Type 1 Diabetes in Adults
The patient who knows the most lives longest.
—Eliot Joslin, MD, Student, educator, patient advocate, innovator, author, diabetes pioneer. 1869-1962.
Historical Perspective: The Discovery of InsulinThe discovery of insulin in 1922 by Frederick Banting and Charles Best remains one of the most dramatic achievements in the history of medicine. Before the availability of insulin, a child newly diagnosed with type 1 diabetes (T1DM) survived on average 1 year.1 Patients were treated with caloric-restricted diets averaging 500 to 700 calories per day. So strict were these dietary restrictions that patients were forced to count out the exact number of berries that they could eat per day and would be labeled as “noncompliant” if they added any extra food to their daily dietary intake. Surviving patients with diabetes would lose an extraordinary amount of weight and yet would remain under the threshold for developing diabetic ketoacidosis (DKA) as long as they could maintain their starvation diets.
Leonard Thompson, 14 years old, was the first patient ever to receive an injection of insulin. Weighing only 65 lb on admission to Toronto General Hospital 2 years after being diagnosed with diabetes, Leonard appeared pale, with a distended abdomen and breath that smelled of acetone. “All of us knew that he was doomed,” wrote a senior medical student in attendance.2 The boy had survived on a caloric intake of only 450 calories daily, just enough to keep him from becoming ketotic. Anxious to try out his unpurified pancreatic extract on human subjects rather than dogs, Dr. Banting, a general surgeon by training, injected Leonard with 15 mL of a “thick brown muck” on January 11, 1922. (The dose chosen was 50% of the dose thought to be appropriate for a dog of equal weight.) Leonard’s blood glucose dropped from 440 to 320 mg per dL and he continued to have ketonuria. Unfortunately, Leonard developed multiple sterile abscesses from the injections. Banting thought that his experiment was a failure, despite the 25% improvement in glycemic response to the extract.
A biochemist, James Collip (who shared the Nobel Prize for Medicine with Banting and Best in 1923), was able to purify the extract in his own laboratory. On January 23, 1922, Leonard Thompson received 5 mL of the purified drug, followed by a second dose of 20 mL 6 hours later. The next day he received two 10-mL injections. His initial blood glucose level of 520 mg per dL fell to 120 mg per dL within 24 hours and his ketonuria disappeared. The patient’s condition continued to improve with the insulin extract.
TABLE 11-1. Currently Marketed Insulin Analogue Preparations | ||||||||||||||||||
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Compliance was one of Leonard’s weaker points. During a celebration marking the 10th anniversary of the discovery of insulin, the world’s poster boy for diabetes became comatose after consuming an excessive amount of alcohol and party pastries. Fortune again prevailed, allowing Leonard to survive another hospitalization until finally succumbing to pneumonia at age 27.
The first commercial insulin preparations contained numerous impurities and varied in potency by up to 25% per lot. In the 1930s, the first long-acting preparation, protamine zinc insulin (PZI), was marketed, which reduced the number of injections required for adequate insulin replacement.3 PZI was used once daily without adding any short-acting insulin, setting a trend that lasted until the 1950s when NPH and zinc insulin (Lente) were marketed. For the next 25 years, diabetes was treated using two injections of NPH and regular insulin featuring the famous 2/3:1/3 ratio, in which higher doses of insulins were given with breakfast. In the 1980s, the introduction of human insulin eliminated commonly observed insulin allergies and the cosmetically disfiguring immune-mediated lipoatrophy requiring patients to “rotate” the sites of their injections to prevent areas of skin atrophy.4 In the 1990s, the relationship between improving glycemic control and reducing diabetes-related complications was confirmed.5,6
The absorption patterns and pharmacologic actions of the standard insulins did not match the physiologic nature of endogenous insulin. Patients experienced wide daily glycemic changes, including hypoglycemia, while maintaining acceptable A1C levels. In an attempt to mimic normal pancreatic endogenous insulin action, insulin analogues were developed. The first insulin analogue, lispro, was introduced in 1996 followed shortly thereafter by insulin aspart. The newest fast-acting analogue, insulin glulisine, became available in 2005. Table 11-1 lists the currently marketed insulin analogue preparations. Insulin analogues are more physiologic than NPH and regular insulin, thereby allowing patients to experience more flexibility and safety with their treatment regimens.
T1DM Disease ClassificationT1DM accounts for 5% to 10% of all individuals diagnosed with diabetes and results from a cellular-mediated autoimmune destruction of the pancreatic β-cells. Markers of the immune destruction of β-cell include islet cell autoantibodies (ICAs), autoantibodies to insulin (IAA), autoantibodies to GAD (GAD65), an antibody to an insulinoma-associated antigen-2 (ICA512), and autoantibodies to the tyrosine phosphatases (IA-2 and IA-2β).7 One and usually more of the autoantibodies are present in 85% to 90% of individuals when fasting hyperglycemia is initially detected.
