Diabetes 1

25.03.
2020
Diabetes Mellitus
Dr. Muhammad Fawad Rasool

Associate Professor & Chairman
Department of Pharmacy Practice,

Bahauddin Zakariya University, Multan
www.bzu.edu.pk
Diabetes Mellitus
▪ Diabetes mellitus (DM) describes a group of chronic metabolic

disorders characterized by hyperglycemia that may result in long-term
microvascular, macrovascular, and neuropathic complications.
These complications contribute to diabetes being the leading cause of,

(a) new cases of blindness among adults,
(b) end-stage renal disease, and
(c) nontraumatic lower limb amputations.
2 Dr. Muhammad Fawad Rasool www.bzu.edu.pk
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Epidemiology
Epidemiology
▪ The worldwide prevalence of DM has risen dramatically over

the past two decades, from an estimated 30 million cases in 1985
to 177 million in 2000.
▪ Based on current trends, >360 million individuals will have
diabetes by the year 2030.
▪ The prevalence of type 2 DM is rising much more rapidly
▪ 6 of the top 10 countries with the highest rates are in Asia.
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Etiology
▪ The increasing prevalence of DM is partly caused by three influences: lifestyle,

ethnicity, and age.
▪ Type 1 DM (T1DM) is usually diagnosed before age 30 years but can develop at
any age.
Etiology
▪ T1DM is an autoimmune disease in which insulin producing β cells in the

pancreas are destroyed.
▪ The presence of human leukocyte antigens (HLAs) are associated with the
development of T1DM.
▪ In addition, these individuals often develop islet cell antibodies, insulin
autoantibodies, or glutamic acid decarboxylase autoantibodies.
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Etiology
▪ At the time of diagnosis of T1DM, it is commonly believed that most patients

have an 80% to 95% loss of β-cell function.
▪ The remaining β-cell function at diagnosis creates a “honeymoon period” during
which blood glucose levels are easier to control and smaller amounts of insulin are
required.
▪ After this remaining β-cell function is lost, and patients become completely
insulin deficient and require more exogenous insulin.
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Etiology
▪ Latent autoimmune diabetes in adults (LADA): slow onset type 1, or type 1.5 DM,
is a form of autoimmune T1DM that occurs in individuals older than the usual age
of T1DM onset.
▪ Patients often are mistakenly thought to have T2DM because the person is older
and may respond initially to treatment with oral blood glucose–lowering agents.
▪ These patients do not have insulin resistance, but antibodies are present in the
blood that are known to destroy pancreatic β cells.
Etiology
▪ C-peptide is the abbreviation for “connecting peptide.” C-peptide is made when

proinsulin is split into insulin and C-peptide. They split before proinsulin is released
from endocytic vesicles within the pancreas one C-peptide for each insulin
molecule
▪ Routine measurement of C-peptide levels, insulin levels, and proinsulin are not
recommended in most patients.
▪ However, C-peptide measurements can be used to distinguish between T1DM
and T2DM. People with T1DM have C-peptide levels below 1 ng/mL (0.33 nmol/L),
whereas those with T2DM will have values greater than 1 ng/mL (0.33 nmol/L).
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Etiology
▪ IFG is defined as having a fasting blood glucose (FBG) level between 100 and 125
mg/dL (5.6 and 6.9 mmol/L).
▪ IGT is defined by a postprandial blood glucose level between 140 and 199 mg/dL
(7.8 and 11.0 mmol/L).
▪ The development of IFG, IGT, or A1c between 5.7% and 6.4% (0.057 and 0.064;
39 and 46 mmol/ mol) places the individual at high risk of eventually developing
diabetes.
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Etiology
▪ T2DM is usually slow and progressive in its development.

▪ Risk factors for T2DM include:
▪ First-degree family history of DM (i.e., parents or siblings)
▪ Overweight or obese
▪ Habitual physical inactivity
▪ Race or ethnicity (Native American, Latino or Hispanic American, Asian
American, African American, and Pacific Islanders)
▪ Previously identified IFG, IGT, or A1c between 5.7% and 6.4% (0.057 and 0.064 or
39 and 46 mmol/mol Hb)
▪ Hypertension (greater than or equal to 140/90 mm Hg or on therapy for
hypertension)
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Etiology
▪ High-density lipoprotein (HDL) less than 35 mg/dL (0.91 mmol/L) and/or a

triglyceride level greater than 250 mg/dL (2.83 mmol/L)
▪ History of gestational diabetes or delivery of a baby weighing greater than 4 kg (9
lb)
▪ History of cardiovascular disease
▪ History of polycystic ovarian syndrome
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Etiology
▪ Gestational diabetes mellitus (GDM) is defined as glucose intolerance in women

during pregnancy.
▪ This complication develops in between 2% and 10% of all pregnancies.
▪ Women who have GDM have a 35% to 60% chance of developing T2DM.
▪ New diagnostic criteria call for all pregnant women not previously known to have
diabetes to undergo screening for GDM between 24 and 28 weeks of gestation.
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Medications That May Affect Glycemic Control
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PATHOPHYSIOLOGY
Normal Carbohydrate Metabolism

▪ The body’s main fuel source is glucose.
▪ Glucose is stored in the liver and muscles as glycogen.
▪ Excess glucose also may be stored in adipose tissue, which may subsequently
undergo lipolysis, yielding free fatty acids.
▪ In the fasting state, free fatty acids supply much of the energy needs for the
body except for the central nervous system, which requires glucose to function
normally.
▪ Although usually reserved for other functions, proteins also can be converted to
glucose through gluconeogenesis.
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PATHOPHYSIOLOGY
▪ Insulin and glucagon are produced in the pancreas by cells in the islets of
Langerhans. β cells make up 70% to 90% of the islets and produce insulin and
amylin, whereas α cells produce glucagon.
▪ The main function of insulin is to decrease blood glucose levels. Glucagon, along
with other counterregulatory hormones such as growth factor, cortisol, and
epinephrine, increases blood glucose levels.
▪ Although blood glucose levels vary, the opposing actions of insulin and
glucagon, along with the counterregulatory hormones, normally maintain
fasting values between 79 and 99 mg/dL (4.4 to 5.5 mmol/L).
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PATHOPHYSIOLOGY
Normal Insulin Action

▪ Fasting insulin levels in the circulation average from 43 to 186 pmol/L (6 to 26
µIU/mL).
▪ After food is consumed, blood glucose levels rise, and the insulin-secretion
response occurs in two phases.
▪ An initial burst, known as first phase insulin response, lasts approximately 5 to
10 minutes and serves to suppress hepatic glucose production and cause
insulin-mediated glucose disposal in adipose tissue.
▪ This bolus of insulin minimizes hyperglycemia during meals and during the
postprandial period.
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PATHOPHYSIOLOGY
▪ The second phase of insulin response is characterized by a gradual increase in

insulin secretion, which lasts 60 to 120 minutes and stimulates glucose uptake
by peripheral insulin-dependent tissues.
▪ Approximately 80% to 85% of glucose metabolism during this time occurs in
muscle.
▪ Slower release of insulin allows the body to respond to the new glucose
entering from digestion while maintaining blood glucose levels.
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PATHOPHYSIOLOGY
▪ Amylin is a naturally occurring hormone that is co-secreted from β cells with

insulin.
▪ People with diabetes have either a relative or complete lack of amylin.
Amylin has three major mechanisms of action:
▪ suppression of postmeal glucagon secretion;
▪ regulation of the rate of gastric emptying from the stomach to the small
intestine, which increases satiety;
▪ and regulation of plasma glucose concentrations in the bloodstream.
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PATHOPHYSIOLOGY
Impaired Insulin Secretion

▪ A pancreas with normal β-cell function is able to adjust insulin production to
maintain normal blood glucose levels.
▪ Hyperinsulinemia, or high blood levels of insulin, is an early finding in the
development of T2DM.
▪ More insulin is secreted to maintain normal blood glucose levels until eventually
the pancreas can no longer produce sufficient insulin.
▪ The resulting hyperglycemia is enhanced by extremely high insulin resistance,
pancreatic burnout in which β cells lose functional capacity, or both.
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PATHOPHYSIOLOGY
▪ Impaired β-cell function results in a reduced ability to produce a first-phase

insulin response sufficient to signal the liver to stop producing glucose after a
meal.
▪ As DM progresses, large numbers of patients with T2DM eventually lose all β-
cell function and require exogenous insulin to maintain blood glucose control.
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PATHOPHYSIOLOGY
Insulin Resistance
▪ Insulin resistance is the primary factor that differentiates T2DM from other
forms of diabetes.
▪ Insulin resistance may be present for several years prior to the diagnosis of DM
▪ Resistance to insulin occurs most significantly in skeletal muscle and the liver.
▪ Insulin resistance in the liver poses a double threat because the liver becomes
nonresponsive to insulin for glucose uptake, and hepatic production of glucose
after a meal does not cease, which leads to elevated fasting and post-meal
blood glucose levels.
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PATHOPHYSIOLOGY
Impaired Glucagon Secretion

