DIABETES MELLITUS

Diabetes is a chronic condition caused by an absolute lack of insulin or relative lack of insulin as
a result of impaired insulin secretion and action. Its hallmark clinical characteristics are
symptomatic glucose intolerance resulting in hyperglycaemia and alterations in lipid and
protein metabolism.
OR
Diabetes mellitus (DM) is a heterogeneous group of metabolic disorders characterized by
hyperglycaemia. It is associated with abnormalities in carbohydrate, fat, and protein
metabolism and may result in chronic complications including micro vascular, macro vascular,
and neuropathic disorders.
OR
Diabetes is a chronic disease that occurs either when the pancreas does not produce enough
insulin or when the body cannot effectively use the insulin it produces. Insulin is a hormone that
regulates blood sugar. Hyperglycaemia, or raised blood sugar, is a common effect of
uncontrolled diabetes and over time leads to serious damage to many of the body's systems,
especially the nerves and blood vessels

EPIDEMIOLOGY

 The number of people with diabetes has risen from 108 million in 1980 to 422 million in
2014.
 The global prevalence of diabetes* among adults over 18 years of age has risen from
4.7% in 1980 to 8.5% in 2014 (1).
 Diabetes prevalence has been rising more rapidly in middle- and low-income countries.
 Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower
limb amputation.
 In 2016, an estimated 1.6 million deaths were directly caused by diabetes. Another 2.2
million deaths were attributable to high blood glucose in 2012**.
 Almost half of all deaths attributable to high blood glucose occur before the age of 70
years. WHO estimates that diabetes was the seventh leading cause of death in 2016.
 Healthy diet, regular physical activity, maintaining a normal body weight and avoiding
tobacco use are ways to prevent or delay the onset of type 2 diabetes.
 Diabetes can be treated and its consequences avoided or delayed with diet, physical
activity, medication and regular screening and treatment for complications.
 Type 1 diabetes may present at any age, but there is a sharp increase around the time of
puberty and a decline thereafter. Approximately 50–60% of patients with type 1 will
present before 20 years of age.
 Type 2 diabetes is much more common than type 1, accounting for 90% of people with
diabetes. It usually occurs in those over the age of 40 years.
 Approximately 5% to 10% of the diagnosed diabetic population has type 1 diabetes,
which usually results from autoimmune destruction of the pancreatic β cells.
 Most people with diabetes have type 2 diabetes, a heterogeneous disorder that is
characterized by obesity, β cell dysfunction, resistance to insulin action, and increased
hepatic glucose production. Both the incidence and prevalence of diabetes increase
 dramatically with age and obesity. The prevalence of self-reported diagnosed diabetes
is 2.6% among persons 20 to 39 years of age and 23.1% among persons age 60 and older.

Classification
Type 1 Diabetes
Type 1 diabetes (previously known as insulin-dependent, juvenile or childhood-onset) is
characterized by deficient insulin production and requires daily administration of insulin. The
cause of type 1 diabetes is not known and it is not preventable with current knowledge.
Symptoms include excessive excretion of urine (polyuria), thirst (polydipsia), constant hunger,
weight loss, vision changes, and fatigue. These symptoms may occur suddenly.
Type 1 diabetes is a disease characterised by the destruction of the insulin-producing pancreatic
β-cells, the development of which is either autoimmune T-cell mediated destruction (type 1A)
or idiopathic (type 1B). In over 90% of cases, β-cell destruction is associated autoimmune
disease. Type 1 diabetes usually develops in the young (below the age of 30), although it can
develop at any age and is usually associated with a faster with onset of symptoms leading to
dependency on extrinsic insulin for survival.

Type 2 diabetes
Type 2 diabetes (formerly called non-insulin-dependent, or adult-onset) results from the body’s
ineffective use of insulin. Type 2 diabetes comprises the majority of people with diabetes around
the world, and is largely the result of excess body weight and physical inactivity.
Most individuals with type 2 diabetes exhibit abdominal obesity which itself causes insulin
resistance. In addition, hypertension, dyslipidemia (high triglyceride levels and low HDL-
cholesterol levels), and elevated inhibitor plasminogen activator-1 (PAI-1) levels are often
present in these individuals. This clustering of abnormalities is referred to as the “insulin
resistance syndrome” or the “metabolic syndrome. “Because of these abnormalities, patients
with type 2 diabetes are at increased risk of developing macro vascular complications
Symptoms may be similar to those of type 1 diabetes, but are often less marked. As a result, the
disease may be diagnosed several years after onset, once complications have already arisen.
Until recently, this type of diabetes was seen only in adults but it is now also occurring
increasingly frequently in children.

