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415 PHCL

Diabetes Mellitus
Raniah A. Al-Jaizani
Lecturer
Clinical Pharmacy Dept.

415 PHCL

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Diabetes Mellitus
• The Centers for Disease Control and Prevention (CDC)
predicts the national incidence of diabetes will rise by
37.5% by the year 2025 and by 170% in developing
countries over the next 30 years.
• Of particular concern is the alarming increase in the
prevalence of type 2 diabetes in both adults and children.
• In 2002, an estimated 18.2 million people, or 6.3% of the
United States population, had diabetes. Of these, 5.2
million or about one-third were undiagnosed.
• Clinical studies have affirmed that type 2 diabetes can be
delayed or prevented in high-risk populations and that
good glycemic control and other interventions can slow the
devastating complications of diabetes

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Definition
• Diabetes is a syndrome that is caused by a
relative or an absolute lack of insulin.
• Clinically, it is characterized by symptomatic
glucose intolerance as well as alterations in lipid
and protein metabolism.
• Over the long term, these metabolic
abnormalities, particularly hyperglycemia,
contribute to the development of complications
such as retinopathy, nephropathy, and
neuropathy.

Risk Factors for Diabetes Mellitus

• Obesity
• Familial history of diabetes mellitus
• Increasing age
• Ethnicity — High risk groups include African–
Americans, Hispanics and native Americans
• Dietary factors

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Endocrine pancreas
• In the pancreas there are endocrine cells found in scattered
clusters called islets of Langerhans.
• These endocrine cells can be classified into three distinct
types:
• - cells that produce the hormone glucagon.
• β - cells that produce insulin.
• -cells that produce somatostatin.

Insulin Function
• Increases glucose transport into tissues.
• Increases glycogen synthesis in liver and
muscle.
• Increases triglyceride synthesis in adipose
tissue and liver.
• Increases amino acid uptake and protein
synthesis.

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Carbohydrate Metabolism
• Homeostatic mechanisms maintain plasma glucose
concentrations between 55 and 140 mg/dL (3.1 to 7.8
mmol/L). A minimum concentration of 40 to 60 mg/dL (2.2
to 3.3 mmol/L) is required to provide adequate fuel for the
central nervous system (CNS), which uses glucose as its
primary energy source and is independent of insulin for
glucose utilization.
• When blood glucose concentrations exceed the
reabsorptive capacity of the kidneys (approximately 180
mg/dL), glucose spills into the urine resulting in a loss of
calories and water.
• Muscle and fat also use glucose as a major source of
energy, but these tissues require insulin for glucose uptake.
If glucose is unavailable, these tissues are able to use other
substrates such as amino acids and fatty acids for fuel.

Postprandial Glucose Metabolism in

the Nondiabetic Individual
• After food is ingested, blood glucose concentrations rise and stimulate
insulin release.
• Insulin is the key to efficient glucose utilization. It promotes the uptake of
glucose, fatty acids, and amino acids as well as their conversion to storage
forms in most tissues:
– In muscle, insulin promotes the uptake of glucose and its storage as
glycogen. It also stimulates the uptake of amino acids and their
conversion to protein.
– In adipose tissue, glucose is converted to free fatty acids and stored as
triglycerides. Insulin also prevents a breakdown of these triglycerides
to free fatty acids, a form that may be transported to other tissues for
utilization.
– The liver does not require insulin for glucose transport, but insulin
facilitates the conversion of glucose to glycogen and free fatty acids.

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Fasting Glucose Metabolism in the

Nondiabetic Individual
• As blood glucose concentrations drop toward normal during the
fasting state, insulin release is inhibited.
• Simultaneously, a number of counter-regulatory hormones that
oppose the effect of insulin and promote an increase in blood sugar
are released (e.g., glucagon, epinephrine, growth hormone,
glucocorticoids).
• As a result, several processes maintain a minimum blood glucose
concentration for the CNS:
 Glycogen in the liver is broken down into glucose
(glycogenolysis).
 Amino acids are transported from muscle to liver, where they
are converted to glucose through gluconeogenesis.
 Uptake of glucose by insulin-dependent tissues is diminished
to conserve glucose for the brain.
 Triglycerides are broken down into free fatty acids, which are
used as alternative fuel sources.

Types of Diabetes
• Type 1 Diabetes (insulin-dependent diabetes
mellitus (IDDM)).
• Type 2 Diabetes (non–insulin-dependent
diabetes mellitus (NIDDM)).
• Gestational diabetes mellitus (GDM).
• Impaired glucose tolerance (IGT).
• Impaired fasting glucose (IFG).