▪ Glucagon is a counterregulatory hormone released by the α cells that raises
blood glucose levels.
▪ The release of insulin and the inhibition of glucagon is glucose stimulated,
meaning that as glucose is consumed, the release of insulin increases and the
release of glucagon decreases in people without diabetes.
▪ Most patients with a 10- to 20-year history of T1DM have lost their ability to
release glucagon, which increases their risk for hypoglycemic unawareness.
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PATHOPHYSIOLOGY
▪ People with T2DM have impaired phase 1 and phase 2 insulin release, and some
have impaired glucagon-like peptide 1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP) release, which further reduces the release of
insulin.
▪ This leads to the liver’s producing and releasing glucose even in the postprandial
state.
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PATHOPHYSIOLOGY
Metabolic Syndrome
▪ Insulin resistance has been associated with a number of other cardiovascular
risks, including abdominal obesity, hypertension, dyslipidemia,
hypercoagulation, and hyperinsulinemia.
▪ The clustering of these risk factors has been termed metabolic syndrome.
▪ The most widely used criteria to define metabolic syndrome were established by
the National Cholesterol Education Program Adult Treatment Panel III
Guidelines.
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Metabolic Syndrome
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Pathophysiology
Incretin Effect
▪ A great deal of research is occurring today to develop compounds that enhance
the incretin effect, either by mimicking its action or by enabling incretin
hormones to remain physiologically active for longer periods of time.
▪ As early as the late 1960s, Perley and others observed that insulin’s response to
oral glucose exceeded that of intravenous (IV) glucose administration.
▪ It was concluded that factors in the gut, or incretins, affected the release of
insulin after a meal is consumed.
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Pathophysiology
▪ When nutrients enter the stomach and intestines, incretin hormones are
released, which stimulates insulin secretion.
▪ This was validated by measuring C-peptide and insulin response to the IV and
oral glucose loads.
▪ GLP-1 and GIP are the two major incretin hormones, with GLP-1 being studied
the most. GLP-1 is secreted by the L cells of the ileum and colon primarily, and
GIP is secreted by the K cells.
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Pathophysiology
▪ GLP-1 secretion is caused by endocrine and neural signals started when

nutrients enter the gastrointestinal (GI) tract.
▪ A glucose dependent release of insulin occurs, and the dipeptidyl peptidase-4
(DPP-4) enzyme cleaves GLP-1 rapidly to an inactive metabolite.
▪ Much of the research on glucose-lowering products involves prolonging the
action of GLP-1.
▪ Other glucose lowering effects of GLP-1 include suppression of glucagon,
slowing gastric emptying, and increasing satiety.
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CLINICAL PRESENTATION AND DIAGNOSIS
Screening
▪ American Diabetes Association (ADA) recommends routine screening for T2DM
every 3 years in all adults starting at 45 years of age.
▪ Testing for T2DM should be considered in any adult, regardless of their age, who
have a BMI greater than or equal to 25 kg/m2.
▪ The ADA does not currently recommend widespread screening for T1DM
because of the relatively low incidence in the general population, although
measurement of islet autoantibodies may be appropriate for high-risk
individuals
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Gestational Diabetes
▪ All pregnant women who have risk factors for T2DM should be screened for
undiagnosed T2DM at their first prenatal visit using standard diagnostic criteria.
▪ Any woman found to have diabetes at that early point in pregnancy is considered
to have T2DM, not GDM.
▪ All other pregnant women, not currently known to have DM should be screened for
GDM with a 75-g oral glucose tolerance test (OGTT) between weeks 24 and 28 of
gestation.
▪ Any woman diagnosed with GDM should be retested at 6 to 12 weeks postpartum.
▪ If screening results are normal at that point, then reassessment for DM should occur
every 3 years.
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ADA Criteria for the Diagnosis of Diabetes
DCCT, Diabetes Control and Complications Trial; NGSP, National Glycohemoglobin

Standardization Program
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ADA Categorization of Glucose Status
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TREATMENT
Goals of Therapy
▪ DM treatment goals include reducing, controlling, and managing long-term
microvascular, macrovascular, and neuropathic complications; preserving β-cell
function; preventing acute complications from high blood glucose levels;
minimizing hypoglycemic episodes; and maintaining the patient’s overall quality
of life.
▪ To achieve the majority of these goals, near-normal blood glucose levels are
fundamental
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TREATMENT
▪ Two landmark trials, the Diabetes Control and Complications Trial (DCCT) and
the United Kingdom Prospective Diabetes Study (UKPDS), showed that lowering
blood glucose levels decreased the risk of developing chronic complications.
▪ A near-normal blood glucose level can be achieved with appropriate patient
education, lifestyle modification, and medications.
▪ Proper care of DM requires goal setting and assessment for glycemic control,
self-monitoring of blood glucose (SMBG), monitoring of blood pressure and lipid
levels, regular monitoring for the development of complications, dietary and
exercise lifestyle modifications, and proper medication use.
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Setting and Assessing Glycemic Targets
▪ Patients and clinicians can evaluate disease state control of the patient’s diabetes
by monitoring daily blood glucose values, A1c or estimated average glucose (eAG)
values, blood pressure, and lipid levels.
▪ SMBG enables patients to obtain their current blood glucose level at any time
easily and relatively inexpensively.
▪ The A1c test provides a weighted-mean blood glucose level from the previous 3
months.
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▪ The ADA premeal plasma glucose goals are 70 to 130 mg/dL (3.9 to 7.2 mmol/L)
and peak postprandial plasma glucose goals are less than 180 mg/dL (10 mmol/L).
▪ The American Association of Clinical Endocrinologists (AACE) supports tighter
SMBG controls with premeal goals of less than 110 mg/dL (6.1 mmol/L) and peak
postmeal goals of less than 140 mg/dL (7.8 mmol/L).
▪ For patients using multiple daily insulin injections or insulin pump therapy, the
ADA recommends that SMBG be performed at least three times daily.
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▪ Some regimen of SMBG among patients with T2DM has been associated with an
A1c reduction of 0.4% (0.004; 4 mmol/mol Hb).
▪ Each patient should be educated regarding how often and when to perform
SMBG
▪ Typically, in SMBG, a drop of blood is placed on a test strip that is then read by a
blood glucose monitor.
▪ Recent technological advancements have decreased the blood sample size
required to as small as 0.3 microliters, provided the capability of alternate-site
testing, and allowed for the delivery of readings in as few as 5 seconds.
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▪ Self-Monitoring of Blood Glucose SMBG is the standard method for routinely

checking blood glucose levels.
▪ Each reading provides a point-in-time evaluation of glucose control that can vary
widely depending on numerous factors, including food, exercise, stress, and time of
day.
▪ By examining multiple individual points of data, patterns of control can be
established.
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▪ Identifying patterns in the patient’s blood glucose data can aid practitioners in
modifying treatment for better glucose control.
▪ Although most testing occurs by lancing the fingertip to produce a blood
droplet, alternate-site testing has been approved for testing the palm, arm, leg,
and abdomen.
▪ Alternate-site testing was developed as a means to decrease the pain
encountered with repeated finger sticks by using body locations that have a
lower concentration of nerve endings.
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▪ Several continuous glucose sensors are now available that work with or
independently of insulin pumps.
▪ These monitors provide blood glucose readings, primarily through interstitial
fluid (ISF).
▪ A small sterile disposable glucose-sensing device called a sensor is inserted into
the subcutaneous tissues.
▪ This sensor measures the change in glucose in ISF and sends the information to
a monitor, which stores the results.
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Hemoglobin A1c
▪ Glucose interacts spontaneously with Hb in red blood cells to form glycated
derivatives. The most prevalent derivative is A1c. Because Hb has a life span of
approximately 3 months, levels of A1c provide a marker reflecting the average
glucose levels over this timeframe.
▪ The ADA goal for persons with DM is less than 7% (0.07; 53 mmol/mol Hb),
whereas the AACE supports a goal of less than or equal to 6.5% (0.065; 48
mmol/mol Hb).
▪ Testing A1c levels should occur at least twice a year for patients who are
meeting treatment goals and four times per year for patients not meeting goals
or those who have had recent changes in therapy.
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▪ Estimated Average Glucose The eAG is used to correlate A1c values with
readings that patients obtain from their home glucose monitors.
▪ The equation to convert from A1c to eAG is: eAG (mg/dL) = 28.7 × A1c − 46.7
(or eAG [mmol/L] = 1.59 × A1c − 2.59 for A1c expressed as a percentage).
▪ The goal eAG is 154 mg/dL (8.5 mmol/L), which corresponds with an A1c of less
than 7%, and an eAG of 240 mg/dL (13.3 mmol/L) would be equivalent to an
A1c of 10%.
▪ In standardized assays, the A1C approximates the following mean plasma
glucose values: an A1C of 6% is 7.5 mmol/L (135 mg/dL), 7% is 9.5 mmol/L (170
mg/dL), 8% is 11.5 mmol/L (205 mg/dL), etc. [A 1% rise in the A1C translates
into a 2.0-mmol/L (35 mg/dL) increase in the mean glucose.]
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▪ Ketone Monitoring Urine and blood ketone testing is important in people with
T1DM, in pregnancy with preexisting diabetes, and in GDM.
▪ People with T2DM may have positive ketones and develop diabetic ketoacidosis
(DKA) if they are ill.
▪ When there is a lack of insulin, peripheral tissues cannot take up and store
glucose.
▪ This causes the body to think it is starving, and because of excessive lipolysis,
ketones, primarily β-hydroxybutyric and acetoacetic acid, are produced as
byproducts of free fatty acid metabolism in the liver.
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▪ Glucose and ketones are osmotically active, and when an excessive amount of
ketones is formed, the body gets rid of them through urine, leading to
dehydration.
▪ Patients with T1DM should test for ketones during acute illness or stress or
when blood glucose levels are consistently elevated above 300 mg/dL (16.7
mmol/L).
▪ This commonly occurs when insulin is omitted or when diabetes is poorly
controlled due to nonadherence, illness, or other reasons.
▪ Women with preexisting diabetes before pregnancy or with GDM should check
ketones using their first morning urine sample or when any symptoms of
ketoacidosis such as nausea, vomiting, or abdominal pain are present.
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▪ Positive ketone readings are found in normal individuals during fasting and in up
to 30% of first morning urine specimens from pregnant women.
▪ Urine ketone tests using nitroprusside- containing reagents can give false-
positive results in the presence of several medications, including captopril.
▪ Falsenegative readings have been reported when test strips have been exposed
to air for an extended period of time or when urine specimens have been highly
acidic, such as after large intakes of ascorbic acid.
▪ Currently, available urine ketone tests are not reliable for diagnosing or
monitoring treatment of ketoacidosis
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▪ Blood ketone testing methods that quantify β-hydroxybutyric acid, the

predominant ketone body, are available and are the preferred way to diagnose
and monitor ketoacidosis.
▪ Home tests for β-hydroxybutyric acid are available.
▪ The specific treatment of DKA may include rehydration, correction of electrolyte
imbalances, and insulin administration.
Blood Pressure, Lipids, and Monitoring for Complications
▪ The ADA standards of medical care address many of the common comorbid
conditions, as well as complications that result from the progression of DM.
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General Approach to Therapy
Type 1 Diabetes Mellitus

