Module 3
Diabetes Assignment
a. Epidemiology
The vast majority of patients with DM are classified into one of two broad
categories: type 1 DM and type 2 DM.3 Patients with type 1 DM have an absolute
insulin deficiency. Patients with type 2 DM have varying degrees of β-cell
dysfunction often coupled with insulin resistance. Women who develop diabetes
during pregnancy are classified as having gestational diabetes (GDM). Less common
types of diabetes are caused by genetic defects, pancreatic destruction, endocrine
disorders, and medications.
Type 1 DM accounts for 5% to 10% of all cases of DM and is most often due
to autoimmune destruction of the pancreatic β-cells.5 The prevalence of β-cell
autoimmunity in a population is directly related to the incidence of type 1 DM. For
example, in Sweden and Finland 3% to 4.5% of the population have circulating islet
cell autoantibodies (ICAs) and this is associated with the highest incidence of type 1
DM in the world: 22 to 35 per 100,000 people. The worldwide prevalence of type 1
DM is increasing but the cause is not fully understood.6 Markers of β-cell
autoimmunity can be found in many adults with diabetes.5 A variant of type 1 DM is
called latent autoimmune diabetes of adults (LADA). These patients often have a poor
response to oral agents and require insulin therapy much sooner than most patients
with type 2 DM.
Idiopathic type 1 diabetes mellitus (DM) is a nonautoimmune variant of
diabetes that presents with unique clinical features distinguishing it from the more
commonly recognized autoimmune type 1 diabetes. Unlike typical type 1 diabetes,
which involves an autoimmune attack on pancreatic beta cells, idiopathic type 1 DM
does not exhibit the autoimmune markers usually associated with the disease. This
form of diabetes is characterized by its unpredictable and fluctuating nature, with
patients experiencing periods of significant hyperglycemia that require careful
monitoring and management.
One of the notable aspects of idiopathic type 1 DM is its demographic
prevalence. It is frequently observed in individuals of African and Asian descent,
suggesting potential genetic or environmental factors contributing to its development.
Despite extensive research, the precise mechanisms underlying this form of diabetes
remain unclear, hence the term "idiopathic," meaning of unknown origin. Patients
with idiopathic type 1 DM often present with episodes of extreme hyperglycemia,
where blood glucose levels rise to dangerously high levels. These hyperglycemic
episodes necessitate medical intervention to stabilize the patient's condition and
prevent acute complications such as diabetic ketoacidosis, a life-threatening state
resulting from the buildup of ketones in the blood due to insufficient insulin.
A distinctive feature of idiopathic type 1 DM is its intermittent requirement for
insulin therapy. Unlike typical type 1 diabetes patients, who require continuous
insulin administration to manage their blood glucose levels, those with idiopathic type
1 DM may only need insulin during periods of hyperglycemia. Between these
episodes, their pancreatic function can be sufficient to maintain relatively normal
blood glucose levels, reducing or eliminating the need for insulin therapy. This
intermittent insulin dependency can pose challenges for both patients and healthcare
providers, as the management of the disease requires careful adjustment of treatment
plans based on the patient's fluctuating insulin needs.
The episodic nature of idiopathic type 1 DM means that patients must remain
vigilant about monitoring their blood glucose levels. Regular self-monitoring and
frequent consultations with healthcare providers are essential to identify and respond
to hyperglycemic episodes promptly. Additionally, patients need to be educated about
recognizing the signs and symptoms of hyperglycemia and hypoglycemia to take
appropriate action swiftly. Lifestyle modifications, including dietary adjustments and
regular physical activity, can also play a crucial role in managing the condition and
minimizing the frequency and severity of hyperglycemic episodes.
In summary, idiopathic type 1 diabetes mellitus is a unique and complex form
of diabetes primarily affecting individuals of African and Asian descent. It is
characterized by nonautoimmune mechanisms, unpredictable periods of profound
hyperglycemia, and an intermittent need for insulin therapy. Understanding and
managing this condition requires a tailored approach, continuous monitoring, and
patient education to effectively navigate its challenges and maintain optimal glycemic
control.
Type 2 DM accounts for 90% to 95% of all cases of DM. The prevalence of
type 2 DM in the United States is about 12.1% in adults and is increasing.2 The risk
of developing type 2 DM increases with age and varies widely among racial and
ethnic groups.7 When compared to people of European ancestry, Native Americans,
Latino/Hispanic Americans, African Americans, Asian Americans, and Pacific
Islanders are more likely to develop type 2 DM. While the prevalence of type 2 DM
increases with age, the disorder is increasingly being diagnosed in adolescence and
young adulthood. This is likely due to the increasing incidence of obesity and lack of
regular physical activity. Genetics play an important role in the development of type 2
DM. Most cases of type 2 DM appear to be polygenic.
The incidence of GDM is increasing and, between 2007 and 2010, it was
estimated to occur in 9% of all pregnancies in the United States.8 Most women
become normoglycemic after pregnancy; however, up to 50% of these women
develop type 2 DM later in life.9 Other less common (1%-2%) forms of DM occur
through a variety of mechanisms.3 Maturity-onset diabetes of the young (MODY) and
neonatal diabetes are inheritable forms of DM caused by specific single-gene
mutations. Endocrine disorders, particularly acromegaly and Cushing syndrome,
commonly induce hyperglycemia.
Diseases that injure or destroy the pancreas, such as cystic fibrosis, chronic
pancreatitis, and pancreatic cancer, can have profound impacts on the endocrine
functions of this vital organ. Specifically, these conditions can damage the β-cells
located in the islets of Langerhans, which are responsible for the production and
secretion of insulin. Insulin is a crucial hormone that regulates blood glucose levels by
facilitating the uptake of glucose into cells for energy production and storage. When
the β-cells are damaged or destroyed, insulin secretion is impaired, leading to
dysregulation of blood glucose levels and subsequent hyperglycemia.
Cystic fibrosis is a genetic disorder that primarily affects the respiratory and
digestive systems, but it also has significant effects on the pancreas. The thick and
sticky mucus characteristic of cystic fibrosis can obstruct the pancreatic ducts, leading
to inflammation and fibrosis. Over time, this can result in the destruction of the
pancreatic tissue, including the insulin-producing β-cells. Consequently, individuals
with cystic fibrosis are at an increased risk of developing cystic fibrosis-related
diabetes (CFRD), which combines elements of both type 1 and type 2 diabetes due to
the mixed nature of insulin deficiency and insulin resistance.
Chronic pancreatitis, characterized by persistent inflammation of the pancreas,
is another condition that can severely affect pancreatic function. Repeated episodes of
inflammation lead to progressive scarring and destruction of the pancreatic tissue,
including the β-cells. This results in a gradual decline in insulin production,
contributing to chronic hyperglycemia. The management of diabetes secondary to
chronic pancreatitis often involves complex therapeutic strategies, including insulin
therapy and lifestyle modifications, to control blood glucose levels effectively.
Pancreatic cancer, particularly adenocarcinoma, can also lead to significant β-
cell destruction. The malignancy can directly invade the pancreatic tissue, disrupting
normal cellular architecture and function. Additionally, surgical treatments for
pancreatic cancer, such as partial or total pancreatectomy, can result in the removal of
a substantial portion of the insulin-producing cells, necessitating lifelong insulin
therapy for the management of diabetes. The relationship between pancreatic cancer
and diabetes is bidirectional, as diabetes can be both a risk factor for and a
consequence of pancreatic cancer, complicating the clinical picture.