In T1DM, the rate of β-cell destruction varies. Whereas infants and children tend to demonstrate rapid β-cell death, adults typically present with a lengthy prodromal phase leading to latent autoimmune diabetes of adulthood (LADA).8 Some patients, particularly children and adolescents, may present with ketoacidosis as the first manifestation of the disease. Others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of infection or other sources of physiologic stress. Still others, particularly adults, may retain residual β-cell function (remaining C-peptide positive) sufficient to prevent ketoacidosis for many years; such individuals eventually become dependent on insulin for survival and are at risk for ketoacidosis. At this latter stage of the disease, there is little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide. Immune-mediated diabetes commonly occurs in childhood and adolescence, but may occur at any age, even in the eighth and ninth decades of life.
Patients with T1DM are prone to other autoimmune disorders such as autoimmune thyroid disease (15% to 30%), celiac disease (4% to 9%), and Addison disease (0.5%). Assays for thyroid peroxidase autoantibodies (TPOAb) in autoimmune thyroid disease, tissue transglutaminase autoantibodies (TTGAb) in celiac disease, and 21-hydroxylase autoantibodies (21OHAb) in Addison disease may be used to screen for asymptomatic patients to identify one’s risk of clinical progression. Thirty-three percent of patients with T1DM screen positive for at least one additional organ-specific autoantibody when initially diagnosed with diabetes, and 19% have evidence of clinical disease. Given the high preponderance of these antibodies at the onset of T1DM, screening for coexisting autoimmune disorders appears to be warranted.9
Nearly 50% of African-American, nonwhite Hispanic, and other minority ethnic group patients with newly diagnosed ketoacidosis may appear to have T1DM when in fact their diagnosis is one of “Flatbush diabetes.” These patients are typically obese, have a strong family history of T2DM, and lack autoantibodies. Their initial clinical symptoms include acute onset of polyuria, polydipsia, weight loss, fatigue, and metabolic decompensation. However, upon initiation of insulin, β-cell function and insulin sensitivity are restored and they begin to secrete measurable and predictable amounts of endogenous insulin. Increased susceptibility to glucose desensitization could be one cause of Flatbush diabetes.10
Patients with near-complete insulin deficiency who remain antibody-negative are classified as having “type 1B diabetes.”11 Most type 1B patients are of African or Asian ancestry. Table 11-2 lists the facts and figures related to T1DM in the United States and worldwide.
Pathogenesis of T1DM: From Cause to CureTwo questions are always asked by patients with T1DM and their family members: “How did I get this disease?” and “When will you find a cure?” Affecting a cure or preventing any disease demands that one understand its pathogenesis, determine the risk factors that heighten one’s susceptibility to the condition, and develop a model that allows one to accurately predict the likely course of disease progression. For diabetes, this assignment is akin to assembling a jigsaw puzzle where the manufacturer forgot to include several important anchoring pieces. Successful completion of the puzzle requires the “players” to initially locate the four anchoring corners. Work then centers on precisely filling in as many pieces of the puzzle as possible as each placement is challenged by other players in the scientific community. Just when one thinks the puzzle is nearing completion, an anchoring corner morphs. The broad picture that was once viewed with anxious anticipation is now just a distant memory. Although we have become better assemblers of jigsaw puzzles for our efforts, the search begins anew for those all-important anchoring corners. For scientists, locating these important four corners of the puzzle is proving to be an elusive task. What are the four anchoring corners of T1DM disease prevention and cure?
• Question #1: What is the triggering mechanism for autoimmune β-cell destruction?
Our first puzzle corner identifies the specific origin of T1DM. Does T1DM result from genetic susceptibility in individuals who perhaps lack a protective mechanism that permits an aggressive
and sustained autoimmune destruction process within the pancreatic islets? To what extent do environmental factors play in triggering the pathogenesis of autoimmune dysfunction in genetically prone patients? Finding genetically prone individuals would allow us to vaccinate against T1DM. Moreover, patients who are noted to have an autoimmune response within their islets can undergo therapeutic interventions to “reboot” their immune system. Therefore, finding this piece of the puzzle is of utmost importance.
and sustained autoimmune destruction process within the pancreatic islets? To what extent do environmental factors play in triggering the pathogenesis of autoimmune dysfunction in genetically prone patients? Finding genetically prone individuals would allow us to vaccinate against T1DM. Moreover, patients who are noted to have an autoimmune response within their islets can undergo therapeutic interventions to “reboot” their immune system. Therefore, finding this piece of the puzzle is of utmost importance.
