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Module 1. Diabetes Defined: Pathophysiology

INTRODUCTION

Diabetes mellitus has become a disease state of epidemic proportion. This is evidenced by a worldwide prevalence of at least 8.8%, according to data from the International Diabetes Federation.1 This equates to a current 425 million people affected worldwide. The global burden of this disease state is estimated to cause a substantial financial impact in which treatment and possible prevention strategies will play key roles.

Most simply, diabetes mellitus is characterized by higher than normal levels of glucose in the blood. Currently, 2 types of diabetes make up the majority of these diagnoses and are known as Type 1 and Type 2 diabetes.2 Type 1 diabetes is characterized as an autoimmune disease in which the body is unable to continue to produce insulin because of the destruction of the insulin-producing beta cells in the pancreas. This type of diabetes typically affects younger individuals who appear to have a thin body type. Type 2 diabetes is thought to be caused by a genetic predisposition and a complex medley of metabolic risk factors, such as poor diet, obesity, and inactivity. Type 2 diabetes typically occurs in those older than 30 years of age who are also overweight. Unfortunately, at this time Type 1 diabetes cannot be prevented. However, there is evidence showing that Type 2 diabetes can at least be delayed, if not prevented, when at least one risk factor for the disease is eliminated.3,4 Other types of diabetes include gestational diabetes, genetically induced diabetes, and types that are caused by exocrine; these types of diabetes are very rare and will only be briefly covered in this module.2 Pharmacists can play a unique role in the management of diabetes through risk factor modification, medication counseling, and ensuring that patients diagnosed with any classification of diabetes receive proper therapies.

PREVALENCE

Currently it is estimated that at least 30.3 million people or 9.4% of individuals in the United States (U.S.) have diabetes.5 In the year 2015 alone, the number of U.S. adults aged 20 years or older newly diagnosed with diabetes was 1.5 million. Additionally, 23.8% of the more than 30 million people in the U.S. with diabetes were not yet diagnosed and another 84 million adults (34% of American adults) had prediabetes. These statistics are staggering and they are projected to continue to grow; estimates currently suggest that 1 in every 3 Americans born today will develop diabetes. The aging population will be most impacted, both in the U.S. and in other countries.6 In 2015, diabetes was reported to be the seventh leading cause of death in the U.S., but this statistic is likely underreported.5 Economically, $245 billion is spent annually on diabetes in the U.S.1 Our present health care system is likely unprepared to handle the complications associated with this disease and the massive financial burden it is expected to bring. In addition, pharmacists and other health care professionals will most certainly be faced with expanding roles in the management of the symptoms and complications of this disease state.

The following 2 primary types of diabetes comprise the majority of these statistics: Type 1 and Type 2. The chart below summarizes the similarities and differences among disease states.

Table 1 - Comparison of Type 1 Diabetes and Type 2 Diabetes7
  Type 1 Diabetes Type 2 Diabetes
Phenotype Usual onset in children and adolescents Usual onset, older than 30 years of age
  Often thin body type or normal BMI (Body Mass Index) Often obese
  Prone to ketoacidosis Ketoacidosis is seldom spontaneous
  Absolute insulin deficiencies—Insulin required for survival Relative insulin deficiency and/or insulin resistance-
  Autoimmune damage to pancreas Not autoimmune in nature
Genotype Identical twin studies: < 50% concordance Identical twin studies: usually > 70% concordance
  HLA association: Yes
(human leukocyte antigen)		 HLA association: No
(human leukocyte antigen)
  Increased prevalence in relatives Increased prevalence in relatives

TYPE 1 DIABETES

Epidemiology

Type 1a diabetes mellitus or immune-mediated diabetes, more commonly known as Type 1 diabetes, comprises only 5% to 10% of all diabetes cases worldwide.2 However, it is one of the most common chronic childhood disease states. Idiopathic Type 1 diabetes or Type 1b diabetes mellitus occurs when patients with no evidence of autoimmunity experience complete insulin deficiency; this type will not be discussed in great detail in this review.8 Type 1 diabetes was previously known as insulin-dependent diabetes or juvenile-onset diabetes and nearly 500,000 children live with it and almost 79,000 develop the disease every year worldwide.1 While this impact is very small compared with the number of individuals with Type 2 diabetes, the incidence of Type 1 diabetes is increasing by approximately 3.2% per year.9 The reasons for the upward trend are not clear, but it is important to remember that individuals diagnosed with Type 1 diabetes can live well into their older adult years if the disease is managed appropriately.