In addition to these diseases, several medications are known to contribute to
hyperglycemia by impairing insulin secretion, increasing insulin resistance, or both.
For example, glucocorticoids, commonly used to treat inflammatory conditions, can
induce hyperglycemia by increasing hepatic glucose production and reducing
peripheral glucose uptake, thereby increasing insulin resistance. Thiazide diuretics,
often prescribed for hypertension, can also impair insulin secretion and action,
exacerbating hyperglycemia. Certain antipsychotic medications, particularly atypical
antipsychotics like olanzapine and clozapine, are associated with significant weight
gain and insulin resistance, further contributing to hyperglycemia.
Other drugs, such as protease inhibitors used in the treatment of HIV, can also
impair glucose metabolism. These medications may increase insulin resistance by
altering the distribution of body fat and by direct effects on insulin signaling
pathways. Similarly, immunosuppressive agents like cyclosporine and tacrolimus,
used to prevent organ transplant rejection, can impair insulin secretion and promote
hyperglycemia.
The complex interplay between pancreatic diseases, medication-induced
hyperglycemia, and the resulting impairment of insulin secretion highlights the need
for comprehensive and individualized approaches to diabetes management. Patients
with these conditions require regular monitoring of blood glucose levels, tailored
therapeutic regimens, and continuous education to effectively manage their diabetes
and prevent complications.
b. Etiology and Pathophysiology
Diabetes mellitus is caused by derangements in the secretion of insulin,
glucagon, and other hormones and results in abnormal carbohydrate and fat
metabolism.5,7 This is often coupled with insulin resistance, particularly in those with
type 2 DM. In many cases, the underlying etiology of the disorder is complex and
poorly understood. After consuming food, carbohydrate ingestion increases the
plasma glucose concentration and stimulates the release of incretin hormones from the
gut and insulin release from the pancreatic β-cells.7 The resultant hyperinsulinemia
(1) suppresses hepatic glucose production, (2) suppresses glucagon release, and (3)
triggers glucose uptake by peripheral tissues. Upwards of 75% of total body glucose
disposal occurs in tissues, including the brain and peripheral nerves, which 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, tissues that require insulin to promote glucose uptake into the cells. During
periods of fasting, approximately 85% of glucose is produced by the liver and the
remainder by the kidney.
Although fat tissue is responsible for only a small portion of total body
glucose disposal, it plays an important role in glucose homeostasis.7 Insulin exerts a
potent antilipolytic effect, reducing plasma-free fatty acid (FFA) levels. Increased
levels of FFAs inhibit the uptake of glucose by muscle and stimulate hepatic
gluconeogenesis. Lower FFA concentrations result in an increased glucose uptake in
muscle and indirectly reduce hepatic glucose production. Glucagon is produced by
pancreatic α cells and is secreted in the fasting state.7 Glucagon stimulates hepatic
glucose production and glycogenolysis. Glucagon and insulin secretion are closely
linked. Appropriate secretion of both hormones is needed to keep plasma glucose
concentrations within a normal range.
Formerly called insulin-dependent diabetes, type 1 DM is the result of
autoimmune destruction of the β-cells of the pancreas.5 Type 1 DM is believed to be
initiated by exposure to an environmental trigger in a genetically susceptible
individual.10 There is a link between currently known genetic markers for
autoimmunity and the development of type 1 DM. However, β-cell autoimmunity
develops in less than 10% of the genetically susceptible individuals and progresses to
type 1 DM in less than 1%. On the other hand, β-cell autoimmunity, including ICAs,
is present at the time of diagnosis in 90% of individuals. Type 1 diabetes most
commonly develops in childhood or young adulthood; however, it can occur at any
age. Children and adolescents typically have a more rapid rate of β-cell destruction
and are more likely to present with DKA. Adults may maintain sufficient insulin
secretion to prevent ketoacidosis for many months or years; this slowly progressive
form of type 1 DM is sometimes referred to as LADA. Several genetic
polymorphisms have been linked to the development of type 1 DM including certain
human leukocyte antigens (HLA) class II alleles on chromosome 6.
Some genetic variants are associated with a higher risk of developing type 1
DM (eg, DRB1*03- DQB1*0201, DRB1*04-DQB1*302, and HLA-B*39) but others
appear to be protective (eg, DRB1*1501-DQA1*0102-DQB1*0602). Genetic
predisposition to the development of type 1 DM has also been associated with certain
polymorphisms in the insulin gene region on chromosome 11. Other genes including
PTPN22, IL2RA, and CTLA-4 may also play a role in some individuals. However, it
should be noted that genetic markers are present in only 30% to 50% of patients with
type 1 DM. Moreover, only 50% of monozygotic twins and approximately 10% of
dizygotic twins develop type 1 DM. Thus, genetic mutations alone do not predict or
explain the etiology of the disease.
In order for type 1 DM to develop, a genetically susceptible individual must be
exposed to a trigger that initiates the autoimmune process and destruction of
pancreatic β-cells. However, it is unknown precisely what the inciting factors are.
Several triggers have been implicated, including early exposure to cow’s milk, lack of
breastfeeding, gut bacteria (ie, intestinal microbiome), and certain viruses (eg,
enterovirus and rotavirus). Although vitamin D deficiency is more prevalent in
patients who develop type 1 DM, it is unclear if the relationship is causal or merely an
association. 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 1 DM is the islet
cell autoantibodies (ICAs). Other antibodies may be formed to insulin, glutamic acid
decarboxylase 65 (GAD65), insulinoma-associated antigen-2 (IA-2), and zinc
transporter 8 (ZnT8). These antibodies are generally considered markers of disease
rather than mediators of β-cell destruction. These markers have been used to identify
individuals at risk for type 1 DM and may be useful screening tests to initiate disease
prevention strategies. Other autoimmune disorders such as Hashimoto’s thyroiditis,
Graves’ disease, Addison’s disease, vitiligo, and celiac sprue are more common in
patients with type 1 DM.
In many patients who develop type 1 DM there is a long preclinical period
during which markers of autoimmunity can be detected.10 β-Cell autoimmunity may
precede the diagnosis of type 1 DM by up to 13 years. Autoimmunity remits in some
individuals or progresses to absolute β-cell failure in others. Hyperglycemia occurs
when 60% to 90% of the β-cells have been destroyed. After the initial diagnosis, there
is occasionally a period of transient remission called the “honeymoon” phase during
which insulin doses can be reduced or withdrawn before continued β-cell destruction
requires lifelong insulin replacement therapy. Amylin is a hormone that is co-secreted
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.
Erroneously called noninsulin-dependent diabetes or adult-onset diabetes, type
2 DM is the result of β-cell dysfunction coupled with some degree of insulin
resistance.7 Over time, there is a progressive loss of β-cells. Most individuals with
type 2 DM are overweight or obese. Abdominal adiposity is a major contributor to
insulin resistance. Genetics play a critical role in the development of type 2 DM as
there is a strong inheritance pattern. Hundreds of gene mutations have been linked to
the development of type 2 DM. The majority of genetic mutations associated with
type 2 DM appear to influence the development and function of β-cells, the sensitivity
of cells to insulin action, or the development of obesity. However, none of these
single-gene mutations have demonstrated a strong association with type 2 DM. Thus,
type 2 DM is likely polygenetic, with more than one genetic defect contributing to its
pathogenesis and a diverse combination of derangements contributing to its
development in different populations.