Gestational diabetes
Gestational diabetes is hyperglycaemia with blood glucose values above normal but below
those diagnostic of diabetes, occurring during pregnancy.
Gestational diabetes mellitus (GDM) is defined as glucose intolerance which is first recognized
during pregnancy. Hormone changes during pregnancy result in increased insulin resistance,
and GDM may ensue when the mother cannot adequately compensate with increased insulin
secretion to maintain normoglycemia. In most, glucose intolerance first appears near the
beginning of the third trimester. However, risk assessment and intervention should begin from
the first prenatal visit. If DM is diagnosed prior to pregnancy, this is not GDM, but rather
pregnancy with pre-existing DM. Detection is important, as therapy will reduce perinatal
morbidity and mortality.
Women with gestational diabetes are at an increased risk of complications during pregnancy
and at delivery. They and their children are also at increased risk of type 2 diabetes in the future.
Gestational diabetes is diagnosed through prenatal screening, rather than through reported
symptoms.
OTHER SPECIFIC TYPES OF DIABETES
Genetic Defects

Maturity onset diabetes of youth (MODY) is characterized by impaired insulin secretion with
minimal or no insulin resistance. Patients typically exhibit mild hyperglycaemia at an early age.
The disease is inherited in an autosomal dominant pattern with at least three different loci
identified to date. Genetic inability to convert proinsulin to insulin results in mild
hyperglycaemia and is inherited in an autosomal dominant pattern.

Aetiology
1. Aetiology of Type 1 Diabetes

Type 1 diabetes is caused by the immune system destroying the cells in the pancreas that make
insulin. This causes diabetes by leaving the body without enough insulin to function normally.
This is called an autoimmune reaction, or autoimmune cause, because the body is attacking
itself.
In type 1 diabetes, it is the beta cells in the pancreas which produce insulin that are wrongfully
targeted and killed off by specific antibodies created by the body’s immune system.
There is no specific diabetes causes, but the following triggers may be involved:
 Viral or bacterial infection
 Chemical toxins within food
 Unidentified component causing autoimmune reaction
TYPE 1 DIABETES TRIGGERS
Researchers have hypothesised that whilst some people are have a genetic predisposition to
type 1 diabetes, there is likely to be an environmental factor that triggers the initial development
of type 1 diabetes.
Some of the possible triggers that have been suggested include:
Viral infection: Studies have shown that enterovirus antibodies have been recorded at higher
levels in pregnant mothers of children that gone on to develop type 1 diabetes. Higher
frequencies of enterovirus infections have also been detected in children which develop type 1
diabetes when compared with siblings that have not developed the condition.
Vaccines: Another theory put forward is that childhood vaccinations could increase the chances
of developing type 1 diabetes. Dr Classen’s research indicates there could be a link between
type 1 diabetes and childhood vaccinations such as smallpox, tuberculosis and Hib vaccines.
Low levels of vitamin D: Studies have also shown that people with lower levels of vitamin D
had a higher incidence rate of developing type 1 diabetes. A number of studies, including the
EURODIAB Substudy 2, have shown that supplementation of vitamin D appears to lower the risk
of developing type 1 diabetes.
Increased insulin demand: Increased demand on insulin has also been put forward as a
contributing factor. A study, carried out by the University of Colorado and published in 2008,
showed that a diet with high glycaemic index foods could speed up the progression to type 1
diabetes in children with signs of islet autoimmunity.
The growth phase that children go through in teenage year’s increases the amount
of insulin released and could lead to extra stress on beta cells, raising the risk of the immune
system attacking the insulin producing cells.
2. Aetiology of Type 2 Diabetes

’
RISK FACTORS FOR TYPE 2 DIABETES

– Family History
– Obesity
– Habitual physical inactivity
– Previously identified impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)
– Hypertension
– Hyperlipidemia