TABLE 11-2. Facts and Figures for T1DM | ||||||||||||||||||
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Studying the genetics of T1DM has been very time intensive. Over 100 candidate genes (a gene suspected to be involved with a particular disease) on 14 different chromosomes have been detected that influence one’s likelihood of either developing T1DM or preventing the disease.12,13 Candidate genes do not appear to have any effect on disease pathogenesis or progression, only on disease protection and susceptibility.
Two combinations of HLA genes (or haplotypes) are of particular importance: DR4-DQ8 and DR3-DQ2 are present in 90% of children with T1DM and are considered susceptibility genes.14 A third haplotype, DR15-DQ6, is found in less than 1% of children with T1DM, compared with more than 20% of the general population, and is considered to be protective against the development of T1DM.15 The genotype combining the two susceptibility haplotypes (DR4-DQ8/DR3-DQ2) contributes the greatest risk of the disease and is most common in children in whom the disease develops very early in life.16 First-degree relatives of these children are themselves at greater risk of T1DM than are the relatives of children in whom the disease develops later.17 The overall risk of an offspring of a mother with T1DM developing T1DM is 3%.18
Can environmental factors trigger T1DM within different ethnic populations? One of the most striking characteristics of T1DM is the large geographic variability in the incidence. Scandinavia and the Mediterranean island of Sardinia have the highest incidence rates of T1DM in the world, whereas Asian populations have the lowest rates.19 For example, a child in Finland is 400 times more likely to develop diabetes than one in China.20 While there is a strong south-north gradient in the incidence, “hot spots” in warm climates have also been reported (Sardinia, Puerto Rico, Kuwait).
Does the geographic and ethnic variability observed within T1DM “hot spots” suggest that an environmental “trigger” activates T1DM in genetically susceptible patients who populate that region? Identification of such environmental factors has proved frustratingly difficult. The most popular candidates are viruses, with enteroviruses, rotavirus, and rubella being suspects. The strongest data to date have supported a role for rubella.21,22 Infants infected with congenital rubella syndrome are said to be at increased risk of T1DM.23 Yet Finland, where vaccination has effectively eradicated rubella, still has the highest incidences of T1DM.24 There is also evidence that some enteroviruses (e.g., Coxsackie B viruses) are less prevalent in countries with high incidences of T1DM (e.g., Finland) than in countries with low incidences but geographically similar populations (e.g., Russian Karelia).25 This observation may be in keeping with the concept of the hygiene hypothesis, which proposes that environmental exposure to microbes, other pathogens, and their products early in life promotes innate immune responses that suppress atopy and perhaps autoimmunity.26 In Western cultures, the developing immune system of the infant is no longer exposed to widespread infection, which may contribute to the current increases in incidence observed in atopic and autoimmune diseases.
Other environmental risk factors that have been linked to T1DM pathogenesis include the frequency and duration of breastfeeding27 and the consumption of cow’s milk.28,29
A study published by Mohr et al.30 suggested an association in the incidence of T1DM and low ultraviolet light radiation. This could support a contributing role of vitamin D in reducing the risk of developing the risk of T1DM. Mohr suggested that a 350-fold range of age-standardized incidence rates of T1DM, from an average of 0.1 per 100,000 in boys less than 14 years of age in China to 37 per 100,000 in boys less than 14 years in Finland.19 Exposure of the skin to sunlight is the source of 80% to 95% of circulating vitamin D and its metabolites. Thus, availability and intensity of sunlight, which are highly related to latitude, are strong correlates of the principal circulating vitamin D metabolite in the serum, 25-hydroxyvitamin D [25(OH)D]. The authors suggest that children aged ≥1 year who live more than 30 degrees from the equator should consume 1,000 to 2,000 IU per day of vitamin D3, especially during winter, to substantially reduce their risk of developing T1DM.
A population-based study by Gorham et al.31 examined electronic medical records of military personnel in the San Diego area from 1990 through 2005. During this time, the age-adjusted incidence rate of new-onset T1DM in military personnel aged 18 to 44 was 17.5 per 100,000 person years (for men), with rates being twice as high in blacks as in whites (31.5 vs. 14.5 per 100,000, p < 0.001). In women, the age-adjusted incidence rate was 13.6 per 100,000 with rates being twice as high in black as for white women (21.8 vs. 9.7% per 100,000, p < 0.001). The incidence of insulin requiring diabetes peaked annually in the winter-spring season. The authors concluded that winter season and black skin pigmentation substantially reduced the photosynthesis of vitamin D3 in the skin of black soldiers, creating a higher prevalence of vitamin D deficiency. This vitamin
deficiency, in turn, was thought to be an environmental contributing factor to the initiation of pathways that could trigger autoimmune destruction of β-cells.
deficiency, in turn, was thought to be an environmental contributing factor to the initiation of pathways that could trigger autoimmune destruction of β-cells.