Most patients who develop type 2 DM have multiple defects that impact the
regulation of plasma glucose: (1) impaired insulin secretion; (2) deficiency and
resistance to incretin hormones; (3) insulin resistance involving muscle, liver, and
adipocytes; (4) excess glucagon secretion; (5) increased hepatic glucose production;
(6) upregulation of the sodium-glucose cotransporter in the kidney; (7) systemic
inflammation; and (8) diminished satiety. The pancreas in people with normal-
functioning β-cells is able to adjust insulin secretion to maintain normal plasma
glucose levels. In nondiabetic, obese individuals, insulin increases in proportion to the
severity of the insulin resistance and plasma glucose remains normal. Impaired insulin
secretion is therefore requisite for the development of type 2 DM. In the early stages
of β-cell dysfunction, first-phase insulin release is deficient, resulting in impaired
glucose tolerance (IGT). First-phase insulin involves the release of stored insulin in
the β-cell and acts to “prime” the liver for nutrient intake. Without appropriate first-
phase insulin release, second-phase insulin must compensate for the subsequent
postprandial carbohydrate load in order to normalize glucose levels.
When insulin release is no longer sufficient to normalize plasma glucose,
dysglycemia, including prediabetes and diabetes, ensue. In patients with type 2 DM,
β-cell mass and function are both reduced. β-cell failure is progressive, starting years
prior to the diagnosis of diabetes. People with type 2 DM lose approximately 5% to
7% of β-cell function per year. Progressive β-cell loss is likely the results of several
factors, including (1) glucotoxicity; (2) lipotoxicity; (3) insulin resistance; (4) age; (5)
genetics; and (6) incretin deficiency. 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
In patients with type 2 DM, decreased postprandial insulin secretion is a result
of both impaired pancreatic β-cell function and diminished stimulus from gut
hormones.7 The role gut hormones play in insulin secretion is best shown by
comparing the response to an oral glucose load versus an intravenous (IV) glucose
infusion. In Decreased incretin effect GLP1 RA TZDs SGLT2 inhibitor TZDs
Increased glucose reabsorption Increased lipolysis GLP1 RA DPP4 inhibitor
Hyperglycaemia Neurotransmitter dysfunction Increased hepatic glucose production
TZDs Metformin GLP1 RA DPP4 inhibitor GLP1 RA Inflammation Decreased
glucose uptake IκB–NF-κB TLR4 MAPK AMPK TNF ROS Macrophages Increased
glucagon secretion α-cell Decreased insulin secretion β-cell SU GLP1 RA DPP4
inhibitor Islet Pathophysiology of type 2 diabetes mellitus. Multiple defects known as
the ominous octet. (Reproduced, with permission, from Defronzo RA. Banting
Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment
of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-95.) individuals who do not
have diabetes, 73% more insulin is released in response to an oral glucose load
compared to IV glucose 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 prompt first-phase insulin secretion.
In patients with type 2 patients, this “incretin effect” is blunted. Insulin secretion is
nearly half of that seen in individuals without diabetes. Two hormones, glucagon-like
peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are
responsible for over 90% of the increased insulin secretion in response to a meal. As
patients progress from normoglycemia to type 2 DM, GLP-1 levels decrease as
glucose values increase. Patients with type 2 DM remain sensitive to GLP-1 but GIP
levels are normal or elevated in type 2 DM, which suggests that some individuals may
be resistant to its effect.
GLP-1 is secreted from the L-cells, found in the distal intestinal and colon
mucosa, in response to mixed meals.12 Since GLP-1 concentrations rise within
minutes of food ingestion, neural signals and possibly proximal gastrointestinal (GI)
tract receptors stimulate GLP-1 secretion. The insulinotropic action of GLP-1 is
glucose dependent, enhancing insulin secretion only when glucose concentrations are
higher than 90 mg/dL (5.0 mmol/L). In addition to stimulating insulin secretion, GLP-
1 suppresses glucagon secretion, slows gastric emptying, and increases satiety thereby
reducing food intake. These effects combine to limit PPG excursions. GIP is secreted
by K-cells in the intestine and may have a role with insulin secretion when glucose
levels are near normal. GIP may also act as an insulin sensitizer in adipocytes.
However, GIP has no effect on glucagon secretion, gastric motility, or satiety. While
GLP-1 deficiency is common in patients with type 2 DM, it is unlikely to be a
primary defect.
A small percentage of patients have the transcription factor 7-like 2 (TCF7L2)
gene defect, which is associated with decreased β-cell response to GLP-1 and likely
contributes to their risk of developing diabetes. GLP-1 and GIP are rapidly inactivated
by dipeptidyl peptidase-4 (DPP-4), an enzyme that removes two N-terminal amino
acids, and their half-lives are less than 10 minutes. Resistance to the actions of insulin
in the liver contributes significantly to excess hepatic glucose production.7 In 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, the liver of an 80-kg person with diabetes produces an
extra 35 g of glucose overnight and causes fasting hyperglycemia. In addition, the
liver inappropriately continues hepatic glucose output after consuming a meal.
Therefore, patients with type 2 DM have two sources of glucose in the postprandial
state, one from the diet and the other from continued glucose production from the
liver.
Peripheral skeletal muscle is a major site for PPG disposal.7 In response to a
physiologic increase in plasma insulin concentration, glucose uptake in to muscle
increases linearly, plateauing at 10 mg/ kg/min. In patients with type 2 DM, the onset
of insulin action in muscle is delayed and glucose uptake in leg muscle is reduced by
50%. Impaired intracellular insulin signaling (eg, the secondary messenger system) is
abnormal in patients with type 2 DM with impairments at almost every step of
activation due to insulin resistance, lipotoxicity, and glucotoxicity. The compensatory
hyperinsulinemia required to overcome impaired insulin signaling can activate an
alternative pathway through MAP kinase, which accelerates atherosclerosis.
Mitochondrial dysfunction may also play a role in insulin resistance in muscle tissue.
Mitochondrial function and density are lower in type 2 DM.
In patients with type 2 DM, fasting plasma FFA levels are elevated and fail to
normalize after carbohydrate ingestion.7 FFAs are stored as triglycerides in
adipocytes and serve as an important energy source during fasting. Insulin is a potent
inhibitor of lipolysis and restrains the release of FFAs from the adipocyte by
inhibiting the lipase enzyme. Chronically elevated plasma FFA concentrations can
impair insulin secretion and lead to insulin resistance in muscle and liver. FFA
products interfere with multiple steps in the insulinsignaling cascade as well as
increase β-cell apoptosis. In addition to elevated FFAs, patients with type 2 DM have
increased stores of intracellular fat in the muscle and liver. This increased fat content
correlates closely with the presence of insulin resistance in these tissues. Excess
lipolysis from fat can contribute to gluconeogenesis indirectly through glycerol and
FFA substrate use as well as increase a number of proinflammatory cytokines.
Weight gain leads to insulin resistance in most individuals, but not all. The
term visceral adipose tissue (VAT) refers to fat cells located within the abdominal
cavity and includes omental, mesenteric, retroperitoneal, and perinephric adipose
tissue. VAT closely correlates with insulin resistance and fat distribution, rather than
obesity per se, and likely explains the variable degree of insulin resistance seen in
obese individuals.7 VAT represents 20% of fat in men and 6% of fat in women.