GESTATIONAL DIABETES CAUSES

The causes of diabetes in pregnancy also known as gestational diabetes remain unknown.
However, there are a number of risk factors that increase the chances of developing this
condition:
 Family history of gestational diabetes
 Overweight or obese
 Suffer from polycystic ovary syndrome
 Have had a large baby weighing over 9lb
Causes of gestational diabetes may also be related to ethnicity – some ethnic groups have a
higher risk of gestational diabetes.
Carbohydrate Metabolism
 An understanding of the signs and symptoms associated with diabetes is based on a
knowledge of glucose metabolism and the metabolic effects of insulin in non-diabetic and
diabetic subjects during the fed (postprandial) and fasting (post absorptive) states
 Homeostatic mechanisms maintain plasma glucose concentrations between 55 and 140
mg/dL.
 A minimum concentration of 40 to 60mg/dL is required to provide adequate fuel for the
central nervous system, which uses glucose as its primary energy source and is
independent of insulin for glucose utilization.
 When blood glucose (BG) concentrations exceed the reabsorptive capacity of the
proximal tubule in the kidneys (∼180 mg/dL), glucose spills into the urine (glucosuria),
resulting in a loss of calories and water.
  Muscle and fat, which use glucose as a major source of energy, require insulin for glucose
uptake. If glucose is unavailable, these tissues are able to use other substrates such as
amino acids and fatty acids for fuel

POSTPRANDIAL (during or relating to the period after dinner or lunch.) GLUCOSE

AND LIPID METABOLISM IN THE NONDIABETIC INDIVIDUAL

» After food is ingested, BG concentrations rise and stimulate insulin release. Insulin is the
key to efficient glucose utilization. It promotes the uptake of glucose, fatty acids, and
amino acids and their conversion to storage forms in most tissues. Insulin also inhibits
hepatic glucose production by suppressing glucagon and its effects.
» In muscle, insulin promotes the uptake of glucose and its storage as glycogen
(GLYCOGENESIS). It also stimulates the uptake of amino acids and their conversion to
protein.
» In adipose tissue, glucose is converted to free fatty acids and stored as triglycerides.
Insulin also prevents a breakdown of these triglycerides to free fatty acids, a form that
may be transported to other tissues for utilization. The liver does not require insulin for
glucose transport, but insulin facilitates the conversion of glucose to glycogen and free
fatty acids.
» Free fatty acids are esterified to triglycerides, which are transported by very-low-density
lipoproteins (VLDLs) to adipose and muscle tissue. Normal insulin signalling suppresses
VLDL secretion by reducing the production of fatty acids in the liver

FASTING GLUCOSE METABOLISM IN THE NONDIABETIC INDIVIDUAL

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

PATHO

 Each of the four major islet cell types produces a different secretory product. Insulin-
secreting β cells are the predominant cell type (60%). The majority of the remaining islet
cells, glucagon-secreting α cells (30%) and somatostatin-secreting δ cells (< 10%),
secrete hormones that counter the effects of insulin. A fourth islet cell type, the pancreatic
polypeptide (PP) – secreting cell (< 1 %), is primarily located in the posterior lobe of the
head of the pancreas, an embryologically distinct region receiving a different blood
supply.
 In the fasting state 75% of total body glucose disposal occurs in tissues, including the
brain and peripheral nerves that do not require insulin. Brain glucose uptake occurs at
the same rate during fed and fasting periods. The remaining 25% of glucose metabolism
takes place in the liver and muscle, which is dependent on insulin. In the fasting state,
approximately 85% of glucose production is derived from the liver, and the remaining
amount is produced by the kidney.
 Glucagon, produced by pancreatic α cells, is secreted in the fasting state to oppose the
action of insulin and stimulate hepatic glucose production and glycogenolysis. Glucagon
 and insulin secretion are closely linked. Appropriate secretion of both hormones is
needed to keep plasma glucose levels normal.
 In the fed state, carbohydrate ingestion increases the plasma glucose concentration and
stimulates insulin release from the pancreatic β-cells. The resultant hyperinsulinemia (1)
suppresses hepatic glucose production, (2) stimulates glucose uptake by peripheral
tissues, and (3) suppresses glucagon release (in conjunction with incretin hormones). The
majority (approximately 80%-85%) of glucose is taken up by muscle. A small amount
(approximately 4%-5%) is metabolized by adipocytes.