The most recent evidence suggest that compromises in proper regulation of self-reactive and protective immune responses may be the result of abnormal activities of a population of T-regulatory (T-reg) cells. Loss of the “T-reg” cells promotes the initiation and progression of the autoimmune process.32 Other studies have implicated stressful lifestyles and dietary practices such as the consumption of artificial sweeteners, caffeine, and even smoked fish.
In summary, one should perhaps consider a multitude of individual environmental triggers that have an effect of dysregulation of normal immune protection over the course of several months or years during one’s prediabetes stage. Hence, many “environmental criminals” have been implicated in T1DM pathogenesis, but none has been convicted by a jury of peer reviewers.26
• Question #2: What are the natural history and progression of T1DM?
The second anchoring piece of the puzzle for T1DM cure and prevention must accurately depict the natural history of T1DM allowing scientists to establish effective points of intervention. In 1986, George Eisenbarth proposed that patients born with a genetic susceptibility to T1DM encounter a disease-inciting environmental agent that elicits an autoimmune reaction within the pancreatic islets resulting in the appearance of autoantibodies.33 Patients with detectable autoantibodies may exhibit loss of β-cell function and first-phase insulin response at different rates. A faster rate of progression to diabetes was observed in subjects with abnormal baseline glucose tolerance than among those with normal baseline glucose tolerance but low first-phase insulin response to an intravenous glucose challenge.40 A recently published study suggests that a combination of metabolic markers derived from oral glucose tolerance tests performed on ICA-positive patients with low first-phase insulin response improves the accuracy of predicting the 5-year progression to T1DM.33a
Still to be explained is why some patients who possess a histocompatibility complex haplotype that favors progression toward T1DM will not develop any signs of impaired glucose metabolism. Others possessing the same haplotypes will develop diabetes at a young age, whereas diabetes onset may be delayed until adult life in others. Forty to fifty percent of the risk for T1DM appears to be associated with the MHC complex or IDDM 1 loci. The MHC genes most associated with diabetes in white people are known as the human leukocyte antigens HLA DR3 and HLA DR4. Other racial groups are less well studied and may have different MHC gene profiles. More than 90% of European ancestry individuals with T1DM will have one or the other of these DR3 or DR4 haplotypes, but about 40% of the general population has one of these gene locations as well. The presence of high-risk haplotypes and evidence of positive antibodies, however, strongly predict the development of diabetes. Some MHC genes are protective against T1DM. Less than 1% of individuals with diabetes have these protective haplotypes.36 Perhaps points of intervention may be based within ethnic and genetic profiling. The inciting environmental event(s) that trigger autoimmunity over time have yet to be identified beyond speculation. More likely, multiple triggers are required to induce autoimmune dysregulation in genetically susceptible individuals. Once β-cell injury occurs, is the loss of mass and function linear, and could one experience periods of remission and β-cell recovery? Unfortunately, we have yet to define the most effective measurement of β-cell mass and function in vivo. Why in some cases does β-cell injury or death progress rapidly and in others the destruction of islets is protracted as in LADA? Can β-cell regeneration occur in some patients who initially experience significant apoptosis? Remember those Flatbush diabetes patients who present with acute onset of DKA only to recover nearly complete β-cell insulin secretion.37
• Question #3: What are the best predictable risk factors for developing T1DM?
Predicting who is likely to develop T1DM and how this information may be clinically applicable provides the next puzzle cornerstone piece. In one study, adult patients who tested positive for GAD65 antibodies, thyroid peroxidase antibodies, and IA-2AB showed a faster disease progression than patients who were positive only for GAD65 antibody. Thus, the number, rather than the specific autoantibody, appears to predict disease progression over a 4-year period.38
Ethical and financial barriers may limit the utility of screening high-risk patients for T1DM. Only 1 person in 300 is diagnosed with T1DM before age 20. Assuming the cost of autoantibody screening ranges between $241 and $788 per patient, one would spend a minimum of $73,000 per single case of T1DM identified that would possibly progress to clinical diabetes.39 Once screened, how could this information be used to prevent or delay the onset of T1DM?40 From a practical standpoint, who should perform and interpret the results of autoantibody testing? Finally, once a patient tests autoantibody positive, how will this information be handled by third-party payers or by government-run health-care programs?
T1DM may be predicted in individuals based upon not only the presence of one or more autoantibodies but the titers of those antibodies obtained at the time of testing. GAD65 and ICA antibodies have the highest predictability for T1DM.41 The combination of GADAs and IA-2As has a high sensitivity and specificity for T1DM in family members, although prospective studies from birth have shown that IAAs are usually the first or among the first antibodies to appear in young children.42 An observational study of 3475 Finnish children who were initially recruited in 1980 for a population-based study on cardiovascular risk collected GAD and IA-2A antibodies. Sera were again collected in 1986 and 2007.43 One-time screening for GAD-65 antibodies and IA-2As was capable of identifying 60% of patients who developed T1DM over 27 years. The highest predictive value was seen in those testing initially positive for both GAD-65 and IA-2As, but the sensitivity dropped from 50% for either test alone to 39%.