Central obesity can easily be assessed using waist circumference, which is a good
surrogate marker for VAT. VAT has a higher rate of lipolysis than subcutaneous fat,
resulting in an increase in FFA production. These fatty acids are released into the
portal circulation and drain into the liver, where they stimulate the production of very-
low-density lipoproteins. They also increase the risk for developing nonalcoholic fatty
liver disease. VAT also produces a number of adipocytokines, such as tissue necrosis
factor-α, interleukin 6, angiotensinogen, PAI-1, and resistin—all of which contribute
to insulin resistance, hypertension, and hypercoagulability.7 Fat cells also produce
adiponectin—a adipocytokine that improves insulin sensitivity. Adiponectin decreases
hepatic glucose production and increases fatty acid oxidation in muscle.
Unfortunately, adiponectin concentrations are inversely related to the amount of VAT.
Type 2 DM patients fail to suppress glucagon in response to a meal and may even
have a paradoxical rise in glucagon levels.7 Several factors contribute: (1) GLP-1
resistance/deficiency, (2) insulin resistance, and (3) insulin deficiency.
Ordinarily, postmeal increases in GLP-1 and insulin would suppress glucagon
secretion. Thus, hyperglucagonemia further contributes to excessive production of
glucose by the liver. Ninety percent of filtered glucose is reabsorbed in the kidney by
sodium glucose cotransporter-2 (SGLT-2), a high-capacity, lowaffinity transporter in
the proximal renal tubular cells.13 The remaining 10% is reabsorbed by sodium
glucose cotransporter-1 (SGLT-1). In normal healthy people, the renal threshold for
glucosuria is at a plasma glucose value of approximately 180 mg/dL (10.0 mmol/L).
In patients with diabetes, the renal threshold is increased to 220 to 240 mg/dL (12.2-
13.3 mmol/L) before glucosuria occurs. The reason for the more active reabsorption
of glucose by proximal renal tubular cells is likely due to an increased expression of
SGLT-2 receptors. Increased reabsorption of glucose in the kidneys further contributes
to hyperglycemia.
GDM develops during pregnancy. If DM is diagnosed prior to pregnancy, this
is not GDM, but rather pregnancy with pre-existing DM. Hormone changes during
pregnancy result in increased insulin resistance, and GDM may ensue if the mother
cannot increase insulin secretion to adequately compensate to maintain
normoglycemia. Women who develop GDM are predisposed to subsequently
developing type 2 DM. GDM and type 2 DM likely share much of the same
etiological causes. In most cases, glucose intolerance first appears near the beginning
of the third trimester. However, risk assessment and intervention should begin from
the first prenatal visit. Detection is important, as therapy will reduce perinatal
morbidity and mortality.
Maturity onset diabetes of youth (MODY) is characterized by impaired insulin
secretion in response to a glucose stimulus with minimal or no insulin resistance.3
Patients typically exhibit mild hyperglycemia at an early age and diagnosis is often
delayed. The disease is inherited in an autosomal-dominant pattern with at least six
different mutations identified to date. MODY 2 and 3 are most common. The
production of mutant insulin molecules has been identified in a few families and also
results in abnormal glucose intolerance. Several genetic mutations have been
described in the insulin receptor and are associated with insulin resistance. Type A
insulin resistance is a clinical syndrome characterized by acanthosis nigricans,
virilization in women, polycystic ovaries, and hyperinsulinemia. Anti-insulin receptor
antibodies may block the binding of insulin. This has been referred to as type B
insulin resistance.
c. Clinical Presentation
The clinical presentation and features of type 1 DM and type 2 DM are
different. Although type 1 DM can develop at any age, most patients are diagnosed
before the age of 20. Patients with type 1 DM are often lean or thin at the time of
diagnosis. In the absence of an adequate supply of insulin, patients with type 1 DM
are prone to developing ketoacidosis and many initially present with DKA. Patients
with type 1 DM often have symptoms in the days or weeks preceding the diagnosis.
These symptoms often include frequent urination (polyuria) due to an osmotic
diuresis from glucosuria, excessive thirst (polydipsia) due to dehydration, increased
appetite (polyphagia) and weight loss due to caloric loss. Fatigue and lethargy are also
common.
The onset of symptoms can be triggered by an infection, trauma, or
psychological stress. In contrast, a majority of patients with type 2 DM are
asymptomatic or have only mild fatigue at the time of diagnosis. Many patients are
incidentally discovered to have type 2 DM based on the results of a routine laboratory
test (eg, plasma glucose or A1C) or development of complications (eg, myocardial
infarction, stroke, renal impairment). Mild hyperglycemia is likely present for many
years prior to the diagnosis and thus explains why both microvascular and
macrovascular complications are often present at the time of diagnosis. Most patients
with type 2 DM are overweight or obese with an elevated waist:hip ratio. Many will
report having first-degree relatives with diabetes.
The diagnosis of diabetes requires the use of glycemic cut points that
discriminate patients with normal BG from patients with impaired fasting glucose,
impaired glucose tolerance, and diabetes. Current diagnostic criteria are slightly above
these cut points. The cut points are meant to reflect the level of glucose above which
microvascular complications have been shown to increase. Cross-sectional studies
have shown a consistent increase in the risk of developing retinopathy at an FPG level
above 99 to 116 mg/dL (5.5-6.4 mmol/L), at a 2-hour PPG level above 125 to 185
mg/dL (6.9-10.3 mmol/L), and an A1C above 5.9 to 6.0% (0.059-0.060; 41-42
mmol/mol Hb).
If a National Glycohemoglobin Standardization Program method is used, the
A1C is the logical test for the diagnosis of diabetes as it measures glycemic exposure
over the last 2 to 3 months, in contrast to a single-day, single-point glucose
measurement. In addition, patients do not need to fast and the A1C is a readily
available test. An A1C of 6.0% to 6.4% (0.06-0.064; 42-46 mmol/mol Hb) denotes a
10-fold increase in risk of developing diabetes, but does not consistently identify
patients with impaired fasting glucose or impaired glucose tolerance. There are slight
racial differences in normal A1C levels. One-third fewer individuals with diabetes are
identified using the A1C ≥ 6.5% (0.065; 48 mmol/mol Hb) threshold versus an FPG ≥
126 mg/dL (7.0 mmol/L), yet providers may be more likely to diagnose diabetes from
an A1C than from an elevated FPG level.
The ADA continues to recommend three other glucose criteria for the
diagnosis of diabetes mellitus in nonpregnant adults. If the patient has symptomatic
hyperglycemia, reconfirming the diagnosis is not required. Serial measurements, at
clinician-defined intervals, can help to identify patients moving toward diabetes and
those who are stable. Patients who have even minor increases in glucose or A1C
values over time should be followed closely as these are likely the patients who will
progress to DM. The A1C measurement can be affected by anemias and several
hemoglobinopathies, which would necessitate the use of one of the plasma glucose
criteria in these individuals.
Given the long-term complications associated with DM and the potential
impact that early interventions can have on worsening hyperglycemia and outcomes,
efforts to screen at-risk patients for impaired FPG and the development of diabetes are
recommended. Screening begins with identifying patients who are at-risk for
developing diabetes and, once identified, encouraging patients to obtain an FPG and
A1C measurement to determine if the patient has hyperglycemia.
The prevalence of type 1 DM is low in the general population. Due to the
acute onset of symptoms in most individuals, screening for type 1 DM in the
asymptomatic children or adults is not recommended.3 Screening for β-cell
autoantibody status in high-risk family members may be appropriate. However, such
screening is only recommended in the context of clinical research trials for the
prevention of type 1 DM.
