimen.
▶ The ADA encourages patients and providers to use carbohydrate counting or
exchange systems to estimate the nutrient content of a meal or snack. Based on
the patient’s estimate of the carbohydrate content of a meal, an insulin-to-
carbohydrate ratio determines the bolus insulin dose for a meal or snack.
▶ MNT must be flexible enough to allow for exercise, and the insulin regimen must
allow for deviations in caloric intake. An important component of MNT in type 1
DM is to minimize the weight gain often associated with intensive diabetes
management.

▶ The goals of MNT in type 2 DM should focus on weight loss and address the
greatly increased prevalence of cardiovascular risk factors (hypertension,
dyslipidemia, obesity) and disease in this population.
▶ The majority of these individuals are obese, and weight loss is strongly
encouraged and should remain an important goal.
▶ Hypocaloric diets and modest weight loss (5–7%) often result in rapid and
dramatic glucose lowering in individuals with new-onset type 2 DM.
▶ Nevertheless, numerous studies document that long-term weight loss is
uncommon.
▶ MNT for type 2 DM should emphasize modest caloric reduction (low-
carbohydrate) and increased physical activity.
▶ Increased consumption of soluble, dietary fiber may improve glycemic control
in individuals with type 2 DM. Weight loss and exercise improve insulin
resistance.

Harrison book based diabetes-Rupak1-3.pptx

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