Type 1 Diabetes PATHOGENESIS

 Type1DMischaracterizedbyanabsolutedeficiencyofinsulin.Most often this is the result of

an immune-mediated destruction of pancreatic β cells, but rare unknown or idiopathic
processes may contribute.


 What is evident are four main features: (1) a long preclinical period marked by the
presence of immune markers when β-cell destruction is thought to occur; (2)
hyperglycemia when 80% to 90% of β cells are destroyed; (3) transient remission (the so-
called, “honeymoon” phase); and (4) established disease with associated risks for
complications and death.
 HONEYMOON PERIOD: Within days or weeks after the initial diagnosis and implementing
treatment, many patients with type 1 diabetes experience an apparent remission, which
is reflected by decreased BG concentrations and markedly decreased insulin
requirements. This is called the honeymoon period because it may last for only a few
weeks to months.
 Unknown is whether there is one or more inciting factors (e.g., cow’s milk, or viral,
dietary, or other environmental exposure) that initiate the autoimmune process
 The autoimmune process is mediated by macrophages and T lymphocytes with
circulating autoantibodies to various β-cell antigens. The most commonly detected
antibody associated with type 1DM is the islet cell antibody
 Insulin lowers blood glucose by a variety of mechanisms, including stimulation of tissue
glucose uptake, suppression of glucose production by the liver, and suppression of free
 fatty acid (FFA) release from fat cells. The suppression of FFAs plays an important role in
glucose homeostasis. Increased levels of FFAs inhibit the uptake of glucose by muscle
and stimulate hepatic gluconeogenesis.
 Amylin is a hormone that is cosecreted from the pancreatic β-cell with insulin. Amylin is
also deficient in patients with type 1 DM secondary to the destruction of β-cells. Amylin
suppresses inappropriate glucagon secretion, slows gastric emptying, and causes central
satiety.

Type 2 Diabetes PATHOGENESIS

Type 2 diabetes is caused by multiple defects including: (1) impaired insulin secretion; (2)
deficiency and resistance to incretin hormones; (3) insulin resistance involving muscle, liver,
and adipocytes; (4) excess glucagon secretion; and (5) sodium-glucose cotransporter
upregulation in the kidney

Impaired Insulin Secretion

 The pancreas in people with a normal-functioning β-cell is able to adjust its secretion of
insulin to maintain normal plasma glucose levels in nondiabetic individuals, insulin
increases in proportion to the severity of the insulin resistance and plasma glucose
remains normal. Impaired insulin secretion is a hallmark finding in type 2 DM.
 In early β-cell dysfunction, first-phase insulin, as seen with an IV bolus of glucose, is
deficient. First phase insulin involves the release of stored insulin in the β-cell and acts to
“prime” the liver to nutrient intake. Without appropriate first phase insulin release,
second phase insulin must compensate for the ensuing postprandial hyperglycemia in
order to normalize glucose levels. When the insulin released is no longer sufficient to
normalize plasma glucose, dysglycemia, including prediabetes and diabetes can ensue.
 People with type 2 DM lose approximately 5% to 7% of β-cell function per year. The
reasons are likely multifactorial including (1) glucose toxicity; (2) lipotoxicity; (3) insulin
resistance; (4) age; (5) genetics; and (6) incretin deficiency. Age results in declining β-
cell responsiveness and possibly mass. High-risk ethnicity/races are predisposed to β-
cell failure. Glucotoxicity occurs when glucose levels chronically exceed 140 mg/dL (7.8
mmol/L). The β-cell is unable to maintain sufficient insulin secretion and, paradoxically,
releases less insulin as glucose levels increase

Incretin Hormone Deficiency/Resistance

 In patients with type 2 DM, decreased postprandial insulin secretion is a result of both
impaired pancreatic β-cell function and reduced stimulus from gut hormones to secrete
insulin
 The role gut hormones play in insulin secretion is best shown by comparing the insulin
response to an oral glucose load versus an isoglycemic intravenous glucose infusion. In
individuals who do not have diabetes, 73% more insulin is released in response to an oral
glucose load compared to an intravenous (IV) glucose load given to mimic plasma
glucose levels achieved during the oral glucose load.
 The increased insulin secretion in response to an oral glucose stimulus is referred to as
“the incretin effect” and is the result of gut hormones, stimulated by oral intake of
nutrients (glucose, fat, or protein), that promote pancreatic insulin secretion. In patients
with type 2 patients, this “incretin effect” is blunted with the increase in insulin secretion
approximately half of that seen in nondiabetic individuals.