The ADA recommends screening for type 2 DM in asymptomatic adults who
are overweight (BMI ≥ 25 kg/m2 or ≥23 kg/m2 in AsianAmericans) and have at least
one other risk factor for the development of type 2 DM. The risk of type 2 DM
increases with age, and all adults, even those without risk factors, should be screened
every 3 years starting at 45 years old. The recommended screening tests are an FPG,
A1C, or 2-hour oral glucose tolerance test (OGTT). The optimal time between
screening tests is not known and it may be prudent to screen patients with multiple
risk factors every year.
Despite a lack of clinical evidence to support widespread testing of children
for type 2 DM, it is clear that more children and adolescents are developing type 2
DM. The ADA recommends screening overweight (defined as BMI >85th percentile
for age and sex, weight for height >85th percentile, or weight >120% of ideal) youths
who have at least one of the following risk factors: a family history of type 2 DM in
first- and second-degree relatives; Native Americans, African Americans, Hispanic
Americans, and Asians/South Pacific Islanders; those with signs or conditions
associated with insulin resistance (eg, acanthosis nigricans, hypertension,
dyslipidemia); or a maternal history of diabetes or GDM during the child’s gestation.3
Screening should be done every 3 years starting at age 10 years or at the onset of
puberty if it occurs at a younger age.
Risk assessment for GDM should occur at the first prenatal visit. Due to the
high prevalence of obesity and undiagnosed DM, women with multiple risk factors
for type 2 DM should be tested as soon as feasible.3 All women, even if the initial
screen test at the first prenatal visit was negative, should undergo testing at 24 to 28
weeks’ gestation. Screening for GDM may be done in one of two ways: (1) a one-step
strategy using a fasting 75-g OGTT, or (2) a two-step strategy starting with a
nonfasting 50-g glucose load test (GLT). With the standard 75-g OGTT, the diagnosis
of GDM is confirmed when fasting, 1-hour, 2-hour, and/or 3-hour glucose values are
greater or equal to cut-off values. If a nonfasting 50-g GLT is performed, a fasting
100-g glucose tolerance test must be performed if the 1-hour value is elevated.
d. General Treatment Approach
During an initial visit, a complete medical evaluation should be completed to
confirm the diagnosis, classify the type of diabetes, evaluate for any complications or
potential comorbid conditions, and review previous treatments and risk factors in
established patients. Past medical, family, and social history should be taken as well
as medication use, adherence, tolerability, and use of diabetes technology. Screening
for psychosocial conditions, self-management education needs, and hypoglycemia
should occur. A thorough physical exam (including height, weight, BMI, blood
pressure, thyroid palpitation, and foot exam) and laboratory evaluation (including
A1C, lipid profile, liver function tests, serum creatinine, and eGFR) should be
performed. A 10-year ASCVD risk score should also be calculated.
The primary goals of therapy for DM are to prevent or delay the progression
of long-term micro- and macrovascular complications including retinopathy,
neuropathy, diabetic kidney disease, and ASCVD. Additional goals of therapy are to
alleviate symptoms of hyperglycemia, minimize hypoglycemia and other adverse
effects, minimize treatment burden, and maintain quality of life. This requires
glycemic control as well as control of comorbidities and CV risk factors. Glycemic
control has demonstrated benefit at reducing long-term complications, but overly
intensive control has also led to poor outcomes. Thus, glycemic targets should be
individualized for each patient and should be based on balanced considerations of
clinical trial evidence and patient-specific factors.
The first trial to evaluate whether good glycemic control could prevent or
delay diabetes-related complications was the Diabetes Complications and Control
Trial (DCCT) which was performed in patients with type 1 DM.18 Patients in the
study group were treated with intensive therapy—three or more injections of insulin
daily or insulin pump, with frequent alterations of insulin therapy based on self-
monitoring of blood glucose (SMBG) results plus frequent contact with a health
professional; or conventional therapy—one or two insulin injections per day. After 6.5
years, retinopathy, neuropathy, and nephropathy were significantly reduced in the
intensive group, but symptomatic and severe hypoglycemia was significantly more
frequent. Long-term follow-up of the trial participants demonstrated a reduction in
macrovascular complications as well as persistent reductions in microvascular
complications, even though the difference in A1C values between treatment groups
disappeared over time.
The United Kingdom Prospective Diabetes Study (UKPDS) was subsequently
performed to evaluate the same question but in patients with type 2 DM. Investigators
recruited 5,102 patients between 1977 and 1991. Patients were followed for an
average of 10 years to determine the impact of intensive versus conventional glycemic
control on the incidence of long-term complications in patients with newly diagnosed
type 2 DM. The results showed that the intensive glycemic control arm (using
sulfonylureas and insulin) achieved an A1C of 7.0% (0.070; 53 mmol/mol Hb)
compared to 7.9% (63 mmol/mol Hb) in the conventional group. This translated into a
modest but significant (12%) reduction in diabetesrelated complications, most of
which was due to a 25% reduction in microvascular complications. There was also a
16% reduction in ASCVD events in the intensive group, but this did not reach
statistical significance.21 Intensive glucose control using metformin as the initial
therapy lowered the risk of diabetes-related complications by 32%, diabetes-related
death by 42%, and all-cause mortality by 36% compared to conventional treatment in
an overweight cohort of patients.22 In the long-term UKPDS follow-up study,
microvascular benefits of early glucose control persisted 10 years after the end of the
original trial and a significant long-term reduction in myocardial infarction (MI) and
all-cause mortality emerged in the intensive glucose control arm.
Three additional large-scale studies were performed after the UKPDS to
compare the effects of different intensities of glycemic control on the risk of
macrovascular complications. These studies were done in patients with advanced type
2 DM who were at high risk for ASCVD. The Action to Control CV Risk in Diabetes
(ACCORD) study (n=10,251) showed that lower A1C levels (achieved mean A1C
6.4% vs. 7.5% [0.064 vs. 0.075; 46 vs. 58 mmol/ mol Hb]) reduced the risk of some
microvascular complications but did not reduce the risk of macrovascular
complications. The risk of hypoglycemia was significantly higher in the intensive
treatment group. Most importantly, this study was stopped early due to an increase in
mortality in the intensive treatment arm.24 The Action in Diabetes and Vascular
Disease: Preterax and Diamicron Modified Release Controlled Evaluation
(ADVANCE) study (n=11,140) similarly showed no significant differences in
ASCVD outcomes between two levels of glycemic control (achieved mean A1C 6.3%
vs. 7.0% [0.063 vs. 0.070; 45 vs. 53 mmol/mol Hb]) but did show that the more
intensive glucose control reduced microvascular complications.25 The Veterans
Affairs Diabetes Trial (VADT; n=1,791) also suggested reduced microvascular
complications but no significant reduction in ASCVD outcomes with more intensive
glycemic control (6.9% vs. 8.5% [0.069 vs. 0.085; 52 vs. 69 mmol/mol Hb).26 Based
on the results of these studies in aggregate, more stringent glucose control requires
more intensive treatment and can increase the risk of severe hypoglycemia when
insulin therapy is used. The shortterm and long-term benefits and risks must be
carefully considered when setting intensive glycemic targets.
Based on the clinical evidence that glycemic control reduces microvascular
complications and also has long-term benefits in reducing macrovascular
complications, several organizations, including the ADA and AACE, recommend
surrogate targets for glycemic control. The ADA Standards of Care indicate that an
A1C < 7% (0.07; 53 mmol/mol Hb) is reasonable for most nonpregnant adults. An
FPG target range of 80 to 130 mg/dL (4.4 and 7.2 mmol/L) and a PPG target of.