Type 1 diabetes usually presents in children and young adults. For individuals younger than 20 years of age, Type 1 diabetes accounts for the majority of new diabetes cases diagnosed in the U.S.10 The age of presentation peaks at the following 2 distinctive points: one peak occurs from 4 to 6 years of age and the other peaks in early puberty (i.e., 10 to 14 years of age).11 Overall, roughly 45% of children with Type 1 diabetes are diagnosed when they are younger than 10 years of age; however, adults comprise one-quarter of all Type 1 diabetes diagnoses.2

Clinical Presentation

Type 1 diabetes can present in several different ways. Children tend to present with the abrupt onset of polydipsia, polyuria, weight loss, and hyperglycemia.12 Hyperglycemia sufficient enough to be classified as diabetes is when glucose exceeds any of the following markers: random plasma glucose of >200 mg/dL with symptoms or fasting plasma glucose of  >126 mg/dL or hemoglobin A1c of greater than or equal to 6.5%.7 Children with these symptoms usually appear slightly ill with nonspecific complaints, such as lethargy and weight loss, although weight loss occurs in only half of children diagnosed.13 Polyuria may present as bed-wetting or daytime increased urinary frequency and/or incontinence in a previously potty-trained child. Other symptoms include blurry vision, drowsiness, poor stamina, frequent skin and bladder infections, and vaginitis. Adults present similarly, but symptoms may not be as abrupt. For adults, longer time frames from the onset of disease to the diagnosis often occur as the result of a decreased rate of beta-cell destruction.2 At the time of diagnosis, 80% to 90% of beta cells have already been destroyed in these patients.

Type 1 diabetes can first present as diabetic ketoacidosis (DKA), which is the most concerning complication associated with this disease. Approximately, 20% to 40% of patients with Type 1 diabetes present in DKA and will require hospitalization.2 Children are more likely than adults to present in DKA and this syndrome is characterized by nausea and vomiting, breathlessness, and abdominal pain.14 Laboratory values will indicate that hyperglycemia, glucosuria, ketonemia, and ketonuria are present. In addition, patients may also develop a fruity-smelling breath and increased drowsiness and lethargy. DKA also leads to profound dehydration associated with polyuria and sometimes acute vomiting. DKA in children is reported to occur approximately 25% to 30% of the time at diagnosis.15 Children younger than 6 or those from an adverse socioeconomic background are more likely to present in DKA.16 Patients with DKA will require abrupt treatment, including rehydration and insulin therapy in the hospital setting.2

After diagnosis, many patients enter a honeymoon phase, in which there is some endogenous insulin production and only small amounts of exogenous insulin is required to maintain glycemic control.17 This time period is transient and beta-cell destruction continues, leading to a complete reliance on exogenous insulin for euglycemia.

Pathophysiology

It has long been assumed that Type 1 diabetes results from an interplay between genetics and environment. More specifically, in a person who is genetically predisposed to the disease, environmental triggers are thought to cause an autoimmune response that leads to destruction of pancreatic beta cells (i.e., cells that excrete insulin) and, ultimately, insulin deficiency and metabolic abnormalities.8 The main autoantigen is unknown, but it may be insulin itself.18 Additionally, there does appear to be a common cascade of events in the lifeline of the immune-mediated illness. These events include a long period of time prior to diagnosis in which immune markers are present and beta-cell destruction is occurring (i.e., reported to be as long as 9 years), high blood glucose levels (during which 80% to 90% of pancreatic beta cells are destroyed), a transient period of remission known as the honeymoon phase (during which the individual appears to produce some insulin) and, finally, established disease.14

On examination, the involved pancreatic islets contain beta cells with enlarged nuclei, variable numbers of degranulated beta cells, and a chronic inflammatory infiltrate that is known as insulitis.19 This infiltrate is made of T lymphocyte cells known as CD8 and CD4 and natural killer cells and macrophages. The involvement of the islets is not uniform. Within the same pancreas, there are areas of complete destruction of beta cells, islets that are intact but surrounded by inflammation, and islets that are left with normal function. The variability seen in the damage of the pancreas may help explain why there is a slow progression to overt hyperglycemia, especially in adults. Healthy beta cells of the pancreas also produce amylin.20 Amylin is a hormone that slows gastric emptying, improves satiety, and suppresses glucagon secretion after meal intake. Because the beta cells no longer function, amylin is also not produced, leading to higher blood sugars after meal intake. Thus, insulin and amylin deficiencies cause many metabolic abnormalities, including impaired glucose, lipid, and protein metabolism.