Insulin Resistance
 Resistance to the actions of insulin in the liver contributes significantly to excess hepatic
glucose production
  Patients with type 2 DM with mild to moderate fasting hyperglycemia (140-200 mg/dL,
7.8-11.1 mmol/L), basal hepatic glucose production is increased by approximately 0.5
mg/kg/min.
 Consequently, during the overnight sleeping hours the liver of an 80-kg person with
diabetes with modest fasting hyperglycemia adds an additional 35 g of glucose to the
systemic circulation. This increase in fasting hepatic glucose production is the cause of
fasting hyperglycemia. In the postprandial state, the liver inappropriately continues
hepatic glucose output.
 Therefore, patients with type 2 DM have two sources of glucose in the postprandial state,
one from the diet and one from continued glucose production from the liver. These
sources of glucose may result in marked hyperglycemia
 Weight gain leads to insulin resistance in most individuals. Obese individuals who do not
have diabetes often have the same degree of insulin resistance as lean type 2 DM patients.
Obese but metabolically normal patients do exist (6%-30%) as well as patients who are
not obese but metabolically abnormal. Thus, obesity does not automatically result in
insulin resistance.

Excess Glucagon Secretion

 Type 2 DM patients fail to suppress glucagon in response to a meal and may even have a
paradoxical rise in glucagon levels. Two main factors contribute: (1) GLP-1
resistance/deficiency; and (2) insulin resistance and/or deficiency, which directly
suppress glucagon. Thus, hepatic insulin resistance, hyperglucagonemia, and GLP-1
deficiency result in excessive production of glucose by the liver.

CLINICAL PRESENTATION

TYPE 1 DIABETES MELLITUS

• The most common initial symptoms are polyuria, polydipsia, polyphagia, weight loss, and
lethargy accompanied by hyperglycemia.
• Individuals are often thin and are prone to develop diabetic ketoacidosis if insulin is withheld
or under conditions of severe stress.
• Between 20% and 40% of patients present with diabetic ketoacidosis after several days of
polyuria, polydipsia, polyphagia, and weight loss.

TYPE 2 DIABETES MELLITUS

• Patients are often asymptomatic and may be diagnosed secondary to unrelated blood testing.
• Lethargy, polyuria, nocturia, and polydipsia can be present. Significant weight loss is less
common; more often, patients are overweight or obese.
DIAGNOSIS

The categories for normal, increased risk for diabetes, and diabetes for fasting plasma glucose
(FPG), A1C, and the oral glucose tolerance test (OGTT) are listed in Table 53-2.7 The Expert
Committee of the ADA has established the diagnostic criteria for diabetes for non-pregnant
individuals of any age. For these individuals, a diagnosis of diabetes can be made when one of
the following is present:

• Criteria for diagnosis of DM include any one of the following:

1. A1C of 6.5% or more
A1C test results are reported as a percentage. The higher the percentage, the higher your blood
sugar levels over the past two to three months. The A1C test can also be used for diagnosis,
based on the following guidelines:
  If your A1C level is between 5.7 and less than 6.5%, your levels have been in
the prediabetes range.
 If you have an A1C level of 6.5% or higher, your levels were in the diabetes range.
Finally: A1C is also defined as ‘estimated average glucose,’ or eAG
2. Fasting (no caloric intake for at least 8 hours) plasma glucose of 126 mg/dL (7.0 mmol/L) or
more
3. Two-hour plasma glucose of 200 mg/dL (11.1 mmol/L) or more during an oral glucose
tolerance test (OGTT) using a glucose load containing the equivalent of 75 g anhydrous glucose
dissolved in water
4. Random plasma glucose concentration of 200 mg/dL (11.1 mmol/L) or more with classic
symptoms of hyperglycemia or hyperglycemic crisis
In the absence of unequivocal hyperglycemia, criteria 1 through 3 should be confirmed by
repeat testing.
• Normal fasting plasma glucose (FPG) is less than 100 mg/dL (5.6 mmol/L).
• Impaired fasting glucose (IFG) is FPG 100 to 125 mg/dL (5.6–6.9 mmol/L).
• Impaired glucose tolerance (IGT) is diagnosed when the 2-hour postload sample of OGTT is
140 to 199 mg per dL (7.8–11.0 mmol/L).
• Pregnant women should undergo risk assessment for GDM at first prenatal visit and have
glucose testing if at high risk (eg, positive family history, personal history of GDM, marked
obesity, or member of a high-risk ethnic group).

