Implications/Analysis of Family History

Although we have not been given any family history, disease susceptibility for type 1 DM depends on the degree of genetic similarity that an individual has with the proband. For example, MM’s monozygotic twin, whose genetic makeup is identical to MM, has a 50% risk of also developing type 1 DM. The remaining risk is thought to be due to environmental factors (see Implications/Analysis of Clinical History).

More than 20 different genes have been identified that contribute to type 1 DM disease susceptibility, but the highest predisposing risks are associated with the inheritance of particular groups of class II MHC antigens. Individuals at highest risk for developing type 1 DM are those whose haplotype includes HLA-DR3, DQ2 and HLA-DR4, DQ8. Risk is somewhat lower, but still substantial, for individuals who express HLA-DR3, DQ2 or HLA-DR4, DQ8 (i.e., not both). Close to half of the patients with type 1 DM express all four of these HLA genes. Interestingly, some patterns of HLA-DR/DQ linkage patterns are protective. Given MM’s age when the disease manifested, one would predict that MM (and his twin) would express the HLA genes that have the highest predisposing risk.

Individuals with type 1 DM and their relatives are at increased risk for a number of autoimmune disorders, including celiac disease, Addison’s disease, pernicious anemia, and autoimmune thyroid dysfunction. About 14% of children with type 1 DM (without celiac disease) have IgA anti-tissue transglutaminase (tTG) autoantibodies. These tTG autoantibodies are also present in about 7% of nondiabetic first-degree relatives (without celiac disease). We would expect, therefore, that a family history would reveal autoimmune disorders in immediate or related family members.

Implications/Analysis of Clinical History

In the last 24 hours, MM’s urine output has been diminished, an indication that dehydration might be a problem. Severe dehydration can lead to hypovolemic shock, and so an intravenous line was inserted and fluid resuscitation begun.

MM has been suffering from a viral-like infection for the past 3 weeks. Type 1 DM is often described in the aftermath of an (inciting?) infectious disease (e.g., coxsackie virus and cytomegalovirus).

Viruses, bovine milk, and toxins are only a few of putative environmental factors that have been investigated as triggers for type 1 DM in susceptible patients. Bovine milk has been included in this list because (in some studies, but not others) a comparison of the incidence of type 1 DM in countries with high/low rates of breast feeding showed that early introduction of bovine milk in an infant’s diet could lead to induction of cross-reactive T cells/antibodies that might have pathogenic potential. Congenital rubella, in susceptible individuals, has also been included in the list of environmental factors that increase the likelihood of becoming diabetic.

Knowing whether MM has been breast fed, has had congenital rubella, or has had other viral infections would not affect the course of treatment or disease outcome, but for completeness this information should be included in the patient’s file.

Implications/Analysis of Laboratory Investigation

The blood glucose concentration is elevated, and so dehydration is of concern. As mentioned, fluid resuscitation and insulin therapy have already been initiated. Potassium levels are decreased, suggesting severe diabetic ketoacidosis (see Etiology), and so potassium chloride was administered. The initial presentation of ketoacidosis is usually accompanied by a normal or elevated plasma potassium level. This is because insulin deficiency leads to the movement of potassium ions from inside cells to the extracellular fluid. Urinalysis was positive for glucose, a classic indicator of diabetes mellitus.

One would expect that the chest radiograph would be normal, as would the white blood cell count and differential; however, the lymphocyte count would be at the high end of normal. The total serum immunoglobulin level would be increased because MM would have significant titers of autoimmune antibodies.

Enzyme-linked immunosorbent assays (ELISAs) for autoantibodies for islet antigens (glutamic acid decarboxylase [GAD], protein tyrosine phosphatase IA-2) and insulin should be requested. Anti-insulin and anti-GAD autoantibodies are often the first to develop, long before clinical symptoms. These autoantibodies serve as markers for disease. Autoantibodies are indicative of type 1A DM, rather than type 1B DM, which presents in a similar manner but patients do not have autoantibodies or any immune involvement.

Additional Laboratory Tests

An enzymatic approach is used to diagnose and monitor one of the ketone bodies (β-hydroxybutyric acid). However, patients can monitor their ketone levels using a urine dipstick assay.