Figure 1 – Pathophysiology of Type 1 Diabetes Timeline19,20
Figure 2 – Natural Progression of Type 2 Diabetes.
MHC = major histocompatibility complex; HLA = human leukocyte antigen; GAD65 = glutamic acid decarboxylase65; IAA = insulin autoantibodies

Risk Factors

Family History
Studies show that the lifetime risk of developing Type 1 diabetes is substantially greater for those who have close relatives with Type 1 diabetes. The risk of Type 1 diabetes in the general population is reported to be approximately 1 in 400 or 0.25%.21 The risk increases 1% to 8% if either the mother or the father has Type 1 diabetes and contributes the disease22; the risk is a bit higher if the father contributes the disease instead of the mother. If both parents are affected with Type 1 diabetes, the risk is substantially greater and reported to be as high as 30%. Additionally, the sibling risk is similar to the risk with one parent contributor, at 3% to 6% for non-twins. The incidence increases to as much as 50% for identical twins.

Race/Ethnicity
Ethnic differences in the incidence of Type 1 diabetes is also apparent in the U.S. The highest prevalence of Type 1 diabetes was seen in non-Hispanic white youths, according to a 2009 study that sampled large multiethnic populations.23 Non-Hispanic whites younger than 20 years of age seem to have the highest incidence of Type 1 diabetes in the U.S., at 23.6 per 100,000 person-years.11 The incidence for African-Americans, Hispanics, Asian-Pacific Islanders, and American Indians followed in respective order, from rates highest to lowest after non-Hispanic youths. These observations of ethnic-specific risk factors are likely contributed to gene polymorphisms.

Genetic Markers
Type 1 diabetes is most definitely a polygenic disorder and more than 40 genetic polymorphisms that confer susceptibility to Type 1a diabetes have been identified.24 Multiple genes are reported to influence the risk of Type 1 diabetes, including human leukocyte antigen (HLA)-DQalpha, HLA-DQBeta, HLA-DR, preproinsulin, the PTPN22 gene, CTLA-4, interferon-induced helicase, interleukin (IL)-2 receptor (CD25), and many others. The genes most responsible for familial aggregation of diabetes are within the major histocompatibility complex (MHC) located in the HLA region on chromosome-6 and are thought to be responsible for more than 40% to 50% of Type 1 diabetes genetic susceptibility.25 Certain combinations of the DQ and DR alleles are associated with a higher risk of Type 1 diabetes. In particular, more than 90% of patients with Type 1 diabetes carry either HLA-DR3, DQB1*0201 or HLA-DR4, DQB1*0302.26 Additionally, DR3/4 heterozygotes are at the greatest susceptibility and carry the DQA1*0501, DQB1*0201, and DQA1*0301, DQB1*0302 gene sequences. These DR3/4 heterozygotes comprise only 2% of the children born in the U.S.; however, these individuals make up 40% of all U.S. children that develop diabetes. In addition, some of the HLA alleles are associated with protection from diabetes including DQA1*0102, DQB1*0602.27 This protective allele occurs in 20% of the general population, but in less than 1% of children who develop Type 1 diabetes.

Non-HLA genes identified as possibly contributing to the development of Type 1 diabetes include the insulin gene (INS) region on chromosome 11, polymorphisms of a promoter of the insulin gene, and an amino acid change of a lymphocyte specific tyrosine phosphatase (PTPN22).28 The association between these genes and the development of diabetes is not as strong as the HLA association. However, MHC susceptibility genes are not sufficient to induce Type 1 diabetes alone, suggesting that polygenic inheritances of non-MHC genes are essential to the development of the disease.27

Autoimmunity
The natural progression of Type 1 diabetes is hypothesized to occur as the result of a combination of genetic susceptibility factors and environmental triggers causing autoimmunity.2 Autoimmunity in Type 1 diabetes is described as the presence of circulating antibodies to islet and/or beta-cell antigens, often long before the disease state becomes evident.29 The exact mechanism as to how beta-cell autoimmunity is initiated after the precipitating environmental factor is not yet proven. Islet cell autoantibodies have been identified in 85% of patients with newly diagnosed Type 1 diabetes, as well as in individuals with prediabetes. Several specific autoantigens have been identified that may play important roles in the initiation of injury to the beta cells, including insulin autoantibodies (IAA), tyrosine phosphatase islet antigen 2 (IA2A), islet-specific-glucose-6-phosphatase catalytic-subunit-related protein (IGRP), glutamic acid decarboxylase 65 (GAD65), zinc transporter of islet beta cells (ZnT8) and others.30 The presence of specific autoantibodies can be a useful tool in establishing diagnosis because the risk of developing Type 1 diabetes is strongly correlated with the number of positive antibodies. However, the absence of pancreatic autoantibodies does not rule out the possibility of developing Type 1 diabetes and it is estimated that 5% to 10% of all patients with Type 1 diabetes are not positive for islet autoantibodies.8 This indicates that other islet autoantigens may exist.