▪ Treatment of T1DM requires providing exogenous insulin to replace the
endogenous loss of insulin from the nonfunctional pancreas.
▪ Ideally, insulin therapy mimics normal insulin physiology. The basal-bolus
approach attempts to reproduce basal insulin response using intermediate- or
long-acting insulin, whereas short- or rapid-acting insulin replicates bolus
release of insulin physiologically seen around a meal in nondiabetics.
▪ As a rule, basal insulin makes up approximately 50% of the total daily dose.
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▪ The remaining half is provided with bolus doses around three daily meals.
▪ Exact doses are individualized to the patient and the amount of food
consumed.
▪ T1DM patients frequently are started on about 0.6 unit/kg/day, and then doses
are titrated until glycemic goals are reached.
▪ Most people with T1DM use between 0.6 and 1 unit/kg/day.
▪ Currently, the most advanced form of insulin delivery is the insulin pump, also
referred to as continuous subcutaneous insulin infusion (CSII).
▪ These pumps are programmed to provide a slow release of small amounts of
insulin as the basal portion of therapy, and larger boluses of insulin are injected
by the patient to account for the consumption of food.
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▪ Pramlintide, a synthetic analog of the naturally occurring hormone amylin, is

another injectable blood glucose–lowering medication that can be used in
people with T1DM or in people with T2DM using insulin for treatment.
Type 2 Diabetes Mellitus
▪ Treatment of patients with T2DM has changed dramatically over the past
decade with the addition of a number of new drugs and recommendations to
maintain tighter glycemic control.
▪ Lifestyle modifications including education, nutrition, and exercise are
paramount to managing the disease successfully.
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▪ Many patients assume that once pharmacologic therapy is initiated, lifestyle

modifications are no longer necessary.
▪ Because T2DM generally tends to be a progressive disease, blood glucose levels
will eventually increase, making insulin therapy and lifestyle modifications the
eventual required therapy in many patients.
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Gestational Diabetes
▪ An individualized meal plan consisting of three meals and three snacks per day is
commonly recommended in GDM.
▪ Preventing ketosis, promoting adequate growth of the fetus, maintaining
satisfactory blood glucose levels, and preventing nausea and other undesired GI
side effects are desired goals in these patients.
▪ Controlling blood sugar levels is important to prevent harm to the baby.
▪ An abundance of glucose causes excessive insulin production by the fetus,
which, if left uncontrolled, can lead to the development of an abnormally large
fetus.
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▪ Infant hypoglycemia at delivery, hyperbilirubinemia, and complications

associated with delivery of a large baby also may occur when blood glucose
levels are not controlled adequately.
▪ Insulin should be used when blood glucose levels are not maintained adequately
at target levels by diet and physical activity.
▪ Even though there have been small studies showing the safety of using
glyburide, metformin, and insulin glargine during pregnancy, the use of these
agents is not recommended as a general rule.
▪ In women who develop GDM and cannot control blood glucose levels with
lifestyle modifications, the use of insulin detemir, insulin aspart, lispro, or
regular insulin has category B safety ratings.
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Initiation and adjustment of insulin regimens

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Algorithm for the metabolic management of type 2 diabetes mellitus
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Nonpharmacologic Therapy
Medical Nutrition Therapy
▪ Despite the popular notion, there is not a “diabetic diet,”
▪ MNT is considered an integral component of diabetes management and diabetes
self-management education.
▪ People with DM should receive individualized MNT, preferably by a registered
dietitian.
▪ As part of the diabetes management plan, MNT should not be a single education
session but rather an ongoing dialog.
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▪ MNT should be customized to take into account cultural, lifestyle, and financial
considerations.
▪ MNT plans should integrate a variety of foods that the patient enjoys and allow
for flexibility to encourage patient empowerment and improve patient adherence.
▪ During these MNT educational and planning sessions, patients receive
instructions on appropriate food selection, preparation, and proper portion
control.
▪ The primary focus of MNT for patients with T1DM is matching optimal insulin
dosing to carbohydrate consumption.
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▪ In T2DM, the primary focus is portion control and controlling blood glucose,
blood pressure, and lipids through individualizing limits of carbohydrates, saturated
fats, sodium, and calories.
▪ Carbohydrates are the primary contributor to postmeal glucose levels.
▪ However, recommended total daily carbohydrate intake should not be less than
130 g for most patients.
▪ The percentages of fat, protein, and carbohydrate included in each meal should
be individualized based on the specific goals of each patient.
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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).
▪ The ADA has issued recommendations for three types of MNT.
▪ Primary prevention measures of MNT are directed at preventing or
delaying the onset of type 2 DM in high-risk individuals (obese or with
pre-diabetes) by promoting weight reduction.
▪ Secondary prevention measures of MNT are directed at preventing
or delaying diabetes-related complications in diabetic individuals by
improving glycemic control.
▪ Tertiary prevention measures of MNT are directed at managing
diabetes-related complications (cardiovascular disease, nephropathy)
in diabetic individuals.
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▪ As for the general population, a diet that includes fruits,

vegetables, fiber-containing foods, and low-fat milk is advised.
▪ 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.
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Glycemic Index
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Dietary Supplements
▪ Patients may seek and use dietary supplements in the treatment of diabetes.
▪ Data from randomized controlled trials do seem to support the efficacy of
Coccinia indica and American ginseng for improving glucose control.
▪ Other studied supplements include chromium, Gymnema sylvestre, aloe vera,
vanadium, Momordica charantia, and nopal.
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Weight Management
▪ Moderate weight loss in patients with T2DM has been shown to reduce
cardiovascular risk, as well as delay or prevent the onset of DM in those with
prediabetes.
▪ The recommended primary approach to weight loss is therapeutic lifestyle
change (TLC), which integrates a 7% reduction in body weight and an increase in
physical activity.
▪ A slow but progressive weight loss of 0.45 to 0.91 kg (1 to 2 lb) per week is
preferred.
▪ Although individual target caloric goals should be set, a general rule for weight
loss diets is that they should supply at least 1,000 to 1,200 kcal/day (about 4,200 to
5,000 kJ/day) for women and 1,200 to 1,600 kcal/day (about 5,000 to 6,700 kJ/day)
for men.
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Weight Management
▪ Because 80% of patients with T2DM are overweight, this strategy works best for
these patients.
▪ Gastric reduction surgeries (gastric banding or procedures that bypass,
transpose, or resect portions of the small intestine), when used as a part of a
comprehensive approach to weight loss, are recommended for consideration in
patients with T2DM and a BMI that exceeds 35 kg/m2.
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Physical Activity
▪ Physical activity is also an important component of a comprehensive DM
management program.
▪ Before initiating a physical activity program, Patients should undergo a detailed
physical examination, including screening for microvascular or macrovascular
complications that may be worsened by a particular activity.
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Physical Activity
▪ Initiation of physical activities in an individual with a history of a sedentary
lifestyle should begin with a modest increase in activity.
▪ Walking, swimming, and cycling are examples of low-impact exercises that could
be encouraged.
▪ At the same time, gardening and usual housecleaning tasks are good exercises as
well.
▪ Recommended physical activity goals for patients with T2DM include 150
minutes per week of moderate to vigorous aerobic exercise spread out during at
least 3 days of the week.
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Psychological Assessment
▪ Clinicians should incorporate psychological assessment and treatment into

routine care.
▪ The ADA guidelines recommend ongoing psychological screening
▪ Patients demonstrating poor self-management should be screened for
diabetesrelated distress, depression, anxiety, an eating disorder, and/ or cognitive
impairment.
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Immunizations
▪ Early influenza vaccinations, commonly called flu shots, are recommended for all
patients with DM 6 months of age or older.
▪ Pneumococcal vaccination is also recommended for patients with DM who are 2
years of age or older as a one-time vaccination.
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Immunizations
▪ Revaccination is also indicated in those with nephrotic syndrome or chronic renal

disease and after transplantation.
▪ The hepatitis B vaccine series should also be administered as per the Center for
Disease Control and Prevention’s recommendations in patients with diabetes.
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Pharmacotherapy
▪ Oral and injectable agents are available to treat patients with T2DM who are
unable to achieve glycemic control through meal planning and physical activity.
▪ The various classes of blood glucose–lowering agents target different organs and
have different mechanisms of action.
▪ Each of these agents may be used individually or in combination with other
medications that target different organs for synergistic effects.
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Sulfonylureas
▪ Sulfonylureas represent the first class of oral blood glucose– lowering agents
approved for use in the United States.
▪ These drugs are classified as being either first- or second-generation agents.
▪ Both classes of sulfonylureas are equally effective when given at equipotent
doses.
▪ Sulfonylureas enhance insulin secretion by blocking ATP-sensitive potassium
channels in the cell membranes of pancreatic β cells.
▪ This action results in membrane depolarization, allowing an influx of calcium to
cause the translocation of secretory granules of insulin to the cell surface, and
enhances insulin secretion in a non–glucose dependent manner.
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Sulfonylureas
▪ However, the extent of insulin secretion depends on the blood glucose level.
▪ Whereas more insulin is released in response to higher blood glucose levels, the
additional insulin secretion from sulfonylureas is less at near-normal glucose levels.
▪ Insulin is then transported through the portal vein to the liver, suppressing
hepatic glucose production.
▪ All sulfonylureas undergo hepatic biotransformation, with most agents being
metabolized by the cytochrome P450 2C9 pathway.
▪ The first-generation sulfonylureas are more likely to cause drug interactions than
second-generation agents.
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Sulfonylureas
▪ All sulfonylureas except tolbutamide require a dosage adjustment or are not
recommended in renal impairment.
▪ In elderly patients or those with compromised renal or hepatic function, lower
starting dosages are necessary.
▪ Sulfonylureas’ blood glucose–lowering effects can be observed in both fasting
and postprandial levels.
▪ Monotherapy with these agents generally produce a 1.5% to 2% (0.015 to 0.02 or
16 to 22 mmol/mol Hg) decline in A1c concentrations and a 60- to 70-mg/dL (3.3 to
3.9 mmol/L) reduction in FBG levels.
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Sulfonylureas
▪ Secondary failure with these drugs occurs at a rate of 5% to 7% per year as a
result of continued pancreatic β-cell destruction.
▪ One limitation of sulfonylurea therapy is the inability of these products to
stimulate insulin release from β cells at extremely high glucose levels, a
phenomenon called glucose toxicity.
▪ Common adverse effects include hypoglycemia and weight gain.
▪ There may be some cross-sensitivity in patients with sulfa allergy.
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Nonsulfonylurea Secretagogues (Glinides)

▪ Although producing the same effect as sulfonylureas, nonsulfonylurea
secretagogues, also referred to as meglitinides, have a much shorter onset and
duration of action.
▪ Glitinide secretagogues also produce a pharmacologic effect by interacting with
ATP-sensitive potassium channels on the β cells; however, this binding is to a
receptor adjacent to those to which sulfonylureas bind.
▪ The primary benefit of nonsulfonylurea secretagogues is in reducing postmeal
glucose levels.
▪ These agents have demonstrated a reduction in A1c levels between 0.8% and 1%
(0.008 and 0.01; 9 to 11 mmol/mol Hb).
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Nonsulfonylurea Secretagogues (Glinides)