Glycemic targets, however, must be individualized based on patient-specific
factors and the potential risks and benefits of treatment. Ideally, glycemic targets
should be established at the time of diagnosis and should be reviewed and re-
evaluated at each visit. When possible, these decisions should be made in
collaboration with the patient. Patient or disease factors to consider include:
treatment-related risks including hypoglycemia and other adverse effects, disease
duration, life expectancy, comorbidities, established vascular complications, patient
attitude and expected treatment effort, resources, and support system. While an A1C <
7% (0.07; 53 mmol/mol Hb) is recommended for most patients, a more stringent goal
(such as or advanced complications.
A higher A1C goal may also be appropriate for a patient in whom it remains
difficult to achieve the goal despite appropriate education, monitoring, and drug
therapy. For those treated with complex medication regimens, especially those that
include insulin, the risk of trying to achieve stringent glycemic goals may outweigh
the benefit. Higher A1C goals should be considered in adolescents and children as
well as patients >65 years old. An A1C goal < 7.5% (0.075; 58 mmol/mol Hb) is
reasonable for healthy older adults, while an A1C goal < 8.0% (0.080; 64 mmol/mol
Hb) or < 8.5% (0.085; 69 mmol/mol Hb) should be considered for those with
coexisting chronic diseases, impairments of activities of daily living, cognitive
impairment, or who reside in long-term care facilities. Clinicians should consider
adjusting the FPG and PPG target ranges to correspond with higher target A1Cs.
e. Nonpharmacologic Therapy
MNT is an evidence-based medical approach to treating diabetes through the
use of an individually tailored nutrition plan. There is no standardized “diabetes diet”
nor is there a single ideal distribution of macronutrients; therefore, meal planning
should be individualized. It is imperative that patients understand the
interrelationships between carbohydrate intake, medications, weight, and glucose
control. A healthy meal plan that is moderate in calories and carbohydrates and low in
saturated fat (ie, less than 7% of total calories) with all of the essential vitamins and
minerals is recommended. Some evidence suggests that a Mediterranean-style diet
rich in mono- and poly-unsaturated fats may have glucose and CV benefits and could
be considered.29 Weight loss or weight maintenance is a crucial element in many
patients with type 2 DM. An initial weight loss goal of at least 5% should be targeted
in all patients who are overweight or obese through calorie restriction. Strategies to
reduce calories include reducing portions and frequency of food intake, decreasing
empty calories, added sugars and solid fats, increasing nutrient-dense foods (eg,
nonstarchy vegetables), employing low-calorie cooking methods, and tracking calorie
intake. Helping the patient adopt healthier eating behaviors that lead to sustained
weight loss over time is more important than a specific diet.
Carbohydrate counting is another valuable component of diabetes care. The
appropriate amount (grams) and type of carbohydrates is controversial. For
individuals with type 1 DM, the focus is more on physiologically regulating insulin
administration. For those on fixed doses of mealtime insulin, consistent intake of
carbohydrates is recommended to improve glucose control and minimize
hypoglycemia. For those on flexible insulin dosing regimens (eg, matching insulin
doses to carbohydrate intake amounts), accurate carbohydrate counting to determine
mealtime insulin doses is required. For patients with type 2 DM, carbohydrate
counting focuses more on a balanced diet with moderate carbohydrate intake at each
meal to minimize glucose excursions. Carbohydrate intake from vegetables, fruits,
legumes, whole grains, dairy products, and those high in fiber is preferred. Sugar-
sweetened beverages and foods with added sugars should be discouraged. Financial
and cultural food issues must also be considered. Discourage bedtime and between-
meal snacks, set realistic goals, determine what the patient is willing to change, and
follow-up to see how and whether those changes occurred.
Most patients with diabetes benefit from regular physical activity. Aerobic
exercise improves insulin sensitivity, modestly improves glycemic control in the
majority of individuals, reduces CV risk, contributes to weight loss or maintenance,
and improves well-being. Patients should choose activities that they enjoy and are
likely to do at regular intervals. Start exercise slowly in previously sedentary patients.
It is unclear if asymptomatic patients should be screened for ASCVD prior to
beginning an exercise regimen. Screening is reasonable in patients with long-standing
disease (more than or equal to 10 years), multiple CV risk factors, microvascular
disease (especially renal disease), or evidence of atherosclerotic disease. If the patient
has uncontrolled hypertension, autonomic neuropathy, insensate feet, or proliferative
retinopathy, restrictions on recommended activities are recommended. Physical
activity goals include at least 150 minutes per week of moderate (50%-70% maximal
heart rate) intensity exercise spread over at least 3 days a week with no more than 2
days between activities. In addition, resistance/strength training is recommended at
least two times a week as long as the patient does not have proliferative diabetic
retinopathy.
Consistent, long-term diabetes control requires patients to have a good
understanding of their disease and participate in routine self-management strategies to
control it. All patients should be offered access to diabetes self-management education
and support (DSME/S) programs. There are four critical times to evaluate the need for
DSME/S: at diagnosis, annually, when complicating factors arise, and when
transitions in care occur.29 The American Association of Diabetes Educators (AADE)
has identified seven selfcare behaviors that can be targeted through DSME/S. The
behaviors include healthy eating, being active, monitoring, taking medications,
problem-solving, reducing risk, and healthy coping.30 The patient must be involved
in the decision-making process and the process must be collaborative. Emphasize that
complications can be prevented or minimized with good glycemic control and
managing risk factors for ASCVD. Motivational interviewing techniques have been
shown to be effective. Briefly, this involves asking open-ended questions that
encourage patients to identify and acknowledge barriers that hinder achieving health
goals, and then work to address them with the educator’s guidance.
Health professionals with formal training and experience in diabetes education
can become certified. Certified diabetes educators (CDEs) must document their
experience providing patient education and pass a certification examination. An
increasing number of nurses, pharmacists, dietitians, and physicians are becoming
CDEs. Formal diabetes education programs often employ several health professionals
including CDEs. Accredited diabetes education programs can receive payment
through Medicare and private health insurance plans. The AADE and ADA accredit
diabetes education programs. It must be noted, however, that there are not enough
CDEs to provide sufficient education to all patients with diabetes.
Health care professionals must possess a comprehensive understanding of the
educational needs related to diet, physical activity, and other self-care behaviors to
effectively support patients in managing their diabetes. This entails not only a deep
knowledge of the pathophysiology of diabetes but also the ability to translate this
knowledge into practical, actionable advice that patients can incorporate into their
daily lives. The educational strategies should be tailored to the individual needs of
each patient, considering factors such as age, cultural background, literacy levels, and
personal preferences.
Dietary education is a cornerstone of diabetes management. Health care
professionals should guide patients on the importance of maintaining a balanced diet
that helps regulate blood glucose levels. This involves teaching patients about the
types of carbohydrates that have a low glycemic index, which can help prevent spikes
in blood sugar levels. Patients should also learn about portion control, the significance
of fiber-rich foods, and the benefits of healthy fats. Practical advice might include
how to read food labels, plan meals, and make healthier choices when dining out.
Additionally, individualized meal plans should be developed in collaboration with
dietitians to ensure that patients’ nutritional needs and personal preferences are met,
thereby enhancing adherence to dietary recommendations.
Physical activity is another critical aspect of diabetes management. Health
care professionals should emphasize the role of regular exercise in improving insulin
sensitivity, aiding weight management, and enhancing overall cardiovascular health.