Additionally, patients with Type 1 diabetes are also more likely to be diagnosed with other autoimmune disorders, including celiac disease, thyroid disorders (e.g., Graves’ disease and Hashimoto’s thyroiditis), Addison’s disease, multiple sclerosis, and others.2 This suggests that simply having an autoimmune disorder may put a person at greater risk for Type 1 diabetes as well.

Environmental Associations
Despite multiple research efforts aimed at identifying specific environmental triggers for diabetes, no clear factor has been linked to islet autoimmunity.17

Geographic location may play a role in predicting the development of Type 1 diabetes. Although the incidence of childhood diabetes is quite variable across the world, specifically in Europe, the risk appears to rise in accordance with one’s distance from the equator.31 The highest reported incidences of Type 1 diabetes occur in Finland and Sardinia, with rates almost 400 times higher than those of children in China and Venezuela, which have the lowest incidence.32,33 However, wide variations in incidence among locations of similar latitude suggest that other factors, besides location, are major contributors.

Perinatal factors, such as maternal age older than 25 years, preeclampsia, maternal diet, maternal infections, jaundice, and neonatal respiratory disease, have been shown to be associated with small increases in risk for developing Type 1 diabetes.34 The observation that Type 1 diabetes autoantibodies often develop early in infancy suggests that fetal exposures may play a role in future disease development. More research is needed in this area for definitive causation to be proven.

Both specific childhood virus exposures and a low overall rate of infection in childhood have been proposed as possible environmental causes of Type 1 diabetes.35 Viruses identified include mumps, rubella, enteroviruses, rotavirus, parvovirus, and cytomegalovirus. Enteroviruses have an affinity for islet cells, specifically, and have been isolated from the islets of patients with Type 1 diabetes. However, this evidence is not conclusive and it is not certain that any of these viruses are involved in causation of the disease. To further confuse the issue, there is evidence that other viruses may protect against the development of Type 1 diabetes, which was suggested by a study that showed increased rates of diabetes in mice that were raised in pathogenic-free environments.36 This theory is similar to the “hygiene hypothesis” and may have to do with the gut microbiome.

It has also been suggested that proteins in cow’s milk may trigger an autoimmune response.37 This is either as a result of early exposure to some component of albumin in the milk or from a cell-mediated response to beta-casein. Longer duration of breast-feeding and supplementation with Vitamin D have been reported to provide partial protection against beta cell autoimmunity and Type 1 diabetes.This research is ongoing as other studies have not found an association between increased rates of type 1 diabetes and early exposure to cow’s milk or lesser duration of breast-feeding.38

TYPE 2 DIABETES

Epidemiology

Type 2 diabetes makes up the majority of diabetes diagnoses and represents approximately 90% to 95% of all diabetes cases worldwide.1 Often referred to as adult-onset diabetes or non-insulin-dependent diabetes, this disease state is generally diagnosed in adults older than 30 years of age but can be diagnosed at any age. This epidemic is most certainly linked to increasing rates of overweight and obese persons in the United States (U.S.) The prevalence of Type 2 diabetes is 3 to 7 times higher for obese adults compared with adults at an optimal body weight.20 It appears to be most common in both the older and non-white population of the U.S. As much as 25% of Americans older than 65 years or older are shown to have diabetes.5 Additional data suggest that the diagnosis of Type 2 diabetes is increasing for the younger population as well. Of the children diagnosed with Type 2 diabetes, 94% are of minority descent, and being overweight or obese especially increases the risk.