▪ Because they have a rapid onset and short duration of action, they are to be
taken 15 to 30 minutes before a meal.
▪ They also may be used in combination therapy with other drugs to achieve
synergistic effects.
▪ Combinations with biguanides are most commonly seen.
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Biguanides
▪ This agent is thought to lower blood glucose by decreasing hepatic glucose

production and increasing insulin sensitivity in both hepatic and peripheral muscle
tissues; however, the exact mechanism of action remains unknown.
▪ Metformin lowers both fasting blood sugar (FBS) and postmeal blood glucose.
▪ It has been shown to reduce A1c levels by 1.5 to 2% (0.015 to 0.02; 16 to 22
mmol/mol Hb) and FPG levels by 60 to 80 mg/dL (3.3 to 4.4 mmol/L) when used as
monotherapy.
▪ Unlike the sulfonylureas, metformin retains the ability to reduce fasting glucose
levels when they are over 300 mg/dL (16.7 mmol/L).
▪ Metformin does not affect insulin release from β cells of the pancreas, so
hypoglycemia is not a common side effect.
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Biguanides
▪ Metformin significantly reduced all-cause mortality and the risk of stroke in

overweight patients with T2DM compared with intensive therapy with sulfonylurea
or insulin.
▪ It also reduced diabetes-related death and myocardial infarction compared with
a conventional therapy arm.
▪ Given that metformin is the only oral antihyperglycemic medication proven to
reduce mortality and is available generically, the ADA treatment algorithm
considers lifestyle modification and metformin as first-line therapy for T2DM.
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Biguanides
▪ Metformin has been shown to produce beneficial effects on serum lipid levels
and has become a first-line agent for T2DM patients with metabolic syndrome.
▪ On average, triglyceride and low-density lipoprotein (LDL) cholesterol levels may
be reduced by as much as 18.69% and 12.09%, respectively, but HDL cholesterol
may improve by as much as 1.17%.
▪ Metformin is often used in combination with a sulfonylurea or a
thiazolidinedione (TZD) for synergistic effects.
▪ Metformin does not undergo significant protein binding and is eliminated from
the body unchanged in the urine.
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Biguanides
▪ Patients with a calculated creatinine clearance of less than 60 mL/min (1.0 mL/s)
should not receive this product.
▪ It is contraindicated in patients with a serum creatinine level greater than or
equal to 1.4 mg/dL (124 µmol/L) in women and 1.5 mg/dL (133 µmol/L) in men.
▪ It should not be initiated in patients 80 years of age or older unless normal renal
function has been established.
▪ Additionally, therapy with metformin should be withheld in patients undergoing
surgery or radiographic procedures in which a nephrotoxic dye is used.
▪ Therapy should be withheld the day of the radiographic procedure, and renal
function should be assessed 48 hours after the procedure. If renal function is
normal, therapy may be resumed.
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Biguanides
▪ Primary side effects associated with metformin therapy are GI in nature,

including decreased appetite, nausea, and diarrhea.
▪ These side effects can be minimized through slow titration of the dose and often
subside within 2 weeks.
▪ Interference with vitamin B12 absorption has also been reported.
▪ Biguanides such as metformin are thought to inhibit mitochondrial oxidation of
lactic acid, thereby increasing the chance of lactic acidosis occurring.
▪ Patients at greatest risk for developing lactic acidosis include those with renal
impairment and those who are of advanced age.
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Biguanides
▪ Metformin should be withheld promptly in cases of hypoxemia, sepsis, or

dehydration.
▪ Patients should avoid consumption of excessive amounts of alcohol while taking
metformin, and use of the drug should be avoided in patients with liver disease.
▪ It is common practice to evaluate liver function before initiation of metformin.
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Thiazolidinediones
▪ Commonly referred to as TZDs or glitazones, thiazolidinediones have established

a role in T2DM therapy.
▪ TZDs are known to increase insulin sensitivity by stimulating peroxisome
proliferator-activated receptor gamma (PPAR-g).
▪ Stimulation of PPAR-g results in a number of intracellular and extracellular
changes including increased insulin sensitivity and decreased plasma fatty acid
levels.
▪ As monotherapy, TZDs reduce FPG levels by around 60 to 70 mg/dL (3.3 to 3.9
mmol/L), and the effect on A1c is an up to 1.5% (0.015; 16 mmol/mol Hb)
reduction.
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Thiazolidinediones
▪ The onset of action for TZDs is delayed for several weeks and may require up to
12 weeks before maximum effects are observed.
▪ Additional effects of TZDs are seen in the lipid profile. Both pioglitazone and
rosiglitazone increase HDL cholesterol, with rosiglitazone increasing HDL an average
of 2.4 mg/dL (0.06 mmol/L) and pioglitazone increasing HDL an average of 5.2
mg/dL (0.13 mmol/L).
▪ Pioglitazone has been shown to decrease serum triglycerides 51.9 mg/dL (0.59
mmol/L) on average, but an increase in triglycerides has been observed with
rosiglitazone. LDL cholesterol concentrations increase by 12.3 mg/dL (0.32 mmol/L)
and 21.3 mg/dL (0.55 mmol/L) on average with pioglitazone and rosiglitazone,
respectively.
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Thiazolidinediones
▪ The TZDs may produce fluid retention and edema; the mechanism by which this
occurs is not completely understood.
▪ It is known that blood volume increases approximately 10% with these agents,
resulting in approximately 4% to 5% of patients developing edema.
▪ Thus, these drugs are contraindicated in situations in which an increased fluid
volume is detrimental such as heart failure.
▪ Fluid retention appears to be dose related and increases when combined with
insulin therapy.
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Thiazolidinediones
▪ A few cases of hepatotoxicity have been reported with rosiglitazone and

pioglitazone, but no serious complications have been reported, and symptoms
typically reverse within several weeks of discontinuing therapy.
▪ Liver function tests should be performed at baseline and periodically.
▪ Patients with a baseline alanine aminotransferase (ALT) level greater than 2.5
times the upper limit of normal should not receive a TZD.
▪ If ALT levels rise to greater than three times the upper limit of normal in patients
receiving a TZD and remain there, the medication should be discontinued.
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Thiazolidinediones
▪ Increased rates of upper and lower limb fractures are also known to occur with
TZD therapy compared with other antihyperglycemic agents and, for this reason,
the patient’s baseline fracture risk should be considered before beginning TZD
therapy.
▪ Premenopausal women may begin to ovulate on TZD therapy, and therefore
counseling should be provided to all women capable of becoming pregnant
regarding this.
▪ As TZD therapy is pregnancy category C, proper precautions to avoid pregnancy
should be used.
▪ In June 2011, the FDA alerted healthcare providers and patients that pioglitazone
was found to be associated with an increased risk of bladder cancer after 1 year of
therapy in an ongoing epidemiologic study.
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Thiazolidinediones
▪ For this reason, patients with active bladder cancer should not use pioglitazone,
and the drug should be used with caution in those with a history of bladder cancer.
▪ A 2007 meta-analysis conducted by Nissen and colleagues reported a
significantly greater risk of myocardial infarction with rosiglitazone compared with
other oral agents.
▪ A subsequent prospective study found rosiglitazone use to be associated with a
nonsignificant increase in myocardial infarction risk and a nonsignificant reduction
in stroke, but a trend toward increased cardiovascular risk in those patients with a
history of ischemic heart disease.
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Thiazolidinediones
▪ In May 2011, the FDA chose to restrict access and distribution of rosiglitazone.
▪ It is currently only available through the Avandia-Rosiglitazone Medicines Access
Program for patients currently clinically benefitting from the drug and in those with
T2DM who cannot achieve adequate disease management with other agents or
who are not willing to use pioglitazone-containing medications after counseling
with their healthcare provider.
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α-Glucosidase Inhibitors
▪ Acarbose and miglitol are α-glucosidase inhibitors currently approved in the

United States.
▪ An enzyme that is along the brush boarder of the intestine cells called α-
glucosidase breaks down complex carbohydrates into simple sugars, resulting in
absorption.
▪ The α-glucosidase inhibitors work by delaying the absorption of carbohydrates
from the intestinal tract, which reduces the rise in postprandial blood glucose
concentrations.
▪ As monotherapy, α-glucosidase inhibitors primarily reduce postprandial glucose
excursions. FPG concentrations have been decreased by between 40 and 50 mg/dL
(2.2 and 2.8 mmol/L); however, A1c reductions range only from 0.3% to 1% (0.003
to 0.01; 3 to 11 mmol/mol Hb).
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α-Glucosidase Inhibitors
▪ Although these agents have been popular in Europe and other parts of the
world, they have failed to gain widespread use in the United States.
▪ High incidences of GI side effects, including flatulence (42% to 74%), abdominal
discomfort (12% to 19%), and diarrhea (29% to 31%), have limited their use.
▪ GI side effects occur as the result of intestinal bacteria in the distal gut
metabolizing undigested carbohydrates and producing carbon dioxide and methane
gas.
▪ Low initial doses followed by gradual titration may minimize GI side effects. The
α-glucosidase inhibitors are contraindicated in patients with short bowel syndrome
or inflammatory bowel disease.
▪ In addition, neither drug in this class is recommended for patients with a serum
creatinine greater than 2 mg/dL (177 µmol/L).
▪97 Dr. Muhammad Fawad Rasool www.bzu.edu.pk
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Dipeptidyl Peptidase-4 Inhibitors (Gliptins)
▪ Sitagliptin, saxagliptin, and linagliptin are agents in a new class of diabetes drugs
called dipeptidyl peptidase-4 (DPP-4) inhibitors.
▪ They are approved as adjunct to diet and exercise to improve glycemic control in
adults with T2DM.
▪ These agents lower blood glucose concentrations by inhibiting DPP-4, the
enzyme that degrades endogenous GLP-1.
▪ DPP-4 inhibitors increase the amount of endogenous GLP-1.
▪ The blood glucose–lowering effect of the gliptins is primarily on postprandial
levels.
▪ Typical A1c reductions are 0.7% to 1% (0.007 to 0.01; 8 to 11 mmol/mol Hb).
▪ Common adverse effects include headache and nasopharyngitis.
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▪ Hypoglycemia is not a common adverse effect with these agents because insulin
secretion results from GLP-1 activation caused by meal-related glucose detection
and not from direct pancreatic β-cell stimulation.
▪ Dosage adjustments for sitagliptin to 50 and 25 mg/day are recommended for
patients with moderate (creatinine clearance, 30 to 49 mL/min [0.5 to 0.82 mL/s])
and severe (creatinine clearance less than 30 mL/ min [0.50 mL/s]) renal
impairment, respectively.
▪ Saxagliptin should be dosed at 2.5 mg/day with creatinine clearance less than 50
mL/min (0.83 mL/s) or if strong CYP3A4/5 inhibitors are being used concomitantly.
▪ Linagliptin, a substrate of CYP3A4, is dosed at 5 mg/day and requires no
adjustment for renal or hepatic impairment.
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▪ The FDA revised the prescribing information for sitagliptin and sitagliptin–
metformin to include information on reported cases of acute pancreatitis in
patients using these products after postmarketing cases of acute pancreatitis,
including hemorrhagic and necrotizing pancreatitis, were reported in patients
taking sitagliptin.
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Sodium-glucose co-transporter(SGLT) 2 inhibitors
▪ Glucose is freely filtered by the kidney glomeruli and is reabsorbed in the