• Question #4: How can T1DM be prevented?
The final keystone piece of the T1DM puzzle identifies means by which the disease can be prevented. T1DM occurs in individuals in whom genetic susceptibility outweighs genetic protection. Distinctive environmental triggers play a supporting role in provoking a cellular-mediated autoimmune process to one or more β-cell proteins (autoantigens). As islet cell destruction occurs, autoantibodies are delivered into the pancreatic lymph nodes where destructive T-effector cells are produced that outnumber the stabilizing T-reg cells. Initially, the decline in β-cell function and loss of β-cell mass presents clinically as loss of first-phase insulin response to an intravenous glucose challenge. Over time, patients progress through stages of “dysglycemia” [glucose values greater than 200 mg per dL at 30, 60, or 90 minutes during an oral glucose tolerance test (OGTT)]. Ultimately, the clinical syndrome of T1DM becomes evident when the majority of β-cell function has been lost and most β-cells have been destroyed. At this juncture, frank hyperglycemia supervenes.
In one study, the metabolic profiles of 54 patients from the Diabetes Prevention Trial-1 were evaluated over time to obtain a clinical profile of metabolic progression to T1DM over a period of 2.5 years before diagnosis.44 All subjects had OGTTs at 6-month intervals beginning 30 months prior to being diagnosed with T1DM. Most had OGTTs at diagnosis. Changes in OGTT glucose and C-peptides (an indicator of one’s endogenous insulin production) were examined and paired between time points. The data indicate that hyperglycemia begins to develop at least 2 years prior to the time of diagnosis after which glucose levels continue to increase gradually until 6 months prior to diagnosis. OGGT levels rise sharply within 6 months of the diagnosis. As hyperglycemia worsens, fasting C-peptide levels remain constant. The consistency of the fasting C-peptide-to-fasting glucose ration indicates that fasting endogenous insulin levels are maintained to a large extent until one is diagnosed with T1DM. Stimulated C-peptide levels tend to fall rapidly beginning 6 months prior to the diagnosis. Thus, with progression to T1DM, fasting insulin secretion is preserved to a greater extent than postprandial glucose.
At what point in this disease progression can T1DM be prevented? To date, no intervention has been developed that can unequivocally prevent the development of T1DM or arrest the progression of immune system destruction of β-cells after diagnosis, although some promising studies have given the field much encouragement. One novel technique uses monoclonal antibodies to “reboot” dysregulated immune functioning in patients newly diagnosed with T1DM. Monoclonal antibodies are produced in a laboratory and target a specific predetermined antigen. Immune destruction of islet cells is mediated by T-lymphocytes that express CD3, CD4, and CD8 receptors on their cell
surface. If one binds a monoclonal antibody (otelixizumab) to a CD3 receptor in newly diagnosed patients with T1DM, endogenous insulin production improves for 4 years. However, disease remission does not occur.45
surface. If one binds a monoclonal antibody (otelixizumab) to a CD3 receptor in newly diagnosed patients with T1DM, endogenous insulin production improves for 4 years. However, disease remission does not occur.45
Rituximab, an anti-CD20 chimeric antibody that depletes B-lymphocytes, has shown encouraging initial clinical results. A recent TrialNet-funded study demonstrated that a four-dose course of rituximab could preserve β-cell function over a 1-year period in patients with newly diagnosed T1DM.46 Vaccination with an alum-formulated GAD65 autoantigen failed to slow the loss of stimulated C-peptide, improve A1C, daily insulin doses, or rates of hypoglycemia in newly diagnosed patients with T1DM when compared with a placebo vaccine.47
Systemic anti-inflammatory agents such as IL-1 receptor antagonists48 and agents that stimulate β-cell proliferation are also being studied as potential components of a multidrug prevention of β-cell destruction.49
Therapies directed at preventing or reversing immune destruction of β-cells appear to have positive effects that are only transient. Attempts to reboot the immune system may be countered by a surge of islet autoantibody production that overwhelm the very protective mechanisms they are designed to protect. Future preventive therapies for T1DM will need to offer combination interventions in order to fully mitigate one’s dysregulated immune.
Another area of research interest involves β-cell regeneration and replacement. This complex restorative process will require a more comprehensive insight into the mechanics of β-cell differentiation and proliferation. Potential sources of β-cells include existing β-cells, stem cells, progenitor cells, and pancreatic ductal cells. Stem cells can proliferate indefinitely and differentiate into any cell type including normal β-cells. However, stem cells have yet to be used in clinical trials, so their efficacy and potential risks, particularly of tumorigenecity, are not known. In addition, stem cell-derived β-cells may be more susceptible to immunologic attack.