Clinical Presentation

Type 2 diabetes is a disease characterized by high blood sugar, similar to Type 1 diabetes. However, unlike Type 1 diabetes, the onset of Type 2 diabetes tends to progress gradually. Typical first symptoms in adults include fatigue, dry skin, poor wound healing, dry mouth, blurred vision, or sometimes there are no symptoms at all.39 Symptoms tend to be poorly differentiated, but can also present overtly, similar to those of Type 1 diabetes, especially if the disease has gone undetected for longer periods of time. The wide range of symptoms at presentation reflects the level of insulin resistance and degree of beta-cell damage that has occurred. Many people already experience long-term complications at initial presentation and this has led scientists to estimate that diabetes may typically be present for 4 to 7 years prior to diagnosis. Examples of these complications include neuropathies, retinopathies, cardiovascular issues, and other microvascular concerns. Because symptoms at presentation vary so widely and are often not recognized, screening of high-risk persons is critical for identifying those with prediabetes or undiagnosed diabetes and preventing the disorder if possible. Hyperglycemia that is pronounced enough to diagnose diabetes is the same criteria used to diagnosis Type 1 diabetes.7 Hyperlipidemia and hypertension are common metabolic comorbidities in these patients and screening all patients with diabetes for blood pressure and lipid abnormalities at diagnosis is recommended.

Type 2 diabetes in children most often occurs in those diagnosed as overweight or obese and in those with a family history of the disease. As many as 85% of children diagnosed with Type 2 diabetes are overweight or obese and as many as 74% to 100% of these children have a first-degree relative with the disease.40 As mentioned before, many of these children are of non-European descent. In general, children present with glycosuria but no evidence of ketonuria, mild thirst complaints, possible slight increase in urination, and little or no weight loss.39 Polycystic ovary syndrome (PCOS) and acanthosis nigricans (thickening and darkening of skin in the neck, groin, or armpit region) are disorders associated with insulin resistance and these are commonly seen in children presenting with Type 2 diabetes as well. The onset of childhood Type 2 diabetes typically occurs around puberty, when insulin sensitivity declines. Metabolic disturbances are also seen in children newly diagnosed and include hypertension (10% to 32%), dyslipidemia (18% to 8%), and microalbuminuria (14% to 22%).

Pathophysiology

Type 2 diabetes is a progressive disease caused by multiple complex metabolic factors that result from defects of specific organ sites. While the mechanism of this process is not completely understood, it is clear that the following abnormalities are occurring: insulin resistance in muscle and adipose tissue, a progressive decline in pancreatic insulin secretion, higher glucagon levels, which cause increased hepatic glucose production, and diminished production of gastrointestinal incretins.2 This process occurs in a progression of clinically defined phases.

Phase 1 is considered the initial stage of the disease during which insulin resistance first occurs, along with impaired insulin sensitivity, and is soon followed by compensatory insulin hypersecretion.39 Almost all patients are asymptomatic at this stage and clinicians are unaware of the disease process. Phase 2 is when pancreatic beta-cell secretion of insulin is impaired even further, so that an abnormal rise of blood sugar occurs after meal intake and fasting glucose levels also rise. This phase is typically called prediabetes. Fasting blood glucose typically rises to 100 mg/dL or higher (100 to 125 mg/dL) and this is referred to as impaired fasting glucose, Upon observation, 2-hour postprandial readings climb to 140 mg/dL or higher (140 to 199 mg/dL) when impaired glucose tolerance occurs and hemoglobin A1c readings can be found slightly elevated to 5.7% or greater (5.7% to 6.4%).7,20 Lastly, in phase 3, overt diabetes occurs as the result of a progressive decline in beta-cell function as well as additional decreases in insulin production. Lack of insulin sensitivity is accompanied by increased hepatic glucose production as well.39 This phase is sufficient enough to produce fasting glucose levels diagnostic of diabetes (126 mg/dL or greater); however, most will still not experience any of the symptoms of diabetes. It is important to remember that progression to diabetes among those with risk factors for diabetes is not inevitable. Several studies, including the Diabetes Prevention Program Research Group, have shown that people with prediabetes who exercise regularly and lose weight can at least delay, if not prevent Type 2 diabetes.4

Figure 2 – Natural Progression of Type 2 Diabetes.41
Figure 2 – Natural Progression of Type 2 Diabetes.

Insulin Resistance

Type 2 diabetes is a complex syndrome characterized by the following 2 defective insulin-mediated processes: impaired glucose metabolism into insulin-sensitive tissues and the decreased effectiveness of insulin to suppress glucose production by the liver.42 Multiple cellular defects in insulin action have been discovered, including impairment of glucose transport, glucose phosphorylation, glycogenesis, and glucose oxidation. Central obesity appears to be one of the most important causes of insulin resistance development. Insulin resistance also contributes to lipid abnormalities, as evidenced by elevations in triglyceride-rich lipoproteins and decreases in high density lipoprotein (HDL) cholesterol levels for those individuals with hyperinsulinemia. When a patient possesses multiple risk factors for heart disease, including central obesity, elevated lipids, increased blood glucose, and/or hypertension; this myriad of risk factors is called metabolic syndrome.2,43 These patients are at especially high risk for diabetes and end organ complications. Epidemiological studies suggest that high insulin levels may be associated with coronary artery disease, as well, and that insulin resistance correlated with carotid intimal medial wall thickness.43 A more precise measure of insulin action is critical for defining the relation between insulin resistance and coronary artery disease.