Metabolic Complications

In the nondisease state, insulin is synthesized and stored within cytosolic granules of β cells of the pancreatic islets (Fig. 24-1) and released into circulation when there is a rise in blood glucose concentration. Insulin increases the rate at which glucose is transported into cells, where it plays a role in several anabolic processes. In type 1 DM, glucose generated from simple or complex dietary carbohydrates is unable to enter cells and so the cells are, in effect, starving. Under these conditions, fatty acids are oxidized in the liver and one of the products (acetyl CoA) is converted to ketone bodies, which can serve as a metabolic fuel. However, elevated levels of ketone bodies in the blood lead to a condition known as ketosis.

FIGURE 24-1 Normal pancreas. Pancreas stained with immunoperoxidase for glucagon (red staining) to show alpha cells in islets of Langerhans (˜30% of islets are alpha cells). (Immunoperoxidase staining for glucagons, ×400.)

Because the majority of ketone bodies are “acids” their high concentration in the circulation triggers buffering systems, which results in the excretion of excess hydrogen ions into the urine. This is accompanied by the loss of water and other ions, including potassium, resulting in dehydration. The high concentration of glucose in the blood leads to urinary excretion of glucose, which is accompanied by a loss of water, owing to the osmotic effect of glucose, further contributing to the dehydration. This results in excessive thirst and decrease in blood volume that is characteristic of uncontrolled type 1 DM.

Breakdown in Tolerance: Stimulation of TLR4

Much of the progress in our understanding of type 1 DM has come from studies with rodents that have served as models for human studies. One pilot study with a heat shock protein (hsp) peptide addressed the relevance of toll-like receptors (TLR) recognition in the immunopathogenesis of type 1 DM. Hsps play an important role, functioning as chaperones for newly synthesized or aberrantly folded proteins. From an evolutionary point of view, hsps are highly conserved in all organisms ranging from bacteria to humans. Hsp60, one of the most studied hsps, has also been shown to activate macrophages and dendritic cells (antigen-presenting cells) after binding to TLR4 on these cells. Peripheral blood cells of both type 1 DM patients and a diabetes-susceptible nonobese diabetic (NOD) strain of mice have a greater number of T cell clones that are specific for hsp60 than do normal populations. In one study, immunization of NOD mice with an hsp60 (amino acids 437 to 460) peptide, prior to the development of overt symptoms of diabetes, led to protection from diabetes. This immunization was associated with a shift from Th1 to Th2 cells specific for the hsp60 peptide. This is consistent with other studies that showed that infusion of Th2 cytokines, particularly IL-4, could ameliorate disease.

Breakdown in Tolerance: Role of Treg Cells

Gut-derived gamma/delta T cells are implicated in regulation of type 1 DM. In animals in which this population of cells was deliberately abolished, diabetes was much easier to induce by deliberate feeding of proinsulin as an autoantigen. Moreover, in these mice, early immunoregulation by gamma/delta TCR+ cells seemed later to evolve to Treg cells, expressing both CD4+ and CD25+.

The CD4+, CD25+ Treg cells have come under intense scrutiny over the past several years as being of major importance in natural immunoregulation, with loss of their function underlying many autoimmune problems (e.g., rheumatoid arthritis, multiple sclerosis, and autoimmune gastritis).

In an interesting model of autoimmune diabetes using a susceptible NOD strain of mouse, induction of such Treg cells by immunization with an insulin peptide (B9-23) was indeed found to protect these mice against diabetes, a protection that could be transferred to other mice by T cells. Similar treatment in pilot studies in humans has been reported to arrest β cell destruction, with preservation of insulin levels at the pretreatment values, along with induction of CD4+, CD25+ Treg.

Role of Autoantibodies

The role of antibodies in the initiation of disease is controversial, although, once generated, they can certainly contribute to the pathogenesis. It is difficult to rationalize a role for antibody in the initiation of disease given reports of type 1 DM in a patient with X-linked agammaglobulinemia (see Case 3). Not surprising, this patient did not have autoantibodies, which are the diagnostic marker of type 1A DM. Rather, involvement of the immune system was shown to be the in vitro proliferation of T cells to islet-specific autoantigens. Additionally, the patient’s class II MHC haplotype was consistent with that for the highest risk susceptibility (see earlier).

Late-Onset Diabetes

Late-onset (adult) diabetes is often caused by other autoimmune conditions (including anti-insulin receptor antibody and general refractoriness of triggering at the cell surface insulin, receptor, etc). Endogenous insulin is still produced but not in adequate quantities. In such cases, stimulation of existing beta cells with oral antidiabetic medications (e.g., glyburide) to secrete insulin leads to a lowering of blood glucose levels.