proximal tubules by the action of sodium-glucose co-transporters (SGLT).
▪ Sodium-glucose co-transporter 2 (SGLT2) accounts for about 90% of glucose
reabsorption and its inhibition causes glycosuria in people with diabetes,
lowering plasma glucose levels.
▪ The SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin are approved
for clinical use.
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Central-Acting Dopamine Agonist
▪ A quick release formulation of a central-acting dopamine agonist, bromocriptine,

was approved by the FDA in May 2009 for the treatment of T2DM.
▪ The mechanism of action for how bromocriptine regulates glycemic control is
unknown, but data indicate that bromocriptine administered in the morning
improves insulin sensitivity, and this is likely a result of its affect on dopamine
oscillations.
▪ When used to treat patients with T2DM, bromocriptine should be taken 2 hours
after waking in the morning with food.
▪ The initial dose is 0.8 mg, titrated up weekly until a maximum dosage of 4.8
mg/day is achieved.
▪ A modest A1c reduction of 0.1% to 0.4% (0.001 to 0.004; 1 to 4 mmol/ mol Hb)
can be expected from this drug.
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Central-Acting Dopamine Agonist
▪ Main side effects include rhinitis, dizziness, asthenia, headache, sinusitis,

constipation, and nausea, and 24% of patients in clinical trials stopped taking
bromocriptine because of untoward effects.
▪ Contraindications include migraine and women who are nursing.
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Bile Acid Sequestrants
▪ Colesevelam is the only bile acid sequestrant currently approved as an adjunctive

therapy to improve glycemic control in conjunction with diet, exercise, and insulin
or oral agents for the treatment of T2DM.
▪ It acts on the intestinal lumen to bind bile acid, but whether this is the drug’s
only action that results in plasma glucose lowering or if a secondary systemic effect
to bile acid binding is unknown.
▪ An A1c reduction of approximately 0.4% (0.004; 4 mmol/mol Hb) can be
expected when added to metformin, sulfonylurea, or insulin. FPG is reduced about
5 to 10 mg/dL (0.3 to 0.6 mmol/L).
▪ LDL cholesterol is reduced 12% to 16%. Dosing for T2DM is six 625-mg tablets
daily, which may be split into three tablets twice daily.
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Bile Acid Sequestrants
▪ Common adverse effects include constipation and dyspepsia.

▪ Drug–drug interactions are possible because of absorption and can be
particularly important in patients who are taking levothyroxine, glyburide, oral
contraceptives, phenytoin, warfarin, and digoxin.
▪ These medications should not be taken together, and they should be separated
by at least 4 hours before dosing colesevelam.
▪ Malabsorption of fat-soluble vitamins (A, D, E, and K) is also a concern.
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Insulin
▪ Can be used in all types of DM and has no specific maximum dose

▪ Insulin is the primary treatment in T1DM, and injected amylin can be added to
decrease fluctuations in blood glucose levels.
▪ Insulin is available commercially in various formulations
▪ Insulin can be divided into two main classes, basal and bolus
▪ Most formulations are available as U-100, indicating a concentration of 100
unit/mL.
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Insulin
▪ Insulin is typically refrigerated, and most vials are good for 28 days at room
temperature.
▪ Insulin detemir can be stored at room temperature for 42 days.
▪ The most common route of administration for insulin is subcutaneous injection
using a syringe or pen device.
▪ Patients should be educated to rotate their injection sites to minimize
lipohypertrophy, a buildup of fat that decreases or prevents proper insulin
absorption.
▪ Additionally, patients should understand that the absorption rate may vary
among injection sites (abdomen, thigh, arm, and buttocks) because of differences in
blood flow, with absorption occurring fastest in the abdomen and slowest in the
buttocks.
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Insulin
▪ Insulin syringes are distinguished according to the syringe capacity, syringe

markings, and needle gauge, and length.
▪ Insulin pens are self-contained systems of insulin delivery.
▪ The primary advantage of the pen system is the patient does not have to draw up
the dose from the insulin vial.
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Bolus Insulins
▪ Regular Insulin. Regular insulin is unmodified crystalline insulin commonly

referred to as natural or human insulin.
▪ It is a clear solution that has a relatively short onset and duration of action and is
designed to cover insulin response to meals.
▪ On subcutaneous injection, regular insulin forms small aggregates called
hexamers that undergo conversion to dimers followed by monomers before
systemic absorption can occur.
▪ Patients should be counseled to inject regular insulin subcutaneously 30 minutes
before consuming a meal.
▪ Regular insulin is the only insulin that can be administered IV.
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Bolus Insulins
▪ Three rapid-acting insulins have been approved in the United States: aspart,
glulisine, and lispro.
▪ Substitution of one or two amino acids in regular insulin results in the unique
pharmacokinetic properties characteristic of these agents.
▪ The onset of action of rapid-acting insulins varies from 15 to 30 minutes, with
peak effects occurring 1 to 2 hours after administration and is dosed before or with
meals.
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Basal Insulins
Intermediate-Duration Insulin
▪ Neutral protamine Hagedorn, better known as NPH insulin, is prepared by a
process in which protamine is conjugated with regular insulin, rendering a product
with a delayed onset but extended duration of action, and is designed to cover
insulin requirements in between meals and/or overnight.
▪ With the advent of the long acting insulins, NPH insulin use has declined because
of
(a) an inability to predict accurately when peak effects occur and
(b) a duration of action of less than 24 hours.
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Basal Insulins
▪ Additionally, protamine is a foreign protein that may increase the possibility of

an allergic reaction.
▪ NPH insulin can be mixed with regular insulin and used immediately or stored for
future use up to 1 month at room temperature or 3 months in refrigeration.
▪ NPH insulin can be mixed with either aspart or lispro insulins, but it must be
injected immediately after mixing.
▪ Whenever mixing insulin products with NPH insulin, the shorter acting insulin
should be drawn into the syringe first.
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Basal Insulins
Long-Duration Insulin
▪ Glargine and detemir are designed as once-daily-dosing basal insulins.
▪ Insulin glargine differs from regular insulin by three amino acids, resulting in a
low solubility at physiologic pH.
▪ The clear solution is supplied at a pH of 4, which precipitates on subcutaneous
administration.
▪ Detemir binds to albumin in the plasma, which gives it sustained action.
▪ Neither glargine nor detemir can be administered IV or mixed with other insulin
products.
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Basal Insulins
▪ Both glargine and detemir have been shown to produce slower, more prolonged
absorption and a relatively constant concentration over 24 hours as compared
with NPH.
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Basal Insulins
Combination Insulin Products

▪ NPH is available in combinations of 70/30 (70% NPH and 30% regular insulin)
and 50/50 (50% NPH and 50% regular insulin).
▪ Two short acting insulin analog mixtures are also available.
▪ Humalog mix 75/25 contains 75% insulin lispro protamine suspension and 25%
insulin lispro.
▪ Novolog mix 70/30 contains 70% insulin aspart protamine suspension and 30%
insulin aspart.
▪ The lispro and aspart insulin protamine suspensions were developed specifically
for these mixture products and are not commercially available separately.
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Insulin Pump Therapy

▪ Insulin pump therapy consists of a programmable infusion device that allows for
basal infusion of insulin 24 hours daily, as well as bolus administration before meals
and snacks.
▪ Regular or rapid-acting insulin is delivered from a reservoir either by infusion set
tubing or through a small canula.
▪ Most pump infusion sets are inserted in the abdomen, arm, or other infusion site
by a small needle.
▪ Most patients prefer insertion in abdominal tissue because this site provides
optimal insulin absorption.
▪ Infusion sets should be changed every 2 to 3 days to reduce the possibility of
infection.
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▪ Patients use a carbohydrate-to-insulin ratio to determine how many units of
insulin are required.
▪ More specifically, an individual’s ratio is calculated to determine how many units
of the specific insulin being used in the pump “covers” for a certain amount of
carbohydrates to be ingested at a particular meal.
▪ The 450 rule (for regular insulin) or the 500 rule (for rapid-acting insulin) is
commonly used.
▪ To calculate the ratio using the 500 rule, the patient would divide 500 by his or
her total daily dose of insulin.
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▪ For example, if a patient were using 25 units of insulin daily, his or her
carbohydrate-to-insulin ratio would be 500:25, or 20:1.
▪ This ratio theoretically means that 1 unit of rapid-acting insulin should cover 20 g
of carbohydrate.
▪ If blood sugar levels are below or above the desired blood glucose target, the
amount of insulin can be adjusted.
▪ Once this ratio is determined, patients can eat more or fewer carbohydrates at a
given meal and adjust the bolus dose accordingly.
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▪ In addition to mealtime boluses, correction doses based on premeal glucose
readings are also used.
▪ The amount of additional insulin for the correction is based on either the 1500
rule for regular insulin or the 1800 rule for rapid-acting insulin.
▪ For example, if using rapid-acting insulin, divide 1800 by the patient’s total daily
insulin dose. The resulting value will represent the reduction in glucose (mg/dL)
produced by one unit of insulin.
▪ If a patient is injecting 10 units of rapid-acting insulin before each of his or her 3
meals and 30 units of Lantus in the evening, his or her total daily dose would be 60
units.
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▪ Using the 1800 rule, we find that 1800 divided by 60 is 30.
▪ Thus, 1 unit of rapid-acting insulin would be added for every 30 mg/dL the
patient’s glucose is above the premeal goal as a correction factor.
▪ The correction dose would be given in addition to the bolus dose needed based
on the patient’s carbohydrate-to-insulin ratio and the amount of carbohydrates
present in the meal he or she is about to consume.
▪ Insulin pump therapy may be used to lower blood glucose levels in any type of
DM; however, patients with T1DM are the most likely candidates to use these
devices.
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▪ Use of an insulin pump may improve blood glucose control, reduce wide
fluctuations in blood glucose levels, and allow individuals to have more flexibility in
timing and content of meals and exercise schedules.
▪ Insulin pump therapy is not for everyone, and the complexity associated with its
use, cost, increased need for blood glucose monitoring, and psychological factors
may prevent individuals from using this technology optimally.
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Noninsulin Injectable Agents
▪ Glucagon-Like Peptide 1 Agonists Glucagon-like peptide 1 (GLP-1) agonists

enhance glucose-dependent insulin secretion while suppressing inappropriately
high glucagon secretion in the presence of elevated glucose, which results in
reduced hepatic glucose production.
▪ Exenatide and liraglutide are both indicated for the treatment of T2DM to
improve glycemic control.
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▪ In a 26-week head-to-head trial in patients with T2DM with a baseline A1c

between 7% and 11% (0.07 and 0.11; 53 and 97 mmol/mol Hb) who were taking
metformin, sulfonylurea, or both, exenatide lowered A1c 0.8% (0.008; 9 mmol/mol
Hb), but liraglutide lowered A1c a significantly greater amount at 1.1% (0.011; 12
mmol/mol Hb).
▪ Both drugs produced similar weight loss, with an average reduction of 3.24 kg
(7.13 lb) for liraglutide and 2.87 kg (6.31 lb) for exenatide.
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▪ GLP-1 agonists lower blood glucose levels by