Beta-Cell Dysfunction

Normally, pancreatic beta cells respond to changes in blood glucose and food intake in a complex fashion that maintains normal blood glucose levels throughout the day.20 Type 2 diabetes impairs beta cell function in several ways. When insulin resistance and increased hepatic glucose output are present, initially pancreatic insulin secretion is increased to compensate for these impairments temporarily. However, persistent fasting hyperglycemia does not allow this compensatory mechanism to continue forever and eventually insulin secretion declines. About 70% of beta-cell function is already lost by the time the 2-hour postprandial glucose level is 120-140 mg/dL.44 Some studies show that a decrease in the beta-cell mass and an increase in beta-cell apoptosis may be the causation of impaired insulin secretion and an overall decrease in beta-cell function.45 Individuals with prediabetes and Type 2 diabetes have been shown to have decreased beta-cell mass compared with their counterparts without diabetes, regardless of weight status.

Hepatic Glucose Production

A secondary cause of increasing blood glucose levels is excessive hepatic glucose production.2 In fasting conditions, glucose is produced by the liver; however, the liver of a person with diabetes will produce substantially more glucose and burden the circulation with extra glucose. This is caused by the excess glucagon levels of people with Type 2 diabetes. Reduced insulin/incretin hormones cannot allow for the normal suppression of glucagon levels in hyperglycemic conditions. In addition, insulin normally causes glucose uptake into the muscle and adipose tissue and a decrease in hepatic glucose production. Insulin is needed to signal the liver to stop glucose production; so, as insulin levels decline, the liver produces more glucose than the body can use and glucose levels in the plasma continue to rise.

Incretin Effect

Incretin hormones in the gastrointestinal tract have been implicated as a factor in the development of Type 2 diabetes. Incretins are naturally occurring hormones that the gut releases throughout the day to facilitate the response of the pancreas and liver to variations in blood glucose.46 The main incretins responsible for this are thought to be glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). The activity level of these incretins is increased substantially when food is ingested. When blood glucose rises, both GIP and GLP-1 stimulate beta cells to secrete insulin and the alpha cells of the pancreas to suppress glucagon release from the liver. Patients with prediabetes and Type 2 diabetes are deficient in GLP-1. This deficiency contributes to excess hepatic glucose production, failure to suppress production of hepatic glucagon after meal intake, and increased appetite. These same people also show increases in dipeptidyl peptidase-4 activity (DPP-4) in the fasting state. DPP-4 enzymes break down GLP-1 hormones in the body and this may explain why GLP-1 secretion is impaired after meal intake in those with Type 2 diabetes.20

Figure 3. Contributing Factors in the Pathophysiology of Type 2 Diabetes2,20,42
Figure 2 – Natural Progression of Type 2 Diabetes.

RISK FACTORS

Family History/Ethnicity

The development of Type 2 diabetes is clearly linked to family history. In fact, at least 39% of patients with Type 2 diabetes have at least one family member with the disease.47 Additionally, Type 2 diabetes prevalence varies tremendously among groups with different ethnic origins, with non-white Americans of African-American, Native American, and Hispanic origin having 2 to 6 times the rate of Type 2 diabetes as compared with whites living in the same environment.48 First-degree relatives of patients with Type 2 diabetes are at least 3 times more likely to develop the disease than those without a family history of the disorder.39 Very high concordance rates, some as high as 90% (i.e., Type 2 diabetes presenting in monozygotic twins), suggest that the heritability of Type 2 diabetes exists.49 This clustering of Type 2 diabetes within family lines is complicated by other factors, such as shared environmental risk factors, like obesity and sedentary lifestyle, making family history likely only partially responsible. Furthermore, Type 2 diabetes is much more common than Type 1 diabetes and the appearance of subsequent family members with the disease may just reflect that commonality.

