Diabetes mellitus (DM) is a disease of inadequate control of
blood levels of glucose. It has many subclassifications, including type 1, type
2, maturity-onset diabetes of the young (MODY), gestational diabetes, neonatal
diabetes, and steroid-induced diabetes. Type 1 and 2 DM are the main subtypes,
each with a different pathophysiology, presentation, and management, but both
have a potential for hyperglycemia. This activity outlines the pathophysiology,
evaluation, and management of DM and highlights the role of the
interprofessional team in managing patients with this condition.
Objectives:
Describe the pathophysiology of diabetes mellitus.
Outline the epidemiology and risk factors of diabetes
mellitus.
Review the treatment considerations and common complications
of diabetes mellitus.
Identify the importance of improving collaboration and care
coordination amongst the interprofessional team to enhance the delivery of care
for patients affected by diabetes mellitus.
Introduction
Diabetes mellitus is taken from the Greek word diabetes, meaning
siphon - to pass through, and the Latin word mellitus meaning sweet. A review of
the history shows that the term "diabetes" was first used by
Apollonius of Memphis around 250 to 300 BC. Ancient Greek, Indian, and Egyptian
civilizations discovered the sweet nature of urine in this condition, and hence
the propagation of the word Diabetes Mellitus came into being. Mering and
Minkowski, in 1889, discovered the role of the pancreas in the pathogenesis of
diabetes. In 1922 Banting, Best, and Collip purified the hormone insulin from
the pancreas of cows at the University of Toronto, leading to the availability
of an effective treatment for diabetes in 1922. Over the years, exceptional
work has taken place, and multiple discoveries, as well as management strategies,
have been created to tackle this growing problem. Unfortunately, even today,
diabetes is one of the most common chronic diseases in the country and
worldwide. In the US, it remains as the seventh leading cause of death.
Diabetes mellitus (DM) is a metabolic disease, involving
inappropriately elevated blood glucose levels. DM has several categories,
including type 1, type 2, maturity-onset diabetes of the young (MODY),
gestational diabetes, neonatal diabetes, and secondary causes due to
endocrinopathies, steroid use, etc. The main subtypes of DM are Type 1 diabetes
mellitus (T1DM) and Type 2 diabetes mellitus (T2DM), which classically result
from defective insulin secretion (T1DM) and/or action (T2DM). T1DM presents in
children or adolescents, while T2DM is thought to affect middle-aged and older
adults who have prolonged hyperglycemia due to poor lifestyle and dietary
choices. The pathogenesis for T1DM and T2DM is drastically different, and
therefore each type has various etiologies, presentations, and treatments.
Etiology
In the islets of Langerhans in the pancreas, there are two
main subclasses of endocrine cells: insulin-producing beta cells and glucagon
secreting alpha cells. Beta and alpha cells are continually changing their
levels of hormone secretions based on the glucose environment. Without the
balance between insulin and glucagon, the glucose levels become inappropriately
skewed. In the case of DM, insulin is either absent and/or has impaired action
(insulin resistance), and thus leads to hyperglycemia.
T1DM is characterized by the destruction of beta cells in
the pancreas, typically secondary to an autoimmune process. The result is the
absolute destruction of beta cells, and consequentially, insulin is absent or
extremely low.
T2DM involves a more insidious onset where an imbalance
between insulin levels and insulin sensitivity causes a functional deficit of
insulin. Insulin resistance is multifactorial but commonly develops from
obesity and aging.
The genetic background for both types is critical as a risk
factor. As the human genome gets further explored, there are different loci
found that confer risk for DM. Polymorphisms have been known to influence the
risk for T1DM, including major histocompatibility complex (MHC) and human
leukocyte antigen (HLA).
T2DM involves a more complex interplay between genetics and
lifestyle. There is clear evidence suggesting that T2DM is has a stronger
hereditary profile as compared to T1DM. The majority of patients with the
disease have at least one parent with T2DM.
Monozygotic twins with one affected twin have a 90%
likelihood of the other twin developing T2DM in his/her lifetime.[3]
Approximately 50 polymorphisms to date have been described to contribute to the
risk or protection for T2DM. These genes encode for proteins involved in
various pathways leading to DM, including pancreatic development, insulin
synthesis, secretion, and development, amyloid deposition in beta cells,
insulin resistance, and impaired gluconeogenesis regulation. A genome-wide association
study (GWAS) found genetic loci for transcription factor 7-like 2 gene
(TCF7L2), which increases the risk for T2DM.[4][5] Other loci that have
implications in the development of T2DM include NOTCH2, JAZF1, KCNQ1, and
WFS1.