Although there are inspiring opportunities in diabetes prevention and reversal, most of these efforts are unfolding at large academic or research-focused medical centers. Nonetheless, there is a vital role for family physicians who work with individuals at high risk for developing T1DM.
In families with established T1DM, all first-degree relatives, including the parents of the patient (if they are less than 45 years of age), are at increased risk for T1DM and should be counseled regarding this risk. Identical twins are at the greatest risk. Second- and third-degree relatives of a patient with T1DM are also at heightened risk if they are less than 21 years of age.
Once apprised of their diabetes risk, individuals should be made aware of T1DM screening and intervention studies such as T1DM TrialNet through the National Institutes of Health (http://www.diabetestrialnet.org/). The advantages of screening for T1DM risk through such research-oriented programs include state-of-the-art antibody determinations in specialized research laboratories, a superb follow-up and support network of T1DM specialists, protection of laboratory data from insurance carriers, and the opportunity to participate in further clinical research studies aimed at diabetes prevention. Participating in a research study incurs no cost to patients or their insurance companies.
Family physicians may also provide effective education that may prevent T1DM. Early use of vitamin D supplementation may protect against T1DM progression, although the exact mechanism is uncertain. Vitamin D is a potent modulator of the immune system and is involved in regulating cell proliferation and differentiation.50 A meta-analysis of data from five observational studies recently indicated that children supplemented with vitamin D had a 29% reduction in T1DM risk compared to their unsupplemented peers.51 Nevertheless, firm conclusions that can be drawn from these data in terms of appropriate recommendations are limited by the lack of specification of dosage, duration, and particular vitamin D preparations. Thus, data from adequately powered, randomized, controlled trials are still needed. Infants should receive 400 IU daily of vitamin D supplementation until supplementation until they are ingesting equivalent amounts of vitamin D through formula milk and other nutrient sources. Infants who have limited sunlight exposure should continue the supplements indefinitely.52
Pathogenesis of T1DMThe term “diabetes” represents a syndrome of disorders all characterized by an impairment of pancreatic β-cell ability to secrete insulin. The American Diabetes Association (ADA) and the World Health Organization (WHO) recognize two forms of diabetes. T1DM results from pancreatic β-cell destruction secondary to an autoimmune process or an uncertain (idiopathic) etiology. These patients are prone to ketoacidosis. Diseases that secondarily result in pancreatic β-cell destruction (cystic fibrosis) are not classified as T1DM. Patients with T2DM have deficient insulin secretion from the pancreatic β-cell in association with peripheral insulin resistance. There is no evidence of autoimmunity in patients with T2DM whose pathophysiology appears to be genetically and environmentally predetermined.
Epidemiologic studies have suggested two distinct peak occurrences of T1DM: during puberty and near age 40.53 Ten to thirty percent of patients with T2DM also develop autoantibodies similar to patients with T1DM. These patients are referred to as having LADA.
Initially, patients with T1DM have a protracted preclinical phase during which autoantibodies can be detected against their pancreatic β-cells in genetically susceptible individuals.54 At least 80% to 90% of the β-cell mass must be lost before the patient develops hyperglycemia. Both a reduction in β-cell mass and the direct inhibition of insulin secretion by cytokines appear to result in a hyperglycemic state.55
Patients who are likely to progress to T1DM develop IAAs, glutamic acid decarboxylase antibodies (GADAbs), ICAs, and insulinoma-associated protein-2 autoantibodies (IA-2Abs). Interestingly, some patients who do not develop diabetes also produce these autoimmune markers. However, unlike patients with T1DM, their autoantibody levels tend to wax and wane over time. Patients who are more at risk for developing T1DM often have two or more autoantibodies present at any given time.56 The presence of IAAs appears to place patients most at risk for developing childhood T1DM.57
LADA is a slowly progressive form of autoimmune diabetes characterized by adult age at diagnosis, the presence of diabetes-associated autoantibodies, and the lack of insulin requirement at the time of diagnosis. The fact that insulin is not required for treatment at the time of diagnosis is intended to distinguish LADA from adult-onset T1DM and T2DM.