Genetics

The genetics of Type 2 diabetes is quite complex and not completely understood. Most cases of Type 2 diabetes involve many genes contributing small parts to the overall condition. More than 36 genes have been identified as contributing to risks for Type 2 diabetes, but only 10% of the heritability of Type 2 diabetes can be explained.20 For most patients, it is impossible to identify a genetic abnormality and environmental factors are more predominate. The genes that have been associated with Type 2 diabetes include transcription factor 7-like 2 (TCF7L2), peroxisome proliferator-activated receptor gamma (PPARG), potassium inwardly rectifying channel - subfamily J - member 11 (KCNJ11), the sulfonylurea urea receptor (ABCC8), Calpain 10, glucose transporter 2 (GLUT 2), the glucagon receptor (GCGR), and many others.50 Defects at TCF7L2 impact beta-cell development and function and studies show that carriers of one risk allele have an approximate risk of Type 2 diabetes that is 40% higher than carriers with a protective allele. Additionally, one genetic variant of the PPARG gene causes decreased insulin sensitivity and increases the risk for Type 2 diabetes by severalfold. This gene is thought to be more common in Caucasians. Calpain 10 and ABCC8 variations contribute to decreased insulin secretion and, thus, increase risk for diabetes. Interestingly, most of the genes identified impact insulin secretion and regulation mediated from the pancreas. In contrast, genes that have been linked to insulin resistance, obesity, and other aspects of glucose metabolism are much less common.

Environmental Factors

Obesity, aging, a longer life span, smoking, insufficient energy consumption, and physical inactivity are all environmental factor examples, affecting the progression of the Type 2 diabetes continuum.51 Central or visceral obesity seems to be specifically problematic and a major contributor to insulin resistance. Decreased daily activity related to modern technology and changes in the American diet, including increased fat intake, increased simple sugar intake, and a decrease in dietary fiber intake, have all contributed to the obesity epidemic as well. Even mild obesity can contribute to glucose intolerance. Those of Japanese origins are especially prone to central obesity and, thus, a lower body mass index (BMI) target has been recently suggested for them (23 BMI).7 Smoking has been shown to be especially detrimental to health and increases the risk for diabetes by 30% to 40% , along with the long-term complications risk.52

Medications that may impair glucose tolerance by decreasing beta-cell insulin secretion, increasing glucose production in the liver, or causing insulin resistance are vast. Glucocorticoids, oral contraceptives, beta-blockers, thiazide diuretics, statins, protease inhibitors, atypical antipsychotics, cyclosporine, tacrolimus, and others comprise this list.53 Pharmacists should be especially vigilant to review all medications for patients with diabetes, or those at risk for diabetes, for possible hyperglycemia adverse reactions.

Intrauterine developmental causes have also been implicated in the development of Type 2 diabetes recently. The theory of the thrifty genotype suggests that insulin resistance is both beneficial and detrimental by improving survival during states of caloric deprivation, but leading to negative consequences in states of caloric excess.54 This theory has been hypothesized to occur during early life in the womb if intrauterine growth restriction and low birth weight are caused by malnutrition. Thus, those infants born with low birth weights (less than 3.5 kg) are at greater risk for developing diabetes in adulthood. Conversely, high birth weight is also a risk factor for diabetes (greater than 4 kg).55 It has been shown that prenatal exposure to hyperglycemia can cause higher birth weights and may increase the risk for Type 2 diabetes, regardless of genetic predisposition. Other studies indicate that premature children may also be at greater risk for diabetes.55 More research is needed to confirm these findings. However, it is apparent that prenatal influences may have great determinants for the risk of developing diabetes in the future.

OTHER TYPES OF DIABETES

Latent autoimmune diabetes in adults (LADA), also known as Type 1.5 diabetes, is a slow, progressive form of Type 1 diabetes that is often misdiagnosed as Type 2 diabetes initially.20 Even though these patients experience the same autoimmune process as those with the classic presentation of Type 1 diabetes, they may not have to inject insulin treatments for many years because of the slow onset of disease. Patients with LADA are typically not obese and are usually older than 35 years of age. They may be able to control blood sugars initially with diet and then progress to oral agent use; however, inevitably, they will require insulin at some point. The time frame from the initial diagnosis of LADA to the use of insulin is variable, depending on the degree of beta-cell dysfunction present. Most patients with LADA will require insulin soon after diagnosis, but some may be able to function without insulin use for longer periods of time. Because of this, LADA is often misdiagnosed as Type 2 diabetes initially.