MODY is a heterogeneous disorder identified by
non-insulin-dependent diabetes diagnosed at a young age (usually under 25
years). It carries an autosomal dominant transmission and does not involve
autoantibodies as in T1DM. Several genes have implications in this disease, including
mutations to hepatocyte nuclear factor-1-alpha (HNF1A) and the glucokinase
(GCK) gene, which occurs in 52 to 65 and 15 to 32 percent of MODY cases,
respectively.[8][9] The genetics of this disease are still unclear as some
patients have mutations but never develop the disease, and others will develop
clinical symptoms of MODY but have no identifiable mutation.
Gestational diabetes is essentially diabetes that manifests
during pregnancy. It is still unknown why it develops; however, some speculate
that HLA antigens may play a role, specifically HLA DR2, 3, and 4. Excessive
proinsulin is also thought to play a role in gestational diabetes, and some
suggest that proinsulin may induce beta-cell stress. Others believe that high
concentrations of hormones such as progesterone, cortisol, prolactin, human
placental lactogen, and estrogen may affect beta-cell function and peripheral
insulin sensitivity.
Several endocrinopathies, including acromegaly, Cushing
syndrome, glucagonoma, hyperthyroidism, hyperaldosteronism, and
somatostatinomas, have been associated with glucose intolerance and diabetes
mellitus, due to the inherent glucogenic action of the endogenous hormones
excessively secreted in these conditions. Conditions like idiopathic
hemochromatosis are associated with diabetes mellitus due to excessive iron
deposition in the pancreas and the destruction of the beta cells.
Epidemiology
Globally, 1 in 11 adults has DM (90% having T2DM). The onset
of T1DM gradually increases from birth and peaks at ages 4 to 6 years and then
again from 10 to 14 years.[11] Approximately 45% of children present before age
ten years.[12] The prevalence in people under age 20 is about 2.3 per 1000.
While most autoimmune diseases are more common in females, there are no apparent
gender differences in the incidence of childhood T1DM. In some populations,
such as in older males of European origin (over 13 years), they may be more
likely to develop T1DM compared to females (3:2 male to female ratio).[13] The
incidence of T1DM has been increasing worldwide. In Europe, Australia, and the
Middle East, rates are rising by 2% to 5% annually.[14][15][16] In the United
States, T1DM rates rose in most age and ethnic groups by about 2% yearly, and
rates are higher in Hispanic youth.[17] The exact reason for this pattern
remains unknown. However, some metrics, such as the United States Military
Health System data repository, found plateauing over 2007 to 2012 with a
prevalence of 1.5 per 1000 and incidence of 20.7 to 21.3 per 1000.
The onset of T2DM is usually later in life, though obesity
in adolescents has led to an increase in T2DM in younger populations. T2DM has
a prevalence of about 9% in the total population of the United States, but
approximately 25% in those over 65 years. The International Diabetes Federation
estimates that 1 in 11 adults between 20 and 79 years had DM globally in 2015.
Experts expect the prevalence of DM to increase from 415 to 642 million by
2040, with the most significant increase in populations transitioning from low
to middle-income levels.[19] T2DM varies among ethnic groups and is 2 to 6
times more prevalent in Blacks, Native Americans, Pima Indians, and Hispanic
Americans compared to Whites in the United States.[20][21] While ethnicity
alone plays a vital role in T2DM, environmental factors also greatly confer
risk for the disease. For example, Pima Indians in Mexico are less likely to
develop T2DM compared to Pima Indians in the United States (6.9% vs. 38%).
Pathophysiology
A patient with DM has the potential for hyperglycemia. The
pathology of DM can be unclear since several factors can often contribute to
the disease. Hyperglycemia alone can impair pancreatic beta-cell function and
contributes to impaired insulin secretion. Consequentially, there is a vicious
cycle of hyperglycemia leading to an impaired metabolic state. Blood glucose
levels above 180 mg/dL are often considered hyperglycemic in this context,
though because of the variety of mechanisms, there is no clear cutoff point.
Patients experience osmotic diuresis due to saturation of the glucose
transporters in the nephron at higher blood glucose levels. Although the effect
is variable, serum glucose levels above 250 mg/dL are likely to cause symptoms
of polyuria and polydipsia.