Some have referred to this disorder as being type 1.5 diabetes mellitus.58 Patients with LADA tend to have a more aggressive disease than T2DM, characterized by a shorter time to failure of oral hypoglycemic agents and progressive β-cell failure leading to insulin deficiency. Eighty to ninety percent of patients with LADA will require insulin within the first few years after diagnosis.59 Therefore, physicians should differentiate LADA from T2DM whenever possible. LADA has also been diagnosed with increasing frequency in children who appeared to have T2DM.60
Several clinical phenotypes are useful in differentiating LADA from T2DM. When compared with T2DM patients, individuals with LADA at the time of their initial diagnosis of diabetes appear to have many of the following clinical and laboratory characteristics61:
Lower body mass index (BMI)
More common symptom presentation such as polyuria and polydipsia
Lower mean waist and hip circumference
Lower waist-to-hip ratio
Shorter duration of diet or oral antidiabetic treatment before requiring insulin therapy
Higher A1C levels
Our ability to classify patients as having either T1DM, LADA, or T2DM is dependent on the evaluation of autoimmune markers in patients who clinically present as having T2DM. Immunologic differences exist between T1DM and LADA. LADA patients are often positive for only a single autoantibody, whereas T1DM patients frequently have two or more autoantibodies detectable at diagnosis.58 LADA patients are more likely to test positive for GAD or ICAs but not IAA and IA-2Ab.58
Because patients with LADA more rapidly lose their ability to produce endogenous insulin within the first few years after their diagnosis, they soon require exogenous insulin for treatment
of their diabetes. Therefore, once a patient is suspected of having LADA, insulin should be initiated to maintain better glycemic control early during the course of the disease, to limit glycemic variability, and to prevent diabetes complications during a variable transition period of β-cell functional decline. The rationale for early insulin intervention though would be improving glycemic control while protecting β-cell function. The exact mechanisms for the apparent beneficial effects of exogenous insulin treatment appear to secondary to the induction of β-cell rest within the autoimmune inflamed islets. Insulin down-regulates β-cell metabolism releasing them from hyperglycemic stress.62 β-cells, producing high amounts of insulin, are more susceptible to immune-mediated killing and are also associated with higher antigen expression.63
of their diabetes. Therefore, once a patient is suspected of having LADA, insulin should be initiated to maintain better glycemic control early during the course of the disease, to limit glycemic variability, and to prevent diabetes complications during a variable transition period of β-cell functional decline. The rationale for early insulin intervention though would be improving glycemic control while protecting β-cell function. The exact mechanisms for the apparent beneficial effects of exogenous insulin treatment appear to secondary to the induction of β-cell rest within the autoimmune inflamed islets. Insulin down-regulates β-cell metabolism releasing them from hyperglycemic stress.62 β-cells, producing high amounts of insulin, are more susceptible to immune-mediated killing and are also associated with higher antigen expression.63
Studies evaluating GLP-1 usage in subjects with T1DM showed reduction of fasting hyperglycemia and glycemic excursions after a meal, accompanied by reduction in glucagon secretion.64 Additionally, in islet transplant recipients, exendin-4 has stimulated insulin secretion and demonstrated an ability to reduce exogenous insulin requirements. Current clinical trials test the hypothesis that its use at the time of islet transplantation might be of help in preserving islet mass.65 Although not evaluated yet in LADA, these agents have a potential therapeutic value in such a setting.
Endocrine Components of EuglycemiaGlucose homeostasis in euglycemic individuals involves a complex web of hormonal interactions. The ultimate goal in patients with T1DM is to approximate normal physiology as closely as possible through intensification of their metabolic defects. Carbohydrates in the form of glucose are the key source of energy for muscles and the brain. The two primary sources of circulating glucose are hepatic glucose production and ingested carbohydrate. In the fasting state, glucagon is secreted from the pancreatic α-cells that stimulates the hepatic production of glucose through glycogenolysis (the breakdown of glycogen) and gluconeogenesis (the formation of glucose from noncarbohydrate molecules, e.g., amino acids and lactic acidosis). This “basal glucose” prevents hypoglycemia while supplying sufficient energy sources for the brain in the fasting state.
Following a meal, the postprandial glucose peak occurs between 1 and 2 hours with a mean peak time of 75 minutes.66 Rapid-acting insulin analogues display a maximum effect at approximately 100 minutes following subcutaneous injection. Thus, injections or bolusing of these analogues should be initiated 15 minutes prior to the start of a meal in order to synchronize the peak insulin action with the rise in the glycemic excursion in the postabsorptive state.67
Insulin is normally secreted into the portal circulation in two phases. In the fasting state, basal insulin is secreted at the approximate rate of 1 U per hour in order to minimized hepatic glucose production.68 Basal insulin also limits lipolysis and excess flux of free fatty acids to the liver, which can result in a state of postabsorptive insulin resistance. The circulating glucose levels are maintained at a level that allows for the extraction of this energy source by obligate glucose consumers such as the central nervous system. The lack of adequate basal insulin stimulates hormone-sensitive lipase and free fatty acid release from fat stores, which, in turn, stimulates hepatic production and release of ketone bodies, leading to ketogenesis and DKA.