TREATMENT

• Goals of Treatment: Ameliorate symptoms, reduce risk of micro vascular and macro
vascular complications, reduce mortality, and improve quality of life.

GENERAL APPROACH
• Early treatment with near-normal glycemia reduces risk of microvascular disease
complications, but aggressive management of cardiovascular risk factors (i.e., smoking
cessation, treatment of dyslipidemia, intensive blood pressure [BP] control, and antiplatelet
therapy) is needed to reduce macrovascular disease risk.
• Appropriate care requires goal setting for glycemia, BP, and lipid levels; regular monitoring
for complications; dietary and exercise modifications; appropriate self monitoring of blood
glucose (SMBG); and laboratory assessment.

NONPHARMACOLOGIC THERAPY
• Medical nutrition therapy is recommended for all patients. For type 1 DM, the focus is on
physiologically regulating insulin administration with a balanced diet to achieve and maintain
healthy body weight. The meal plan should be moderate in carbohydrates and low in saturated
fat, with a focus on balanced meals. Patients with type 2 DM often require caloric restriction to
promote weight loss.
• Aerobic exercise can improve insulin sensitivity and glycemic control and may reduce
cardiovascular risk factors, contribute to weight loss or maintenance, and improve well-being.
PHARMACOLOGIC THERAPY: DRUG CLASS INFORMATION
Insulin

• Regular insulin has a relatively slow onset of action when given subcutaneously (SC),
requiring injection 30 minutes prior to meals to achieve optimal postprandial glucose control
and prevent delayed post meal hypoglycemia.
• Lispro, aspart, and glulisine insulins are analogs that are more rapidly absorbed, peak
faster, and have shorter durations of action than regular insulin. This permits more convenient
dosing within 10 minutes of meals (rather than 30 min prior), produces better efficacy in
lowering postprandial blood glucose than regular insulin in type 1 DM, and minimizes delayed
post meal hypoglycemia.
• Neutral protamine Hagedorn (NPH) is intermediate-acting. Variability in absorption,
inconsistent preparation by the patient, and inherent pharmacokinetic differences may
contribute to a labile glucose response, nocturnal hypoglycemia, and fasting hyperglycemia.
• Glargine and detemir are long-acting “peakless” human insulin analogs that result in less
nocturnal hypoglycemia than NPH insulin when given at bedtime.
• In type 1 DM, the average daily insulin requirement is 0.5 to 0.6 units/kg. Requirements may
fall to 0.1 to 0.4 units/kg in the honeymoon phase. Higher doses (0.5–1 unit/kg) are warranted
during acute illness or ketosis. In type 2 DM, a dosage range of 0.7 to 2.5 units/kg is often
required for patients with significant insulin resistance.
• Hypoglycemia and weight gain are the most common adverse effects of insulin. Treatment of
hypoglycemia is as follows:

✓ Glucose (10–15 g) given orally for conscious patients.

✓ Dextrose IV may be required for unconscious patients.

✓ Glucagon, 1 g intramuscularly, is preferred in unconscious patients when IV access cannot be

established.
Insulin Basics

Premixed insulin can be helpful for people who have trouble drawing up insulin out of two
bottles and reading the correct directions and dosages. It is also useful for those who have poor
eyesight or dexterity and is convenient for people whose diabetes has been stabilized on this
combination.
In 2015 an inhaled insulin product, Afrezza, became available in the U.S. Afrezza is a rapid-
acting inhaled insulin that is administered at the beginning of each meal and can be used by
adults with type 1 or type 2 diabetes. Afrezza is not a substitute for long-acting insulin. Afrezza
must be used in combination with injectable long-acting insulin in patients with type 1 diabetes
and in type 2 patients who use long-acting insulin.
 Inhaled insulin begins working within 12 to 15 minutes, peaks by 30 minutes, and is out
of your system in 180 minutes. Types: Technosphere insulin-inhalation system (Afrezza)
Characteristics of insulin
Insulin has 3 characteristics:

Onset is the length of time before insulin reaches the bloodstream and begins lowering blood
sugar.
Peak time is the time during which insulin is at maximum strength in terms of lowering blood
sugar.
Duration is how long insulin continues to lower blood glucose.
Insulin strength
All insulins come dissolved or suspended in liquids. The standard and most commonly used
strength in the United States today is U-100, which means it has 100 units of insulin per milliliter
of fluid, though U-500 insulin is available for patients who are extremely insulin resistant.

Glucagon-like Peptide 1 (GLP-1) Agonists

• Exenatide (Byetta, Bydureon) enhances insulin secretion and reduces hepatic glucose
production. It also increases satiety, slows gastric emptying, and promotes weight loss.

A1C reduction is ~0.9% with twice-daily exenatide. ✓Byetta: Initial dose 5 mcg SC twice daily,
titrated to 10 mcg twice daily in 1 month if needed and as tolerated. Inject 0 to 60 minutes before
morning and evening meals.

✓Bydureon: Extended-release product administered as 2 mg SC once weekly at any time of

day, with or without meals.
The most common adverse effects are nausea, vomiting, and diarrhea. Injection site reactions
(nodules, erythema) may occur with extended-release product.
• Liraglutide (Victoza) has pharmacologic and adverse effects similar to exenatide. Longer half-
life permits once-daily dosing. Average A1C reduction is ~1.1%, and liraglutide lowers FPG and
postprandial glucose levels by 25 to 40 mg/dL (1.4–2.2 mmol/L).
Dosing: Begin with 0.6 mg SC once daily (independent of meals) for at least 1 week, then
increase to 1.2 mg daily for at least 1 week. If necessary, increase to maximum dose of 1.8 mg
daily after at least 1 week.

Amylinomimetic
• Pramlintide (Symlin) suppresses inappropriately high postprandial glucagon secretion,
decreases prandial glucose excursions, increases satiety, and slows gastric emptying. It has
little effect on FPG. Average A1C reduction is ~0.6%, but optimizing concurrent insulin may
further decrease A1C.
If a prandial insulin dose is used, reduce it by 30% to 50% when pramlintide is started to
minimize severe hypoglycemia. In type 2 DM, starting dose is 60 mcg SC prior to major meals;
titrate up to 120 mcg per dose as tolerated and as warranted based on postprandial plasma
glucose levels. In type 1 DM, start with 15 mcg prior to each meal, titrating up in 15 mcg
increments to maximum 60 mcg prior to each meal if tolerated and warranted.

Sulfonylureas
• Sulfonylureas exert hypoglycemic action by stimulating pancreatic secretion of insulin. All
sulfonylureas are equally effective in lowering blood glucose when administered in equipotent
doses. On average, the A1C falls by 1.5% to 2% with FPG reductions of 60 to 70 mg/dL (3.3–3.9
mmol/L)
• The most common side effect is hypoglycemia, which is more problematic with long half-life
drugs.
• Recommended starting doses (Table 19–4) should be reduced in elderly patients who may
have compromised renal or hepatic function. Dosage can be titrated as soon as every 2 weeks
(longer interval with chlorpropamide) to achieve glycemic goals.

Short-acting Insulin Secretagogues (Meglitinides)

• Similar to sulfonylureas, meglitinides lower glucose by stimulating pancreatic insulin
secretion, but insulin release is glucose dependent and diminishes at low blood glucose
concentrations.
Hypoglycemic risk appears to be less with meglitinides than with sulfonylureas. Average A1C
reduction is 0.8% to 1%. These agents can be used to provide increased insulin secretion during
meals (when needed) in patients who are close to glycemic goals.
They should be administered before each meal (up to 30 minutes prior). If a meal is skipped, the
medication should also be skipped.

✓ Repaglinide (Prandin): Start with 0.5 to 2 mg orally with maximum 4 mg per meal (up to four
meals daily or 16 mg/day).