Insulin resistance is attributable to excess fatty acids and
proinflammatory cytokines, which leads to impaired glucose transport and
increases fat breakdown. Since there is an inadequate response or production of
insulin, the body responds by inappropriately increasing glucagon, thus further
contributing to hyperglycemia. While insulin resistance is a component of T2DM,
the full extent of the disease results when the patient has inadequate
production of insulin to compensate for their insulin resistance.
Chronic hyperglycemia also causes nonenzymatic glycation of
proteins and lipids. The extent of this is measurable via the glycation
hemoglobin (HbA1c) test. Glycation leads to damage in small blood vessels in
the retina, kidney, and peripheral nerves. Higher glucose levels hasten the
process. This damage leads to the classic diabetic complications of diabetic
retinopathy, nephropathy, and neuropathy and the preventable outcomes of
blindness, dialysis, and amputation, respectively.
History and Physical
During patient history, questions about family history,
autoimmune diseases, and insulin-resistant are critical to making the diagnosis
of DM. It often presents asymptomatically, but when symptoms develop, patients
usually present with polyuria, polydipsia, and weight loss. On physical
examination of someone with hyperglycemia, poor skin turgor (from dehydration)
and a distinctive fruity odor of their breath (in patients with ketosis) may be
present. In the setting of diabetic ketoacidosis (DKA), clinicians may note
Kussmaul respirations, fatigue, nausea, and vomiting. Funduscopic examination
in a patient with DM may show hemorrhages or exudates on the macula. In frank
diabetic retinopathy, retinal venules may appear dilated or occluded. The
proliferation of new blood vessels is also a concern for ophthalmologists and
can hasten retinal hemorrhages and macular edema, ultimately resulting in
blindness. While T1DM and T2DM can present similarly, they can be distinguished
based on clinical history and examination. T2DM patients are typically
overweight/obese and present with signs of insulin resistance, including
acanthosis nigricans, which are hyperpigmented, velvety patches on the skin of
the neck, axillary, or inguinal folds. Patients with a longer course of
hyperglycemia may have blurry vision, frequent yeast infections, numbness, or
neuropathic pain. The clinicians must ask the patient bout any recent skin
changes in their feet during each visit. The diabetic foot exam, including the
monofilament test, should be a part of the routine physical exam.
Evaluation
The diagnosis of T1DM is usually through a characteristic
history supported by elevated serum glucose levels (fasting glucose greater
than 126 mg/dL, random glucose over 200 mg/dL, or hemoglobin A1C (HbA1c
exceeding 6.5%) with or without antibodies to glutamic acid decarboxylase (GAD)
and insulin.
Fasting glucose levels and HbA1c testing are useful for the
early identification of T2DM. If borderline, a glucose tolerance test is an
option to evaluate both fasting glucose levels and serum response to an oral
glucose tolerance test (OGTT). Prediabetes, which often precedes T2DM, presents
with a fasting blood glucose level of 100 to 125 mg/dL or a 2-hour post-oral
glucose tolerance test (post-OGTT) glucose level of 140 to 200 mg/dL.
According to the American Diabetes Association (ADA), a
diagnosis of diabetes is through any of the following: An HbA1c level of 6.5%
or higher; A fasting plasma glucose level of 126 mg/dL (7.0 mmol/L) or higher
(no caloric intake for at least 8 hours); A two-hour plasma glucose level of
11.1 mmol/L or 200 mg/dL or higher during a 75-g OGTT; A random plasma glucose
of 11.1 mmol/L or 200 mg/dL or higher in a patient with symptoms of
hyperglycemia (polyuria, polydipsia, polyphagia, weight loss) or hyperglycemic
crisis.[24] The ADA recommends screening adults aged 45 years and older
regardless of risk, while the United States Preventative Service Task Force
suggests screening individuals between 40 to 70 years who are overweight.
To test for gestational diabetes, all pregnant patients have
screening between 24 to 28 weeks of gestation with a 1-hour fasting glucose
challenge test. If blood glucose levels are over 140mg/dL, patients have a
3-hour fasting glucose challenge test to confirm a diagnosis. A positive
3-hours OGTT test is when there is at least one abnormal value (greater than or
equal to 180, 155, and 140 mg/dL for fasting one-hour, two-hour, and 3-hour
plasma glucose concentration, respectively).