Eating prompts a 5- to 10-fold increase in prandial insulin release from the pancreatic β-cells in euglycemic individuals. With each meal, a rapid first-phase insulin response occurs, limiting the rise in ambient plasma glucose levels. First-phase insulin response terminates quickly so that hypoglycemia does not occur. The second-phase insulin release follows limiting glycemic excursions as carbohydrates are absorbed from the gastrointestinal tract. This postabsorptive state may last between 4 and 6 hours and is dependent upon the food content of each meal. High-fat meals (such as pizza) prolong the postabsorptive state.69
Fat is stored in the body as triglycerides and converted to free fatty acids plus glycerol by lipolysis. Following ingestion of a fatty meal, the fat is stored in adipose tissue or may be transported to the muscle where it becomes oxidized and used as an energy source. Excessive levels of triglycerides and circulating free fatty acids can inhibit insulin signaling resulting in postprandial insulin resistance.70
Glucagon is a counterregulatory hormone, which, when released from the pancreatic α-cell, promotes hepatic gluconeogenesis and reversal of hypoglycemia. A euglycemic individual would signal glucagon secretion via a reduction in insulin release by the pancreatic β-cell coupled with low glucose stimulation of the α-cell.10 However, in patients with T1DM, a signaling defect between the β- and α-cells may account for failure to mount an acceptable counterregulatory response in a hypoglycemic state. With the autoimmune loss of glucose-dependent β-cell insulin secretion, signaling pathways between the α- and β-cells appear to be disrupted.71
Amylin is a peptide hormone that is cosecreted from pancreatic β-cells with insulin and is thus deficient in patients with diabetes. Amylin inhibits glucagon secretion, delays gastric emptying, and acts to improve satiety. Amylin also suppresses postprandial triglyceride concentrations and is known to reduce markers of oxidative stress as well as endothelial cell dysfunction.72
Catecholamines, cortisol, and growth hormone also assist in the prevention and reversal of hypoglycemia. Fasting hyperglycemia often occurs in patients with diabetes as physiologic basal insulin secretion is not sufficient to overcome the proglycemic effects of variable growth hormone secretion.73
• Physiologic Insulin Replacement Therapy
The ultimate goal of insulin replacement therapy is to mimic the normal insulin response to hyperglycemia in both the fasting and postprandial states. Euglycemic individuals produce enough insulin to maintain blood glucose values in a very narrow range (85 to 140 mg per dL). The concentration of glucose in plasma of healthy individuals remains within this normal range despite large fluctuations in nutritional intake and physical activity.
Physiologic insulin replacement regimens include the use of basal-bolus insulin preparations and continuous subcutaneous insulin infusion (insulin pump therapy—see Chapter 13).74 Nonphysiologic regimens include NPH with or without a rapid-acting insulin, the use of premixed insulin analogues, and a single dose of analogue basal insulin given once or twice daily because these interventions fail to mimic normal β-cell production and secretion of insulin observed in euglycemia. Physiologic insulin therapies should be individualized and titrated based upon the factors shown in Table 11-3.
Patients can increase the likelihood of success with a given prescribed insulin regimen by understanding the pharmacokinetic and glucodynamic profiles of the prescribed insulins. Once insulin is initiated, self-blood glucose monitoring and paired glucose testing (see Chapter 12) can be used to identify patterns reflective of hypoglycemia, fasting hyperglycemia, and postprandial hyperglycemia. Pattern recognition is the first step in allowing patients to safely and efficiently achieve their targeted glycemic goals.75,76
The insulins that have been used historically to manage diabetes have pharmacodynamic effects (variability of absorption from injection site, time to peak effect, duration of action) and glycodynamic effects (ability to reduce hyperglycemia) that are often not physiologic. The glucodynamics and pharmacodynamics of insulin analogues are more predictable when compared with NPH and regular human insulin (RHI).77,78,79 In general, studies have shown that rapid-acting analogues are also superior to RHI for lowering glycosylated hemoglobin levels in patients who receive insulin by continuous subcutaneous infusion.80
Insulin Analogue Formulations• Basal Insulin Analogues
The two available basal analogue insulins glargine (lantus) and detemir (levemir) are described in detail in Chapter 12. Because insulin glargine is clear and NPH insulin is cloudy, clinical trials comparing these two insulins in patients with T1DM have been open label. In general, the trials have shown no differences or occasional improvements in glycemic control with insulin glargine,
although a reduction in the risk of hypoglycemia, especially nocturnal hypoglycemia, has been the rule with insulin glargine.
although a reduction in the risk of hypoglycemia, especially nocturnal hypoglycemia, has been the rule with insulin glargine.
TABLE 11-3. Factors That Should Be Considered When Prescribing Physiologic Insulin Replacement Therapy | |||||||||||||||||
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