Education should cover different types of physical activities, such as aerobic
exercises, strength training, and flexibility exercises, and how each contributes to
managing diabetes. Patients should be encouraged to incorporate physical activity into
their daily routines in enjoyable and sustainable ways. For instance, walking, cycling,
swimming, or participating in group exercise classes can be effective strategies.
Health care providers should also address potential barriers to physical activity, such
as time constraints, physical limitations, or lack of access to facilities, and help
patients develop practical solutions to overcome these obstacles.
In addition to diet and exercise, other self-care behaviors are essential for
effective diabetes management. Health care professionals must educate patients on the
importance of regular blood glucose monitoring, which helps patients understand how
their lifestyle choices affect their blood sugar levels and allows for timely adjustments
in their management plans. Patients should be instructed on how to use glucose
meters, interpret results, and recognize signs of hypo- and hyperglycemia. Moreover,
education on foot care is crucial, as diabetes can lead to complications such as
neuropathy and poor circulation, increasing the risk of foot ulcers and infections.
Patients should be taught how to perform daily foot inspections, maintain proper
hygiene, and choose appropriate footwear.
Smoking cessation is another vital component of diabetes care. Smoking
exacerbates the risk of cardiovascular diseases, which are already elevated in
individuals with diabetes. Therefore, patients should be advised not to smoke, and
smoking cessation counseling should be a routine component of diabetes care. Health
care professionals should be equipped to provide resources and support for quitting
smoking, including behavioral counseling, pharmacotherapy options such as nicotine
replacement therapy, and connecting patients with smoking cessation programs.
Furthermore, stress management is an often overlooked but critical aspect of
diabetes self-care. Chronic stress can negatively impact blood glucose control by
affecting hormone levels and promoting unhealthy coping behaviors. Health care
professionals should discuss stress management techniques such as mindfulness,
meditation, deep-breathing exercises, and the importance of adequate sleep.
Encouraging patients to seek support from mental health professionals when needed is
also essential.
Finally, fostering a strong therapeutic relationship between health care
professionals and patients is fundamental to the success of diabetes management. This
relationship should be built on trust, open communication, and mutual respect. Health
care providers should actively listen to patients' concerns, provide empathetic support,
and engage patients in shared decision-making processes. By doing so, patients are
more likely to feel empowered and motivated to adhere to their management plans,
leading to better health outcomes.
In summary, health care professionals must be well-versed in various aspects
of diabetes education, including diet, physical activity, self-monitoring of blood
glucose, foot care, smoking cessation, and stress management. By providing
comprehensive education and reinforcement of these crucial management strategies,
health care professionals can help patients achieve optimal diabetes control and
improve their overall quality of life.
f. Pharmacologic Therapies
Endogenously produced insulin is cleaved from the larger proinsulin peptide
in the β-cell to the active peptide of insulin and inactive C-peptide. All commercially
available insulin preparations contain only the active insulin peptide and are produced
and manufactured exclusively using recombinant DNA technology. “Human” insulins
(NPH, regular) are recombinant DNA–derived human insulin, while insulin analogs
have had amino acids substitutions in the insulin molecule that change the onset or
duration of action. Most insulin products are administered subcutaneously for the
chronic management of diabetes, except for inhaled human insulin which is a dry
powder of human recombinant DNA regular insulin which is inhaled and absorbed
through pulmonary tissue. The main advantage of insulin over other
antihyperglycemic agents is that it can achieve a wide range of glucose targets and the
dose can be individualized based on glycemic levels. Disadvantages include the risk
of hypoglycemia, the need for injection(s), weight gain, and treatment burden.
Insulin is available in several concentrations containing 100 units/mL (U-100),
200 units/mL (U-200), 300 units/mL (U-300), or 500 units/mL (U-500). The most
commonly used insulin concentration is U-100. Concentrated insulins containing
more than 100 units/mL may be considered for individuals that require larger doses of
insulin to control their diabetes. The pharmacokinetics and pharmacodynamics of
insulin products are characterized by the onset, peak, and duration of appearance and
action. Absorption of insulin from a subcutaneous depot is dependent on several
factors, including source of insulin, concentration of insulin, additives to the insulin
preparations (eg, zinc and protamine), blood flow to the area (rubbing of injection
area, increased skin temperature, and exercise in muscles near the injection site may
enhance absorption), and injection site. The abdomen provides the most consistent
absorption for insulin.
Basal insulin, also called background insulin, refers to longer acting insulins
that regulate BG levels in between meals by suppressing hepatic glucose production
and maintaining near-normal glycemic levels in the fasting state. Bolus insulin refers
to short or rapid-acting insulins that cover meals (also called prandial insulin) or
glycemic excursions (also called correction insulin). Basal insulin is the preferred and
most convenient initial insulin formulation in patients with type 2 DM while patients
with type 1 DM require a combination of basal and bolus insulin to achieve adequate
glycemic control.
Basal insulin options include NPH, detemir, glargine U-100, glargine U-300,
degludec U-100, or degludec U-200. From a pharmacokinetic/pharmacodynamic
(PK/PD) perspective, NPH is the least ideal basal insulin as it has a distinct peak and
a duration of action much less than 24 hours. While it can be given once daily in some
patients with type 2 DM, it usually is dosed twice daily. Detemir also has a peak and
often lasts less than 24 hours, but has a more ideal profile compared to NPH. It can be
given once daily in some patients but should be dosed twice daily at low doses (less
than 0.3 units/kg). Insulin glargine U-100 offers a slightly better profile; it is
considered to be peakless and can usually be given once daily. The longer acting
agents (glargine U-300 and degludec) have no peak and a longer duration of action
compared to glargine U-100 and detemir. They are given once daily. It is important to
consider whether these PK/PD differences translate into clinically meaningful
differences in patient outcomes. Clinical trial evidence indicates that all basal insulins
can achieve similar A1C reductions if dosed and titrated properly; but the longer
acting basal insulins have a lower risk of hypoglycemia, particularly nocturnal
hypoglycemia, and may result in less glucose variability. They do however cost more,
so the benefits and risks need to be considered on a patient-specific level.
Bolus insulin options include short-acting regular, rapid-acting insulins
(aspart, lispro, and glulisine), and ultra-rapid insulins (inhaled human insulin and fast-
acting insulin aspart [Fiasp]). Similar to basal insulins, the PK/PD profiles of bolus
insulins have improved over time with the rapid-acting insulins offering a faster onset
and shorter duration of action compared to regular insulin and the ultra-rapid insulins
offering an even faster onset. Rapid and ultra-rapid acting agents may more closely
mimic prandial endogenous insulin release. This is likely more relevant to patients
with type 1 DM, where therapy is aiming to mimic a functioning pancreas that
secretes insulin rapidly after a meal. Rapid-acting insulins have a modestly lower risk
of hypoglycemia compared to regular insulin; however, efficacy can be achieved with
all prandial insulins and the differences in cost can be substantial. Therefore, when
selecting a bolus insulin, a patient-specific evaluation of the benefits and risks should
be done.
The most common adverse effects reported with insulin is hypoglycemia. It is
more common in patients on intensive insulin therapy regimens. Patients with type 1
DM experience more hypoglycemic events when compared to type 2 DM patients
who use insulin. In the UKPDS study, the percentage of type 2 DM patients who
needed third-party assistance due to a severe hypoglycemic reaction was 2.3%.21 In
the DCCT study, intensive glycemic control increased the risk of severe
hypoglycemia threefold when compared to conventional therapy in patients with type
1 DM.18 Insulin use is associated with an increased risk of hospitalizations in older
adults based on public health surveillance data.34 Insulin also causes dose-dependent
weight gain, which predominantly occurs in truncal fat. Weight gain can be
minimized by using physiologic insulin replacement strategies or combining insulin
therapy with other medications that mitigate weight gain or promote weight loss.