Several lab tests are useful in the management of chronic
DM. Home glucose testing can show trends of hyper- and hypoglycemia. The HbA1c
test indicates the extent of glycation due to hyperglycemia over three months
(the life of the red blood cell). Urine albumin testing can identify the early
stages of diabetic nephropathy. Since patients with diabetes are also prone to
cardiovascular disease, serum lipid monitoring is advisable at the time of
diagnosis. Similarly, some recommend monitoring thyroid status by obtaining a
blood level of thyroid-stimulating hormone annually due to a higher incidence
of hypothyroidism.
Treatment / Management
The physiology and treatment of diabetes are complex and
require a multitude of interventions for successful disease management.
Diabetic education and patient engagement are critical in management. Patients
have better outcomes if they can manage their diet (carbohydrate and overall
caloric restriction), exercise regularly (more than 150 minutes weekly), and
independently monitor glucose.[28] Lifelong treatment is often necessary to
prevent unwanted complications. Ideally, glucose levels should be maintained at
90 to 130 mg/dL and HbA1c at less than 7%. While glucose control is critical,
excessively aggressive management may lead to hypoglycemia, which can have
adverse or fatal outcomes.
Since T1DM is a disease primarily due to the absence of
insulin, insulin administration through daily injections, or an insulin pump,
is the mainstay of treatment. In T2DM, diet and exercise may be adequate
treatments, especially initially. Other therapies may target insulin
sensitivity or increase insulin secretion by the pancreas. The specific
subclasses for drugs include biguanides (metformin), sulfonylureas,
meglitinides, alpha-glucosidase inhibitors, thiazolidinediones,
glucagonlike-peptide-1 agonist, dipeptidyl peptidase IV inhibitors (DPP-4),
selective, amylinomimetics, and sodium-glucose transporter-2 (SGLT-2)
inhibitors. Metformin is the first line of the prescribed diabetic medications
and works by lowering basal and postprandial plasma glucose. Insulin
administration may also be necessary for T2DM patients, especially those with
inadequate glucose management in the advanced stages of the disease. In
morbidly obese patients, bariatric surgery is a possible means to normalize
glucose levels. It is recommended for individuals who have been unresponsive to
other treatments and who have significant comorbidities.[29] The GLP-1 agonists
liraglutide and semaglutide correlate with improved cardiovascular outcomes.
The SGLT-2 inhibitors empagliflozin and canagliflozin have also shown to
improve cardiovascular outcomes along with potential renoprotection as well as
prevention for the development of heart failure.
Regular screenings are necessary since microvascular
complications are a feared complication of diabetes. Regular diabetic retinal
exams should be performed by qualified medical personnel to assess for diabetic
retinopathy. Neurologic examination with monofilament testing can identify
patients with neuropathy at risk for amputation. Clinicians can also recommend
patients perform daily foot inspections to identify foot lesions that may go
unnoticed due to neuropathy. Low-dose tricyclic antidepressants, duloxetine,
anticonvulsants, topical capsaicin, and pain medications may be necessary to
manage neuropathic pain in diabetes. Urine microalbumin testing can also assess
for early renal changes from diabetes with albuminuria greater than 30mg/g
creatinine along with the estimated GFR. The antiproteinuric effect of the
angiotensin-converting enzyme (ACE) inhibitors and the angiotensin receptor
blockers (ARBs) makes them the preferred agents to delay the progression from
microalbuminuria to macroalbuminuria in patients with both Type 1 or Type 2
diabetes mellitus.
The FDA has approved pregabalin and duloxetine for the
treatment of diabetic peripheral neuropathy. Tricyclic antidepressants and
anticonvulsants have also seen use in the management of the pain of diabetic
neuropathy with variable success.
The ADA also recommends regular blood pressure screening for
diabetics, with the goal being 130 mmHg systolic blood pressure and 85 mmHg
diastolic blood pressure.[30] Pharmacologic therapy for hypertensive diabetics
typically involves angiotensin-converting enzyme inhibitors, angiotensin
receptor blockers, diuretics, beta-blockers, and/or calcium channel blockers.
The ADA recommends lipid monitoring for diabetics with a goal of low-density
lipoprotein cholesterol (LDL-C) being less than 100 mg/dL if no cardiovascular
disease (CVD) and less than 70 mg/dl if atherosclerotic cardiovascular disease
(ASCVD) is present. Statins are the first-line treatment for the management of
dyslipidemia in diabetics. The ADA suggests that low dose aspirin may also be
beneficial for diabetic patients who are at high risk for cardiovascular
events; however, the role of aspirin in reducing cardiovascular events in
patients with diabetes remains unclear
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