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Type 1 Diabetes
• Pathogenesis:
• The loss of insulin secretion in type 1 diabetes mellitus
results from autoimmune destruction of the insulin-
producing β-cells in the pancreas(such as viruses or toxins)
or may be Idiopathic (without evidence of autoimmunity).
• This form of diabetes is associated closely with
histocompatibility antigens (HLA- DR3 or HLA-DR4) and the
presence of circulating insulin and islet cell antibodies (ICAs).
• β-Cell destruction may occur rapidly but is more likely to
take place over a period of weeks, months, or even years.

Type 1 Diabetes Cont’d

• Pathogenesis:
• Fasting hyperglycemia occurs when β-cell mass is reduced
by 80% to 90%.
• On presentation, approximately 65% to 85% of patients
have circulating antibodies directed against islet cells and
20% to 60% of patients have measurable antibodies
directed against insulin.
• Within 8 to 10 years following clinical presentation, β-cell
loss is complete and insulin deficiency is absolute.
Circulating ICAs can no longer be detected.

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Type 1 Diabetes Cont’d

• Clinical Presentation:
• Polyuria.
• Polydipsia.
• Polyphagia.
• weight loss.
• Recurrent respiratory, vaginal, and other
infections.

Honeymoon Period
• Within days or weeks after the initial diagnosis, many
patients with type 1 diabetes experience an apparent
remission, which is reflected by decreased blood glucose
concentrations and markedly decreased insulin
requirements.
• It may last for only a few weeks to months.
• Once hyperglycemia, metabolic acidosis, and ketosis
resolve, endogenous insulin secretion recovers temporarily.
• Honeymoon period may last for up to a year.
• During this time, patients should be maintained on insulin
even if the dose is very low, because interrupted treatment
is associated with a greater incidence of resistance and
allergy to insulin.

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Type 2 Diabetes
• Pathogenesis: Metabolic Syndrome (Insulin Resistance
Syndrome, Syndrome X):
• Impaired insulin secretion and resistance to the action of
insulin characterize patients with type 2 diabetes.
• In the presence of insulin resistance, glucose utilization by
tissues is impaired, hepatic glucose output or production is
increased, and excess glucose accumulates in the
circulation. This hyperglycemia stimulates the pancreas to
produce more insulin in an effort to overcome the insulin
resistance.

Type 2 Diabetes
• Pathogenesis: Metabolic Syndrome (Insulin Resistance Syndrome,
Syndrome X):
• The simultaneous elevation of both glucose and insulin is
strongly suggestive of insulin resistance.
• Type 2 diabetes is associated with a variety of disorders,
including obesity, atherosclerosis, hyperlipidemia, and
hypertension.
• People with type 2 diabetes have a stronger family history
of diabetes than do those with type 1 diabetes. Circulating
ICAs are absent, and there is no association with human
lymphocyte antigen (HLA) types.

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Type 2 Diabetes
• Clinical Presentation:
• Symptoms are so mild and their onset so
gradual.
• When giving a history of their illness, people
with type 2 diabetes acknowledge fatigue,
polyuria, and polydipsia.
• Weight loss is uncommon in these individuals
because relatively high endogenous insulin
levels promote lipogenesis.

Types of Diabetes
Table 50-1 Type 1 and Type 2 Diabetes
Characteristics Type 1 Type 2
Other names Previously, type I; insulin- Previously, type II; non–insulin-dependent
dependent diabetes mellitus diabetes mellitus (NIDDM); adult onset
(IDDM); juvenile-onset diabetes mellitus
diabetes mellitus
Percentage of 5–10% 90%
diabetic
population
Age at onset Usually <30 yr; peaks at 12–14 Usually >40 yr, but increasing prevalence
yr; rare before 6 mo; some among obese children
adults develop type 1 during
the fifth decade
Pancreatic Usually none, although some Insulin present in low, “normal,” or high
function residual C-peptide can amounts
sometimes be detected at
diagnosis, especially in adults

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Types of Diabetes
Table 50-1 Type 1 and Type 2 Diabetes
Characteristics Type 1 Type 2
Pathogenesis Associated with certain HLA Defect in insulin secretion; tissue
types; presence of islet cell resistance to insulin; ↑ hepatic glucose
antibodies suggests autoimmune output
process
Family history Generally not strong Strong
Obesity Uncommon unless Common (60–90%)
“overinsulinized” with exogenous
insulin
History of Often present Rare, except in circumstances of unusual
ketoacidosis stress (e.g., infection)
Clinical presentation Moderate to severe symptoms that Mild polyuria, fatigue; often diagnosed
generally progress relatively on routine physical or dental examination
rapidly (days to weeks): polyuria,
polydipsia, fatigue, weight loss,
ketoacidosis

HLA, human leukocyte antigen.