▪ (a) producing glucose-dependent insulin secretion;
▪ (b) reducing postmeal glucagon secretion, which decreases postmeal glucose
output;
▪ (c) increasing satiety which decreases food intake; and
▪ (d) regulating gastric emptying, which allows nutrients to be absorbed into the
circulation more smoothly.
▪ For exenatide, the tmax is approximately 2 hours, and the plasma half-life is
around 3.3 to 4 hours.
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▪ Plasma concentrations are detected up to 10 hours after injection, although

pharmacodynamic action lasts for approximately 6 hours.
▪ Hence, exenatide is recommended for twice-daily dosing in its immediate-
release dosage form.
▪ A once weekly extended-release dosage form is also available.
▪ Liraglutide’s half-life is 13 hours, making it suitable for once daily dosing.
▪ Exenatide is eliminated renally and is not recommended in patients with a
creatinine clearance of less than 30 mL/ min (0.50 mL/s).
▪ No specific dose adjustments are recommended for liraglutide in renal
impairment.
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▪ An increased risk of hypoglycemia occurs when GLP-1 agonists are used in

combination with a sulfonylurea.
▪ Hypoglycemia is not encountered when used as monotherapy or in conjunction
with metformin and/or thiazolidinedione therapy.
▪ The main side effects of GLP-1 agonist therapy include nausea, vomiting, and
diarrhea. These GI adverse effects tend to lessen over time.
▪ No major drug interactions have been found with exenatide.
▪ GLP-1 agonists delay absorption of other medications, so it is best to take
concomitant medications 1 hour before or 3 hours after a GLP-1 agonist if rapid
absorption of the concomitant medication is required.
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▪ GLP-1 agonists have been associated with cases of acute pancreatitis.

▪ For this reason, neither drug should be used in a patient with a history of
pancreatitis.
▪ Any patient presenting with symptoms of acute pancreatitis, including abdominal
pain, nausea, and vomiting, should have GLP-1 agonist therapy discontinued until
pancreatitis can be ruled out.
▪ Both liraglutide and exenatide extended-release packagings contain a black box
warning about thyroid C-cell tumors.
▪ They are contraindicated in patients with a personal or family history of
medullary thyroid cancer and in those with a history of multiple endocrine tumors.
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▪ Exenatide is currently available in 5- and 10-mcg injectable prefilled disposable

pens and a 2 mg extended-release injectable suspension.
▪ Initial therapy of the immediate-release product is 5 mcg twice daily, injected
zero to 60 minutes before the morning and evening meals.
▪ Patients who do not eat breakfast can take their first dose before lunch.
▪ Doses are then increased after a month to 10 mcg if the patient’s blood glucose
is improving and nausea is limited.
▪ Exenatide extended-release 2 mg is administered by subcutaneous injection once
every 7 days immediately after the powder is suspended and can be dosed at any
time of day and without regard to meals.
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▪ Liraglutide is available in 6-mg/3 mL prefilled disposable pens that can be dialed

to the desired dose of 0.6, 1.2, or 1.8 mg.
▪ Liraglutide should be dosed at 0.6 mg/day for at least 1 week and then increased
to 1.2 mg/day for at least 1 week before being increased to the maximum dose of
1.8 mg if needed.
▪ Liraglutide can be dosed at any time of day regardless of meals.
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Amylin
▪ Pramlintide acetate is a synthetic analog of human amylin, which is a naturally
occurring neuroendocrine peptide that is cosecreted by the β cells of the
pancreas in response to food.
▪ Amylin secretion is completely deficient in patients with T1DM, or relatively
deficient in patients with T2DM.
▪ Pramlintide is given by subcutaneous injection before meals to lower
postprandial blood glucose elevations.
▪ Pramlintide generally results in an average weight loss of 1 to 2 kg (2.2 to 4.4 lb).
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25.03.2020
▪ Pramlintide is indicated as combination therapy with insulin in patients with

types 1 or 2 DM.
▪ It has been shown to decrease A1c by an additional 0.4% to 0.5% (0.004 to
0.005; 4 to 5 mmol/mol Hb).
▪ Pramlintide slows gastric emptying without altering absorption of nutrients,
suppresses glucagon secretion, and leads to a reduction in food intake by increasing
satiety.
▪ By slowing gastric emptying, the normal initial postmeal spike in blood glucose is
reduced.
137
▪ Hypoglycemia, nausea, and vomiting are the most common side effects
encountered with pramlintide therapy, although pramlintide itself does not
produce hypoglycemia.
▪ To decrease the risk of hypoglycemia, doses of short-acting, rapid-acting, or
premixed insulins should be reduced by 50% before pramlintide is initiated.
▪ Some practitioners will not decrease the premeal insulin dose this much because
of fear of loss of glucose control.
▪ Primarily, the kidneys metabolize pramlintide, but dosage adjustments in liver or
kidney impairment are not required.
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▪ Pramlintide has the potential to delay the absorption of orally administered

medications.
▪ When rapid absorption is needed for the efficacy of an agent, pramlintide should
be administered 2 hours before or 1 hour after this drug.
▪ Pramlintide should not be used in patients receiving medications that alter GI
motility, such as anticholinergic agents, or drugs that slow the absorption of
nutrients such as α-glucosidase inhibitors.
▪ A disposable pen formulation is now on the market and available as SymlinPen
60 for patients with T1DM and SymlinPen 120 for people with T2DM.
▪ The number of days the pen will last will vary depending on the daily dose.
▪ The amount of medication is 1.5 mL in the SymlinPen 60 and 2.7 mL in the
SymlinPen 120.
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Treatment of Concomitant Conditions

Glucose Control and Cardiovascular Health
▪ The results of three trials have recently been released showing the relationship
between glucose control and cardiovascular health.
▪ The Action to Control Cardiovascular Risk in Diabetes (ACCORD),Action in
Diabetes and Vascular Disease (ADVANCE), and Veterans Affairs Diabetes Trial
(VADT) examined if cardiovascular risks could be decreased or prevented with
intensive glucose lowering.
▪ Although ACCORD was stopped early after interim analysis showed an increased
risk of mortality in the intensive treatment group, both ADVANCE and VADT
found that intensive therapy was no different than standard glycemic control in
terms of macrovascular event rates.
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Treatment of Concomitant Conditions

▪ The findings of these trials, when taken into context with long term follow-up
information from the UKPDS and DCCT trials, seem to show the following:
▪ (1) 3 to 5 years of intensive glycemic control does not improve the risk of
macrovascular complications in patients with longstanding T2DM and
▪ (2) a decrease in macrovascular risk from improved glycemic control may take
more than a decade to be realized.
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Coronary Heart Disease
▪ Cardiovascular disease is the major cause of morbidity and mortality for patients
with DM.
▪ Interventions targeting smoking cessation, blood pressure control, lipid
management, antiplatelet therapy, and lifestyle changes (including diet and
exercise) can reduce the risk of cardiovascular events and should be considered as
important as glycemic control in the management of a patient with DM.
▪ All DM patients with a history of cardiovascular disease should be prescribed
aspirin 75 to 162 mg/day as a secondary prevention strategy.
▪ For those with aspirin allergy, another antiplatelet option such as clopidogrel 75
mg/day should be used.
143
Coronary Heart Disease
▪ Choosing if antiplatelet therapy is appropriate for a patient with DM and no

history of cardiovascular disease can be more difficult because evidence is less clear
regarding benefit.
▪ The ADA currently recommends that antiplatelet therapy should be considered
for any patient with DM as a primary prevention strategy if that patient’s risk of
cardiovascular event is considered to be greater than 10% over 10 years.
▪ This includes most men older than 50 years of age and most women older than
60 years of age who have at least one additional cardiovascular risk factor.
▪ Clinical judgment is required for patients with an estimated cardiovascular risk of
5% to 10% to determine if the possible benefit of antiplatelet therapy outweighs
the potential for harm from bleeding.
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Dyslipidemia
▪ The National Cholesterol Education Program Adult Treatment Panel III guidelines
classify the presence of DM to be of the same risk equivalence as coronary heart
disease (CHD).
▪ The primary target for lipid-lowering treatment in most patients with DM is LDL
cholesterol with a goal of less than 100 mg/dL (2.59 mmol/L).
▪ For patients at high cardiovascular risk, including those with a history of
cardiovascular disease, the LDL target may be set more stringently at 70 mg/dL
(1.81 mmol/L).
▪ Only when triglyceride levels exceed 500 mg/dL (5.65 mmol/L) should they
replace LDL as the patient’s primary therapeutic goal.
145
Dyslipidemia
▪ Because of potent LDL cholesterol-lowering ability and the known benefit in