Insulin can cause injection site reactions including redness, pain, itching,
urticaria, edema, and inflammation. Administration of insulin subcutaneously can
result in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or
thickening of tissue) in some patients. Lipohypertrophy is caused by repeated
injections into the same injection site. Due to insulin’s anabolic actions, fat
accumulates at the injection site and absorption at this site becomes variable.
Lipoatrophy, in contrast, is due to insulin antibodies or allergic-type reactions that
destroy the fat at the site of injection. Routinely rotating injection sites prevents these
problems from developing and, when lipodystrophy is detected, the injection site
should be avoided. Concerns have been raised about a potential risk of cancer with
insulin glargine, but trial results have been conflicting. While some studies using
administrative data have found an association between insulin glargine and cancer,
other meta-analyses and prospective studies have not.
Inhaled human insulin can cause cough and upper respiratory infections and
its use in chronic obstructive pulmonary disease and asthma is contraindicated due to
bronchospasm risk. Inhaled insulin use has been associated with a small decline in
pulmonary function and patients should have spirometry tests performed at baseline, 6
months, and annually thereafter. If a 20% reduction or greater in forced expiratory
volume in 1 second is observed, inhaled insulin should be discontinued. Insulin is
degraded in the liver, muscle, and kidney. Liver deactivation is 20% to 50% in a
single passage through the liver. Approximately 15% to 20% of insulin metabolism
occurs in the kidney. This may explain the lower insulin dosage requirements and
longer duration of activity observed in patients with end-stage renal disease.
The dose of insulin must be individualized. In type 1 DM, the average daily
requirement for insulin is 0.5 to 0.6 units/kg, with approximately 50% being delivered
as basal insulin, and the remaining 50% dedicated to meal coverage. During the
honeymoon phase, it may fall to 0.1 to 0.4 units/kg. During acute illness or with
ketosis or states of relative insulin resistance, the need for higher dosages is common.
In type 2 DM, a higher dosage is required for those patients with significant insulin
resistance. Dosages vary widely depending on degree of insulin resistance and
concomitant antihyperglycemic medication use. More specific information on insulin
dosing is included in the “General Approach to Hyperglycemia Management” section.
Metformin is the only biguanide available in the United States. It is oral and
available as an immediate-release formulation that is dosed twice daily or an
extended-release (XR) formulation that is dosed once or twice daily. Its benefits in
relation to glucose lowering are complex and not yet fully understood. At the cellular
level, metformin activates AMP kinase. Metformin has been shown to decrease
hepatic glucose production, yet not all of its effects can be explained by that
mechanism and there is increasing evidence of mechanisms in the gut. Additionally,
metformin’s effects may be partially related to enhanced insulin sensitivity in
peripheral (muscle) tissues, which allows for an increased uptake of glucose into
muscle cells. Metformin has no direct effect on the β-cell, but insulin concentrations
are reduced due to improved insulin sensitivity.
Metformin is the drug of choice in patients with type 2 DM due to extensive
experience, high efficacy, minimal hypoglycemia risk, positive or neutral effects on
weight, potential positive impact on CV risk, manageable side-effect profile, and low
cost. Current treatment guidelines recommend initiating metformin as first-line
pharmacotherapy unless a contraindication or intolerability exists.31,32 Metformin
consistently reduces A1C levels by 1.5% to 2.0% (0.015 and 0.020; 16 and 22
mmol/mol Hb) and FPG levels by 60 to 80 mg/dL (3.3 to 4.4 mmol/L) in drug naïve
patients with A1C values of approximately 9% (0.09; 75 mmol/mol Hb). Metformin
does not cause weight gain, and may actually lead to a modest (2-3 kg) weight loss.
Since metformin does not directly increase insulin secretion from the pancreas, it has
a low risk of hypoglycemia. Metformin also has positive effects on several
components of the insulin resistance syndrome. Metformin decreases plasma
triglycerides and low-density lipoprotein cholesterol (LDL-C) by approximately 8%
to 15% and modestly increases high-density lipoprotein cholesterol (HDLC) by 2%.
Metformin reduced the composite of all diabetes-related endpoints by 32%,
diabetes-related death by 42%, and all-cause mortality by 36% in overweight subjects
in the UKPDS compared to conventional treatment. Intensive treatment with
metformin was also significantly better than intensive treatment with sulfonylureas or
insulin at reducing any diabetes-related endpoint, all-cause mortality, and stroke.
However, meta-analyses have not confirmed these benefits.22,38,39 Metformin
frequently causes GI side effects, including diarrhea, abdominal discomfort, and/or
stomach upset. These side effects are usually dose-dependent, transient, mild in
nature, and can be minimized with slow dose titration. Patients should take metformin
with or immediately after meals. When initiating therapy, it is important to use a low
dose, typically 500 mg given with the largest meal, to minimize GI adverse effects.
The dose is then increased in 500 mg increments over several weeks. Approximately
5% to 10% of patients cannot tolerate metformin despite the slow dose titration.
Extended-release metformin may lessen some of the GI side effects, but a recent
head-to-head comparison of immediate-release versus extended-release metformin
found no significant differences in rates of GI adverse effects.
Sulfonylureas are oral agents, available in either immediate-release or
extended-release formulations, typically dosed once or twice daily. They enhance
insulin secretion by binding to a specific sulfonylurea receptor (SUR1) on pancreatic
β-cells. Binding closes an adenosine triphosphate-dependent K+ channel, leading to
decreased potassium efflux and subsequent depolarization of the membrane. Voltage-
dependent Ca+2 channels open and allow an inward flux of Ca+2 . Increases in
intracellular Ca+2 bind to calmodulin on insulin secretory granules, causing
translocation of secretory granules of insulin to the cell surface and resultant
exocytosis of the granule of insulin. Elevated secretion of insulin from the pancreas
travels via the portal vein and subsequently suppresses hepatic glucose production.
Pioglitazone and rosiglitazone are the two currently FDA-approved
thiazolidinediones (TZDs) for the treatment of type 2 DM. They are oral agents,
dosed once daily. TZDs work by binding to the peroxisome proliferator activator
receptor-γ (PPAR-γ), a nuclear receptor that is predominantly located on fat cells and
vascular cells. Activation of PPAR-γ alters the transcription of several genes involved
in glucose and lipid metabolism and energy balance. TZDs enhance insulin sensitivity
at muscle, liver, and fat tissues. TZDs cause preadipocytes to differentiate into mature
fat cells in subcutaneous fat stores. Small fat cells are more sensitive to insulin and
more able to store FFAs. This allows a flux of FFAs out of the plasma, visceral fat,
and liver into subcutaneous fat, a less insulin-resistant storage tissue. Muscle
intracellular fat products, which contribute to insulin resistance, also decline. TZDs
also affect adipokines (eg, angiotensinogen, tissue necrosis factor-α, interleukin 6,
PAI-1), which can positively affect insulin sensitivity, endothelial function, and
inflammation. Of particular note, adiponectin is reduced with obesity and diabetes,
but is increased with TZD therapy, which improves endothelial function, insulin
sensitivity, and has a potent anti-inflammatory effect.