Types of Diabetes
Table 50-1 Type 1 and Type 2 Diabetes
Characteristics Type 1 Type 2
Treatment Insulin Diet
Diet Exercise
Exercise Oral antidiabetic agents (α-glucosidase
inhibitors, biguanides, non-sulfonylurea
insulin secretagogues, sulfonylureas,
thiazolidinediones)
Insulin

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Gestational Diabetes Mellitus

(GDM)
• Affects about 7% of all pregnancies.
• Any carbohydrate intolerance with onset or first
recognition during pregnancy.
• Most commonly seen during the third trimester of
pregnancy.
• Resolves itself in most patients after birth but a certain
percentage(50 to 60%) will go on to develop diabetes
mellitus in the years following the pregnancy.
• May be associated with an increased risk of fetal
abnormalities.
• Currently recommended that all pregnant women be
screened for the presence of gestational diabetes

Impaired glucose tolerance (IGT)

• Subclinical glucose intolerance or “prediabetes”.

• Patients with IGT do not meet the criteria for diagnosis of DM.
• Patients are at high risk of DM.
• Patients with normal fasting plasma glucose levels (> 110 & <126
mg/dl) but values during an OGTT are > 200 mg/dl at 0.5, 1, or
1.5 hr & 140 – 200 mg/dl at 2 hr.

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Impaired fasting glucose (IFG).

• Subclinical glucose intolerance or “prediabetes”.

• Patients with IFG do not meet the criteria for diagnosis of DM.
• Patients are at high risk of DM.
• Patients with fasting plasma glucose levels (> 110 & <126 mg/dl).

Diagnosis
• Diagnosis of diabetes can be made when one of the
following is present:
• Classic signs and symptoms of diabetes (polyuria,
polydipsia, ketonuria, and rapid weight loss)
combined with a random plasma glucose ≥200
mg/dL.
• A fasting plasma glucose (FPG) ≥126 mg/dL.
• Oral glucose tolerance test (OGTT): Plasma
glucose concentration is ≥200 mg/dL at 2 hours
and at least one other time during the test (0.5, 1,
1.5 hours).

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Fasting Blood Glucose

• The categories of FPG values are as follows:
• A normal FPG is <100 mg/dL.
• An FPG 100–125 mg/dL is IFG.
• An FPG ≥126 mg/dL indicates a provisional diagnosis of
diabetes.

IFG: Impaired fasting glucose.

Oral Glucose Tolerance Test

• The corresponding categories when the OGTT is used for
diagnosis are as follows:
• A 2-hour postload glucose (2-hPG) <140 mg/dL indicates
normal glucose tolerance.
• A 2-hPG ≥140 mg/dL and <200 mg/dL indicates IGT.
• A 2-hPG ≥200 mg/dL indicates a provisional diagnosis of
diabetes.

IGT : Impaired glucose Tolerance.

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Oral Glucose Tolerance Test

• Many factors can impair glucose tolerance or increase plasma glucose, and
these must be excluded before a firm diagnosis of diabetes is made. For
example:
– An individual who has not fasted for a minimum of 8 hours may have an
elevated FPG.
– One who has fasted too long (>16 hours) or has ingested insufficient
carbohydrates before testing may have an IGT.
– Patients who are tested for glucose tolerance during, or soon after, an
acute illness (e.g., a myocardial infarction [MI]) may be misdiagnosed
because of the presence of high concentrations of counter-regulatory
hormones that increase glucose concentrations.
– Pregnancy, many forms of stress, and lack of physical activity can affect
the glucose tolerance similarly.
– Many drugs may alter glucose tolerance due to their effects on insulin
release and tissue response to insulin, as well as through direct cytotoxic
effects on the pancreas.

Complications
 Acute metabolic complications:
• Diabetic ketoacidosis (DKA).
• Hyperglycemic, hyperosmolar, nonketotic
coma (HHNK).
• Hypoglycemia (< 70 mg/dl).
 Chronic long term complications:
• Macrovascular complications (coronary
artery disease, peripheral artery disease,
stroke).
• Microvascular complications (retinopathy,
nephropathy, and neuropathy).

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Homework

415 PHCL

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