terms of improved cardiovascular morbidity and mortality, statins are considered
first-line therapy for hyperlipidemia.
▪ Because statin therapy has been shown to benefit even patients with relatively
low-baseline LDL cholesterol levels, it is also important to note that the ADA
guidelines currently call for all patients with DM to be prescribed a statin who fall
into either of the following two categories:
▪ (1) those who have overt cardiovascular disease and
▪ (2) those who do not have overt cardiovascular disease but are older than age
40 years and have one or more other cardiovascular disease risk factors.
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Dyslipidemia
▪ Once LDL cholesterol goals are achieved with statin therapy, some patients will
continue to have elevated non HDL cholesterol produced by elevated triglyceride
levels and low HDL cholesterol.
▪ Although it was common practice in the past to add niacin or fibrate therapy
onto statin therapy in such patients, cardiovascular outcome benefit has not been
proven with combination therapy over statin therapy alone in patients with prior
cardiovascular disease or DM.
147
Hypertension
▪ Uncontrolled blood pressure plays a major role in the development of
macrovascular events as well as microvascular complications, including retinopathy
and nephropathy, in patients with DM.
▪ The ADA recommends that systolic blood pressure goals for patients with DM be
individualized but generally set at less than 130 mm Hg.
▪ The diastolic blood pressure goal for patients with DM is less than 80 mm Hg.
▪ In addition, there are several general principles regarding the treatment of
hypertension in diabetes patients.
▪ Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor
blockers are recommended as initial therapy because of their beneficial effects on
renal function.
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Hypertension
▪ Initial combination therapy with an ACE inhibitor and dihydropyridine calcium
channel blocker has been shown to reduce cardiovascular morbidity and mortality
versus those receiving ACE inhibitor therapy combined with a thiazide diuretic.
▪ However, thiazide diuretics work synergistically with ACE inhibitors and
angiotensin II receptor blockers and can be added on for those who fail to reach
blood pressure goals with a single agent alone as long as the patient’s estimated
glomerular filtration rate remains at 30 mL/min/1.73 m2 (0.29 mL/s/m2) or higher.
▪ Alternatively, a loop diuretic can be used.
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Hypertension
▪ It can be expected that most patients will require more than one agent to reach
blood pressure goal.
▪ Renal function and serum potassium levels should be monitored closely in all
patients taking an ACE inhibitor, angiotensin II receptor blocker, and/or diuretic.
▪ ACE inhibitors and angiotensin II receptor blockers are contraindicated in
patients who are pregnant and in those with bilateral renal artery stenosis.
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Human Immunodeficiency Virus (HIV) and

Acquired Immune Deficiency Syndrome (AIDS)
▪ Patients with risk factors for diabetes are more likely to develop diabetes when
exposed to highly active antiretroviral therapy.
▪ Universal screening of all HIV patients for diabetes is controversial, but most
clinicians support screening for those with risk factors, especially if those risk
factors include positive family history and central adiposity.
▪ Disturbances in glucose homeostasis are a known side effect of protease
inhibitor therapy.
▪ Indinavir and ritonavir block insulin-mediated glucose disposal, causing insulin
resistance, but amprenavir and atazanzvir have no effect on this pathway.
▪ Indinavir also increases hepatic glucose production and release and causes
insulin to lose its ability to suppress hepatic glucose production.
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Human Immunodeficiency Virus (HIV) and

Acquired Immune Deficiency Syndrome (AIDS)
▪ Nelfinavir, lopinavir, and saquinavir cause a 25% reduction in β-cell function,
reducing first-phase insulin release.
▪ Drug selection for treating protease inhibitor–induced hyperglycemia should
address the mechanism behind the adverse effect.
▪ Protease inhibitor therapy avoidance should be considered in patients with
preexisting glucose abnormalities and in those with a first-degree relative with
diabetes.
▪ Metformin should be used with caution in patients taking the nucleoside reverse
transcriptase inhibitors stavudine, zidovudine, and didanosine because of an
increased risk for lactic acidemia.
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Antipsychotic Drug Therapy

▪ An association has been recognized between second generation antipsychotics
and the development of diabetes.
▪ Risk seems to be highest with clozapine and olanzapine, but data are conflicting
for risperidone and quetiapine.
▪ Aripiprazole and ziprasione have not, as of yet, shown an increased risk for
diabetes with their use.
▪ Nutrition and physical activity counseling is recommended for all patients with
mental illness who are overweight or obese, especially if they are beginning
second-generation antipsychotic therapy.
▪ After therapy initiation, the patient’s weight should be assessed at weeks 4, 8,
and 12 and then every 3 months.
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Antipsychotic Drug Therapy

▪ In the event of weight gain greater than or equal to 5% of the patient’s baseline
weight, a therapeutic adjustment should be considered.
▪ For patients who develop worsening glycemia or dyslipidemia while on
antipsychotic therapy, it is recommended that a switch to a second-generation
antipsychotic with less weight gain or diabetes potential be considered.
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Treatment of Acute Complications: Hypoglycemia

▪ Hypoglycemia, or low blood sugar, can be defined clinically as a blood glucose
level of less than 50 mg/dL (2.8 mmol/L).
▪ Individuals with DM can experience symptoms of hypoglycemia at varying blood
glucose levels.
▪ Patients who have regular blood glucose levels as high as 300 to 400 mg/dL (16.7
to 22.2 mmol/L) may experience symptoms of hypoglycemia when blood glucose
levels are lowered to the middle to upper 100 mg/dL (5.6 mmol/L) range.
▪ Most people whose blood glucose levels are controlled adequately may
experience symptoms when levels fall below 70 mg/dL (3.9 mmol/L).
▪ Symptoms of hypoglycemia include shakiness, sweating, fatigue, hunger,
headaches, and confusion.
155

▪ Common causes of hypoglycemia include delayed or inadequate amounts of
food intake, especially carbohydrates, excessive doses of medications (e.g.,
sulfonylureas and insulin), exercising when insulin doses are reaching peak effect,
or inadequately adjusted drug therapy in patients with impaired renal or hepatic
function.
▪ Patients experiencing symptoms of hypoglycemia should check their blood
glucose level, consume 15 g of carbohydrate, and wait 10 to 15 minutes for
symptom resolution.
▪ Examples of acceptable treatments may include a small box of raisins, 4 oz
(approximately 120 mL) of orange juice, 8 oz (approximately 240 mL) of skim milk,
or three to six glucose tablets.
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▪ In patients receiving an α-glucosidase inhibitor in combination with a sulfonylurea

or insulin, hypoglycemia should be treated with glucose tablets or skim milk owing to
the mechanism of action of the α-glucosidase inhibitors.
▪ For patients whose blood glucose levels have dropped below 50 mg/dL (2.8
mmol/L), as much as 30 g of carbohydrate may be necessary to raise blood glucose
levels adequately.
▪ For patients with hypoglycemia experiencing a loss of consciousness, a glucagon
emergency kit should be administered by the intramuscular or subcutaneous route.
157
Diabetic Ketoacidosis
▪ Diabetic ketoacidosis is a reversible but potentially life threatening medical
emergency that results from a relative or absolute deficiency in insulin.
▪ Without insulin, the body cannot use glucose as an energy source and must
obtain energy via lipolysis.
▪ This process produces ketones and leads to acidosis.
▪ Although DKA occurs frequently in young patients with T1DM on initial
presentation, it can occur in adults as well.
▪ Often, precipitating factors such as infection, omission, or inadequate
administration of insulin can cause DKA.
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▪ Signs and symptoms develop rapidly within 1 day or so and commonly include
fruity or acetone breath; nausea; vomiting; dehydration; polydipsia; polyuria; and
deep, rapid breathing.
▪ Hallmark diagnostic criteria for DKA include hyperglycemia (greater than 250
mg/dL, 13.9 mmol/L), ketosis (anion gap greater than 12 mEq/L [12 mmol/L]), and
acidosis (arterial pH less than or equal to 7.3).
▪ Typical fluid deficit is 5 to 7 L or more, and major deficits of serum sodium and
potassium are common.
▪ The severity of DKA depends on the magnitude of the decrease in arterial pH,
serum bicarbonate levels, and the mental state rather than the magnitude of the
hyperglycemia.
159
▪ Treatment goals of DKA consist of reversing the underlying metabolic
abnormalities, rehydrating the patient, and normalizing the serum glucose.
▪ Fluid replacement with normal saline at 1 to 1.5 L/h for the first hour is
recommended to rehydrate the patient and to ensure the kidneys are perfused.
▪ Potassium and other electrolytes are supplemented as indicated by laboratory
assessment.
▪ The use of sodium bicarbonate in DKA is controversial and generally only
recommended when the pH is less than or equal to 7 after 1 hour of hydration.
▪ Regular insulin at 0.1 unit/kg/h by continuous IV infusion is the preferred
treatment in DKA to regain metabolic control rapidly.
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▪ When plasma glucose values drop below 250 mg/dL (13.9 mmol/L), dextrose 5%
should be added to the IV fluids.
▪ During the recovery period, it is recommended to continue administering insulin
and to allow patients to eat as soon as possible.
▪ Dietary carbohydrates combined with insulin assist in the clearance of ketones.
161
Management of Diabetic Ketoacidosis
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Hyperosmolar Hyperglycemic State

▪ Hyperosmolar hyperglycemic state (HHS) is a life-threatening condition similar to
DKA that also arises from inadequate insulin, but HHS occurs primarily in older
patients with T2DM.
▪ DKA and HHS also differ in that HHS lacks the lipolysis, ketonemia, and acidosis
associated with DKA.
▪ Patients with hyperglycemia and dehydration lasting several days to weeks are at
the greatest risk of developing HHS.
▪ Infection; silent myocardial infarction; cerebrovascular accident; mesenteric
ischemia; acute pancreatitis; and the use of medications such as steroids, thiazide
diuretics, calcium channel blockers, propranolol, and phenytoin are known
precipitating causes of HHS.
163
Hyperosmolar Hyperglycemic State

▪ Two main diagnostic criteria for HHS are a plasma glucose value of greater than
600 mg/dL (33.3 mmol/L) and a serum osmolality of greater than 320 mOsm/kg
(320 mmol/kg).
▪ The extreme hyperglycemia and large fluid deficits resulting from osmotic
diuresis are major challenges to overcome with this condition.
▪ Similar to DKA, the treatment of HHS consists of aggressive rehydration,
correction of electrolyte imbalances, and continuous insulin infusion to normalize
serum glucose. However, in patients with HHS, blood glucose levels should be
reduced gradually to minimize the risk of cerebral edema.
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Treatment of Long-Term Complications

Retinopathy
▪ Diabetic retinopathy occurs when the microvasculature that supplies blood to
the retina becomes damaged.
▪ This damage permits leakage of blood components through the vessel walls.
▪ Diabetic retinopathy is the leading cause of blindness in adults 20 to 74 years of
age in the United States.
▪ The risk of retinopathy is increased in patients with longstanding DM, chronic
hyperglycemia, hypertension, and nephropathy.
▪ Glaucoma, cataracts, and other eye disorders occur earlier and more frequently
in patients with DM.
▪ The ADA recommends that patients with DM receive a dilated eye examination
annually by an ophthalmologist or optometrist.
165
Treatment of Long-Term Complications

Retinopathy
▪ Examinations should begin within 5 years of diagnosis of T1DM and shortly after
diagnosis of T2DM.
▪ Glycemic control is the best prevention for slowing the progression of
retinopathy along with optimal blood pressure control.
▪ Early retinopathy may be reversed with improved glucose control.
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Neuropathy
▪ Peripheral neuropathy is a common complication reported in T2DM.