✓ Nateglinide (Starlix): 120 mg orally three times daily before each meal. Initial dose may be
lowered to 60 mg per meal in patients who are near goal A1C.

Biguanides
• Metformin enhances insulin sensitivity of hepatic and peripheral (muscle) tissues, allowing for
increased glucose uptake. It reduces A1C levels by 1.5% to 2%, FPG levels by 60 to 80 mg/dL
(3.3–4.4 mmol/L), and retains ability to reduce FPG levels when very high (>300 mg/dL or >16.7
mmol/L).
• Metformin is logical in overweight/obese type 2 DM patients (if tolerated and not
contraindicated) because it is the only oral antihyperglycemic medication shown to reduce the
risk of total mortality.

✓ Metformin immediate-release: Start at 500 mg orally twice daily with the largest meals and
increase by 500 mg weekly as tolerated until reaching glycemic goals or 2500 mg/day.
Metformin 850 mg can be dosed once daily and then increased every 1 to 2 weeks to maximum
850 mg three times daily (2550 mg/day).

✓ Metformin extended-release (Glucophage XR): Start with 500 mg orally with the evening meal
and increase by 500 mg weekly as tolerated to maximum single evening dose of 2000 mg/day.
Administration two or three times daily may reduce GI side effects and improve glycemic
control. The 750 mg tablets can be titrated weekly to maximum dose of 2250 mg/day.

Thiazolidinediones (Glitazones)
• These agents enhance insulin sensitivity in muscle, liver, and fat tissues indirectly. Insulin must
be present in significant quantities. When given for 6 months at maximal doses, pioglitazone and
rosiglitazone reduce A1C by ~1.5% and FPG by 60 to 70 mg/dL (3.3–3.9 mmol/L).

✓ Pioglitazone (Actos): Start at 15 mg orally once daily; maximum dose 45 mg/day.

✓ Rosiglitazone (Avandia): Initiate with 2 to 4 mg orally once daily; maximum dose 8 mg/day.
A dose of 4 mg twice daily can reduce A1C by 0.2% to 0.3% more than 8 mg taken once daily.

α-Glucosidase Inhibitors
• These agents prevent breakdown of sucrose and complex carbohydrates in the small intestine,
prolonging carbohydrate absorption. Net effect is reduction in postprandial glucose (40–50
mg/dL; 2.2–2.8 mmol/L) with relatively unchanged FBG (~10% reduction). Efficacy is modest,
with average A1C reduction 0.3% to 1%

✓ Acarbose (Precose) and miglitol (Glyset): Initiate therapy with very low dose (25 mg orally
with one meal a day) and increase very gradually (over several months) to maximum 50 mg
three times daily for patients weighing 60 kg or more, or 100 mg three times daily for patients
above 60 kg. The drugs should be taken with the first bite of the meal so the drug is present to
inhibit enzyme activity.

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

• DPP-4 inhibitors partially reduce the inappropriately elevated glucagon postprandially and
stimulate glucose-dependent insulin secretion. Average A1C reduction 0.7% to 1% at maximum
dose.

✓ Sitagliptin (Januvia): Usual dose 100 mg orally once daily. Use 50 mg daily if CLcr 30 to 50
mL/min and 25 mg daily if CLcr less than 30 mL/min.

✓ Saxagliptin (Onglyza): Usual dose 5 mg orally daily. Reduce to 2.5 mg daily if CLcr less than
50 mL/min or strong CYP-3A4/5 inhibitors are used concurrently.

✓ Linagliptin (Tradjenta): 5 mg orally daily; dose adjustment not required in renal

insufficiency or with concomitant drug therapy.

✓ Alogliptin (Nesina): Usual dose 25 mg once daily. Decrease to 12.5 mg daily when CLcr less
than 60 mL/min and 6.25 mg when CLcr less than 30 mL/min.

Bile Acid Sequestrants

• Colesevelam (Welchol) binds bile acid in the intestinal lumen, decreasing the bile acid pool
for reabsorption. Its mechanism in lowering plasma glucose levels is unknown.
• Colesevelam dose for type 2 DM is six 625-mg tablets daily (total 3.75 g/day); may split into
three tablets twice daily if desired. Administer each dose with meals because colesevelam binds
to bile released during the meal.