Idiopathic diabetes is a form of Type 1b diabetes with no known etiology.7 Patients with this disorder are prone to ketoacidosis and exhibit varying degrees of insulin deficiency, but have no evidence of autoimmunity. This form of the disease appears to be strongly tied to family inheritance and most of those affected by it are of Asian or African ancestry.

Maturity-onset diabetes of the young (MODY) is a rare form of diabetes that results from a defect in a single gene.7,20 Abnormalities at 6 genetic loci on different chromosomes have been identified as contributors. Monogenic in nature and very rare, this type of diabetes only accounts for 1% to 5% of all diabetes diagnoses in young people. MODY does tend to run in families and typically occurs in adolescence or early adulthood. People with MODY are usually not overweight and do not present with other risk factors for diabetes. MODY can be treated with oral antihyperglycemic agents and often does not require insulin.

Gestational diabetes is termed as any degree of glucose intolerance with onset during pregnancy.7 The incidence of gestational diabetes varies among populations and ethnicities; but, it is estimated that of the 6% to 7% of pregnancies affected by diabetes, 90% of them are gestational diabetes. The rate of gestational diabetes is increasing and this is most likely a result of the increasing number of overweight and obese women in their childbearing years.57 Physical activity and a well-balanced diet are key counseling points when discussing how to reduce newborn complications for patients with gestational diabetes. In addition, some expectant mothers may have glycemic levels sufficient enough to warrant medication therapies. Insulin, sulfonylurea, and metformin are the only medicinal therapies used by women with gestational diabetes. The risks posed by the medicinal therapy chosen should not outweigh the benefits of lowering glucose levels. Women who are diagnosed with gestational diabetes are also at greater risk for Type 2 diabetes in their lifetime and should be monitored regularly after delivery of the child.

Neonatal diabetes occurs within the first 6 months of life and is extremely rare.7 It has not been shown to be an autoimmune process like Type 1a diabetes. This type of diabetes can be transient or permanent depending on the genetic defect. If it is permanent, treatment options depend on the genetic defect and include sulfonylurea options and/or insulin therapies.

Cystic fibrosis-related diabetes is the most common comorbidity for people with cystic fibrosis.2,7 Partial destruction of the islet mass causes decreased insulin production in this population and nearly 40% to 50% of adults with cystic fibrosis are affected by this condition. These patients are generally treated with insulin.

Various other secondary forms of diabetes exist; however, they are quite rare and make up less than 2% of all diabetes statistics.7

SUMMARY

Diabetes is an increasing concern within the U.S., as well as the world. Its remarkable growth rate has reached an epidemic proportion in recent years. While the majority of diabetes cases diagnosed in the U.S. are of Type 2 diabetes, cases of Type 1 diabetes are also increasing.1,5 It is difficult to pinpoint the exact causation for diabetes, but it is clear that environmental exposures, lifestyle factors, and genetics all play an integral part. Regardless of the etiology, all types of diabetes are associated with long-term complications. Disappointing data show that hemoglobin A1c values tend to increase by 1% every 2 years, even with the most aggressive interventions.58 Patients with diabetes require repeated intervention and compliance to therapies for success. Pharmacists in clinical roles can be advocates for evidence-based practices to decrease the clinical inertia related to diabetes treatment as well as an important point of contact to patients for medication counseling and adherence assistance. Additionally, future attempts to prevent and/or reverse diabetes are most likely to succeed if they include the most recent advances in the understanding of the complex pathogenesis of the disease. Pharmacists play an important role communicating medical information to patients about diabetes and need to stay updated on new prevention techniques, treatment devices, and therapies.

Potential Counseling Tips for Pharmacists
Category Potential Counseling Tips
Prevention
  • Research has shown that the development of type 2 diabetes can be delayed or prevented by eating healthier foods, exercising, or losing weight if necessary.4
  • Preventing diabetes in you and your loved ones will not only lead to better health, but will also help you avoid hassle (i.e., less visits to the physician and less time in the hospital) and costs (i.e., costs of medical care and lost work).
  • You can potentially prevent diabetes complications by staying in good control.3 This is a great point to bring out to your patients.
Screening
  • Because symptoms at presentation vary so widely and are often not recognized, screening of high-risk persons is critical. The pharmacist can then offer to screen the patient or refer him/her to the next health fair, during which screenings will be performed at low or no cost.
  • Patients diagnosed with diabetes type 2 should also receive screenings for high cholesterol and blood pressure.
  • Know how to identify the symptoms of diabetes in your patients. Some common symptoms to watch out for are increased thirst, increased urination, and unexplained weight loss.

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