▪ This complication generally presents as pain, tingling, or numbness in the
extremities.
▪ The feet are affected more often than the hands and fingers.
▪ Current options include pregabalin, gabapentin, low-dose tricyclic antidepressants,
duloxetine, venlafaxine, topiramate, nonsteroidal anti-inflammatory drugs, and topical
capsaicin.
▪ Autonomic neuropathy is also a common complication as DM progresses.
▪ The clinical presentation of autonomic neuropathy may include gastroparesis,
resting tachycardia, orthostatic hypotension, impotence, constipation, and
hypoglycemic autonomic failure.
▪ Therapy for each individual autonomic complication is addressed separately.
167
Microalbuminuria and Nephropathy

▪ Diabetes mellitus is the leading contributor to end-stage renal disease.
▪ Early evidence of nephropathy is the presence of albumin in the urine.
▪ Therefore, as the disease progresses, larger amounts of protein spill into the
urine.
▪ The ADA recommends urine protein tests annually in T2DM patients.
▪ For children with T1DM, annual urine protein testing should begin with the onset
of puberty or 5 years after the diagnosis of diabetes.
▪ The most common form of screening for protein in the urine is a random
collection for measurement of the urine albumin-to-creatinine ratio.
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Microalbuminuria and Nephropathy

▪ The desirable value is less than 30 mcg of albumin per milligram of creatinine (3.4
mg/ mmol creatinine).
▪ Microalbuminuria is defined as between 30 and 300 mcg of albumin per milligram
of creatinine (3.4 to 34 mg/mmol creatinine). The presence of microalbuminuria is a
strong risk factor for future kidney disease in T1DM patients.
▪ In patients with T2DM, microalbuminuria has been found to be a strong risk factor
for macrovascular disease.
▪ Glycemic control and blood pressure control are primary measures for the
prevention of progression of nephropathy.
▪ ACE inhibitors and angiotensin II receptor blockers prevent the progression of renal
disease in patients with T2DM.
▪ Treatment of advanced nephropathy includes dialysis and kidney transplantation.
169
Foot Ulcers
▪ Lower extremity amputations are one of the most feared and disabling sequelae
of long-term uncontrolled DM.
▪ A foot ulcer is an open sore that develops and penetrates to the subcutaneous
tissues.
▪ Complications of the feet develop primarily as a result of peripheral vascular
disease, neuropathies, and foot deformations.
▪ Peripheral vascular disease causes ischemia to the lower limbs.
▪ This decreased blood flow deprives the tissues of oxygen and nutrients and
impairs the ability of the immune system to function adequately.
▪ Symptoms of peripheral vascular disease include intermittent claudication, cold
feet, pain at rest, and loss of hair on the feet and toes.
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Foot Ulcers
▪ Smoking cessation is the single most important treatment for peripheral

vascular disease.
▪ In addition, exercising by walking to the point of pain and then resting and
resuming can be a vital therapy to maintain or improve the symptoms of peripheral
vascular disease.
▪ Pharmacologic intervention with pentoxifylline or cilostazol also may be useful to
improve blood flow and reduce the symptoms of peripheral vascular disease.
▪ Neuropathies play a large part in the development of foot ulcers. Loss of
sensation in the feet allows trauma to go unnoticed.
▪ Autonomic neuropathy can cause changes in blood flow, perspiration, skin
hydration, and possibly, bone composition of the foot.
171
Foot Ulcers
▪ Motor neuropathy can lead to muscle atrophy, resulting in weakness and

changes in the shape of the foot.
▪ To prevent foot complications, the ADA recommends daily visual examination of
the feet and a foot check performed at every physician visit.
▪ Sensory testing with a 10-gauge monofilament can detect areas of neuropathy.
▪ Treatment consists of glycemic control, preventing infection, debriding dead
tissues, applying dressings, treating edema, and limiting ambulation.
▪ Untreated foot problems may develop gangrene, necessitating surgical
intervention.
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Special Situations: Hospitalized Care
▪ The NICE-SUGAR (intensive versus conventional glucose in critically ill patients)

trial compared intensive (81 to 108 mg/dL [4.5 to 6.0 mmol/L]) with conventional
(less than 180 mg/ dL [10.0 mmol/L]) glucose control using IV insulin in 6,104
intensive care unit patients.
▪ At 90 days, intensively controlled patients had an increased absolute risk of
death of 2.6% (829 patients in the intensively controlled and 751 patients in the
conventionally controlled groups died).
▪ Significantly more hypoglycemia was observed in the intensively controlled
group.
▪ Current recommendations call for critically ill patients to be started on IV insulin
therapy at a threshold of 180 mg/ dL (10.0 mmol/L).
173
▪ A goal range of 140 to 180 mg/dL (7.8 to 10.0 mmol/L) is recommended for the
majority of patients.
▪ More stringent goals may be considered for selected critically ill patients, but
only if hypoglycemia can be avoided.
▪ Scheduled subcutaneous insulin regimens with basal, nutritional, and correction
components are recommended for patients who are not critically ill.
▪ Goals of less than 140 mg/dL (7.8 mmol/L) for fasting glucose and less than 180
mg/ dL (10.0 mmol/L) for random glucose are recommended for noncritically ill
patients.
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▪ Blood glucose levels can be measured by several methods.

▪ Arterial samples are usually 5 mg/dL (0.3 mmol/L) higher than capillary values
and 10 mg/dL (0.6 mmol/L) greater than venous values.
▪ When preparing an insulin infusion for a patient, several factors must be
considered. Insulin will absorb to glass and plastic, reducing the amount of insulin
actually delivered by 20% to 30%.
▪ Priming the tubing decreases the variability of insulin infused.
▪ Therefore, when patients can be converted safely from infusion to needle and
syringe therapy, the total daily dose should be reduced by 20% to 50% of the daily
infusion amount.
175
▪ When transferring someone from IV insulin drip to subcutaneous insulin, basal

insulin should be administered several hours before the drip is discontinued to
prevent loss of glycemic control.
▪ IV drip protocols are institution specific.
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Sick Days
▪ Patients should monitor their blood glucose levels more frequently during sick
days because it is common for illness to increase blood glucose values.
▪ Patients with T1DM should check their glucose and urine for ketones every 4
hours when sick.
▪ Patients with T2DM may also need to check for ketones when their blood
glucose levels are greater than 300 mg/dL (16.7 mmol/L).
▪ Patients should continue to take their medications while sick.
▪ T1DM patients may require additional insulin coverage, and some with T2DM
who are currently on oral medication regimens may require insulin during an acute
illness.
177
Sick Days
▪ Patients should be advised to maintain their normal caloric and carbohydrate

intake while ill as well as to drink plenty of noncaloric beverages to avoid
dehydration.
▪ When having difficulty eating a normal diet, patients may be advised to use non
diet beverages, sports drinks, broths, crackers, soups, and non diet gelatins to
provide normal caloric and carbohydrate intake and avoid hypoglycemia.
▪ With proper management, patients can decrease their chance of illness-induced
hospitalization, particularly DKA and HHS.
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OUTCOME EVALUATION
▪ The success of therapy for DM is measured by the ability of the patient to

manage his or her disease appropriately between healthcare provider visits.
▪ Appropriate therapy necessitates adequate patient education about the disease,
development of a meal plan to which patients can comply, and integration of a
regular exercise program.
▪ Patient care plans should include a number of daily evaluations to be performed
by the patient, such as examining the feet for any sores, cuts, or abrasions; checking
the skin for dryness to prevent cracking and chafing; and monitoring blood glucose
values as directed.
▪ Weekly appraisals of weight and blood pressure are also advised.
179
OUTCOME EVALUATION
▪ Until A1c levels are at goal, quarterly visits with the patient’s primary healthcare
provider are recommended.
▪ The practitioner should review SMBG data and a current A1c level for progress
and address any therapeutic or educational issues.
▪ At a minimum, yearly laboratory evaluation of serum lipids, urinary
microalbumin, and serum creatinine should be performed.
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25.03.

Dr. Muhammad Fawad Rasool

Department of Pharmacy Practice,

▪ Diabetes mellitus (DM) describes a group of chronic metabolic

These complications contribute to diabetes being the leading cause of,

2 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

3 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

▪ The worldwide prevalence of DM has risen dramatically over

4 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

▪ The increasing prevalence of DM is partly caused by three influences: lifestyle,

5 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

▪ T1DM is an autoimmune disease in which insulin producing β cells in the

6 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

▪ At the time of diagnosis of T1DM, it is commonly believed that most patients

7 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

8 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

9 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

▪ C-peptide is the abbreviation for “connecting peptide.” C-peptide is made when

10 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

11 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

▪ T2DM is usually slow and progressive in its development.

▪ High-density lipoprotein (HDL) less than 35 mg/dL (0.91 mmol/L) and/or a

13 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

▪ Gestational diabetes mellitus (GDM) is defined as glucose intolerance in women

14 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

Medications That May Affect Glycemic Control

15 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

Normal Carbohydrate Metabolism

16 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

17 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

Normal Insulin Action

18 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

▪ The second phase of insulin response is characterized by a gradual increase in

19 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

▪ Amylin is a naturally occurring hormone that is co-secreted from β cells with

20 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

Impaired Insulin Secretion

21 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

▪ Impaired β-cell function results in a reduced ability to produce a first-phase

22 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

23 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

Impaired Glucagon Secretion

24 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

25 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

26 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

27 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

28 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

29 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

▪ GLP-1 secretion is caused by endocrine and neural signals started when

30 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

31 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

CLINICAL PRESENTATION AND DIAGNOSIS

32 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

CLINICAL PRESENTATION AND DIAGNOSIS

33 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

CLINICAL PRESENTATION AND DIAGNOSIS

34 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

35 Dr. Muhammad Fawad Rasool www.bzu.edu.pk

ADA Criteria for the Diagnosis of Diabetes

DCCT, Diabetes Control and Complications Trial; NGSP, National Glycohemoglobin